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    Clinical Trial Results:
    A trial investigating the efficacy and safety of insulin degludec/insulin aspart (IDegAsp) once daily plus insulin aspart (IAsp) for the remaining meals versus insulin detemir (IDet) once or twice daily plus meal time insulin aspart in children and adolescents with type 1 diabetes mellitus

    Summary
    EudraCT number
    2012-003566-41
    Trial protocol
    CZ   SI   ES   BE   HR  
    Global end of trial date
    07 Nov 2014

    Results information
    Results version number
    v2(current)
    This version publication date
    16 Mar 2016
    First version publication date
    21 May 2015
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    AE data to be updated

    Trial information

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    Trial identification
    Sponsor protocol code
    NN5401-3816
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01835431
    WHO universal trial number (UTN)
    U1111-1133-0958
    Sponsors
    Sponsor organisation name
    Novo Nordisk A/S
    Sponsor organisation address
    Novo Allé, Soeborg, 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)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-000479-PIP01-08
    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
    Final
    Date of interim/final analysis
    27 Mar 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Nov 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Nov 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To confirm the efficacy of insulin degludec/insulin aspart administered once daily plus meal-time insulin aspart for the remaining meals in controlling glycaemia with respect to change from baseline in HbA1c after 16 weeks of treatment. This is done by comparing the difference in change from baseline in HbA1c between insulin degludec/insulin aspart + meal-time insulin aspart for the remaining meals and insulin detemir + meal-time insulin aspart to a non-inferiority limit of 0.4%, and if non-inferiority is confirmed, to a superiority limit of 0%.
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki (Ethical Principles for Medical Research Involving Human Subjects. Last amended by the 64th WMA General Assembly, Fortaleza, Brazil. World Medical Association. 20 A.D) and International Conference on Harmonisation (ICH) Good Clinical Practice (ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice. J Postgrad Med 2001; 47(3):199-203) and 21 Code of Federal Regulations (CFR) 312.120.
    Background therapy
    Not Applicable
    Evidence for comparator
    Not Applicable
    Actual start date of recruitment
    17 Oct 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Slovenia: 4
    Country: Number of subjects enrolled
    South Africa: 12
    Country: Number of subjects enrolled
    Spain: 15
    Country: Number of subjects enrolled
    United States: 114
    Country: Number of subjects enrolled
    Belgium: 13
    Country: Number of subjects enrolled
    Brazil: 7
    Country: Number of subjects enrolled
    Canada: 11
    Country: Number of subjects enrolled
    Croatia: 12
    Country: Number of subjects enrolled
    Czech Republic: 19
    Country: Number of subjects enrolled
    Israel: 34
    Country: Number of subjects enrolled
    Macedonia, the former Yugoslav Republic of: 20
    Country: Number of subjects enrolled
    Poland: 28
    Country: Number of subjects enrolled
    Russian Federation: 46
    Country: Number of subjects enrolled
    Serbia: 27
    Worldwide total number of subjects
    362
    EEA total number of subjects
    91
    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)
    1
    Children (2-11 years)
    203
    Adolescents (12-17 years)
    158
    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
    The trial was conducted at 63 sites in 14 countries as follows: Belgium: 3 sites; Brazil: 1 sites; Canada: 3 sites; Czech Republic 3 sites; Croatia: 2 sites; Israel: 6 sites; Macedonia: 2 sites; Poland: 3 sites; Russia: 5 sites; Serbia: 4 sites; Slovenia: 1 sites; South Africa: 2 sites; Spain: 5 sites; and United States: 23 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
    Blinding implementation details
    Open label trial.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    IDegAsp OD +IAsp
    Arm description
    IDegAsp OD with a main meal + IAsp for the remaining meals
    Arm type
    Experimental

    Investigational medicinal product name
    IDegAsp
    Investigational medicinal product code
    Other name
    Insulin degludec/Insulin Aspart
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    IDegAsp was to be administered subcutaneously in the thigh, upper arm (deltoid area) or abdomen OD in connection with a main meal. The dosing time could be moved to a different main meal at any time during the trial.

    Investigational medicinal product name
    IAsp
    Investigational medicinal product code
    Other name
    Insulin Aspart
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    IAsp was to be administered subcutaneously according to local labelling as mealtime insulin.

    Arm title
    IDet+IAsp
    Arm description
    IDet once or twice daily + meal‑time IAsp.
    Arm type
    Active comparator

    Investigational medicinal product name
    IDet
    Investigational medicinal product code
    Other name
    Insulin Detemir
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    IDet was to be administered subcutaneously according to local labelling. Subjects randomised into the IDet treatment group continued with their pre-trial dosing scheme (OD or BID) and were allowed to switch from OD to BID dosing.

    Investigational medicinal product name
    IAsp
    Investigational medicinal product code
    Other name
    Insulin Aspart
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    IAsp was to be administered subcutaneously as mealtime insulin.

    Number of subjects in period 1
    IDegAsp OD +IAsp IDet+IAsp
    Started
    182
    180
    Completed
    174
    168
    Not completed
    8
    12
         Other
    -
    2
         Non Compliance with protocol
    1
    -
         Adverse event, non-fatal
    1
    -
         Withdrawal criteria
    6
    10

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Study
    Reporting group description
    -

    Reporting group values
    Overall Study Total
    Number of subjects
    362 362
    Age categorical
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    1 1
        Children (2-11 years)
    203 203
        Adolescents (12-17 years)
    158 158
        Adults (18-64 years)
    0 0
        From 65-84 years
    0 0
        85 years and over
    0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    10.6 ± 4.5 -
    Gender categorical
    Units: Subjects
        Female
    187 187
        Male
    175 175

    End points

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    End points reporting groups
    Reporting group title
    IDegAsp OD +IAsp
    Reporting group description
    IDegAsp OD with a main meal + IAsp for the remaining meals

    Reporting group title
    IDet+IAsp
    Reporting group description
    IDet once or twice daily + meal‑time IAsp.

    Primary: Change from baseline in HbA1c (%-point)

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    End point title
    Change from baseline in HbA1c (%-point)
    End point description
    Percentage point change in glycosylated haemoglobin A1c (HbA1c) from baseline (week 0) to 16 Weeks.
    End point type
    Primary
    End point timeframe
    After 16 weeks of treatment
    End point values
    IDegAsp OD +IAsp IDet+IAsp
    Number of subjects analysed
    173
    165
    Units: percentage-point
        arithmetic mean (standard deviation)
    -0.3 ± 1
    -0.3 ± 0.9
    Statistical analysis title
    Change from baseline in HbA1c (%-point)
    Comparison groups
    IDegAsp OD +IAsp v IDet+IAsp
    Number of subjects included in analysis
    338
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [1]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.04
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.23
         upper limit
    0.15
    Notes
    [1] - If non-inferiority was confirmed, superiority of IDegAsp over IDet was investigated for the FAS. Non-inferiority will be considered confirmed if the upper bound of the two-sided 95% confidence interval is below or equal to 0.4% corresponding to one-sided test at the 2.5% level. The subjects in this analysis is 350/362 from FAS who had baseline and atleast one post-baseline assessment.

    Secondary: Change from baseline in fasting plasma glucose

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    End point title
    Change from baseline in fasting plasma glucose
    End point description
    FPG was analysed on blood samples from fasting subjects which were analysed centrally.
    End point type
    Secondary
    End point timeframe
    After 16 weeks of treatment
    End point values
    IDegAsp OD +IAsp IDet+IAsp
    Number of subjects analysed
    162
    148
    Units: mmol/L
        arithmetic mean (standard deviation)
    -0.3 ± 6.4
    -0.1 ± 4.8
    No statistical analyses for this end point

    Secondary: Incidence of Treatment Emergent Adverse Events (TEAEs)

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    End point title
    Incidence of Treatment Emergent Adverse Events (TEAEs)
    End point description
    A Treatment Emergent Adverse Event (TEAE) was defined as an event with onset date on or after the first day of exposure to randomised treatment and no later than 7 days after the last day on randomised treatment.
    End point type
    Secondary
    End point timeframe
    After 16 weeks of treatment.
    End point values
    IDegAsp OD +IAsp IDet+IAsp
    Number of subjects analysed
    181
    179
    Units: Number of events
    501
    460
    No statistical analyses for this end point

    Secondary: Treatment emergent confirmed hypoglycaemic episodes

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    End point title
    Treatment emergent confirmed hypoglycaemic episodes
    End point description
    Treatment emergent hypoglycaemic episodes (PG < 3.1 mmol/L (56 mg/dL) or severe hypoglycaemia). Confirmed hypoglycaemic episodes were defined as episodes that were either: 1. Severe (i.e. the child is having altered mental status and cannot assist in their care, is semiconscious or unconscious or in coma with or without convulsions and may require parenteral therapy (glucagon or i.v. glucose), or 2. An episode biochemically confirmed by PG value of <3.1 mmol/L (56 mg/dL), with or without symptoms consistent with hypoglycaemia.
    End point type
    Secondary
    End point timeframe
    After 16 weeks of treatment
    End point values
    IDegAsp OD +IAsp IDet+IAsp
    Number of subjects analysed
    181
    179
    Units: Number of treatment emergent episodes
        Confirmed
    2532
    2672
    No statistical analyses for this end point

    Secondary: Treatment emergent nocturnal confirmed hypoglycaemic episodes

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    End point title
    Treatment emergent nocturnal confirmed hypoglycaemic episodes
    End point description
    The confirmed hypoglycaemic episodes occurring between 23:00 and 07:00 were considered for this endpoint.
    End point type
    Secondary
    End point timeframe
    After 16 weeks of treatment
    End point values
    IDegAsp OD +IAsp IDet+IAsp
    Number of subjects analysed
    181
    179
    Units: Number of treatment emergent episodes
        Confirmed
    316
    291
    No statistical analyses for this end point

    Secondary: Hyperglycaemic episodes

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    End point title
    Hyperglycaemic episodes
    End point description
    Number of hyperglycaemic episodes (PG > 14.0 mmol/L (250 mg/dL) where subject looks/feels ill.
    End point type
    Secondary
    End point timeframe
    After 16 weeks of treatment
    End point values
    IDegAsp OD +IAsp IDet+IAsp
    Number of subjects analysed
    181
    179
    Units: Number of hyperglycaemic episodes
    599
    449
    No statistical analyses for this end point

    Secondary: Hyperglycaemic episodes with ketosis

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    End point title
    Hyperglycaemic episodes with ketosis
    End point description
    Number of hyperglycaemic episodes (PG > 14.0 mmol/L (250 mg/dL) where subject looks/feels ill with ketosis (blood ketones > 1.5 mmol/L)
    End point type
    Secondary
    End point timeframe
    After 16 weeks of treatment
    End point values
    IDegAsp OD +IAsp IDet+IAsp
    Number of subjects analysed
    181
    179
    Units: Number of hyperglycaemic episodes
        Hyperglycaemic episodes with ketones(.1.5mmol/L)
    6
    12
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Onset date on or after the first day of exposure to randomised treatment and no later than 7 days after the last day on randomised treatment.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17
    Reporting groups
    Reporting group title
    IDegAsp OD + IAsp
    Reporting group description
    IDegAsp OD with a main meal + IAsp for the remaining meals

    Reporting group title
    IDet +IAsp
    Reporting group description
    IDet once or twice daily + meal‑time IAsp.

    Serious adverse events
    IDegAsp OD + IAsp IDet +IAsp
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 181 (6.08%)
    7 / 179 (3.91%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibula Fracture
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia Fracture
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Developmental glaucoma
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 179 (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
    Hypoglycaemic seizure
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Compartment syndrome
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 181 (0.55%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    5 / 181 (2.76%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    4 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Laryngitis
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 181 (0.55%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    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
    IDegAsp OD + IAsp IDet +IAsp
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    96 / 181 (53.04%)
    97 / 179 (54.19%)
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    13 / 181 (7.18%)
    9 / 179 (5.03%)
         occurrences all number
    16
    9
    Oropharyngeal pain
         subjects affected / exposed
    9 / 181 (4.97%)
    13 / 179 (7.26%)
         occurrences all number
    13
    14
    Nervous system disorders
    Headache
         subjects affected / exposed
    23 / 181 (12.71%)
    32 / 179 (17.88%)
         occurrences all number
    47
    64
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    17 / 181 (9.39%)
    10 / 179 (5.59%)
         occurrences all number
    26
    15
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    10 / 181 (5.52%)
    7 / 179 (3.91%)
         occurrences all number
    13
    13
    Abdominal pain upper
         subjects affected / exposed
    14 / 181 (7.73%)
    17 / 179 (9.50%)
         occurrences all number
    22
    26
    Vomiting
         subjects affected / exposed
    22 / 181 (12.15%)
    12 / 179 (6.70%)
         occurrences all number
    25
    13
    Infections and infestations
    Influenza
         subjects affected / exposed
    9 / 181 (4.97%)
    10 / 179 (5.59%)
         occurrences all number
    10
    12
    Nasopharyngitis
         subjects affected / exposed
    36 / 181 (19.89%)
    32 / 179 (17.88%)
         occurrences all number
    43
    42
    Pharyngitis
         subjects affected / exposed
    3 / 181 (1.66%)
    10 / 179 (5.59%)
         occurrences all number
    3
    13
    Upper respiratory tract infection
         subjects affected / exposed
    11 / 181 (6.08%)
    17 / 179 (9.50%)
         occurrences all number
    12
    18

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Apr 2013
    The protocol was updated upon request from FDA; the use of Last observation carried forward (LOCF) in the statistical analyses was discarded in favour of mixed effect model repeat measurement (MMRM). Furthermore, the blood volume needed for blood sampling in the age group below 6 years was updated to a smaller volume due to a miscalculation. Furthermore, the text in the master subject information related to the use of Lantus® was updated. In addition, a few typing errors in Section 17 (Statistical considerations) were discovered and corrected.
    22 Apr 2014
    Error corrected regarding definition of the Full Analysis Set (FAS).

    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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