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    Clinical Trial Results:
    A Trial comparing the Pharmacokinetic Properties of Fast-acting Insulin Aspart between Children, Adolescents and Adults with Type 1 Diabetes

    Summary
    EudraCT number
    		 2017-002014-31
    Trial protocol
    		 DE  
    Global end of trial date
    05 Jul 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Jan 2019
    First version publication date
    05 Jan 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NN1218-4371
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03407599
    WHO universal trial number (UTN)
    		 U1111-1197-0428
    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)
    No
    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
    13 Dec 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Jul 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Jul 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the total exposure of faster aspart between children, adolescents and adult subjects with type 1 diabetes.
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki and International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Good Clinical Practice, including archiving of essential documents and 21 Code of Federal Regulations (CFR) 312.120.
    Background therapy
    		 Not applicable
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    08 Jan 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 43
    Worldwide total number of subjects
    43
    EEA total number of subjects
    43
    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)
    12
    Adolescents (12-17 years)
    16
    Adults (18-64 years)
    15
    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 one site in Germany.

    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, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Three sets of black sealed codes/labels containing information about the treatment were prepared for each subject. The sets were kept by the trial site (throughout the entire trial period), the local Novo Nordisk affiliate and the Novo Nordisk Global Safety department.

    Arms
    Arm title
    		 Total population
    Arm description
    		 Each subject was randomly allocated to a treatment sequence (faster aspart followed by NovoRapid® or NovoRapid® followed by faster aspart) consisting of 2 treatment periods. The two treatment periods (between first dosing visit and second dosing visit) were separated by a wash-out period of 3-22 days.
    Arm type
    		 Cross-over (experimental & active comparator)

    Investigational medicinal product name
    Faster aspart
    Investigational medicinal product code
    Other name
    Fiasp®
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects were administered with a single dose of faster aspart 0.2 U/kg body weight just prior to a standard meal. Faster aspart was administered subcutaneously (s.c.) into a lifted skin fold of the lower abdominal wall above the inguinal area (lower lateral parts of the abdomen).

    Investigational medicinal product name
    Insulin aspart
    Investigational medicinal product code
    Other name
    NovoRapid®
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects were administered with a single dose of NovoRapid® 0.2 U/kg body weight just prior to a standard meal. NovoRapid® was administered s.c. into a lifted skin fold of the lower abdominal wall above the inguinal area (lower lateral parts of the abdomen).

    Number of subjects in period 1
    		Total population
    Started
    43
    Completed
    43

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Total population
    Reporting group description
    		 Each subject was randomly allocated to a treatment sequence (faster aspart followed by NovoRapid® or NovoRapid® followed by faster aspart) consisting of 2 treatment periods. The two treatment periods (between first dosing visit and second dosing visit) were separated by a wash-out period of 3-22 days.

    Reporting group values
    		 Total population Total
    Number of subjects
    		 43 43
    Age Categorical
    Units: Subjects
        Children (2-11 years)
    		 12 12
        Adolescents (12-17 years)
    		 16 16
        Adults (18-64 years)
    		 15 15
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 15.2 ( 4.1 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 23 23
        Male
    		 20 20

    End points

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    End points reporting groups
    Reporting group title
    Total population
    Reporting group description
    		 Each subject was randomly allocated to a treatment sequence (faster aspart followed by NovoRapid® or NovoRapid® followed by faster aspart) consisting of 2 treatment periods. The two treatment periods (between first dosing visit and second dosing visit) were separated by a wash-out period of 3-22 days.

    Subject analysis set title
    Faster aspart - Children
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Children subjects (6–11 years) received single dose of faster aspart in a cross-over manner in both treatment periods 1 and 2.

    Subject analysis set title
    Faster aspart - Adolescents
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Adolescent subjects (12–17 years) received single dose of faster aspart in a cross-over manner in both treatment periods 1 and 2.

    Subject analysis set title
    Faster aspart - Adults
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Adult subjects (18–64 years) received single dose of faster aspart in a cross-over manner in both treatment periods 1 and 2.

    Subject analysis set title
    NovoRapid® - Children
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Children subjects (6–11 years) received single dose of NovoRapid® in a cross-over manner in both treatment periods 1 and 2.

    Subject analysis set title
    NovoRapid® - Adolescents
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Adolescent subjects (12–17 years) received single dose of NovoRapid® in a cross-over manner in both treatment periods 1 and 2.

    Subject analysis set title
    NovoRapid® - Adults
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Adult subjects (18–64 years) received single dose of NovoRapid® in a cross-over manner in both treatment periods 1 and 2.

    Primary: AUCIAsp,0–12h, area under the serum insulin aspart concentration-time curve

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    End point title
    		 AUCIAsp,0–12h, area under the serum insulin aspart concentration-time curve
    End point description
    This endpoint represents data for the free insulin aspart concentration for AUCIAsp,0–12h. Results are based on the full analysis set (FAS), which included all randomised subjects receiving at least one dose of one of the two investigational medicinal products (IMPs; faster aspart or NovoRapid®). Number of subjects analyzed = subjects with available data.
    End point type
    Primary
    End point timeframe
    From 0 to 12 hours
    End point values
    		 Faster aspart - Children Faster aspart - Adolescents Faster aspart - Adults NovoRapid® - Children NovoRapid® - Adolescents NovoRapid® - Adults
    Number of subjects analysed
    12
    16
    13
    12
    16
    15
    Units: pmol*h/L
        geometric mean (geometric coefficient of variation)
    493 ( 23 )
    604 ( 16 )
    684 ( 15 )
    499 ( 21 )
    648 ( 20 )
    690 ( 12 )
    Statistical analysis title
    		 Children: Faster aspart versus NovoRapid®
    Statistical analysis description
    The endpoint was log-transformed and analysed using a linear mixed model with age group, treatment, period, and age group-by-treatment interaction as fixed effects, and subject as a random effect. Due to cross-over design of the study, the following “number of subjects included in analysis” is being erroneously displayed as 24. Actual “number of subjects included in analysis” is 12.
    Comparison groups
    NovoRapid® - Children v Faster aspart - Children
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Treatment ratio
    Point estimate
    0.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.88
         upper limit
    		 1.11
    Statistical analysis title
    		 Adolescents: Faster aspart versus NovoRapid®
    Statistical analysis description
    The endpoint was log-transformed and analysed using a linear mixed model with age group, treatment, period, and age group-by-treatment interaction as fixed effects, and subject as a random effect. Due to cross-over design of the study, the following “number of subjects included in analysis” is being erroneously displayed as 32. Actual “number of subjects included in analysis” is 16.
    Comparison groups
    Faster aspart - Adolescents v NovoRapid® - Adolescents
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Treatment ratio
    Point estimate
    0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.87
         upper limit
    		 1
    Statistical analysis title
    		 Adults: Faster aspart versus NovoRapid®
    Statistical analysis description
    The endpoint was log-transformed and analysed using a linear mixed model with age group, treatment, period, and age group-by-treatment interaction as fixed effects, and subject as a random effect. Due to cross-over design of the study, the following “number of subjects included in analysis” is being erroneously displayed as 28. Actual “number of subjects included in analysis” is 15.
    Comparison groups
    Faster aspart - Adults v NovoRapid® - Adults
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Treatment ratio
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.94
         upper limit
    		 1.07
    Statistical analysis title
    		 Faster aspart: Children versus adults
    Statistical analysis description
    The endpoint was log-transformed and analysed using a linear mixed model with age group, treatment, period, and age group-by-treatment interaction as fixed effects, and subject as a random effect.
    Comparison groups
    Faster aspart - Children v Faster aspart - Adults
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Treatment ratio
    Point estimate
    0.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.61
         upper limit
    		 0.83
    Statistical analysis title
    		 Faster aspart: Adolescents versus adults
    Statistical analysis description
    The endpoint was log-transformed and analysed using a linear mixed model with age group, treatment, period, and age group-by-treatment interaction as fixed effects, and subject as a random effect.
    Comparison groups
    Faster aspart - Adolescents v Faster aspart - Adults
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Treatment ratio
    Point estimate
    0.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.78
         upper limit
    		 0.98
    Statistical analysis title
    		 NovoRapid®: Children versus adults
    Statistical analysis description
    The endpoint was log-transformed and analysed using a linear mixed model with age group, treatment, period, and age group-by-treatment interaction as fixed effects, and subject as a random effect.
    Comparison groups
    NovoRapid® - Children v NovoRapid® - Adults
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Treatment ratio
    Point estimate
    0.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.62
         upper limit
    		 0.84
    Statistical analysis title
    		 NovoRapid®: Adolescents versus adults
    Statistical analysis description
    The endpoint was log-transformed and analysed using a linear mixed model with age group, treatment, period, and age group-by-treatment interaction as fixed effects, and subject as a random effect.
    Comparison groups
    NovoRapid® - Adolescents v NovoRapid® - Adults
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Treatment ratio
    Point estimate
    0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.84
         upper limit
    		 1.05

    Secondary: Cmax,IAsp, maximum observed serum insulin aspart concentration

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    End point title
    		 Cmax,IAsp, maximum observed serum insulin aspart concentration
    End point description
    This endpoint represents data for the free insulin aspart concentration for Cmax,IAsp. Results are based on the FAS. Number of subjects analyzed = subjects with available data.
    End point type
    Secondary
    End point timeframe
    Not applicable
    End point values
    		 Faster aspart - Children Faster aspart - Adolescents Faster aspart - Adults NovoRapid® - Children NovoRapid® - Adolescents NovoRapid® - Adults
    Number of subjects analysed
    12
    16
    13
    12
    16
    15
    Units: pmol/L
        geometric mean (geometric coefficient of variation)
    258 ( 50 )
    253 ( 25 )
    290 ( 18 )
    256 ( 39 )
    255 ( 32 )
    292 ( 20 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Day 1 to day 7 in both the treatment periods. Results are based on the safety analysis set, which included all subjects receiving at least one dose of one of the two IMPs.
    Adverse event reporting additional description
    An AE was defined as treatment emergent if, for each treatment period, the onset of the AE was in the period from time of first trial product administration to 7 days (7 times 24 hours) after trial product administration.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Frequency threshold for reporting non-serious adverse events: 5%
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: No non-serious adverse events with a prevalence of 5% are available for this trial. Number of subjects in individual treatment group with at least one non-serious adverse event areas follows: 3 subjects in faster aspart - children, 4 subjects in faster aspart- adolescents, 1 subject in faster aspart – adults, 2 subjects in NovoRapid® -children,1 subject in NovoRapid® - adolescents, and 1 subject in NovoRapid® - Adults.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Mar 2018
    The date, time, and dose of the last trial product administration were modified to cover the last insulin administration prior to the hypoglycaemic episode. The amendment allowed the reporting of blood glucose (BG) values via subjects’ own BG meters in case they experienced a hypoglycaemic episode outside the clinical site. It was specified that an un-blinded monitor will receive a copy of the randomisation list in order to check that the trial products have been administered in accordance with the planned randomisation. The protocol was updated to specify that the destruction of the trial product will be performed upon completion of the trial after finalization of the drug accountability. It was specified that in case the target plasma glucose level cannot be established before 10:00 hours, the subject can be rescheduled once as per standard procedure. Administration of the meal by intravenous infusion was also allowed in addition to the subcutaneous route.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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