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    Clinical Trial Results:
    Efficacy and safety of liraglutide in combination with metformin versus metformin monotherapy on glycaemic control in children and adolescents with type 2 diabetes A 26-week double-blind, randomised, parallel group, placebo controlled multi-centre trial followed by a 26-week open-label extension

    Summary
    EudraCT number
    2011-002605-29
    Trial protocol
    GR   GB   HU   DE   BE   ES   DK   NO   SE   PL   AT   FR   PT   NL  
    Global end of trial date
    23 May 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    05 Dec 2018
    First version publication date
    05 Dec 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NN2211-3659
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01541215
    WHO universal trial number (UTN)
    U1111-1121-8743
    Sponsors
    Sponsor organisation name
    Novo Nordisk A/S
    Sponsor organisation address
    Novo Allé, Bagsvaerd, Denmark, 2880
    Public contact
    Clinical Reporting Anchor and Disclosure (1452), Novo Nordisk A/S, clinicaltrials@novonordisk.com
    Scientific contact
    Clinical Reporting Anchor and Disclosure (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-000128-PIP01-07
    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
    02 Nov 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Nov 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    23 May 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To confirm the superiority of liraglutide at the maximum tolerated dose (0.6 mg, 1.2 mg or 1.8 mg)versus placebo when added to metformin with or without basal insulin treatment in controlling glycaemia in children and adolescents (ages 10–17 years) with type 2 diabetes
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki and ICH Good Clinical Practice, including archiving of essential documents and FDA 21 CFR 312.120.
    Background therapy
    Metformin was characterised as background treatment.
    Evidence for comparator
    Not applicable
    Actual start date of recruitment
    13 Nov 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    2 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 1
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Canada: 3
    Country: Number of subjects enrolled
    Spain: 1
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    Hungary: 3
    Country: Number of subjects enrolled
    Israel: 13
    Country: Number of subjects enrolled
    India: 6
    Country: Number of subjects enrolled
    Lebanon: 3
    Country: Number of subjects enrolled
    Macedonia, the former Yugoslav Republic of: 6
    Country: Number of subjects enrolled
    Mexico: 16
    Country: Number of subjects enrolled
    Malaysia: 2
    Country: Number of subjects enrolled
    New Zealand: 6
    Country: Number of subjects enrolled
    Poland: 1
    Country: Number of subjects enrolled
    Portugal: 1
    Country: Number of subjects enrolled
    Russian Federation: 13
    Country: Number of subjects enrolled
    Thailand: 1
    Country: Number of subjects enrolled
    Turkey: 5
    Country: Number of subjects enrolled
    Taiwan: 3
    Country: Number of subjects enrolled
    United States: 45
    Country: Number of subjects enrolled
    Morocco: 4
    Worldwide total number of subjects
    135
    EEA total number of subjects
    8
    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)
    16
    Adolescents (12-17 years)
    119
    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 84 sites in 25 countries.

    Pre-assignment
    Screening details
    Eligible subjects entered an 11- to 12-week run-in period where they were to undergo a 3-4 week titration of metformin to a maximum tolerated dose of metformin (≥1000 mg and ≤2000 mg per day) followed by an 8-week maintenance period.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator
    Blinding implementation details
    The trial was designed to be double-blind during the first 26 weeks of randomised treatment

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Liraglutide
    Arm description
    After the run-in period, subjects were randomized to receive liraglutide subcutaneous injections once daily (in combination with metformin with or without basal insulin, on a background of diet and exercise) for 52 weeks (26 weeks double blind treatment period followed by a 26-week open-label extension period). Subjects treated with liraglutide for more than 3 months were asked to return for follow-up visits one and two years after the end of the open label period (after trial drug cessation at week 52).
    Arm type
    Experimental

    Investigational medicinal product name
    Liraglutide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Liraglutide (6.0 mg/ml solution) was administered once daily by s.c. injections, either in the abdomen, thigh or upper arm. The liraglutide dosing was started at 0.6 mg/day during the first week and escalated in weekly increments of 0.6 mg over the following 2-3 weeks. Dose escalation was based on tolerability, as judged by the investigator and on the average of three fasting plasma glucose (FPG) measurements performed by the subject at home on the 3 consecutive days before the dose escalation visit being >6.1 mmol/L (110 mg/dL). Subjects were treated with doses of 0.6, 1.2 or 1.8 after dose escalation.

    Arm title
    Placebo
    Arm description
    After the run-in period, subjects were randomized to receive placebo (in combination with metformin with or without basal insulin, on a background of diet and exercise) for a 26 weeks double blind treatment period. After 26 weeks, participants discontinued placebo and continued treatment with metformin (with or without basal insulin) during the open-label period.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Liraglutide placebo was administered once daily by s.c. injections, either in the abdomen, thigh or upper arm. The liraglutide placebo was administered once daily subcutaneously in equivalent volume as liraglutide.

    Number of subjects in period 1 [1]
    Liraglutide Placebo
    Started
    66
    68
    Completed
    56
    53
    Not completed
    10
    15
         Non-compliance
    4
    4
         Adverse Event
    -
    1
         Unclassified
    -
    3
         Withdrawal criteria
    6
    7
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: In total, 135 subjects were randomised (66 subjects to liraglutide and 69 subjects to placebo); of these, one subject in the placebo group was not exposed to treatment. Thus, 134 subjects were exposed to either liraglutide or placebo (66 subjects to liraglutide and 68 subjects to placebo).

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Liraglutide
    Reporting group description
    After the run-in period, subjects were randomized to receive liraglutide subcutaneous injections once daily (in combination with metformin with or without basal insulin, on a background of diet and exercise) for 52 weeks (26 weeks double blind treatment period followed by a 26-week open-label extension period). Subjects treated with liraglutide for more than 3 months were asked to return for follow-up visits one and two years after the end of the open label period (after trial drug cessation at week 52).

    Reporting group title
    Placebo
    Reporting group description
    After the run-in period, subjects were randomized to receive placebo (in combination with metformin with or without basal insulin, on a background of diet and exercise) for a 26 weeks double blind treatment period. After 26 weeks, participants discontinued placebo and continued treatment with metformin (with or without basal insulin) during the open-label period.

    Reporting group values
    Liraglutide Placebo Total
    Number of subjects
    66 68 134
    Age Categorical
    Units: Subjects
        10-14 years at end of treatment
    21 19 40
        > 14 years at end of treatment
    45 49 94
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    14.57 ± 1.73 14.57 ± 1.73 -
    Gender Categorical
    Units: Subjects
        Female
    41 42 83
        Male
    25 26 51
    Race
    Units: Subjects
        American Indian or Alaska Native
    2 1 3
        Asian
    10 8 18
        Native Hawaiian or Other Pacific Islander
    0 0 0
        Black or African American
    9 7 16
        White
    42 45 87
        More than one race
    0 0 0
        Unknown or Not Reported
    3 7 10
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    16 23 39
        Not Hispanic or Latino
    50 45 95
    Glycosylated hemoglobin (HbA1c)
    Units: Percentage of HbA1c
        arithmetic mean (standard deviation)
    7.87 ± 1.35 7.69 ± 1.34 -

    End points

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    End points reporting groups
    Reporting group title
    Liraglutide
    Reporting group description
    After the run-in period, subjects were randomized to receive liraglutide subcutaneous injections once daily (in combination with metformin with or without basal insulin, on a background of diet and exercise) for 52 weeks (26 weeks double blind treatment period followed by a 26-week open-label extension period). Subjects treated with liraglutide for more than 3 months were asked to return for follow-up visits one and two years after the end of the open label period (after trial drug cessation at week 52).

    Reporting group title
    Placebo
    Reporting group description
    After the run-in period, subjects were randomized to receive placebo (in combination with metformin with or without basal insulin, on a background of diet and exercise) for a 26 weeks double blind treatment period. After 26 weeks, participants discontinued placebo and continued treatment with metformin (with or without basal insulin) during the open-label period.

    Primary: Change in HbA1c - week 26

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    End point title
    Change in HbA1c - week 26
    End point description
    Change in HbA1c from baseline to week 26. All available data were used for the primary analysis, including data collected after treatment discontinuation and initiation of rescue medication. Full analysis set (FAS) – included all randomised subjects receiving at least one dose of liraglutide/placebo.
    End point type
    Primary
    End point timeframe
    From baseline to week 26
    End point values
    Liraglutide Placebo
    Number of subjects analysed
    66
    68
    Units: Percentage of HbA1c
        least squares mean (standard error)
    -0.643 ± 0.215
    0.415 ± 0.216
    Statistical analysis title
    Liraglutide 1.8 mg vs. Placebo
    Statistical analysis description
    Analysis using a pattern mixture model of observed data with missing observations imputed from the placebo arm based on multiple (x10.000) imputations. The data for week 26 were then analysed with an ANCOVA model containing treatment, sex and age group as fixed effects and baseline value as covariate. The estimated treatment differences and confidence intervals were combined using Rubins formula.
    Comparison groups
    Liraglutide v Placebo
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    < 0.001
    Method
    Pattern Mixture Model
    Parameter type
    Treatment difference
    Point estimate
    -1.058
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.653
         upper limit
    -0.464
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.304
    Notes
    [1] - Stepwise hierarchical testing procedure was applied for confirmatory endpoints: Step 1: Primary analysis: change from baseline to week 26 in HbA1c Superiority of liraglutide over placebo was to be concluded if the 95% confidence interval for the treatment difference for change from baseline in HbA1c (%) after 26 weeks of randomised treatment was entirely below 0%, implying that the two sided p-value was less than 5%.

    Secondary: Change from baseline in fasting plasma glucose (FPG) - week 26

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    End point title
    Change from baseline in fasting plasma glucose (FPG) - week 26
    End point description
    Change in FPG from baseline to week 26. All available data were used for the analysis, including data collected after treatment discontinuation and initiation of rescue medication. Analysis was based on full analysis set.
    End point type
    Secondary
    End point timeframe
    Week 0, week 26
    End point values
    Liraglutide Placebo
    Number of subjects analysed
    66
    68
    Units: mmol/L
        least squares mean (standard error)
    -1.076 ± 0.436
    0.801 ± 0.449
    Statistical analysis title
    Liraglutide 1.8 mg vs Placebo
    Statistical analysis description
    Analysis using a pattern mixture model of observed data with missing observations imputed from the placebo arm based on multiple (x10.000) imputations. The data for weeks 26 were then analysed with an ANCOVA model containing treatment, sex and age group as fixed effects and baseline value as covariate. The estimated treatment differences and confidence intervals were combined using Rubins formula.
    Comparison groups
    Liraglutide v Placebo
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    superiority [2]
    P-value
    = 0.002
    Method
    Pattern Mixture Model
    Parameter type
    Treatment difference
    Point estimate
    -1.878
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.093
         upper limit
    -0.662
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.62
    Notes
    [2] - Stepwise hierarchical testing procedure was applied for confirmatory endpoints: Step 2: Change from baseline in FPG after 26 weeks of treatment.

    Secondary: Number of subjects having HbA1c below 7.0% - week 26

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    End point title
    Number of subjects having HbA1c below 7.0% - week 26
    End point description
    Estimated percentage of subjects having HbA1c <7.0% at week 26. All available data were used for the analysis including data collected after treatment discontinuation and initiation of rescue medication. Analysis was based on full analysis set.
    End point type
    Secondary
    End point timeframe
    Week 26
    End point values
    Liraglutide Placebo
    Number of subjects analysed
    66
    68
    Units: Percentage of subjects
        number (not applicable)
    63.7
    36.5
    Statistical analysis title
    Liraglutide 1.8 mg vs Placebo
    Statistical analysis description
    Missing data was imputed using pattern mixture model. For each imputed data set the binary response was analysed in a logistic regression model using a logit link with treatment and stratification group (gender*age group) as fixed factors and baseline HbA1c as covariate.The estimated treatment effects and confidence intervals were combined using Rubin´s formula.
    Comparison groups
    Liraglutide v Placebo
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    superiority [3]
    P-value
    < 0.001
    Method
    Logistic Regression Model
    Parameter type
    Treatment odds ratio
    Point estimate
    5.353
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.105
         upper limit
    13.615
    Notes
    [3] - Stepwise hierarchical testing procedure was applied for confirmatory endpoints: Step 3: HbA1c < 7.0% after 26 weeks of treatment.

    Secondary: Change from baseline in body mass index (BMI) standard deviation score (SDS) - week 26

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    End point title
    Change from baseline in body mass index (BMI) standard deviation score (SDS) - week 26
    End point description
    Change in BMI SDS from baseline to week 26. BMI SDS was calculated using the following formula: Z=[(value /M)^L - 1] / S*L; where L, M and S are median (M), skewness (L) and variation coefficient (S) of children/adolescents’ BMI provided for each sex and age. For each subject, a standard deviation score Z (SDS) was calculated based on age and sex referring to the values L, M and S. The method is described in the world health organisation (WHO) Multicentre Growth Reference, which also contains the values for L, M and S by age and sex. For Z (SDS) scores below −3 and above 3, the score was adjusted as described in the WHO instruction. All available data were used for the analysis including data collected after treatment discontinuation and initiation of rescue medication. Full analysis set. Number of participants analysed=participants with available data.
    End point type
    Secondary
    End point timeframe
    Week 0, week 26
    End point values
    Liraglutide Placebo
    Number of subjects analysed
    66
    68
    Units: SDS score
        least squares mean (standard error)
    -0.254 ± 0.039
    -0.208 ± 0.039
    Statistical analysis title
    Liraglutide 1.8 mg vs Placebo
    Statistical analysis description
    Analysis using a pattern mixture model of observed data with missing observations imputed from the placebo arm based on multiple (x10.000) imputations. The data for weeks 26 were then analysed with an ANCOVA model containing treatment, sex and age group as fixed effects and baseline value as covariate. The estimated treatment differences and confidence intervals were combined using Rubins formula.
    Comparison groups
    Liraglutide v Placebo
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    superiority [4]
    P-value
    = 0.392
    Method
    Pattern Mixture Model
    Parameter type
    Treatment difference
    Point estimate
    -0.047
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.153
         upper limit
    0.06
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.055
    Notes
    [4] - Stepwise hierarchical testing procedure was applied for confirmatory endpoints: Step 4: Change from baseline in BMI SDS after 26 weeks of treatment.

    Secondary: Number of subjects having HbA1c below 7.0% - week 52

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    End point title
    Number of subjects having HbA1c below 7.0% - week 52
    End point description
    Number of subjects achieving HbA1c <7.0% after 52 weeks. All available data were used for the analysis including data collected after treatment discontinuation and initiation of rescue medication. Full analysis set. Number of participants analysed=participants with available data.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    Liraglutide Placebo
    Number of subjects analysed
    56
    52
    Units: participants
        Yes
    27
    16
        No
    29
    36
    No statistical analyses for this end point

    Secondary: Number of subjects having HbA1c maximum 6.5% - week 26

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    End point title
    Number of subjects having HbA1c maximum 6.5% - week 26
    End point description
    Number of subjects achieving HbA1c <=6.5% after 26 weeks. All available data were used for the analysis including data collected after treatment discontinuation and initiation of rescue medication. Full analysis set. Number of participants analysed=participants with available data.
    End point type
    Secondary
    End point timeframe
    Week 26
    End point values
    Liraglutide Placebo
    Number of subjects analysed
    59
    58
    Units: participants
        Yes
    28
    19
        No
    31
    39
    No statistical analyses for this end point

    Secondary: Number of subjects having HbA1c maximum 6.5% - week 52

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    End point title
    Number of subjects having HbA1c maximum 6.5% - week 52
    End point description
    Number of subjects achieving HbA1c <=6.5% after 52 weeks. All available data were used for the analysis including data collected after treatment discontinuation and initiation of rescue medication. Full analysis set. Number of participants analysed=participants with available data.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    Liraglutide Placebo
    Number of subjects analysed
    56
    52
    Units: participants
        Yes
    25
    13
        No
    31
    39
    No statistical analyses for this end point

    Secondary: Number of subjects having HbA1c below 7.0% without severe or minor hypoglycaemic episodes - week 26

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    End point title
    Number of subjects having HbA1c below 7.0% without severe or minor hypoglycaemic episodes - week 26
    End point description
    Number of subjects achieving HbA1c <7.0% without severe or minor hypoglycaemic episodes after 26 weeks. Severe hypoglycaemia: An episode requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. Minor hypoglycaemia was defined as meeting either of the below criteria: 1) an episode with symptoms consistent with hypoglycaemia with confirmation by blood glucose <2.8 mmol/L (50 mg/dL) or plasma glucose <3.1 mmol/L (56 mg/dL), and which was handled by the subject him/herself 2) any asymptomatic blood glucose value <2.8 mmol/L (50 mg/dL) or plasma glucose value <3.1 mmol/L (56 mg/dL) All available data were used for the analysis including data collected after treatment discontinuation and initiation of rescue medication. Analysis was based on full analysis set. Number of participants analysed=participants with available data.
    End point type
    Secondary
    End point timeframe
    Week 26
    End point values
    Liraglutide Placebo
    Number of subjects analysed
    59
    58
    Units: participants
        Yes
    31
    21
        No
    28
    37
    No statistical analyses for this end point

    Secondary: Number of subjects having HbA1c below 7.0% without severe or minor hypoglycaemic episodes - week 52

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    End point title
    Number of subjects having HbA1c below 7.0% without severe or minor hypoglycaemic episodes - week 52
    End point description
    Number of subjects achieving HbA1c <7.0% without severe or minor hypoglycaemic episodes after 52 weeks. Severe hypoglycaemia: An episode requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. Minor hypoglycaemia was defined as meeting either of the below criteria: 1) an episode with symptoms consistent with hypoglycaemia with confirmation by blood glucose <2.8 mmol/L (50 mg/dL) or plasma glucose <3.1 mmol/L (56 mg/dL), and which was handled by the subject him/herself 2) any asymptomatic blood glucose value <2.8 mmol/L (50 mg/dL) or plasma glucose value <3.1 mmol/L (56 mg/dL) All available data were used for the analysis including data collected after treatment discontinuation and initiation of rescue medication. Analysis was based on full analysis set. Number of participants analysed=participants with available data.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    Liraglutide Placebo
    Number of subjects analysed
    56
    52
    Units: participants
        Yes
    22
    16
        No
    34
    36
    No statistical analyses for this end point

    Secondary: Change in FPG - week 52

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    End point title
    Change in FPG - week 52
    End point description
    Change in FPG from baseline to week 52. All available data were used for the analysis, including data collected after treatment discontinuation and initiation of rescue medication. Analysis was based on full analysis set. Number of participants analysed=participants with available data.
    End point type
    Secondary
    End point timeframe
    Week 0, week 52
    End point values
    Liraglutide Placebo
    Number of subjects analysed
    56
    53
    Units: mmol/L
        arithmetic mean (standard deviation)
    -1.627 ± 2.717
    0.983 ± 3.954
    No statistical analyses for this end point

    Secondary: Change in mean 7-point self-measured plasma glucose - week 26

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    End point title
    Change in mean 7-point self-measured plasma glucose - week 26
    End point description
    Change in mean 7-point self-measured plasma glucose after 26 weeks. Subjects were instructed to measure their plasma glucose at following timepoints: before breakfast, 90 minutes after start of breakfast, before lunch, 90 minutes after start of lunch, before dinner, 90 minutes after start of dinner and at bedtime. Mean 7-point SMPG was defined as the area under the profile (calculated using the trapezoidal method) divided by time. All available data were used for the analysis including data collected after treatment discontinuation and initiation of rescue medication. Analysis was based on full analysis set. Number of participants analysed=participants with available data.
    End point type
    Secondary
    End point timeframe
    Week 0, week 26
    End point values
    Liraglutide Placebo
    Number of subjects analysed
    39
    46
    Units: mmol/L
        arithmetic mean (standard deviation)
    -2.384 ± 2.638
    0.198 ± 2.056
    No statistical analyses for this end point

    Secondary: Change from baseline in 7-point self-measured plasma glucose - week 52

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    End point title
    Change from baseline in 7-point self-measured plasma glucose - week 52
    End point description
    Change in mean 7-point self-measured plasma glucose after 52 weeks. Subjects were instructed to measure their plasma glucose at following timepoints: before breakfast, 90 minutes after start of breakfast, before lunch, 90 minutes after start of lunch, before dinner, 90 minutes after start of dinner and at bedtime. Mean 7-point SMPG was defined as the area under the profile (calculated using the trapezoidal method) divided by time. All available data were used for the analysis including data collected after treatment discontinuation and initiation of rescue medication. Analysis was based on full analysis set. Number of participants analysed=participants with available data.
    End point type
    Secondary
    End point timeframe
    Week 0, week 52
    End point values
    Liraglutide Placebo
    Number of subjects analysed
    41
    39
    Units: mmol/L
        arithmetic mean (standard deviation)
    -2.309 ± 2.968
    -0.748 ± 1.944
    No statistical analyses for this end point

    Secondary: Change from baseline in body weight - week 26

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    End point title
    Change from baseline in body weight - week 26
    End point description
    Change from baseline in body weight after 26 weeks. All available data were used for the analysis including data collected after treatment discontinuation and initiation of rescue medication. Analysis was based on full analysis set. Number of participants analysed=participants with available data.
    End point type
    Secondary
    End point timeframe
    Week 0, week 26
    End point values
    Liraglutide Placebo
    Number of subjects analysed
    60
    58
    Units: kg
        arithmetic mean (standard deviation)
    -2.48 ± 5.59
    -0.87 ± 3.84
    No statistical analyses for this end point

    Secondary: Change from baseline in body weight - week 52

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    End point title
    Change from baseline in body weight - week 52
    End point description
    Change from baseline in body weight after 52 weeks. All available data were used for the analysis including data collected after treatment discontinuation and initiation of rescue medication. Analysis was based on full analysis set. Number of participants analysed=participants with available data.
    End point type
    Secondary
    End point timeframe
    Week 0, week 52
    End point values
    Liraglutide Placebo
    Number of subjects analysed
    56
    53
    Units: kg
        arithmetic mean (standard deviation)
    -2.27 ± 8.05
    1.02 ± 4.64
    No statistical analyses for this end point

    Secondary: Change from baseline in BMI standard deviation score (SDS) - week 52

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    End point title
    Change from baseline in BMI standard deviation score (SDS) - week 52
    End point description
    Change in BMI SDS from baseline to week 52. BMI SDS was calculated using the following formula: Z=[(value /M)^L - 1] / S*L; where L, M and S are median (M), skewness (L) and variation coefficient (S) of children/adolescents’ BMI provided for each sex and age. For each subject, a standard deviation score Z (SDS) was calculated based on age and sex referring to the values L, M and S. The method is described in the WHO Multicentre Growth Reference, which also contains the values for L, M and S by age and sex. For Z (SDS) scores below −3 and above 3, the score was adjusted as described in the WHO instruction. All available data were used for the analysis including data collected after treatment discontinuation and initiation of rescue medication. Analysis was based on full analysis set. Number of participants analysed=participants with available data.
    End point type
    Secondary
    End point timeframe
    Week 0, week 52
    End point values
    Liraglutide Placebo
    Number of subjects analysed
    56
    53
    Units: SDS Score
        arithmetic mean (standard error)
    -0.361 ± 0.542
    -0.166 ± 0.330
    No statistical analyses for this end point

    Secondary: Number of adverse events - week 26

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    End point title
    Number of adverse events - week 26
    End point description
    Total number of adverse events during 26 weeks. Analysis was based on safety analysis set which included all subjects receiving at least one dose of liraglutide/placebo
    End point type
    Secondary
    End point timeframe
    0-26 weeks
    End point values
    Liraglutide Placebo
    Number of subjects analysed
    66
    68
    Units: events
    310
    230
    No statistical analyses for this end point

    Secondary: Number of adverse events - week 52

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    End point title
    Number of adverse events - week 52
    End point description
    Total number of adverse events during entire treatment period (during 52 weeks). Analysis was based on the safety analysis set.
    End point type
    Secondary
    End point timeframe
    0-52 weeks
    End point values
    Liraglutide Placebo
    Number of subjects analysed
    66
    68
    Units: events
    426
    321
    No statistical analyses for this end point

    Secondary: Number of serious adverse events - week 26

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    End point title
    Number of serious adverse events - week 26
    End point description
    Total number of serious adverse events during 26 weeks. Analysis was based on the safety analysis set.
    End point type
    Secondary
    End point timeframe
    0-26 weeks
    End point values
    Liraglutide Placebo
    Number of subjects analysed
    66
    68
    Units: events
    7
    4
    No statistical analyses for this end point

    Secondary: Number of serious adverse events - week 52

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    End point title
    Number of serious adverse events - week 52
    End point description
    0-52 weeks
    End point type
    Secondary
    End point timeframe
    Total number of serious adverse events during entire treatment period (during 52 weeks). Analysis was based on the safety analysis set.
    End point values
    Liraglutide Placebo
    Number of subjects analysed
    66
    68
    Units: events
    10
    5
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Week 0 to week 52
    Adverse event reporting additional description
    Safety Analysis Set.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21
    Reporting groups
    Reporting group title
    Liraglutide 1.8 mg
    Reporting group description
    After the run-in period, subjects were randomized to receive liraglutide subcutaneous injections once daily (in combination with metformin with or without basal insulin, on a background of diet and exercise) for 52 weeks (26 weeks double blind treatment period followed by a 26-week open-label extension period). Subjects treated with liraglutide for more than 3 months were asked to return for follow-up visits one and two years after the end of the open label period (after trial drug cessation at week 52).

    Reporting group title
    Placebo
    Reporting group description
    After the run-in period, subjects were randomized to receive placebo (in combination with metformin with or without basal insulin, on a background of diet and exercise) for a 26 weeks double blind treatment period. After 26 weeks, participants discontinued placebo and continued treatment with metformin (with or without basal insulin) during the open-label period.

    Serious adverse events
    Liraglutide 1.8 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 66 (13.64%)
    4 / 68 (5.88%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Glycosylated haemoglobin increased
         subjects affected / exposed
    1 / 66 (1.52%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Fibroadenoma of breast
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 68 (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
    Nervous system disorder
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 68 (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
    Scoliosis
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 68 (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
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 66 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 66 (1.52%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess neck
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis perforated
         subjects affected / exposed
    0 / 66 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 66 (0.00%)
    1 / 68 (1.47%)
         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 / 66 (1.52%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Liraglutide 1.8 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    45 / 66 (68.18%)
    49 / 68 (72.06%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 66 (0.00%)
    4 / 68 (5.88%)
         occurrences all number
    0
    5
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 66 (6.06%)
    4 / 68 (5.88%)
         occurrences all number
    7
    5
    Oropharyngeal pain
         subjects affected / exposed
    4 / 66 (6.06%)
    6 / 68 (8.82%)
         occurrences all number
    6
    10
    Rhinorrhoea
         subjects affected / exposed
    1 / 66 (1.52%)
    4 / 68 (5.88%)
         occurrences all number
    2
    4
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    8 / 66 (12.12%)
    2 / 68 (2.94%)
         occurrences all number
    10
    4
    Headache
         subjects affected / exposed
    14 / 66 (21.21%)
    13 / 68 (19.12%)
         occurrences all number
    27
    39
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    4 / 66 (6.06%)
    5 / 68 (7.35%)
         occurrences all number
    5
    5
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    11 / 66 (16.67%)
    5 / 68 (7.35%)
         occurrences all number
    22
    6
    Abdominal pain upper
         subjects affected / exposed
    2 / 66 (3.03%)
    8 / 68 (11.76%)
         occurrences all number
    3
    9
    Constipation
         subjects affected / exposed
    4 / 66 (6.06%)
    1 / 68 (1.47%)
         occurrences all number
    4
    1
    Diarrhoea
         subjects affected / exposed
    15 / 66 (22.73%)
    11 / 68 (16.18%)
         occurrences all number
    21
    13
    Dyspepsia
         subjects affected / exposed
    5 / 66 (7.58%)
    1 / 68 (1.47%)
         occurrences all number
    6
    1
    Nausea
         subjects affected / exposed
    19 / 66 (28.79%)
    9 / 68 (13.24%)
         occurrences all number
    25
    12
    Vomiting
         subjects affected / exposed
    17 / 66 (25.76%)
    6 / 68 (8.82%)
         occurrences all number
    46
    8
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    3 / 66 (4.55%)
    6 / 68 (8.82%)
         occurrences all number
    10
    11
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    4 / 66 (6.06%)
    1 / 68 (1.47%)
         occurrences all number
    5
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    4 / 66 (6.06%)
    3 / 68 (4.41%)
         occurrences all number
    4
    3
    Hyperglycaemia
         subjects affected / exposed
    4 / 66 (6.06%)
    4 / 68 (5.88%)
         occurrences all number
    4
    4
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    7 / 66 (10.61%)
    2 / 68 (2.94%)
         occurrences all number
    8
    2
    Influenza
         subjects affected / exposed
    4 / 66 (6.06%)
    6 / 68 (8.82%)
         occurrences all number
    6
    9
    Nasopharyngitis
         subjects affected / exposed
    11 / 66 (16.67%)
    19 / 68 (27.94%)
         occurrences all number
    16
    28
    Pharyngitis
         subjects affected / exposed
    4 / 66 (6.06%)
    4 / 68 (5.88%)
         occurrences all number
    5
    6
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 66 (9.09%)
    5 / 68 (7.35%)
         occurrences all number
    10
    8

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Aug 2012
    Protocol changes were primarily driven by the EMA PDCO’s acceptance of the request for PIP modification. Some of the changes to the trial design were requested by the FDA. Other minor changes concerned inconsistencies and typos. The key changes involved: - extension of metformin titration period and lowering the lower limit for metformin MTD. - allowing subjects entering the trial on >2000 mg/day of metformin to continue on current dose. - extension of metformin maintenance period during the run-in from 3 to 8 weeks. - extension of liraglutide dose escalation period from 2 to 3 weeks - changing the timing of the anti-liraglutide antibody measurement from week 52 to week 53 - extension of the double-blind treatment period from 14 to 26 weeks - allowing liraglutide dose escalation (to maximum 1.8 mg) as a rescue option - for subjects treated with placebo, allowing the addition of a second anti-diabetic agent as a rescue option - inclusion of testicular volume assessment by trained personnel in the Tanner staging assessment - requirement for the 52-week treatment period completion prior to subject reaching 17 years and 11 months - requirement of 30% of subjects to be aged between 10-14 years - exclusion from the trial of subjects previously treated with liraglutide (new exclusion criterion added) - use of another primary analysis method that does not rely on LOCF for the handling of missing data. A multiple imputation approach was to be used to handle missing data in the new primary analysis.
    19 Nov 2012
    Protocol changes were primarily driven by the FDA Paediatric Committee’s request to include yearly bone age assessment due to a potential nonclinical safety signal for liraglutide of advancement of puberty. In addition, the text regarding the use of rescue medication was clarified. Other minor corrections and clarifications were implemented. The key changes involved: - inclusion of X-ray of left hand and wrist at randomisation and week 52 (all subjects) and at 1- and 2-year follow-up visits for subjects treated with liraglutide for >3 months - update of withdrawal criterion and rewording of the section on rescue medication
    22 Jun 2013
    An additional blood sample was included to ensure that FPG, biochemistry parameters an calcitonin were monitored during the open-label period. In addition, a number of protocol clarifications were implemented. The key changes included: 1. addition of a fasting blood sample at visit 22 (week 42) 2. clarification of age definition of ≤14 years 3. new reporting timelines for MESI
    19 Mar 2015
    Significant delays in subject recruitment led to this protocol amendment implemented in order to facilitate recruitment. The key changes included: 1. reducing the required duration of diabetes at screening from 90 to 30 days 2. inclusion of children and adolescents currently treated with basal insulin 3. change in method to evaluate randomisation criterion #1 (FPG measured prior to the randomisation visit (visit 7), must be ≥126 mg/dL (7.0 mmol/L) and ≤220 mg/dL (12.2 mmol/L). The measurement must be based on an average of fasting SMPG values taken on the 3 consecutive days leading up to the randomisation visit (visit 7)) 4. use of basal insulin as initial rescue therapy in both liraglutide and placebo treatment arms 5. elimination of the requirement for randomised treatment unblinding prior to rescue treatment initiation, since subjects in both treatment arms were to receive the same initial rescue treatment (basal insulin) 6. changes to trial completion timeline 7. reduction of sample size from 172 to 150 randomised subjects
    18 Apr 2017
    Due to recruitment difficulties, the planned sample size was reduced from 150 to 94 randomised subjects. The primary analysis was changed to a PMM analysis using a multiple imputations approach to account for missing data. Additional revisions and clarifications were also made to the “Statistical Considerations” section of the protocol.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

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