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    Clinical Trial Results:
    A double-blinded, randomised, four -period crossover euglycemic clamp trial investigating the dose-response and dose-exposure relationship of Biochaperone insulin lispro in three different doses in subjects with type 1 Diabetes

    Summary
    EudraCT number
    		 2014-000949-77
    Trial protocol
    		 DE  
    Global end of trial date
    28 Jul 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Sep 2020
    First version publication date
    09 Sep 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BC3-CT008
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02146651
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Adocia
    Sponsor organisation address
    115 Avenue Lacassagne, LYON, France, 69003
    Public contact
    Deputy General Manager, Adocia, +33 472610610, o.soula@adocia.com
    Scientific contact
    Director of Clinical Development, Adocia, +33 472610610, g.meiffren@adocia.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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    08 Dec 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Jul 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Jul 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the dose-response and the dose-exposure relationships of BioChaperone insulin lispro.
    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 Practices.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 May 2014
    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: 38
    Worldwide total number of subjects
    38
    EEA total number of subjects
    38
    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)
    38
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The Clinical Trial was conducted at one site in Germany

    Pre-assignment
    Screening details
    		 Subjects with Type 1 Diabetes Mellitus Aged from 18 to 64 years With a total daily insulin requirements <1.2 (I)U/kg/day BMI between 18.5 and 28.0 kg/m²

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor
    Blinding implementation details
    This was a double-blind trial. An authorised person (unblinded person) prepared and administered the trial drug according to the randomisation based assignment to one of the predefined treatment sequences. Except for the unblinded persons involved in the preparation and administration of the trial drug (these persons were not involved in any other clinical trial activities), everyone in the trial, including the PK laboratory, were blinded.

    Arms
    Arm title
    		 BioChaperone insulin Lispro / Humalog®
    Arm description
    		 Each subject was randomly allocated to a sequence of four treatments, i.e. with one of three single doses of BC lispro (0.1 0.2 or 0.4 U/kg body weight) or one single dose of Humalog®, containing 0.2 U/kg body weight on four separate dosing visits. Subjects came in a fasted state to the clinical trial center in the morning of each dosing day and stayed at the clinical trial center until the 12-hour clamp procedures have been terminated. The four dosing visits were separated by a wash-out period of 3-15 days.
    Arm type
    		 Cross-over (experimental & active comparator)

    Investigational medicinal product name
    Biochaperone lispro 0.1 U/Kg
    Investigational medicinal product code
    Other name
    BC lispro 0.1U/kg
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous administration of BC lispro at a dose of 0.1 U/kg body weight during an euglycemic clamp procedure.

    Investigational medicinal product name
    Biochaperone lispro 0.2 U/kg
    Investigational medicinal product code
    Other name
    BC lispro 0.2U/kg
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous administration of BC lispro at a dose of 0.2 U/kg body weight during an euglycemic clamp procedure.

    Investigational medicinal product name
    Biochaperone lispro 0.4 U/kg
    Investigational medicinal product code
    Other name
    BC lispro 0.4U/kg
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous administration of BC lispro at a dose of 0.4 U/kg body weight during an euglycemic clamp procedure.

    Investigational medicinal product name
    Humalog® 0.2U/kg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous administration of Humalog® at a dose of 0.2 U/kg body weight during an euglycemic clamp procedure.

    Number of subjects in period 1
    		BioChaperone insulin Lispro / Humalog®
    Started
    38
    Completed
    37
    Not completed
    1
         Consent withdrawn by subject
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial (overall period)
    Reporting group description
    		 Overall population as this is a cross-over trial

    Reporting group values
    		 Overall trial (overall period) Total
    Number of subjects
    		 38 38
    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)
    		 38 38
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 0 0
        Male
    		 38 38
    Subject analysis sets

    Subject analysis set title
    Safety Analysis set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety analysis set includes all subjects receiving at least one dose of the investigationnal product or its comparator

    Subject analysis set title
    BC lispro 0.1U/kg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects who received one dose of BC lispro 0.1U/kg body weight in a cross over manner.

    Subject analysis set title
    BC Lispro 0.2U/kg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects who received one dose of BC lispro 0.2U/kg body weight in a cross over manner.

    Subject analysis set title
    BC lispro 0.4U/kg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects who received one dose of BC lispro 0.4U/kg body weight in a cross over manner.

    Subject analysis set title
    Humalog® 0.2U/kg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects who received one dose of Humalog® 0.2U/body weight in a cross over manner.

    Subject analysis sets values
    		 Safety Analysis set BC lispro 0.1U/kg BC Lispro 0.2U/kg BC lispro 0.4U/kg Humalog® 0.2U/kg
    Number of subjects
    38
    37
    38
    38
    37
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
    0
    0
        Adults (18-64 years)
    38
    37
    38
    38
    37
        From 65-84 years
    0
    0
    0
    0
    0
        85 years and over
    0
    0
    0
    0
    0
    Age continuous
    Units:
        
    ( )
    ( )
    ( )
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    0
    0
    0
    0
    0
        Male
    38
    37
    38
    38
    37

    End points

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    End points reporting groups
    Reporting group title
    BioChaperone insulin Lispro / Humalog®
    Reporting group description
    		 Each subject was randomly allocated to a sequence of four treatments, i.e. with one of three single doses of BC lispro (0.1 0.2 or 0.4 U/kg body weight) or one single dose of Humalog®, containing 0.2 U/kg body weight on four separate dosing visits. Subjects came in a fasted state to the clinical trial center in the morning of each dosing day and stayed at the clinical trial center until the 12-hour clamp procedures have been terminated. The four dosing visits were separated by a wash-out period of 3-15 days.

    Subject analysis set title
    Safety Analysis set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety analysis set includes all subjects receiving at least one dose of the investigationnal product or its comparator

    Subject analysis set title
    BC lispro 0.1U/kg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects who received one dose of BC lispro 0.1U/kg body weight in a cross over manner.

    Subject analysis set title
    BC Lispro 0.2U/kg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects who received one dose of BC lispro 0.2U/kg body weight in a cross over manner.

    Subject analysis set title
    BC lispro 0.4U/kg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects who received one dose of BC lispro 0.4U/kg body weight in a cross over manner.

    Subject analysis set title
    Humalog® 0.2U/kg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects who received one dose of Humalog® 0.2U/body weight in a cross over manner.

    Primary: AUCGIR(0-last)

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    End point title
    		 AUCGIR(0-last)
    End point description
    Area under the glucose infusion rate time curve from t=0 hours to the end of Clamp
    End point type
    Primary
    End point timeframe
    Form t=0 up to 12hour after dosing
    End point values
    		 BC lispro 0.1U/kg BC Lispro 0.2U/kg BC lispro 0.4U/kg Humalog® 0.2U/kg
    Number of subjects analysed
    37
    38
    38
    37
    Units: mg/kg
        arithmetic mean (standard deviation)
    733.83 ( 230.67 )
    1353.5 ( 442.96 )
    2424.2 ( 521.28 )
    1306.4 ( 374.12 )
    Statistical analysis title
    		 BC lispro 0.1U/kg vs 0.2U/kg
    Statistical analysis description
    ANOVA With Untransformed AUC-GIR 0-last (mg/kg) as Response, Treatment, Period and Sequence as Fixed Effect and Subject Within Sequence as Random Effect
    Comparison groups
    BC lispro 0.1U/kg v BC Lispro 0.2U/kg
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 < 0.0001
    Method
    		 ANOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    -630.957
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -768.3273
         upper limit
    		 -493.5859
    Notes
    [1] - Dose response difference
    Statistical analysis title
    		 BC lispro 0.1U/kg vs 0.4U/kg
    Statistical analysis description
    ANOVA With Untransformed AUC-GIR 0-last (mg/kg) as Response, Treatment, Period and Sequence as Fixed Effect and Subject Within Sequence as Random Effect
    Comparison groups
    BC lispro 0.1U/kg v BC lispro 0.4U/kg
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 < 0.0001
    Method
    		 ANOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    -1696.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1833.7132
         upper limit
    		 -1559.3256
    Notes
    [2] - Dose response difference
    Statistical analysis title
    		 BC lispro 0.2U/kg vs 0.4U/kg
    Statistical analysis description
    ANOVA With Untransformed AUC-GIR 0-last (mg/kg) as Response, Treatment, Period and Sequence as Fixed Effect and Subject Within Sequence as Random Effect
    Comparison groups
    BC Lispro 0.2U/kg v BC lispro 0.4U/kg
    Number of subjects included in analysis
    76
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 < 0.0001
    Method
    		 ANOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    -1065.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1201.4413
         upper limit
    		 -929.6842
    Notes
    [3] - Dose response difference
    Statistical analysis title
    		 BC lispro 0.2U/kg vs Humalog 0.2U/kg
    Statistical analysis description
    ANOVA with untransformed AUC-GIR 0-last (mg/kg) as Response, Treatment, Period and Sequence as Fixed Effect and Subject within Sequence as Random Effect
    Comparison groups
    Humalog® 0.2U/kg v BC Lispro 0.2U/kg
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 = 0.4464
    Method
    		 ANOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    53.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -88.1325
         upper limit
    		 195.6135
    Notes
    [4] - Difference

    Primary: GIRmax

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    End point title
    		 GIRmax
    End point description
    Maximum glucose infusion rate
    End point type
    Primary
    End point timeframe
    From t=0 to t=12 hours
    End point values
    		 BC lispro 0.1U/kg BC Lispro 0.2U/kg BC lispro 0.4U/kg Humalog® 0.2U/kg
    Number of subjects analysed
    37
    38
    38
    37
    Units: mg/kg/min
        arithmetic mean (standard deviation)
    4.806 ( 1.8491 )
    7.363 ( 2.7416 )
    10.164 ( 2.5151 )
    6.631 ( 2.2980 )
    Statistical analysis title
    		 Bc lispro 0.1U/kg vs 0.2U/kg
    Statistical analysis description
    ANOVA With Untransformed GIRmax (mg/kg/min) as Response, Treatment, Period and Sequence as Fixed Effect and Subject Within Sequence as Random Effect
    Comparison groups
    BC lispro 0.1U/kg v BC Lispro 0.2U/kg
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 < 0.0001
    Method
    		 ANOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    -2.612
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.3262
         upper limit
    		 -1.8984
    Notes
    [5] - Dose response difference
    Statistical analysis title
    		 BC lispro 0.1U/kg vs 0.4U/kg
    Statistical analysis description
    ANOVA With Untransformed GIRmax (mg/kg/min) as Response, Treatment, Period and Sequence as Fixed Effect and Subject Within Sequence as Random Effect
    Comparison groups
    BC lispro 0.1U/kg v BC lispro 0.4U/kg
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 < 0.0001
    Method
    		 ANOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    -5.393
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.1056
         upper limit
    		 -4.6797
    Notes
    [6] - Dose response difference
    Statistical analysis title
    		 BC lispro 0.2U/kg vs 0.4U/kg
    Statistical analysis description
    ANOVA With Untransformed GIRmax (mg/kg/min) as Response, Treatment, Period and Sequence as Fixed Effect and Subject Within Sequence as Random Effect
    Comparison groups
    BC Lispro 0.2U/kg v BC lispro 0.4U/kg
    Number of subjects included in analysis
    76
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    P-value
    		 < 0.0001
    Method
    		 ANOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    -2.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.4863
         upper limit
    		 -2.0744
    Notes
    [7] - Dose response difference
    Statistical analysis title
    		 BC lispro 0.2U/kg vs Humalog 0.2U/kg
    Statistical analysis description
    ANOVA with untransformed GIRmax (mg/kg/min) as Response, Treatment, Period and Sequence as Fixed Effect and Subject within Sequence as Random Effect
    Comparison groups
    BC Lispro 0.2U/kg v Humalog® 0.2U/kg
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 other [8]
    P-value
    		 = 0.0661
    Method
    		 ANOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    0.806
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.0567
         upper limit
    		 1.669
    Notes
    [8] - Difference

    Primary: AUCLisp(0-Last)

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    End point title
    		 AUCLisp(0-Last)
    End point description
    Area under the glucose infusion rate time curve from t=0 hours to the end of clamp
    End point type
    Primary
    End point timeframe
    From t=0 to t=12 hours
    End point values
    		 BC lispro 0.1U/kg BC Lispro 0.2U/kg BC lispro 0.4U/kg Humalog® 0.2U/kg
    Number of subjects analysed
    37
    38
    38
    37
    Units: h.mU/L
        arithmetic mean (standard deviation)
    98.341 ( 30.016 )
    202.24 ( 64.794 )
    441.51 ( 100.34 )
    209.22 ( 64.10 )
    Statistical analysis title
    		 0.1U vs 0.2U
    Statistical analysis description
    Treatment Difference was Analyzed Using Wilcoxon's Signed Rank Test
    Comparison groups
    BC Lispro 0.2U/kg v BC lispro 0.1U/kg
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    P-value
    		 < 0.0001
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Hodges-Lehmann estimate
    Point estimate
    -96.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -110.022
         upper limit
    		 -81.1004
    Notes
    [9] - Dose response difference
    Statistical analysis title
    		 0.1U vs 0.4U
    Statistical analysis description
    Treatment Difference was Analyzed Using Wilcoxon's Signed Rank Test
    Comparison groups
    BC lispro 0.1U/kg v BC lispro 0.4U/kg
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 other [10]
    P-value
    		 < 0.0001
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Hodges-Lehmann estimate
    Point estimate
    -328.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -350.7408
         upper limit
    		 -307.2081
    Notes
    [10] - Dose response difference
    Statistical analysis title
    		 0.2U vs 0.4U
    Comparison groups
    BC Lispro 0.2U/kg v BC lispro 0.4U/kg
    Number of subjects included in analysis
    76
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    P-value
    		 < 0.0001
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Hodges-Lehmann estimate
    Point estimate
    -233.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -256.723
         upper limit
    		 -207.4862
    Notes
    [11] - Dose response difference
    Statistical analysis title
    		 BC lispro 0.2U vs Humalog 0.2U
    Statistical analysis description
    Treatment Difference was Analyzed Using Wilcoxon's Signed Rank Test
    Comparison groups
    BC Lispro 0.2U/kg v Humalog® 0.2U/kg
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 other [12]
    P-value
    		 = 0.4184
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Hodges-Lehmann estimate
    Point estimate
    -5.591
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -23.714
         upper limit
    		 10.6985
    Notes
    [12] - Treatment difference

    Primary: Cmax(Lisp)

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    End point title
    		 Cmax(Lisp)
    End point description
    Maximum observed serum insulin lispro concentration
    End point type
    Primary
    End point timeframe
    From t=0 up to t=12 hours
    End point values
    		 BC lispro 0.1U/kg BC Lispro 0.2U/kg BC lispro 0.4U/kg Humalog® 0.2U/kg
    Number of subjects analysed
    37
    38
    38
    37
    Units: mU/L
        arithmetic mean (standard deviation)
    52.220 ( 15.662 )
    99.014 ( 34.872 )
    190.19 ( 52.490 )
    90.202 ( 28.196 )
    Statistical analysis title
    		 Bc lispro 0.1U/kg vs 0.2U/kg
    Statistical analysis description
    ANOVA With Log-transformed Cmax-Lisp (mU/L) as Response, Treatment, Period and Sequence as Fixed Effect and Subject Within Sequence as Random Effect
    Comparison groups
    BC lispro 0.1U/kg v BC Lispro 0.2U/kg
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 other [13]
    P-value
    		 < 0.0001
    Method
    		 ANOVA
    Parameter type
    		 LS Mean Ratio
    Point estimate
    0.532
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4897
         upper limit
    		 0.5788
    Notes
    [13] - Dose response difference
    Statistical analysis title
    		 BC lispro 0.1U/kg vs 0.4U/kg
    Statistical analysis description
    ANOVA With Log-transformed Cmax-Lisp (mU/L) as Response, Treatment, Period and Sequence as Fixed Effect and Subject Within Sequence as Random Effect
    Comparison groups
    BC lispro 0.1U/kg v BC lispro 0.4U/kg
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 other [14]
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Ratio
    Point estimate
    0.271
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.2495
         upper limit
    		 0.2948
    Notes
    [14] - Dose response difference
    Statistical analysis title
    		 BC lispro 0.2U/kg vs 0.4U/kg
    Statistical analysis description
    ANOVA With Log-transformed Cmax-Lisp (mU/L) as Response, Treatment, Period and Sequence as Fixed Effect and Subject Within Sequence as Random Effect
    Comparison groups
    BC Lispro 0.2U/kg v BC lispro 0.4U/kg
    Number of subjects included in analysis
    76
    Analysis specification
    Pre-specified
    Analysis type
    		 other [15]
    P-value
    		 < 0.0001
    Method
    		 ANOVA
    Parameter type
    		 LS Mean Ratio
    Point estimate
    0.509
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.469
         upper limit
    		 0.5532
    Notes
    [15] - Dose response difference
    Statistical analysis title
    		 BC lispro 0.2U/kg vs Humalog 0.2U/kg
    Statistical analysis description
    ANOVA with log transformed Cmax-Lisp (mU/L) as Response, Treatment, Period and Sequence as Fixed Effect and Subject within Sequence as Random Effect
    Comparison groups
    BC Lispro 0.2U/kg v Humalog® 0.2U/kg
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 other [16]
    P-value
    		 = 0.0404
    Method
    		 ANOVA
    Parameter type
    		 LS Mean Ratio
    Point estimate
    1.103
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.0046
         upper limit
    		 1.2104
    Notes
    [16] - Treatment difference

    Secondary: Early t0.5(GIRmax)

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    End point title
    		 Early t0.5(GIRmax)
    End point description
    Time to first observed half maximum glucose infusion rate
    End point type
    Secondary
    End point timeframe
    From t=0 up to T=12hours
    End point values
    		 BC lispro 0.1U/kg BC Lispro 0.2U/kg BC lispro 0.4U/kg Humalog® 0.2U/kg
    Number of subjects analysed
    37
    38
    38
    37
    Units: Hours
        arithmetic mean (standard deviation)
    0.517 ( 0.1376 )
    0.559 ( 0.1695 )
    0.533 ( 0.0967 )
    0.754 ( 0.2043 )
    Statistical analysis title
    		 Bc lispro 0.1U/kg vs 0.2U/kg
    Statistical analysis description
    Treatment Difference was Analyzed Using Wilcoxon's Signed Rank Test
    Comparison groups
    BC Lispro 0.2U/kg v BC lispro 0.1U/kg
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 other [17]
    P-value
    		 = 0.5521
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Hodges-Lehmann estimate
    Point estimate
    -0.033
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1
         upper limit
    		 0.05
    Notes
    [17] - Dose response difference
    Statistical analysis title
    		 BC lispro 0.1U/kg vs 0.4U/kg
    Statistical analysis description
    Treatment Difference was Analyzed Using Wilcoxon's Signed Rank Test
    Comparison groups
    BC lispro 0.1U/kg v BC lispro 0.4U/kg
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 other [18]
    P-value
    		 = 0.9733
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Hodges-Lehmann estimate
    Point estimate
    -0.017
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.0667
         upper limit
    		 0.05
    Notes
    [18] - Dose response difference
    Statistical analysis title
    		 BC lispro 0.2U/kg vs 0.4U/kg
    Statistical analysis description
    Treatment Difference was Analyzed Using Wilcoxon's Signed Rank Test
    Comparison groups
    BC Lispro 0.2U/kg v BC lispro 0.4U/kg
    Number of subjects included in analysis
    76
    Analysis specification
    Pre-specified
    Analysis type
    		 other [19]
    P-value
    		 = 0.641
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Hodges-Lehmann estimate
    Point estimate
    0.017
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.05
         upper limit
    		 0.0667
    Notes
    [19] - Dose response difference
    Statistical analysis title
    		 BC lispro 0.2U/kg vs Humalog 0.2U/kg
    Statistical analysis description
    Treatment Difference was Analyzed Using Wilcoxon's Signed Rank Test
    Comparison groups
    BC Lispro 0.2U/kg v Humalog® 0.2U/kg
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 other [20]
    P-value
    		 < 0.0001
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Hodges-Lehmann estimate
    Point estimate
    -0.183
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.2667
         upper limit
    		 -0.1167
    Notes
    [20] - Treatment difference

    Secondary: Early t0.5max(Lisp)

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    End point title
    		 Early t0.5max(Lisp)
    End point description
    Time to first observed half maximum observed serum insulin lispro concentration
    End point type
    Secondary
    End point timeframe
    From t=0 up to t=12 hours
    End point values
    		 BC lispro 0.1U/kg BC Lispro 0.2U/kg BC lispro 0.4U/kg Humalog® 0.2U/kg
    Number of subjects analysed
    37
    38
    38
    37
    Units: hours
        arithmetic mean (standard deviation)
    0.256 ( 0.0852 )
    0.262 ( 0.0857 )
    0.260 ( 0.0870 )
    0.440 ( 0.1165 )
    Statistical analysis title
    		 Bc lispro 0.1U/kg vs 0.2U/kg
    Statistical analysis description
    Treatment Difference was Analyzed Using Wilcoxon's Signed Rank Test
    Comparison groups
    BC lispro 0.1U/kg v BC Lispro 0.2U/kg
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 other [21]
    P-value
    		 = 0.623
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Hodges-Lehmann estimate
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.05
         upper limit
    		 0.0333
    Notes
    [21] - Dose response difference
    Statistical analysis title
    		 BC lispro 0.1U/kg vs 0.4U/kg
    Statistical analysis description
    Treatment Difference was Analyzed Using Wilcoxon's Signed Rank Test
    Comparison groups
    BC lispro 0.1U/kg v BC lispro 0.4U/kg
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 other [22]
    P-value
    		 = 0.5217
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Hodges-Lehmann estimate
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.05
         upper limit
    		 0.0333
    Notes
    [22] - Dose response difference
    Statistical analysis title
    		 BC lispro 0.2U/kg vs 0.4U/kg
    Statistical analysis description
    Treatment Difference was Analyzed Using Wilcoxon's Signed Rank Test
    Comparison groups
    BC Lispro 0.2U/kg v BC lispro 0.4U/kg
    Number of subjects included in analysis
    76
    Analysis specification
    Pre-specified
    Analysis type
    		 other [23]
    P-value
    		 = 0.706
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Hodges-Lehmann estimate
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.0333
         upper limit
    		 0.05
    Notes
    [23] - Dose response difference
    Statistical analysis title
    		 BC lispro 0.2U/kg vs Humalog 0.2U/kg
    Statistical analysis description
    Treatment Difference was Analyzed Using Wilcoxon's Signed Rank Test
    Comparison groups
    BC Lispro 0.2U/kg v Humalog® 0.2U/kg
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 other [24]
    P-value
    		 < 0.0001
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Hodges-Lehmann estimate
    Point estimate
    -0.183
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.2333
         upper limit
    		 -0.1333
    Notes
    [24] - Treatment difference

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first study intervention until the safety follow-up visit
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    BC Lispro 0.1U/kg
    Reporting group description
    		 -

    Reporting group title
    BC Lispro 0.2U/kg
    Reporting group description
    		 -

    Reporting group title
    BC Lispro 0.4U/Kg
    Reporting group description
    		 -

    Reporting group title
    Humalog® 0.2U/kg
    Reporting group description
    		 -

    Reporting group title
    Before first dosing
    Reporting group description
    		 -

    Serious adverse events
    		 BC Lispro 0.1U/kg BC Lispro 0.2U/kg BC Lispro 0.4U/Kg Humalog® 0.2U/kg Before first dosing
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 BC Lispro 0.1U/kg BC Lispro 0.2U/kg BC Lispro 0.4U/Kg Humalog® 0.2U/kg Before first dosing
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 37 (18.92%)
    8 / 38 (21.05%)
    7 / 38 (18.42%)
    5 / 37 (13.51%)
    3 / 38 (7.89%)
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 38 (2.63%)
    1 / 38 (2.63%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Cardiac disorders
    Presyncope
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 38 (0.00%)
    1 / 37 (2.70%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 38 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Headache
         subjects affected / exposed
    1 / 37 (2.70%)
    2 / 38 (5.26%)
    2 / 38 (5.26%)
    2 / 37 (5.41%)
    0 / 38 (0.00%)
         occurrences all number
    1
    2
    2
    2
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 38 (0.00%)
    1 / 37 (2.70%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Injection site erythema
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 38 (0.00%)
    1 / 37 (2.70%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Pyrexia
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    1 / 38 (2.63%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 38 (2.63%)
    1 / 38 (2.63%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    1
    1
    1
    0
    0
    Vomiting
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 38 (5.26%)
    1 / 38 (2.63%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    2
    1
    0
    0
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    4 / 37 (10.81%)
    4 / 38 (10.53%)
    3 / 38 (7.89%)
    0 / 37 (0.00%)
    3 / 38 (7.89%)
         occurrences all number
    4
    9
    4
    0
    4

    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.
    None reported
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