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    Clinical Trial Results:
    This trial is a randomized, single-centre, double-blind, two-period cross-over glucose clamp trial to test for bioequivalence between two SIBA (IDeg) formulations in healthy subjects. This trial is part of two PIPs with EMA decision numbers P/44/2010 and P/96/2011

    Summary
    EudraCT number
    		 2011-002949-35
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    02 Oct 2009

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

    Trial information

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    Trial identification
    Sponsor protocol code
    NN1250-1988
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00966368
    WHO universal trial number (UTN)
    		 U1111-1122-2992
    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-000456-PIP01-08 EMEA-000479-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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    10 Jun 2010
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    02 Oct 2009
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Oct 2009
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to test for bioequivalence between two formulations of Insulin Degludec (I454) based on AUCI454,0-120h,SD and Cmax,I454,SD.
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki 59th WMA General Assembly, Seoul,October 2008, and ICH Good Clinical Practice 01-May-1996.
    Background therapy
    		 Not Applicable
    Evidence for comparator
    		 Not Applicable
    Actual start date of recruitment
    04 Aug 2009
    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: 26
    Worldwide total number of subjects
    26
    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)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    26
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 One site in United States.

    Pre-assignment
    Screening details
    		 Not Applicable

    Period 1
    Period 1 title
    Period 1
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    Double - blind, randomised, 2 period cross-over study. Novo Nordisk study staff were also blinded in this study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 IDeg (E) in period 1
    Arm description
    		 Subjects received IDeg (E), an insulin degludec formulation used in the phase 2 trials, in period 1
    Arm type
    		 Cross over

    Investigational medicinal product name
    IDeg(E)
    Investigational medicinal product code
    Other name
    Insulin Degludec, insulin 454, I454, SIBA
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Each subject was allocated to a single injection of trial product on 2 occasions (Visits 2 and 3 -Treatment period Day 1-6), and was therefore to receive 1 injection of each IDeg formulation during the trial. The dose level of IDeg was 0.4 U/kg body weight. Trial products were administered as a subcutaneous injection into a lifted skin fold of the anterior surface of the thigh using an appropriate 1 mL syringe.

    Arm title
    		 IDeg (M) in period 1
    Arm description
    		 Subjects received IDeg (M), an insulin degludec formulation used in the phase 3 trials, in period 1
    Arm type
    		 Cross over

    Investigational medicinal product name
    IDeg (M)
    Investigational medicinal product code
    Other name
    Insulin Degludec, insulin 454, I454, SIBA
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Each subject was allocated to a single injection of trial product on 2 occasions (Visits 2 and 3-Treatment period Day 1-6), and was therefore to receive 1 injection of each IDeg formulation during the trial. The dose level of IDeg was 0.4 U/kg body weight. Trial products were administered as a subcutaneous injection into a lifted skin fold of the anterior surface of the thigh using an appropriate 1 mL syringe.

    Number of subjects in period 1
    		IDeg (E) in period 1 IDeg (M) in period 1
    Started
    13
    13
    Completed
    13
    13
    Period 2
    Period 2 title
    Period 2
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    Double blind, 2 period crossover study. Novo Nordisk study staff were also blinded in this study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 IDeg (E) in period 2
    Arm description
    		 Subjects received IDeg (E), an insulin degludec formulation used in the phase 2 trials, in period 2
    Arm type
    		 Cross over

    Investigational medicinal product name
    IDeg(E)
    Investigational medicinal product code
    Other name
    Insulin Degludec, insulin 454, I454, SIBA
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Each subject was allocated to a single injection of trial product on 2 occasions (Visits 2 and 3-Treatment period Day 1-6), and was therefore to receive 1 injection of each IDeg formulation during the trial. The dose level of IDeg was 0.4 U/kg body weight. Trial products were administered as a subcutaneous injection into a lifted skin fold of the anterior surface of the thigh using an appropriate 1 mL syringe.

    Arm title
    		 IDeg (M) in period 2
    Arm description
    		 Subjects received IDeg (M), an insulin degludec formulation used in the phase 3 trials, in period 2.
    Arm type
    		 Cross over

    Investigational medicinal product name
    IDeg (M)
    Investigational medicinal product code
    Other name
    Insulin Degludec, insulin 454, I454, SIBA
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Each subject was allocated to a single injection of trial product on 2 occasions (Visits 2 and 3-Treatment period Day 1-6 ), and was therefore to receive 1 injection of each IDeg formulation during the trial. The dose level of IDeg was 0.4 U/kg body weight. Trial products were administered as a subcutaneous injection into a lifted skin fold of the anterior surface of the thigh using an appropriate 1 mL syringe.

    Number of subjects in period 2
    		IDeg (E) in period 2 IDeg (M) in period 2
    Started
    13
    13
    Completed
    12
    13
    Not completed
    1
    0
         Non Compliance
    1
    -
    Period 3
    Period 3 title
    Period 3 (Completers)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    Double blind, 2 period crossover study. Novo Nordisk study staff were also blinded in this study.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 IDeg (E)
    Arm description
    		 Subjects received IDeg (E), an insulin degludec formulation used in the phase 2 trials.
    Arm type
    		 Experimental

    Investigational medicinal product name
    IDeg(E)
    Investigational medicinal product code
    Other name
    Insulin Degludec, insulin 454, I454, SIBA
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Each subject was allocated to a single injection of trial product on 2 occasions (Visits 2 and 3-Treatment period Day 1-6), and was therefore to receive 1 injection of each IDeg formulation during the trial. The dose level of IDeg was 0.4 U/kg body weight. Trial products were administered as a subcutaneous injection into a lifted skin fold of the anterior surface of the thigh using an appropriate 1 mL syringe.

    Arm title
    		 IDeg (M)
    Arm description
    		 Subjects received IDeg (M), an insulin degludec formulation used in the phase 3 trials
    Arm type
    		 Experimental

    Investigational medicinal product name
    IDeg (M)
    Investigational medicinal product code
    Other name
    Insulin Degludec, insulin 454, I454, SIBA
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Each subject was allocated to a single injection of trial product on 2 occasions (Visits 2 and 3-Treatment period Day 1-6), and was therefore to receive 1 injection of each IDeg formulation during the trial. The dose level of IDeg was 0.4 U/kg body weight. Trial products were administered as a subcutaneous injection into a lifted skin fold of the anterior surface of the thigh using an appropriate 1 mL syringe.

    Number of subjects in period 3
    		IDeg (E) IDeg (M)
    Started
    26
    26
    Completed
    25
    26
    Not completed
    1
    0
         Non Compliance
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Period 1
    Reporting group description
    		 -

    Reporting group values
    		 Period 1 Total
    Number of subjects
    		 26 26
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 26 26
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 36.62 ( 9.59 ) -
    Gender categorical
    Units: Subjects
        Female
    		 7 7
        Male
    		 19 19

    End points

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    End points reporting groups
    Reporting group title
    IDeg (E) in period 1
    Reporting group description
    		 Subjects received IDeg (E), an insulin degludec formulation used in the phase 2 trials, in period 1

    Reporting group title
    IDeg (M) in period 1
    Reporting group description
    		 Subjects received IDeg (M), an insulin degludec formulation used in the phase 3 trials, in period 1
    Reporting group title
    IDeg (E) in period 2
    Reporting group description
    		 Subjects received IDeg (E), an insulin degludec formulation used in the phase 2 trials, in period 2

    Reporting group title
    IDeg (M) in period 2
    Reporting group description
    		 Subjects received IDeg (M), an insulin degludec formulation used in the phase 3 trials, in period 2.
    Reporting group title
    IDeg (E)
    Reporting group description
    		 Subjects received IDeg (E), an insulin degludec formulation used in the phase 2 trials.

    Reporting group title
    IDeg (M)
    Reporting group description
    		 Subjects received IDeg (M), an insulin degludec formulation used in the phase 3 trials

    Primary: AUCI454,0-120h,SD -Area under the serum IDeg concentration time curve.

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    End point title
    		 AUCI454,0-120h,SD -Area under the serum IDeg concentration time curve.
    End point description
    Area under the serum insulin 454 (IDeg) concentration-time curve
    End point type
    Primary
    End point timeframe
    0-120 hours after single dose.
    End point values
    		 IDeg (E) IDeg (M)
    Number of subjects analysed
    25
    26
    Units: pmol*h/L
        geometric mean (geometric coefficient of variation)
    84346 ( 14.02 )
    83817 ( 15.89 )
    Statistical analysis title
    		 AUC IDeg (0-120 h)
    Comparison groups
    IDeg (M) v IDeg (E)
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [1]
    Method
    		 ANOVA
    Parameter type
    		 Treatment ratio
    Point estimate
    1
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.94
         upper limit
    		 1.05
    Notes
    [1] - For AUCI454,0-120h,SD bioequivalence between the 2 IDeg formulations will be claimed if the 90% CI of the treatment ratio for both AUC (0-120h) and Cmax is fully within the interval [80%;125%]. Please note that the analysis type is bioequivalence. The "Number of subjects included in analysis" is 26, not 51 as stated in the above table (due to EudraCT IT system error).

    Primary: Cmax I454,SD-Maximum observed serum IDeg concentration after single-dose

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    End point title
    		 Cmax I454,SD-Maximum observed serum IDeg concentration after single-dose
    End point description
    Maximum observed serum IDeg concentration after single-dose.
    End point type
    Primary
    End point timeframe
    within 0 to 120 hours after dosing
    End point values
    		 IDeg (E) IDeg (M)
    Number of subjects analysed
    25
    26
    Units: pmol/L
        geometric mean (geometric coefficient of variation)
    2345 ( 21.41 )
    2280 ( 28.87 )
    Statistical analysis title
    		 Cmax IDeg, SD
    Comparison groups
    IDeg (M) v IDeg (E)
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [2]
    Method
    		 ANOVA
    Parameter type
    		 Treatment ratio
    Point estimate
    0.97
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.89
         upper limit
    		 1.05
    Notes
    [2] - For Cmax,I454,SD, bioequivalence between the 2 IDeg formulations will be claimed if the 90% CI of the treatment ratio for both AUC (0-120h) and Cmax is fully within the interval [80%;125%]. Please note the analysis type is bioequivalence. The "Number of subjects included in analysis" is 26, not 51 as stated in the above table (due to EudraCT IT system error).

    Secondary: tmax I454,SD,Time to maximum observed serum IDeg concentration after dosing

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    End point title
    		 tmax I454,SD,Time to maximum observed serum IDeg concentration after dosing
    End point description
    Time to maximum observed serum IDeg concentration after dosing.
    End point type
    Secondary
    End point timeframe
    within 0 to 120 hours after dosing
    End point values
    		 IDeg (E) IDeg (M)
    Number of subjects analysed
    25
    26
    Units: Hours
        median (full range (min-max))
    13 (6 to 22)
    13.5 (6 to 36)
    No statistical analyses for this end point

    Secondary: AUCI454,0-24h,SD-Area under the serum IDeg concentration-time curve after single dose.

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    End point title
    		 AUCI454,0-24h,SD-Area under the serum IDeg concentration-time curve after single dose.
    End point description
    Area under the serum IDeg concentration-time curve after single dose.
    End point type
    Secondary
    End point timeframe
    0-24 hours after single dose
    End point values
    		 IDeg (E) IDeg (M)
    Number of subjects analysed
    25
    26
    Units: pmol*h/L
        geometric mean (geometric coefficient of variation)
    39358 ( 17.78 )
    37567 ( 28.08 )
    No statistical analyses for this end point

    Secondary: t½,I454-Terminal half-life for IDeg (within 0-120 hours after dosing)

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    End point title
    		 t½,I454-Terminal half-life for IDeg (within 0-120 hours after dosing)
    End point description
    Terminal half-life for IDeg within 0-120 hours after dosing
    End point type
    Secondary
    End point timeframe
    0-120 hours after dosing
    End point values
    		 IDeg (E) IDeg (M)
    Number of subjects analysed
    25
    26
    Units: hours
        median (full range (min-max))
    16.3 (6.5 to 45.5)
    18.4 (5.5 to 36.8)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment to follow-up
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    12.1
    Reporting groups
    Reporting group title
    IDeg (E)
    Reporting group description
    		 Subjects received IDeg (E), an insulin degludec formulation used in the phase 2 trials.

    Reporting group title
    IDeg (M)
    Reporting group description
    		 Subjects received IDeg (M), an insulin degludec formulation used in the phase 3 trials.

    Serious adverse events
    		 IDeg (E) IDeg (M)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 26 (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
    		 IDeg (E) IDeg (M)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 25 (8.00%)
    2 / 26 (7.69%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 25 (8.00%)
    2 / 26 (7.69%)
         occurrences all number
    2
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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.
    Not Applicable
    For support, Contact us.
    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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