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    Clinical Trial Results:
    A 52-Week, Multinational, Multi-Centre, Open-Labelled, Randomised, Parallel, Efficacy and Safety Comparison of Insulin Detemir and NPH Insulin in Children and Adolescents 2-16 years with Type 1 Diabetes on a Basal-Bolus Regimen with Insulin Aspart as Bolus Insulin

    Summary
    EudraCT number
    		 2006-000051-18
    Trial protocol
    		 HU   FI   CZ   DK   BG   FR  
    Global end of trial date
    03 Sep 2008

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

    Trial information

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    Trial identification
    Sponsor protocol code
    NN304-1689
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00435019
    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)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000412-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
    09 Oct 2009
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Sep 2008
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Sep 2008
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the glycaemic control, measured as HbA1c, of insulin detemir administered once or twice daily plus mealtime insulin aspart with NPH insulin administered once or twice daily plus mealtime insulin aspart in children and adolescents with type 1 diabetes.
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki (October 2000, amended 2002 and 2004) and ICH Good Clinical Practice (01-May-1996).
    Background therapy
    		 Not applicable.
    Evidence for comparator
    		 Not applicable.
    Actual start date of recruitment
    12 Feb 2007
    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
    Denmark: 19
    Country: Number of subjects enrolled
    Finland: 18
    Country: Number of subjects enrolled
    France: 6
    Country: Number of subjects enrolled
    Czech Republic: 38
    Country: Number of subjects enrolled
    Hungary: 28
    Country: Number of subjects enrolled
    Bulgaria: 38
    Country: Number of subjects enrolled
    Macedonia, the former Yugoslav Republic of: 24
    Country: Number of subjects enrolled
    Poland: 50
    Country: Number of subjects enrolled
    Russian Federation: 82
    Country: Number of subjects enrolled
    Turkey: 31
    Country: Number of subjects enrolled
    United Kingdom: 13
    Worldwide total number of subjects
    347
    EEA total number of subjects
    210
    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)
    221
    Adolescents (12-17 years)
    126
    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
    		 A total of 35 centres in 11 countries: 3 in Bulgaria, 3 in the Czech Republic, 3 in Denmark, 5 in Finland, 2 in France, 2 in Hungary, 1 in Macedonia, 4 in Poland, 4 in the Russian Federation, 4 in Turkey and 4 in the UK.

    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
    Not applicable.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Insulin detemir
    Arm description
    		 Individually adjusted insulin detemir dose injected subcutaneously once daily (evening) or twice daily (morning and evening) + insulin aspart with larger meals
    Arm type
    		 Experimental

    Investigational medicinal product name
    Insulin detemir
    Investigational medicinal product code
    Other name
    Insulin detemir
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    s.c. injection, once or twice daily

    Investigational medicinal product name
    Insulin aspart
    Investigational medicinal product code
    Other name
    Insulin aspart
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    s.c. injection, at main meals

    Arm title
    		 NPH Insulin
    Arm description
    		 Individually adjusted NPH insulin dose injected subcutaneously once daily (evening) or twice daily (morning and evening) + insulin aspart with larger meals
    Arm type
    		 Experimental

    Investigational medicinal product name
    NPH insulin
    Investigational medicinal product code
    Other name
    insulin human
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    s.c. injection, once or twice daily

    Investigational medicinal product name
    Insulin aspart
    Investigational medicinal product code
    Other name
    Insulin aspart
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    s.c. injection, at main meals

    Number of subjects in period 1
    		Insulin detemir NPH Insulin
    Started
    177
    170
    Exposed to Study Drug
    177
    170
    Completed
    164
    161
    Not completed
    13
    9
         Adverse event, non-fatal
    1
    -
         Unclassified
    8
    6
         Protocol deviation
    3
    1
         Lack of efficacy
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Insulin detemir
    Reporting group description
    		 Individually adjusted insulin detemir dose injected subcutaneously once daily (evening) or twice daily (morning and evening) + insulin aspart with larger meals

    Reporting group title
    NPH Insulin
    Reporting group description
    		 Individually adjusted NPH insulin dose injected subcutaneously once daily (evening) or twice daily (morning and evening) + insulin aspart with larger meals

    Reporting group values
    		 Insulin detemir NPH Insulin Total
    Number of subjects
    		 177 170 347
    Age categorical
    Units: Subjects
        <=18 years
    		 177 170 347
        Between 18 and 65 years
    		 0 0 0
        >=65 years
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 10 ( 4.09 ) 9.8 ( 3.9 ) -
    Gender categorical
    Units: Subjects
        Female
    		 94 73 167
        Male
    		 83 97 180
    Body weight
    Units: Kg
        arithmetic mean (standard deviation)
    		 37.1 ( 16.4 ) 36.2 ( 16.1 ) -
    Body mass index (BMI)
    Units: Kg/m2
        arithmetic mean (standard deviation)
    		 18 ( 2.74 ) 17.99 ( 2.65 ) -
    HbA1c
    Units: Percentage
        arithmetic mean (standard deviation)
    		 8.41 ( 1.11 ) 8.4 ( 1.1 ) -
    Fasting plasma glucose (FPG)
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 8.36 ( 4.38 ) 8.7 ( 4.59 ) -
    Serum ALAT
    Units: U/L
        arithmetic mean (standard deviation)
    		 19.15 ( 8.37 ) 20.24 ( 9.88 ) -
    Serum Lactate dehydrogenase
    Units: U/L
        arithmetic mean (standard deviation)
    		 204 ( 48.12 ) 204.5 ( 39.32 ) -
    Serum albumin
    Units: g/dL
        arithmetic mean (standard deviation)
    		 4.32 ( 0.22 ) 4.32 ( 0.23 ) -
    Serum alkaline phosphatase
    Units: U/L
        arithmetic mean (standard deviation)
    		 243.5 ( 84.96 ) 257.7 ( 84.09 ) -
    Serum creatinine
    Units: umol/L
        arithmetic mean (standard deviation)
    		 44.82 ( 11.38 ) 44.55 ( 11.38 ) -
    Serum potassium
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 4.35 ( 0.37 ) 4.37 ( 0.37 ) -
    Serum sodium
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 138.4 ( 2.06 ) 138.2 ( 2.47 ) -
    Serum total proteins
    Units: g/dL
        arithmetic mean (standard deviation)
    		 7.05 ( 0.42 ) 7.06 ( 0.45 ) -
    Blood haemoglobin
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 8.39 ( 0.57 ) 8.33 ( 0.67 ) -
    Blood leukocytes
    Units: 10^9/L
        arithmetic mean (standard deviation)
    		 6.22 ( 1.7 ) 6.58 ( 2.09 ) -
    Blood thrombocytes
    Units: 10^9/L
        arithmetic mean (standard deviation)
    		 304.8 ( 70.51 ) 312.4 ( 82.51 ) -
    Diastolic Blood Pressure, Sitting
    Units: mmHg
        arithmetic mean (standard deviation)
    		 65.5 ( 9.6 ) 65.4 ( 10.8 ) -
    Systolic Blood Pressure, Sitting
    Units: mmHg
        arithmetic mean (standard deviation)
    		 104 ( 11.7 ) 104 ( 13.8 ) -
    Pulse, Sitting
    Units: beats/min
        arithmetic mean (standard deviation)
    		 85.6 ( 13.1 ) 86.1 ( 12.5 ) -

    End points

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    End points reporting groups
    Reporting group title
    Insulin detemir
    Reporting group description
    		 Individually adjusted insulin detemir dose injected subcutaneously once daily (evening) or twice daily (morning and evening) + insulin aspart with larger meals

    Reporting group title
    NPH Insulin
    Reporting group description
    		 Individually adjusted NPH insulin dose injected subcutaneously once daily (evening) or twice daily (morning and evening) + insulin aspart with larger meals

    Primary: Glycosylated haemoglobin A1c (HbA1c), at the end of trial.

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    End point title
    		 Glycosylated haemoglobin A1c (HbA1c), at the end of trial.
    End point description
    Glycosylated haemoglobin A1c (HbA1c) measured after 52 weeks of treatment and analysed by central laboratory. N = number of subject participated; N (detemir) = 171 and N (NPH) = 168
    End point type
    Primary
    End point timeframe
    After 52 weeks of treatment
    End point values
    		 Insulin detemir NPH Insulin
    Number of subjects analysed
    177 [1]
    170 [2]
    Units: Percent (%) glycosylated haemoglobin
        least squares mean (standard error)
    8.75 ( 0.11 )
    8.64 ( 0.11 )
    Notes
    [1] - Full analysis set for Insulin detemir arm has 177 subjects.
    [2] - Full analysis set for NPH Insulin arm has 170 subjects.
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Insulin detemir v NPH Insulin
    Number of subjects included in analysis
    347
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.12
         upper limit
    		 0.36
    Notes
    [3] - The null hypothesis for the non-inferiority test was that the mean HbA1c with insulin detemir was greater than or equal to the mean HbA1c with NPH insulin plus 0.4%.

    Secondary: Insulin detemir specific, insulin aspart specific and insulin detemir/aspart cross-reacting antibodies during treatment.

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    End point title
    		 Insulin detemir specific, insulin aspart specific and insulin detemir/aspart cross-reacting antibodies during treatment.
    End point description
    Insulin detemir specific antibodies, insulin aspart specific antibodies and insulin detemir/insulin aspart cross-reacting antibodies during 52 weeks of treatment. N = number of subject participated. 1. Insulin detemir specific, week 0 , N (detemir) = 127, N (NPH) = 112 and week 52, N (detemir) =125, N (NPH)=128. 2. Cross-reacting insulin, week 0, N (detemir) = 130, N (NPH) = 113 and week 52, N (detemir) =132, N (NPH)=135. 3. Insulin aspart specific, week 0 N (detemir) = 126, N (NPH) = 111 and week 52, N (detemir) = 128, N (NPH) =133.
    End point type
    Secondary
    End point timeframe
    During 52 weeks of treatment
    End point values
    		 Insulin detemir NPH Insulin
    Number of subjects analysed
    177 [4]
    170 [5]
    Units: Percent bound of total
    arithmetic mean (standard deviation)
        Insulin detemir specific, week 0
    3.23 ( 1.03 )
    2.95 ( 1.23 )
        Insulin detemir specific, week 52
    5.15 ( 3.3 )
    3.01 ( 1.66 )
        Cross-reacting insulin, week 0
    27.06 ( 19.1 )
    27.26 ( 18.6 )
        Cross-reacting insulin, week 52
    43.7 ( 15.6 )
    30.19 ( 17.3 )
        Insulin aspart specific, week 0
    2.26 ( 2.32 )
    2.24 ( 2.99 )
        Insulin aspart specific, week 52
    4.2 ( 4.35 )
    2.68 ( 3.6 )
    Notes
    [4] - Safety analysis set for Insulin detemir arm has 177 subjects.
    [5] - safety analysis set for NPH Insulin arm has 170 subjects.
    No statistical analyses for this end point

    Secondary: Fasting plasma glucose (FPGlab), end of trial

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    End point title
    		 Fasting plasma glucose (FPGlab), end of trial
    End point description
    Fasting plasma glucose (FPGlab), measured after 52 weeks of treatment and analysed by central laboratory. N = number of subject participated. N (detemir) = 171, N (NPH) = 168.
    End point type
    Secondary
    End point timeframe
    After 52 weeks of treatment
    End point values
    		 Insulin detemir NPH Insulin
    Number of subjects analysed
    177 [6]
    170 [7]
    Units: mmol/L
        least squares mean (standard error)
    7.99 ( 0.42 )
    8.61 ( 0.43 )
    Notes
    [6] - Full analysis set for Insulin detemir arm has 177 subjects.
    [7] - Full analysis set for NPH Insulin arm has 170 subjects.
    No statistical analyses for this end point

    Secondary: 9-points plasma glucose (PG) profile, end of trial

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    End point title
    		 9-points plasma glucose (PG) profile, end of trial
    End point description
    9-points plasma glucose (PG) profile, after 52 weeks of treatment
    End point type
    Secondary
    End point timeframe
    After 52 weeks of treatment
    End point values
    		 Insulin detemir NPH Insulin
    Number of subjects analysed
    177 [8]
    170 [9]
    Units: mmol/L
    least squares mean (standard error)
        Before Breakfast
    8.24 ( 0.35 )
    8.44 ( 0.34 )
        90 min after start of breakfast
    9.74 ( 0.4 )
    9.66 ( 0.39 )
        Before Lunch
    8.75 ( 0.37 )
    8.75 ( 0.36 )
        90 min after start of lunch
    8.73 ( 0.36 )
    8.61 ( 0.35 )
        Before dinner
    9.53 ( 0.4 )
    8.91 ( 0.39 )
        90 min after start of dinner
    9.19 ( 0.35 )
    8.23 ( 0.34 )
        Bedtime
    10.4 ( 0.4 )
    9.45 ( 0.39 )
        At 3.00 am
    9.51 ( 0.39 )
    9.05 ( 0.38 )
        Before breakfast the next day
    8.39 ( 0.36 )
    9.27 ( 0.35 )
    Notes
    [8] - Full analysis set for Insulin detemir arm has 177 subjects.
    [9] - Full analysis set for NPH Insulin arm has 170 subjects.
    No statistical analyses for this end point

    Secondary: Nocturnal plasma glucose, end of trial

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    End point title
    		 Nocturnal plasma glucose, end of trial
    End point description
    Nocturnal plasma glucose after 52 weeks of treatment. N = number of subject participated. N (detemir) = 125, N (NPH) = 132
    End point type
    Secondary
    End point timeframe
    After 52 weeks of treatment.
    End point values
    		 Insulin detemir NPH Insulin
    Number of subjects analysed
    177 [10]
    170 [11]
    Units: mmol/L
        arithmetic mean (standard deviation)
    9.07 ( 3.83 )
    8.65 ( 4.28 )
    Notes
    [10] - Full analysis set for Insulin detemir arm has 177 subjects.
    [11] - Full analysis set for NPH Insulin arm has 170 subjects.
    No statistical analyses for this end point

    Secondary: Body weight (kg), end of trial.

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    End point title
    		 Body weight (kg), end of trial.
    End point description
    Body weight (kg) after 52 weeks of treatment. N = number of subject participated N (detemir) = 172, N (NPH) = 166
    End point type
    Secondary
    End point timeframe
    After 52 weeks of treatment
    End point values
    		 Insulin detemir NPH Insulin
    Number of subjects analysed
    177 [12]
    170 [13]
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    40.43 ( 17.2 )
    40.82 ( 17.3 )
    Notes
    [12] - Safety analysis set for Insulin detemir arm has 177 subjects.
    [13] - Safety analysis set for NPH Insulin arm has 170 subjects.
    No statistical analyses for this end point

    Secondary: Body mass index (BMI), end of trial

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    End point title
    		 Body mass index (BMI), end of trial
    End point description
    Body mass index (BMI), after 52 weeks of treatment. N = number of subject participated. N (detemir) = 172, N (NPH) = 166
    End point type
    Secondary
    End point timeframe
    After 52 weeks of treatment
    End point values
    		 Insulin detemir NPH Insulin
    Number of subjects analysed
    177 [14]
    170 [15]
    Units: kg/m2
        arithmetic mean (standard deviation)
    18.3 ( 3 )
    18.8 ( 3.1 )
    Notes
    [14] - Safety analysis set for Insulin detemir arm has 177 subjects.
    [15] - Safety analysis set for NPH Insulin arm has 170 subjects.
    No statistical analyses for this end point

    Secondary: SD-score (Z-score) for body weight, end of trial

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    End point title
    		 SD-score (Z-score) for body weight, end of trial
    End point description
    SD-score (Z-score) for body weight, after 52 weeks of treatment. N = number of subject participated. N (detemir) = 172, N (NPH) = 166
    End point type
    Secondary
    End point timeframe
    After 52 weeks of treatment
    End point values
    		 Insulin detemir NPH Insulin
    Number of subjects analysed
    177 [16]
    170 [17]
    Units: Number
        arithmetic mean (standard deviation)
    0.16 ( 0.97 )
    0.42 ( 1 )
    Notes
    [16] - Safety analysis set for Insulin detemir arm has 177 subjects.
    [17] - Safety analysis set for NPH Insulin arm has 170 subjects.
    No statistical analyses for this end point

    Secondary: Safety laboratory parameters haematology, end of trial

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    End point title
    		 Safety laboratory parameters haematology, end of trial
    End point description
    Safety laboratory parameters haematology, after 52 weeks of treatment. N = number of subject participated. N (detemir): Blood leukocytes, N = 168; Blood thrombocytes, N = 169 N (NHP): Blood leukocytes, N = 163; Blood thrombocytes, N = 160
    End point type
    Secondary
    End point timeframe
    After 52 weeks of treatment
    End point values
    		 Insulin detemir NPH Insulin
    Number of subjects analysed
    177 [18]
    170 [19]
    Units: 10^9/L
    arithmetic mean (standard deviation)
        Blood leukocytes
    6.59 ( 1.93 )
    6.94 ( 1.79 )
        Blood thrombocytes
    287.1 ( 67.08 )
    310.9 ( 79.5 )
    Notes
    [18] - Safety analysis set for Insulin detemir arm has 177 subjects.
    [19] - Safety analysis set for NPH Insulin arm has 170 subjects.
    No statistical analyses for this end point

    Secondary: Safety laboratory parameters haematology and biochemistry, end of trial

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    End point title
    		 Safety laboratory parameters haematology and biochemistry, end of trial
    End point description
    Safety laboratory parameters haematology and biochemistry, after 52 weeks of treatment N = number of subject participated. N (detemir): Blood haemoglobin, serum sodium and serum potassium, N = 169 N (NPH): Blood haemoglobin, N = 163; serum sodium, N = 166; serum potassium, N = 166
    End point type
    Secondary
    End point timeframe
    After 52 weeks of treatment
    End point values
    		 Insulin detemir NPH Insulin
    Number of subjects analysed
    177 [20]
    170 [21]
    Units: mmol/L
    arithmetic mean (standard deviation)
        Blood haemoglobin
    8.22 ( 0.58 )
    8.07 ( 0.69 )
        Serum sodium
    140.5 ( 3.2 )
    140.6 ( 2.86 )
        Serum potassium
    4.35 ( 0.48 )
    4.38 ( 0.42 )
    Notes
    [20] - Safety analysis set for Insulin detemir arm has 177 subjects.
    [21] - Safety analysis set for NPH Insulin arm has 170 subjects.
    No statistical analyses for this end point

    Secondary: Safety laboratory parameters biochemistry, end of trial

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    End point title
    		 Safety laboratory parameters biochemistry, end of trial
    End point description
    Safety laboratory parameters biochemistry, after 52 weeks of treatment. N = number of subject participated. N (detemir) = 169 and N (NPH) = 166
    End point type
    Secondary
    End point timeframe
    After 52 weeks of treatment
    End point values
    		 Insulin detemir NPH Insulin
    Number of subjects analysed
    177 [22]
    170 [23]
    Units: g/dL
    arithmetic mean (standard deviation)
        Serum albumin
    4.38 ( 0.2 )
    4.33 ( 0.22 )
        Serum total proteins
    7.13 ( 0.4 )
    7.07 ( 0.46 )
    Notes
    [22] - Safety analysis set for Insulin detemir arm has 177 subjects.
    [23] - Safety analysis set for NPH Insulin arm has 170 subjects.
    No statistical analyses for this end point

    Secondary: Safety laboratory parameters biochemistry, end of trial

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    End point title
    		 Safety laboratory parameters biochemistry, end of trial
    End point description
    Safety laboratory parameters biochemistry, after 52 weeks of treatment. N = number of subject participated. N (detemir) = 169 and N (NPH) = 166
    End point type
    Secondary
    End point timeframe
    After 52 weeks of treatment
    End point values
    		 Insulin detemir NPH Insulin
    Number of subjects analysed
    177 [24]
    170 [25]
    Units: U/L
    arithmetic mean (standard deviation)
        Serum alkaline phosphatase
    252.4 ( 106.5 )
    266.7 ( 99.1 )
        Serum ALAT
    19.89 ( 9.64 )
    21.95 ( 24.74 )
        Serum Lactate dehydrogenase
    195.8 ( 42.47 )
    203.1 ( 42.85 )
    Notes
    [24] - Safety analysis set for Insulin detemir arm has 177 subjects.
    [25] - Safety analysis set for NPH Insulin arm has 170 subjects.
    No statistical analyses for this end point

    Secondary: Occurrence of ketoacidosis requiring hospitalisation during treatment

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    End point title
    		 Occurrence of ketoacidosis requiring hospitalisation during treatment
    End point description
    Occurrence of ketoacidosis requiring hospitalisation during 52 weeks of treatment
    End point type
    Secondary
    End point timeframe
    During 52 weeks of treatment
    End point values
    		 Insulin detemir NPH Insulin
    Number of subjects analysed
    177 [26]
    170 [27]
    Units: Number of events
    3
    4
    Notes
    [26] - Safety analysis set for Insulin detemir arm has 177 subjects.
    [27] - Safety analysis set for NPH Insulin arm has 170 subjects.
    No statistical analyses for this end point

    Secondary: Insulin detemir dose, at end of trial

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    End point title
    		 Insulin detemir dose, at end of trial [28]
    End point description
    Insulin detemir dose after 52 weeks of treatment. N = number of subject participated; N (detemir) = 134
    End point type
    Secondary
    End point timeframe
    After 52 weeks of treatment
    Notes
    [28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only insulin detemir arm is presented here as the unit of measurement for it is U/kg. The other arm has different unit of measurement so it could not be possible to present both arms together.
    End point values
    		 Insulin detemir
    Number of subjects analysed
    177 [29]
    Units: U/kg
    arithmetic mean (standard deviation)
        Basal dose
    0.6 ( 0.26 )
        Bolus dose
    0.48 ( 0.18 )
    Notes
    [29] - Safety analysis set for Insulin detemir arm has 177 subjects.
    No statistical analyses for this end point

    Secondary: Injection pain assessment using a facial visual analogue scale (VAS), at end-of-trial.

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    End point title
    		 Injection pain assessment using a facial visual analogue scale (VAS), at end-of-trial.
    End point description
    Injection pain assessment using a facial visual analogue scale (VAS), during 52 weeks of treatment. Visual Analogue Scale (VAS) range = 0 to 100; from no pain (0) to the worst possible pain (100). N = number of subject participated; N (detemir) = 133 and N (NPH) = 138
    End point type
    Secondary
    End point timeframe
    After 52 weeks of treatment
    End point values
    		 Insulin detemir NPH Insulin
    Number of subjects analysed
    177 [30]
    170 [31]
    Units: VAS score
        arithmetic mean (standard deviation)
    39.6 ( 19.5 )
    33.9 ( 18.1 )
    Notes
    [30] - Safety analysis set for Insulin detemir arm has 177 subjects.
    [31] - Safety analysis set for NPH Insulin arm has 170 subjects.
    No statistical analyses for this end point

    Secondary: Vital signs, end of trial

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    End point title
    		 Vital signs, end of trial
    End point description
    Vital signs after 52 weeks of treatment. N = number of subject participated. Mean blood pressure-systolic, N (detemir) = 171 and N (NPH) = 163. Mean blood pressure-diastolic, N (detemir) = 171 and N (NPH) = 163. Mean pulse, N (detemir) = 170 and N (NPH) = 164
    End point type
    Secondary
    End point timeframe
    After 52 weeks of treatment
    End point values
    		 Insulin detemir NPH Insulin
    Number of subjects analysed
    177 [32]
    170 [33]
    Units: Number
        Mean blood pressure (mmHg, systolic)
    107
    106
        Mean blood pressure (mmHg, diastolic)
    65
    65
        Mean pulse (beats/min)
    84
    84
    Notes
    [32] - Safety analysis set for Insulin detemir arm has 177 subjects.
    [33] - Safety analysis set for NPH Insulin arm has 170 subjects.
    No statistical analyses for this end point

    Secondary: Incidence of all 24 hours hypoglycaemia (mild, moderate or severe) episodes during treatment

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    End point title
    		 Incidence of all 24 hours hypoglycaemia (mild, moderate or severe) episodes during treatment
    End point description
    Incidence of all 24 hours hypoglycaemia (mild, moderate or severe) episodes during 52 weeks of treatment. Detemir: 3 severe episodes were reported by 3 subjects; 370 moderate episodes were reported by 30 subjects; 5956 mild episodes were reported by 148 subjects. NPH: 15 severe episodes were reported by 12 subjects; 947 moderate episodes were reported by 28 subjects; 7189 mild episodes were reported by 151 subjects.
    End point type
    Secondary
    End point timeframe
    During 52 weeks of treatment
    End point values
    		 Insulin detemir NPH Insulin
    Number of subjects analysed
    177 [34]
    170 [35]
    Units: Number of episodes
        Severe
    3
    15
        Moderate
    370
    947
        Mild
    5956
    7189
    Notes
    [34] - Safety analysis set for Insulin detemir arm has 177 subjects.
    [35] - Safety analysis set for NPH Insulin arm has 170 subjects.
    No statistical analyses for this end point

    Secondary: Incidence of daytime hypoglycaemia (mild, moderate or severe) episodes during treatment

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    End point title
    		 Incidence of daytime hypoglycaemia (mild, moderate or severe) episodes during treatment
    End point description
    Incidence of daytime hypoglycaemia (mild, moderate or severe) episodes during treatment. Detemir: 3 severe episodes were reported by 3 subjects; 311 moderate episodes were reported by 27 subjects; 5244 mild episodes were reported by146 subjects. NPH: 9 severe episodes were reported by 8 subjects; 835 moderate episodes were reported by 27 subjects; 6050 mild episodes were reported by150 subjects.
    End point type
    Secondary
    End point timeframe
    During 52 weeks of treatment
    End point values
    		 Insulin detemir NPH Insulin
    Number of subjects analysed
    177 [36]
    170 [37]
    Units: Number
        Severe
    3
    9
        Moderate
    311
    835
        Mild
    5244
    6050
    Notes
    [36] - Safety analysis set for Insulin detemir arm has 177 subjects.
    [37] - Safety analysis set for NPH Insulin arm has 170 subjects.
    No statistical analyses for this end point

    Secondary: Incidence of nocturnal hypoglycaemia (mild, moderate or severe) episodes during treatment

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    End point title
    		 Incidence of nocturnal hypoglycaemia (mild, moderate or severe) episodes during treatment
    End point description
    Incidence of nocturnal hypoglycaemia (mild, moderate or severe) episodes during 52 weeks of treatment. Detemir: No severe episodes were reported; 59 moderate episodes were reported by 15 subjects; 712 mild episodes were reported by100 subjects. NPH: 6 severe episodes were reported by 5 subjects; 112 moderate episodes were reported by 14 subjects; 1139 mild episodes were reported by111 subjects.
    End point type
    Secondary
    End point timeframe
    During 52 weeks of treatment
    End point values
    		 Insulin detemir NPH Insulin
    Number of subjects analysed
    177 [38]
    170 [39]
    Units: Number
        Severe
    0
    6
        Moderate
    59
    112
        Mild
    712
    1139
    Notes
    [38] - Safety analysis set for Insulin detemir arm has 177 subjects.
    [39] - Safety analysis set for NPH Insulin arm has 170 subjects.
    No statistical analyses for this end point

    Secondary: Safety laboratory parameter biochemistry, end of trial

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    End point title
    		 Safety laboratory parameter biochemistry, end of trial
    End point description
    Safety laboratory parameter biochemistry, after 52 weeks of treatment. N = number of subject participated; N (detemir) = 169 and N (NPH) = 166
    End point type
    Secondary
    End point timeframe
    After 52 weeks of treatment
    End point values
    		 Insulin detemir NPH Insulin
    Number of subjects analysed
    177 [40]
    170 [41]
    Units: umol/L
    arithmetic mean (standard deviation)
        Serum creatinine
    47.8 ( 13.21 )
    48.77 ( 13.51 )
    Notes
    [40] - Safety analysis set for Insulin detemir arm has 177 subjects.
    [41] - Safety analysis set for NPH Insulin arm has 170 subjects.
    No statistical analyses for this end point

    Secondary: Insulin NPH dose at the end of trial

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    End point title
    		 Insulin NPH dose at the end of trial [42]
    End point description
    Insulin NPH dose after 52 weeks of treatment. N = number of subject participated; N (NPH) = 140
    End point type
    Secondary
    End point timeframe
    After 52 weeks of treatment
    Notes
    [42] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only NPH insulin arm is presented here as the unit of measurement for it is IU/kg. The other arm has different unit of measurement so it could not be possible to present both arms together.
    End point values
    		 NPH Insulin
    Number of subjects analysed
    170 [43]
    Units: IU/kg
    arithmetic mean (standard deviation)
        Basal dose
    0.58 ( 0.22 )
        Bolus dose
    0.45 ( 0.17 )
    Notes
    [43] - Safety analysis set for NPH Insulin arm has 170 subjects.
    No statistical analyses for this end point

    Secondary: Adverse events during treatment

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    End point title
    		 Adverse events during treatment
    End point description
    Adverse events reported during 52 weeks of treatment. Detemir: 537 adverse events were reported by 132 subjects NPH: 554 adverse events were reported by 135 subjects
    End point type
    Secondary
    End point timeframe
    During 52 weeks of treatment.
    End point values
    		 Insulin detemir NPH Insulin
    Number of subjects analysed
    177 [44]
    170 [45]
    Units: Number of events
    537
    554
    Notes
    [44] - Safety analysis set for Insulin detemir arm has 177 subjects.
    [45] - Safety analysis set for NPH Insulin arm has 170 subjects.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from week 0 to week 52.
    Adverse event reporting additional description
    Safety analysis set (SAS): all randomised subjects exposed to at least one dose of trial product, classified according to actual treatment
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    11.1
    Reporting groups
    Reporting group title
    Insulin detemir
    Reporting group description
    		 Individually adjusted insulin detemir dose injected subcutaneously once daily (evening) or twice daily (morning and evening) + insulin aspart with larger meals

    Reporting group title
    NPH Insulin
    Reporting group description
    		 Individually adjusted NPH insulin dose injected subcutaneously once daily (evening) or twice daily (morning and evening) + insulin aspart with larger meals

    Serious adverse events
    		 Insulin detemir NPH Insulin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    14 / 177 (7.91%)
    20 / 170 (11.76%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Burns second degree
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Medication error
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Dyspepsia
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 177 (0.00%)
    2 / 170 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Adenoidal Hypertrophy
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephropathy
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    4 / 177 (2.26%)
    2 / 170 (1.18%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis shigella
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis Viral
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis Media Acute
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 170 (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
    3 / 177 (1.69%)
    4 / 170 (2.35%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 177 (0.56%)
    3 / 170 (1.76%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes Mellitus Inadequate Control
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemic Unconsciousness
         subjects affected / exposed
    0 / 177 (0.00%)
    2 / 170 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Insulin detemir NPH Insulin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    131 / 177 (74.01%)
    134 / 170 (78.82%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    26 / 177 (14.69%)
    23 / 170 (13.53%)
         occurrences all number
    65
    44
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    9 / 177 (5.08%)
    7 / 170 (4.12%)
         occurrences all number
    10
    7
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    75 / 177 (42.37%)
    81 / 170 (47.65%)
         occurrences all number
    147
    179
    Pharyngitis
         subjects affected / exposed
    19 / 177 (10.73%)
    15 / 170 (8.82%)
         occurrences all number
    29
    16
    Upper respiratory tract infection
         subjects affected / exposed
    18 / 177 (10.17%)
    16 / 170 (9.41%)
         occurrences all number
    32
    32
    Gastroenteritis
         subjects affected / exposed
    15 / 177 (8.47%)
    12 / 170 (7.06%)
         occurrences all number
    20
    13
    Influenza
         subjects affected / exposed
    10 / 177 (5.65%)
    18 / 170 (10.59%)
         occurrences all number
    14
    25
    Viral infection
         subjects affected / exposed
    12 / 177 (6.78%)
    14 / 170 (8.24%)
         occurrences all number
    14
    17
    Bronchitis
         subjects affected / exposed
    9 / 177 (5.08%)
    12 / 170 (7.06%)
         occurrences all number
    11
    15

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Sep 2006
    Global substantial amendment 1: The NN304-1689 trial was planned as a post approval commitment trial requested by the EU Authorities to follow the insulin antibody formation in children between 6 and 16 years. Since then, the protocol has developed to include a trial population down to 2 years. As insulin detemir is not yet approved for children below 6 years, the phase of the trial should be changed to phase 3b.
    12 Dec 2006
    Global substantial amendment 2: 1.1 Insulin Antibodies. To determine insulin detemir specific antibodies, insulin aspart specific antibodies and insulin detemir/aspart cross-reacting antibodies, a blood sample will be obtained at baseline (Visit 2) and at Visits 8, 9, 10. To minimise assay interference from excess insulin detemir, NPH insulin, aspart insulin, blood should be collected, when the blood levels of these drugs are the lowest. The most optimal time would be immediately before dinner and before injecting pre-dinner insulin aspart. For practical purposes, blood sampling should take place in the afternoon at least 3 hours after the pre-lunch insulin aspart injection and the following data should be recorded: • Date, time and dose of last basal insulin dose prior to blood sampling • Date, time and dose of last bolus insulin dose prior to blood sampling • Date and time of blood sample 1.2 Clinical Supplies IV/WRS Management Due to the introduction of Clinical Supplies IV/WRS (Interactive Voice/Web Response System) Management (CSIM) the protocol has been updated to be in accordance with the CSIM procedures. In addition the Trial Materials section has been updated to correspond with new standards of wording. Finally, the text has been updated and it is now correctly stated, that NPH insulin can be kept for 6 weeks, after the seal has been broken. There will be no changes with regards to trial design, subject treatment or methods/assessments.

    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/21418455
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