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    Clinical Trial Results:
    A randomised, double-blind, placebo-controlled trial to assess safety, tolerability, pharmacokinetics and pharmacodynamics of liraglutide in obese children aged 7 to 11 years

    Summary
    EudraCT number
    		 2014-004454-34
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    13 Apr 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Oct 2017
    First version publication date
    25 Oct 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NN8022-4181
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02696148
    WHO universal trial number (UTN)
    		 U1111-1162-9171
    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-000128-PIP02-09
    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
    18 Sep 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    13 Apr 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Apr 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the safety and tolerability of multiple once-daily doses of liraglutide at doses up to 3.0 mg in obese children aged 7−11 years and at Tanner stage 1.
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki (64th WMA General Assembly, Fortaleza, Brazil. 1 Oct 2013) and ICH Good Clinical Practice (10 Jun 1996) and 21 CFR 312.120.
    Background therapy
    		 Not applicable.
    Evidence for comparator
    		 Not applicable.
    Actual start date of recruitment
    14 Mar 2016
    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
    United States: 24
    Worldwide total number of subjects
    24
    EEA total number of subjects
    0
    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)
    24
    Adolescents (12-17 years)
    0
    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 3 sites in the United States.

    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
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    Liraglutide and placebo were supplied in similar 3 mL FlexPen® devices and were visually identical, and packed and labelled to fulfil the requirements for double-blind procedures. Equal volumes of liraglutide and placebo were administered.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Liraglutide
    Arm description
    		 Subjects received liraglutide once daily. Treatment was initiated with 0.3 mg liraglutide daily for one week and increased in weekly steps until a maximum dose of 3.0 mg liraglutide or maximum tolerated dose. Following was the dose escalation regimen for liraglutide: week 1: 0.3 mg, week 2: 0.6 mg, week 3: 0.9 mg, week 4: 1.2 mg, week 5: 1.8 mg, week 6: 2.4 mg, and week 7: 3.0 mg. The treatment period consisted of 7 mandatory treatment weeks with 6 optional flex weeks (one flex week between each of the 7 treatment weeks). A flex week on an unchanged or lowered dose was to be included in case the dose escalation criteria were not met at the end of a mandatory treatment week. Thus, the duration of the treatment period could be prolonged from 7 to 13 weeks, in case a flex week was needed between all 7 treatment weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Liraglutide
    Investigational medicinal product code
    Other name
    Saxenda®
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Liraglutide, 6.0 mg/mL in a 3 mL FlexPen® was administered once daily via subcutaneous (s.c.) abdominal injections in the morning (9 a.m. ±2 hours).

    Arm title
    		 Placebo
    Arm description
    		 Subjects received liraglutide matching placebo once daily. Each placebo injection volume was based on the correspondent liraglutide dose (0.3 mg, 0.6 mg, 0.9 mg, 1.2 mg, 1.8 mg, 2.4 mg, and 3.0 mg). The treatment period consisted of 7 mandatory treatment weeks with 6 optional flex weeks (one flex week between each of the 7 treatment weeks). A flex week on an unchanged or lowered dose was to be included in case the dose escalation criteria were not met at the end of a mandatory treatment week. Thus, the duration of the treatment period could be prolonged from 7 to 13 weeks, in case a flex week was needed between all 7 treatment weeks.
    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 in a 3 mL FlexPen® was administered once daily via s.c. abdominal injections in the morning (9 a.m. ±2 hours).

    Number of subjects in period 1
    		Liraglutide Placebo
    Started
    16
    8
    Completed
    14
    6
    Not completed
    2
    2
         Consent withdrawn by subject
    1
    -
         Lost to follow-up
    1
    -
         Withdrawal by parent/guardian
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Liraglutide
    Reporting group description
    		 Subjects received liraglutide once daily. Treatment was initiated with 0.3 mg liraglutide daily for one week and increased in weekly steps until a maximum dose of 3.0 mg liraglutide or maximum tolerated dose. Following was the dose escalation regimen for liraglutide: week 1: 0.3 mg, week 2: 0.6 mg, week 3: 0.9 mg, week 4: 1.2 mg, week 5: 1.8 mg, week 6: 2.4 mg, and week 7: 3.0 mg. The treatment period consisted of 7 mandatory treatment weeks with 6 optional flex weeks (one flex week between each of the 7 treatment weeks). A flex week on an unchanged or lowered dose was to be included in case the dose escalation criteria were not met at the end of a mandatory treatment week. Thus, the duration of the treatment period could be prolonged from 7 to 13 weeks, in case a flex week was needed between all 7 treatment weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received liraglutide matching placebo once daily. Each placebo injection volume was based on the correspondent liraglutide dose (0.3 mg, 0.6 mg, 0.9 mg, 1.2 mg, 1.8 mg, 2.4 mg, and 3.0 mg). The treatment period consisted of 7 mandatory treatment weeks with 6 optional flex weeks (one flex week between each of the 7 treatment weeks). A flex week on an unchanged or lowered dose was to be included in case the dose escalation criteria were not met at the end of a mandatory treatment week. Thus, the duration of the treatment period could be prolonged from 7 to 13 weeks, in case a flex week was needed between all 7 treatment weeks.

    Reporting group values
    		 Liraglutide Placebo Total
    Number of subjects
    		 16 8 24
    Age Categorical
    Units: Subjects
        Children (2-11 years)
    		 16 8 24
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 9.7 ( 1.1 ) 10.4 ( 1.1 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 8 1 9
        Male
    		 8 7 15

    End points

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    End points reporting groups
    Reporting group title
    Liraglutide
    Reporting group description
    		 Subjects received liraglutide once daily. Treatment was initiated with 0.3 mg liraglutide daily for one week and increased in weekly steps until a maximum dose of 3.0 mg liraglutide or maximum tolerated dose. Following was the dose escalation regimen for liraglutide: week 1: 0.3 mg, week 2: 0.6 mg, week 3: 0.9 mg, week 4: 1.2 mg, week 5: 1.8 mg, week 6: 2.4 mg, and week 7: 3.0 mg. The treatment period consisted of 7 mandatory treatment weeks with 6 optional flex weeks (one flex week between each of the 7 treatment weeks). A flex week on an unchanged or lowered dose was to be included in case the dose escalation criteria were not met at the end of a mandatory treatment week. Thus, the duration of the treatment period could be prolonged from 7 to 13 weeks, in case a flex week was needed between all 7 treatment weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received liraglutide matching placebo once daily. Each placebo injection volume was based on the correspondent liraglutide dose (0.3 mg, 0.6 mg, 0.9 mg, 1.2 mg, 1.8 mg, 2.4 mg, and 3.0 mg). The treatment period consisted of 7 mandatory treatment weeks with 6 optional flex weeks (one flex week between each of the 7 treatment weeks). A flex week on an unchanged or lowered dose was to be included in case the dose escalation criteria were not met at the end of a mandatory treatment week. Thus, the duration of the treatment period could be prolonged from 7 to 13 weeks, in case a flex week was needed between all 7 treatment weeks.

    Primary: Number of treatment emergent adverse events

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    End point title
    		 Number of treatment emergent adverse events [1]
    End point description
    A treatment emergent adverse event (TEAE) was defined as an event that either: 1) had an onset time after the first time of exposure to investigational medicinal product (IMP), liraglutide or placebo and no later than the follow-up visit (i.e., 10-17 days after the last dose) 2) or had an onset time before the first time of exposure to IMP and increased in severity during the treatment period and no later than the follow-up visit. Results are based on the safety analysis set, which included all subjects who were exposed to at least one dose of the IMP.
    End point type
    Primary
    End point timeframe
    Recorded from the time of first dosing and until completion of follow up visit (59-108 days after first dosing)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The primary endpoint investigated safety and was analysed using descriptive statistics, and thus no statistical analysis was performed.
    End point values
    		 Liraglutide Placebo
    Number of subjects analysed
    16 [2]
    8 [3]
    Units: Number of events
    37
    12
    Notes
    [2] - Out of 16 subjects analysed, 9 subjects were reported with 37 AEs.
    [3] - Out of 8 subjects analysed, 5 subjects were reported with 12 AEs.
    No statistical analyses for this end point

    Secondary: Area under the liraglutide concentration curve from 0-24 hours (AUC0-24h) at steady state

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    End point title
    		 Area under the liraglutide concentration curve from 0-24 hours (AUC0-24h) at steady state [4]
    End point description
    Results are based on the full analysis set, which included all subjects who were randomised and received at least one dose of trial product. Number of subjects analysed = number of subjects contributed to the analysis.
    End point type
    Secondary
    End point timeframe
    Following the last dose (49-91 days after first dosing)
    Notes
    [4] - 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: For this endpoint, only samples from subjects treated with liraglutide were included. Therefore, the placebo-treated subjects did not contribute to the analyses.
    End point values
    		 Liraglutide
    Number of subjects analysed
    13
    Units: h x nmol/L
        geometric mean (confidence interval 95%)
    1161 (1002 to 1398)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the time of first dosing and until completion of follow up visit (59-108 days after first dosing).
    Adverse event reporting additional description
    All the following mentioned AEs are treatment emergent, i.e., TEAEs. Results are based on the safety analysis set.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20
    Reporting groups
    Reporting group title
    Liraglutide
    Reporting group description
    		 Subjects received liraglutide once daily. Treatment was initiated with 0.3 mg liraglutide daily for one week and increased in weekly steps until a maximum dose of 3.0 mg liraglutide or maximum tolerated dose. Following was the dose escalation regimen for liraglutide: week 1: 0.3 mg, week 2: 0.6 mg, week 3: 0.9 mg, week 4: 1.2 mg, week 5: 1.8 mg, week 6: 2.4 mg, and week 7: 3.0 mg. The treatment period consisted of 7 mandatory treatment weeks with 6 optional flex weeks (one flex week between each of the 7 treatment weeks). A flex week on an unchanged or lowered dose was to be included in case the dose escalation criteria were not met at the end of a mandatory treatment week. Thus, the duration of the treatment period could be prolonged from 7 to 13 weeks, in case a flex week was needed between all 7 treatment weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received liraglutide matching placebo once daily. Each placebo injection volume was based on the correspondent liraglutide dose (0.3 mg, 0.6 mg, 0.9 mg, 1.2 mg, 1.8 mg, 2.4 mg, and 3.0 mg). The treatment period consisted of 7 mandatory treatment weeks with 6 optional flex weeks (one flex week between each of the 7 treatment weeks). A flex week on an unchanged or lowered dose was to be included in case the dose escalation criteria were not met at the end of a mandatory treatment week. Thus, the duration of the treatment period could be prolonged from 7 to 13 weeks, in case a flex week was needed between all 7 treatment weeks.

    Serious adverse events
    		 Liraglutide Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 8 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Liraglutide Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 16 (56.25%)
    5 / 8 (62.50%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 8 (12.50%)
         occurrences all number
    1
    1
    Headache
         subjects affected / exposed
    2 / 16 (12.50%)
    3 / 8 (37.50%)
         occurrences all number
    3
    4
    General disorders and administration site conditions
    Influenza like illness
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Injection site erythema
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Injection site induration
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    Injection site reaction
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Orbital oedema
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 8 (0.00%)
         occurrences all number
    3
    0
    Abdominal pain upper
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    6
    0
    Diarrhoea
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Dyspepsia
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Nausea
         subjects affected / exposed
    3 / 16 (18.75%)
    0 / 8 (0.00%)
         occurrences all number
    3
    0
    Salivary hypersecretion
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Vomiting
         subjects affected / exposed
    4 / 16 (25.00%)
    0 / 8 (0.00%)
         occurrences all number
    5
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Nasal congestion
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Sinus congestion
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Muscle spasms
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Muscle tightness
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Infections and infestations
    Gastritis viral
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Feb 2016
    1) A discrepancy in the key inclusion criteria regarding the time of tanner stage was corrected in the summary. 2) Self-injection with test medium at visit 1 (in week 1) was added to the Flow char for clarification. 3) The PK sampling time window for liraglutide at visit 12 (follow-up visit) was updated for more flexibility for the subjects. 4) The subject information (SI)/informed consent (IC) for parents or legally acceptable representative (LARs) was updated with inclusion of the findings from the pre-clinical juvenile toxicity study as per FDA request. The protocol was updated accordingly ensuring the full information is reflected in the protocol. 5) A discrepancy regarding the number of days from visit 2 (in week 0) to visit 3-8 (in weeks 1-6) was corrected. 6) The protocol was updated with specifications of procedures in case a subject fails to attend a visit fasting, or has forgotten to perform self-measured plasma glucose (SMPG) and/or withhold their daily liraglutide/liraglutide placebo dose before coming to the trial site.
    06 Jul 2016
    1) Based on external advisor and Investigators feedback, children with obesity enter puberty earlier than other children. The request to modify the inclusion criterion to allow children with premature adrenarche (development of pubic hair without the children having entered true puberty) was based on the association of this finding with increased body mass index. 2) The SI/IC for parents or LARs was also updated with the change in inclusion criteria related to Tanner stage 1. 3) The protocol was updated with information describing that arrangements can be made with the investigator to stay at site overnight before a visit, as needed.
    06 Jul 2016
    With amendment no. 2, the trial protocol population was modified to include prepubertal children (Tanner stage 1) and prepubertal children with premature adrenarche. This amendment no. 3 updated the trial protocol with information on how to document the exclusion of conditions other than premature adrenache.

    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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