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    Clinical Trial Results:
    A single-centre, randomised, double-blind, cross-over trial comparing the within-subject variability of the pharmacokinetic profiles of insulin detemir and insulin glargine in children and adolescents with type 1 diabetes

    Summary
    EudraCT number
    		 2004-001692-19
    Trial protocol
    		 DE  
    Global end of trial date
    09 Oct 2005

    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
    NN304-1633
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01497574
    WHO universal trial number (UTN)
    		 -
    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?
    Yes
    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
    01 Apr 2008
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Oct 2005
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Oct 2005
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the within-subject variability of the pharmacokinetic profiles of insulin detemir and insulin glargine in children and adolescents (6 to 17 years) with type 1 diabetes.
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice.
    Background therapy
    		 Not applicable.
    Evidence for comparator
    		 Not applicable.
    Actual start date of recruitment
    26 May 2005
    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
    Germany: 32
    Worldwide total number of subjects
    32
    EEA total number of subjects
    32
    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)
    8
    Adolescents (12-17 years)
    24
    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 a single site in Germany.

    Pre-assignment
    Screening details
    		 Not applicable.

    Period 1
    Period 1 title
    Period 1
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    The trial products could not be blinded due to different colour of the code caps of the cartridges, and double-blinding was assured by permitting a qualified person not otherwise involved in the trial to perform the trial product dose preparation and administration.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 IDet-IGlar
    Arm description
    		 Subjects received insulin detemir (IDet) followed by insulin glargine (IGlar).
    Arm type
    		 Cross-over assignment

    Investigational medicinal product name
    Insulin detemir (IDet)
    Investigational medicinal product code
    Other name
    Levemir
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    One injection of insulin detemir (0.4 U/kg) administered subcutaneously on first dosing visit (visit 2) and another injection on second dosing visit (visit 3).

    Investigational medicinal product name
    Insulin glargine (IGlar)
    Investigational medicinal product code
    Other name
    Lantus
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    One injection of insulin glargine (0.4 IU/kg) administered subcutaneously on first dosing visit (visit 2) and another injection on second dosing visit (visit 3).

    Arm title
    		 IGlar-IDet
    Arm description
    		 Subjects received insulin glargine (IGlar) followed by insulin detemir (IDet).
    Arm type
    		 cross-over assignment

    Investigational medicinal product name
    Insulin detemir (IDet)
    Investigational medicinal product code
    Other name
    Levemir
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    One injection of insulin detemir (0.4 U/kg) administered subcutaneously on first dosing visit (visit 2) and another injection on second dosing visit (visit 3).

    Investigational medicinal product name
    Insulin glargine (IGlar)
    Investigational medicinal product code
    Other name
    Lantus
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    One injection of insulin glargine (0.4 IU/kg) administered subcutaneously on first dosing visit (visit 2) and another injection on second dosing visit (visit 3).

    Number of subjects in period 1
    		IDet-IGlar IGlar-IDet
    Started
    17
    15
    Completed
    16
    14
    Not completed
    1
    1
         Adverse event, non-fatal
    1
    -
         Poor condition of vein
    -
    1
    Period 2
    Period 2 title
    Period 2
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    The trial products could not be blinded due to different colour of the code caps of the cartridges, and double-blinding was assured by permitting a qualified person not otherwise involved in the trial to perform the trial product dose preparation and administration.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 IDet-IGlar
    Arm description
    		 Subjects received insulin detemir (IDet) followed by insulin glargine (IGlar). Within a period of 7 to 31 days of completion of visit 2, subject of IGlar-IDet arm (of period 1) were received one injection of IDet on visit 3, day 1 followed by one injection of IGlar after a 24 hours interval (visit 3, day 2).
    Arm type
    		 Cross-over assignment

    Investigational medicinal product name
    Insulin detemir (IDet)
    Investigational medicinal product code
    Other name
    Levemir
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    One injection of insulin detemir (0.4 U/kg) administered subcutaneously on first dosing visit (visit 2) and another injection on second dosing visit (visit 3).

    Investigational medicinal product name
    Insulin glargine (IGlar)
    Investigational medicinal product code
    Other name
    Lantus
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    One injection of insulin glargine (0.4 IU/kg) administered subcutaneously on first dosing visit (visit 2) and another injection on second dosing visit (visit 3).

    Arm title
    		 IGlar-IDet
    Arm description
    		 Subjects received insulin glargine (IGlar) followed by insulin detemir (IDet). Within a period of 7 to 31 days of completion of visit 2, subject of IDet-IGlar arm (of period 1) were received one injection of IGlar (0.4 IU/kg) on visit 3, day 1 followed by one injection of IDet (0.4 IU/kg) after a 24 hours interval (visit 3, day 2).
    Arm type
    		 Cross-over assignment

    Investigational medicinal product name
    Insulin detemir (IDet)
    Investigational medicinal product code
    Other name
    Levemir
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    One injection of insulin detemir (0.4 U/kg) administered subcutaneously on first dosing visit (visit 2) and another injection on second dosing visit (visit 3).

    Investigational medicinal product name
    Insulin glargine (IGlar)
    Investigational medicinal product code
    Other name
    Lantus
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    One injection of insulin glargine (0.4 IU/kg) administered subcutaneously on first dosing visit (visit 2) and another injection on second dosing visit (visit 3).

    Number of subjects in period 2
    		IDet-IGlar IGlar-IDet
    Started
    14
    16
    Completed
    14
    16
    Period 3
    Period 3 title
    Period 3
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    The trial products could not be blinded due to different colour of the code caps of the cartridges, and double-blinding was assured by permitting a qualified person not otherwise involved in the trial to perform the trial product dose preparation and administration.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 IGlar
    Arm description
    		 All the subjects, who had received both the doses of IGlar (first dose on first dosing visit-visit 2 and second dose on second dosing visit-visit 3) were included in this arm.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Insulin glargine (IGlar)
    Investigational medicinal product code
    Other name
    Lantus
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    One injection of insulin glargine (0.4 IU/kg) administered subcutaneously on first dosing visit (visit 2) and another injection on second dosing visit (visit 3).

    Arm title
    		 IDet
    Arm description
    		 All the subjects, who had received both the doses of IDet (first dose on first dosing visit-visit 2 and second dose on second dosing visit-visit 3) were included in this arm.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Insulin detemir (IDet)
    Investigational medicinal product code
    Other name
    Levemir
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    One injection of insulin detemir (0.4 U/kg) administered subcutaneously on first dosing visit (visit 2) and another injection on second dosing visit (visit 3).

    Arm title
    		 IGlar: Children (6-12 years)
    Arm description
    		 All the children, who had received both the doses of IGlar (first dose on first dosing visit-visit 2 and second dose on second dosing visit-visit 3) were included in this arm.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Insulin glargine (IGlar)
    Investigational medicinal product code
    Other name
    Lantus
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    One injection of insulin glargine (0.4 IU/kg) administered subcutaneously on first dosing visit (visit 2) and another injection on second dosing visit (visit 3).

    Arm title
    		 IGlar: Adolescents (13-17 years)
    Arm description
    		 All the adolescents, who had received both the doses of IGlar (first dose on first dosing visit-visit 2 and second dose on second dosing visit-visit 3) were included in this arm.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Insulin glargine (IGlar)
    Investigational medicinal product code
    Other name
    Lantus
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    One injection of insulin glargine (0.4 IU/kg) administered subcutaneously on first dosing visit (visit 2) and another injection on second dosing visit (visit 3).

    Arm title
    		 IDet : Children (6-12 years)
    Arm description
    		 All the children, who had received both the doses of IDet (first dose on first dosing visit-visit 2 and second dose on second dosing visit-visit 3) were included in this arm.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Insulin detemir (IDet)
    Investigational medicinal product code
    Other name
    Levemir
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    One injection of insulin detemir (0.4 U/kg) administered subcutaneously on first dosing visit (visit 2) and another injection on second dosing visit (visit 3).

    Arm title
    		 IDet: Adolescents (13-17 years)
    Arm description
    		 All the adolescents, who had received both the doses of IDet (first dose on first dosing visit-visit 2 and second dose on second dosing visit-visit 3) were included in this arm.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Insulin detemir (IDet)
    Investigational medicinal product code
    Other name
    Levemir
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    One injection of insulin detemir (0.4 U/kg) administered subcutaneously on first dosing visit (visit 2) and another injection on second dosing visit (visit 3).

    Number of subjects in period 3
    		IGlar IDet IGlar: Children (6-12 years) IGlar: Adolescents (13-17 years) IDet : Children (6-12 years) IDet: Adolescents (13-17 years)
    Started
    30
    30
    13
    17
    13
    17
    Completed
    30
    30
    13
    17
    13
    17

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Period 1
    Reporting group description
    		 Each subject were randomly allocated to a treatment sequence consisting of 2 dosing visits separated by a wash-out period of 7-31 days.

    Reporting group values
    		 Period 1 Total
    Number of subjects
    		 32 32
    Age categorical
    Units: Subjects
        Children (6-12 years)
    		 13 13
        Adolescents (13-17 years)
    		 19 19
    Age continuous
    Not applicable.
    Units: years
        arithmetic mean (standard deviation)
    		 13 ( 2.5 ) -
    Gender categorical
    Not applicable.
    Units: Subjects
        Female
    		 19 19
        Male
    		 13 13
    Body mass index (BMI)
    Units: kg/m^2
        arithmetic mean (standard deviation)
    		 21.4 ( 2.94 ) -
    Body weight
    Units: Kg
        arithmetic mean (standard deviation)
    		 55 ( 13.1 ) -

    End points

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    End points reporting groups
    Reporting group title
    IDet-IGlar
    Reporting group description
    		 Subjects received insulin detemir (IDet) followed by insulin glargine (IGlar).

    Reporting group title
    IGlar-IDet
    Reporting group description
    		 Subjects received insulin glargine (IGlar) followed by insulin detemir (IDet).
    Reporting group title
    IDet-IGlar
    Reporting group description
    		 Subjects received insulin detemir (IDet) followed by insulin glargine (IGlar). Within a period of 7 to 31 days of completion of visit 2, subject of IGlar-IDet arm (of period 1) were received one injection of IDet on visit 3, day 1 followed by one injection of IGlar after a 24 hours interval (visit 3, day 2).

    Reporting group title
    IGlar-IDet
    Reporting group description
    		 Subjects received insulin glargine (IGlar) followed by insulin detemir (IDet). Within a period of 7 to 31 days of completion of visit 2, subject of IDet-IGlar arm (of period 1) were received one injection of IGlar (0.4 IU/kg) on visit 3, day 1 followed by one injection of IDet (0.4 IU/kg) after a 24 hours interval (visit 3, day 2).
    Reporting group title
    IGlar
    Reporting group description
    		 All the subjects, who had received both the doses of IGlar (first dose on first dosing visit-visit 2 and second dose on second dosing visit-visit 3) were included in this arm.

    Reporting group title
    IDet
    Reporting group description
    		 All the subjects, who had received both the doses of IDet (first dose on first dosing visit-visit 2 and second dose on second dosing visit-visit 3) were included in this arm.

    Reporting group title
    IGlar: Children (6-12 years)
    Reporting group description
    		 All the children, who had received both the doses of IGlar (first dose on first dosing visit-visit 2 and second dose on second dosing visit-visit 3) were included in this arm.

    Reporting group title
    IGlar: Adolescents (13-17 years)
    Reporting group description
    		 All the adolescents, who had received both the doses of IGlar (first dose on first dosing visit-visit 2 and second dose on second dosing visit-visit 3) were included in this arm.

    Reporting group title
    IDet : Children (6-12 years)
    Reporting group description
    		 All the children, who had received both the doses of IDet (first dose on first dosing visit-visit 2 and second dose on second dosing visit-visit 3) were included in this arm.

    Reporting group title
    IDet: Adolescents (13-17 years)
    Reporting group description
    		 All the adolescents, who had received both the doses of IDet (first dose on first dosing visit-visit 2 and second dose on second dosing visit-visit 3) were included in this arm.

    Primary: AUC 0-16h, area under the insulin concentration-time curve from 0 to 16 hours

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    End point title
    		 AUC 0-16h, area under the insulin concentration-time curve from 0 to 16 hours
    End point description
    The area under the insulin concentration-time curve (AUC) from 0 to 16 hours was measured. Within-subject variability for AUC 0-16h was estimated for all subject, for children and for adolescents, separately.
    End point type
    Primary
    End point timeframe
    0-16 hours
    End point values
    		 IGlar IDet IGlar: Children (6-12 years) IGlar: Adolescents (13-17 years) IDet : Children (6-12 years) IDet: Adolescents (13-17 years)
    Number of subjects analysed
    30
    30
    13
    17
    13
    17
    Units: pmol/L*h
        least squares mean (confidence interval 95%)
    900 (753 to 1075)
    29839 (26073 to 34149)
    830 (605 to 1138)
    978 (793 to 1208)
    31005 (22904 to 41970)
    28958 (25950 to 32315)
    Statistical analysis title
    		 Within-subject variability, all subjects
    Comparison groups
    IGlar v IDet
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 < 0.0001
    Method
    		 F test
    Parameter type
    		 Ratio between within-subject variances
    Confidence interval
    Notes
    [1] - Test of no difference between the two insulin types with respect to within-subject variation
    Statistical analysis title
    		 Within-subject variability, in children
    Comparison groups
    IGlar: Children (6-12 years) v IDet : Children (6-12 years)
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 0.0026
    Method
    		 F test
    Parameter type
    		 Ratio between within-subject variances
    Confidence interval
    Notes
    [2] - Test of no difference between the two insulin types with respect to within-subject variation.
    Statistical analysis title
    		 Within-subject variability, in adolescents
    Comparison groups
    IGlar: Adolescents (13-17 years) v IDet: Adolescents (13-17 years)
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 < 0.0001
    Method
    		 F test
    Parameter type
    		 Ratio between within-subject variances
    Confidence interval
    Notes
    [3] - Test of no difference between the two insulin types with respect to within-subject variation

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected and reported from the first trial-related activity after the subject has signed the informed consent and until the end of the post-treatment follow-up period.
    Adverse event reporting additional description
    Treatment emergent adverse event is defined as the adverse event that occurs after first dose and within 7 days after last dose.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10
    Reporting groups
    Reporting group title
    IDet
    Reporting group description
    		 All the subjects who had received at least one dose of IDet during the treatment period.

    Reporting group title
    IGlar
    Reporting group description
    		 All the subjects who had received at least one dose of IGlar during the treatment period.

    Serious adverse events
    		 IDet IGlar
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 31 (3.23%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Thrombophlebitis
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 31 (3.23%)
         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
    		 IDet IGlar
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 31 (38.71%)
    7 / 31 (22.58%)
    Investigations
    Body temperature increased
         subjects affected / exposed
    3 / 31 (9.68%)
    0 / 31 (0.00%)
         occurrences all number
    3
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 31 (6.45%)
    4 / 31 (12.90%)
         occurrences all number
    2
    4
    Headache
         subjects affected / exposed
    4 / 31 (12.90%)
    3 / 31 (9.68%)
         occurrences all number
    6
    5
    General disorders and administration site conditions
    Malaise
         subjects affected / exposed
    2 / 31 (6.45%)
    1 / 31 (3.23%)
         occurrences all number
    2
    1
    Infections and infestations
    Rhinitis
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 31 (0.00%)
         occurrences all number
    2
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Dec 2004
    One substantial protocol amendment was issued, implementing the following changes: • The upper BMI limit (inclusion criteria No. 4) was increased from 20 to 24 kg/m2 in children and from 25 to 29 kg/m2 in adolescents. • Children and adolescents with thyroiditis (treated or no treatment necessary) were allowed to be included in the trial. • Children and adolescents treated with Semilente® prior to trial initiation were to take their last insulin injection 12 hours before trial product administration instead of being transferred to NPH insulin, 48 hours before trial product administration.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/18761644
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