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    Clinical Trial Results:
    A randomized, double-blind trial of single doses of ZP4207 administered s.c. to hypoglycemic Type 1 diabetic patients to describe the pharmacokinetics and pharmacodynamics of ZP4207 as compared to marketed glucagon

    Summary
    EudraCT number
    		 2015-005287-41
    Trial protocol
    		 DE  
    Global end of trial date
    03 Jun 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Nov 2020
    First version publication date
    18 Nov 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    ZP4207-15126
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02660008
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Zealand Pharma A/S
    Sponsor organisation address
    Sydmarken 11, Søborg, Denmark, 2860
    Public contact
    Lena Skærbye List, Zealand Pharma A/S, +45 5060 3842, llist@zealandpharma.com
    Scientific contact
    Ramin Tehranchi, Zealand Pharma A/S, +45 5060 3793, rtehranchi@zealandpharma.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
    06 Jan 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Jun 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Jun 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To characterize the pharmacokinetic (PK) and pharmacodynamic (PD) properties of ZP4207 in the final formulation following a single s.c. dose administered to hypoglycaemic Type 1 diabetic (T1D) patients
    Protection of trial subjects
    The trial was conducted in accordance of the World Medical Asssociation Declaration of Helsinki, current guidelines for GCP and local regulations
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Jan 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
    Germany: 58
    Worldwide total number of subjects
    58
    EEA total number of subjects
    58
    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)
    58
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 The patients were recruited from a single centre in Germany.

    Pre-assignment
    Screening details
    		 76 patients were screened and 58 patients were eligible and randomized.

    Period 1
    Period 1 title
    Overall trial period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Group 1 0.1 mg dasiglucagon
    Arm description
    		 Group 1 parallel design 0.1 mg dasiglucagon or 1.0 mg GlucaGen
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dasiglucagon
    Investigational medicinal product code
    ZP4207
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.1 mg administered as a single dose

    Arm title
    		 Group 2 0.3 mg dasiglucagon
    Arm description
    		 Group 2 crossover design 0.3 mg dasiglucagon with 0.5 mg GlucaGen
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dasiglucagon
    Investigational medicinal product code
    ZP4207
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.3 mg administered as a single dose

    Arm title
    		 Group 3 0.6 mg dasiglucagon
    Arm description
    		 Group 3 crossover design 0.6 mg dasiglucagon with 1.0 mg GlucaGen
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dasiglucagon
    Investigational medicinal product code
    ZP4207
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.6 mg administered as a single dose

    Arm title
    		 Group 4 1.0 mg dasiglucagon
    Arm description
    		 Group 4 crossover design 1.0 mg dasiglucagon with 1.0 mg GlucaGen
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dasiglucagon
    Investigational medicinal product code
    ZP4207
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1.0 mg administered as a single dose

    Arm title
    		 Group 2 0.5 mg GlucaGen
    Arm description
    		 Group 2 crossover design 0.3 mg dasiglucagon with 0.5 mg GlucaGen
    Arm type
    		 Active comparator

    Investigational medicinal product name
    GlucaGen Hypokit
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.5 mg administered as a single dose

    Arm title
    		 Group 3 1.0 mg GlucaGen
    Arm description
    		 Group 3 crossover design 0.6 mg dasiglucagon with 1.0 mg GlucaGen
    Arm type
    		 Active comparator

    Investigational medicinal product name
    GlucaGen Hypokit
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1.0 mg administered as a single dose

    Arm title
    		 Group 1 1.0 mg GlucaGen
    Arm description
    		 Group 1 parallel design 0.1 mg dasiglucagon or 1.0 mg GlucaGen
    Arm type
    		 Active comparator

    Investigational medicinal product name
    GlucaGen
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1.0 mg administered as a single dose

    Arm title
    		 Group 4 1.0 mg GlucaGen
    Arm description
    		 Group 4 crossover design 1.0 mg dasiglucagon with 1.0 mg GlucaGen
    Arm type
    		 Active comparator

    Investigational medicinal product name
    GlucaGen Hypokit
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1.0 mg administered as a single dose

    Number of subjects in period 1
    		Group 1 0.1 mg dasiglucagon Group 2 0.3 mg dasiglucagon Group 3 0.6 mg dasiglucagon Group 4 1.0 mg dasiglucagon Group 2 0.5 mg GlucaGen Group 3 1.0 mg GlucaGen Group 1 1.0 mg GlucaGen Group 4 1.0 mg GlucaGen
    Started
    6
    17
    17
    16
    17
    17
    2
    16
    Completed
    6
    16
    17
    16
    17
    16
    2
    16
    Not completed
    0
    1
    0
    0
    0
    1
    0
    0
         Consent withdrawn by subject
    -
    1
    -
    -
    -
    1
    -
    -

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Overall trial period
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial period Total
    Number of subjects
    		 58 58
    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)
    		 58 58
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 36.4 ( 8.76 ) -
    Gender categorical
    Units: Subjects
        Female
    		 27 27
        Male
    		 31 31
    Height
    Units: meter
        arithmetic mean (standard deviation)
    		 1.748 ( 0.0737 ) -
    Weight
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    		 76.53 ( 7.493 ) -
    BMI
    Units: kilogram(s)/square meter
        arithmetic mean (standard deviation)
    		 25.09 ( 2.486 ) -
    HbA1c
    Units: percent
        arithmetic mean (standard deviation)
    		 7.14 ( 0.539 ) -
    Duration of diabetes
    Units: years
        arithmetic mean (standard deviation)
    		 18.9 ( 9.17 ) -
    Subject analysis sets

    Subject analysis set title
    Group 2 subjects
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects in group 2 treated with 0.3mg dasiglucagon and/or 0.5mg GlucaGen

    Subject analysis set title
    Group 3 subjects
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects in group 3 treated with 0.6 mg dasiglucagon and/or 1.0mg GlucaGen

    Subject analysis set title
    Group 4 subjects
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects in group 4 treated with 1.0mg dasiglucagon and/or 1.0mg GlucaGen. For summaries of PK and PD endpoints the data for 1.0 mg GlucaGen from groups 1, 3 and 4 were pooled.

    Subject analysis set title
    Group 1 subjects
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects in group 1 treated with 0.1 mg dasiglucagon or 1.0 mg GlucaGen

    Subject analysis sets values
    		 Group 2 subjects Group 3 subjects Group 4 subjects Group 1 subjects
    Number of subjects
    17
    17
    16
    8
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
    0
        Adults (18-64 years)
    17
    17
    16
    8
        From 65-84 years
    0
    0
    0
    0
        85 years and over
    0
    0
    0
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    35.4 ( 8.66 )
    34.0 ( 9.17 )
    37.5 ( 8.15 )
    41.6 ( 8.31 )
    Gender categorical
    Units: Subjects
        Female
    10
    8
    6
    3
        Male
    7
    9
    10
    5
    Height
    Units: meter
        arithmetic mean (standard deviation)
    1.766 ( 0.0721 )
    1.734 ( 0.0712 )
    1.731 ( 0.0857 )
    1.771 ( 0.0491 )
    Weight
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    76.81 ( 6.368 )
    78.67 ( 7.897 )
    73.94 ( 8.777 )
    76.56 ( 5.494 )
    BMI
    Units: kilogram(s)/square meter
        arithmetic mean (standard deviation)
    24.65 ( 1.945 )
    26.21 ( 2.776 )
    24.74 ( 2.962 )
    24.39 ( 0.960 )
    HbA1c
    Units: percent
        arithmetic mean (standard deviation)
    6.88 ( 0.494 )
    7.24 ( 0.585 )
    7.19 ( 0.571 )
    7.41 ( 0.210 )
    Duration of diabetes
    Units: years
        arithmetic mean (standard deviation)
    18.4 ( 10.28 )
    19.2 ( 10.43 )
    18.6 ( 5.29 )
    19.9 ( 11.49 )

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Group 1 0.1 mg dasiglucagon
    Reporting group description
    		 Group 1 parallel design 0.1 mg dasiglucagon or 1.0 mg GlucaGen

    Reporting group title
    Group 2 0.3 mg dasiglucagon
    Reporting group description
    		 Group 2 crossover design 0.3 mg dasiglucagon with 0.5 mg GlucaGen

    Reporting group title
    Group 3 0.6 mg dasiglucagon
    Reporting group description
    		 Group 3 crossover design 0.6 mg dasiglucagon with 1.0 mg GlucaGen

    Reporting group title
    Group 4 1.0 mg dasiglucagon
    Reporting group description
    		 Group 4 crossover design 1.0 mg dasiglucagon with 1.0 mg GlucaGen

    Reporting group title
    Group 2 0.5 mg GlucaGen
    Reporting group description
    		 Group 2 crossover design 0.3 mg dasiglucagon with 0.5 mg GlucaGen

    Reporting group title
    Group 3 1.0 mg GlucaGen
    Reporting group description
    		 Group 3 crossover design 0.6 mg dasiglucagon with 1.0 mg GlucaGen

    Reporting group title
    Group 1 1.0 mg GlucaGen
    Reporting group description
    		 Group 1 parallel design 0.1 mg dasiglucagon or 1.0 mg GlucaGen

    Reporting group title
    Group 4 1.0 mg GlucaGen
    Reporting group description
    		 Group 4 crossover design 1.0 mg dasiglucagon with 1.0 mg GlucaGen

    Subject analysis set title
    Group 2 subjects
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects in group 2 treated with 0.3mg dasiglucagon and/or 0.5mg GlucaGen

    Subject analysis set title
    Group 3 subjects
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects in group 3 treated with 0.6 mg dasiglucagon and/or 1.0mg GlucaGen

    Subject analysis set title
    Group 4 subjects
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects in group 4 treated with 1.0mg dasiglucagon and/or 1.0mg GlucaGen. For summaries of PK and PD endpoints the data for 1.0 mg GlucaGen from groups 1, 3 and 4 were pooled.

    Subject analysis set title
    Group 1 subjects
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects in group 1 treated with 0.1 mg dasiglucagon or 1.0 mg GlucaGen

    Primary: AUC(0-30min)

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    End point title
    		 AUC(0-30min) [1]
    End point description
    Area under the plasma dasiglucagon or GlucaGen concentration vs. time curve from 0 to 30 min post-dose. The GlucaGen endpoints are displayed as derived from baseline-adjusted profiles.
    End point type
    Primary
    End point timeframe
    0-30min post dose
    Notes
    [1] - 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: GlucaGen 1.0 mg data available for Groups 1, 3 and 4 were pooled
    End point values
    		 Group 1 0.1 mg dasiglucagon Group 2 0.3 mg dasiglucagon Group 3 0.6 mg dasiglucagon Group 4 1.0 mg dasiglucagon Group 2 0.5 mg GlucaGen Group 3 1.0 mg GlucaGen
    Number of subjects analysed
    5
    16
    16
    16
    17
    16 [2]
    Units: pmol*h/L
        geometric mean (geometric coefficient of variation)
    95.4 ( 32.2 )
    292 ( 26.1 )
    413 ( 36.8 )
    833 ( 34.7 )
    362 ( 27.8 )
    576 ( 29.9 )
    Notes
    [2] - Number of subjects was 33 as GlucaGen 1.0 mg data available for Groups 1, 3 and 4 were pooled
    Statistical analysis title
    		 0.3mg dasiglucagon vs 0.5mg Glucagen
    Statistical analysis description
    Analysis of variance (ANOVA) with log-transformed response, treatment, period, sequence and patient within sequence as fixed effect. The ratio of geometric LS-means of treatments (ZP4207/GlucaGen) is presented within each group. Please note that the results are of an exploratory nature since there was no formal sample size calculation and no H0-hypothesis was defined.
    Comparison groups
    Group 2 0.3 mg dasiglucagon v Group 2 0.5 mg GlucaGen
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [3]
    P-value
    		 = 0.0478
    Method
    		 ANOVA
    Parameter type
    		 least squares mean ratio
    Point estimate
    0.811
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.684
         upper limit
    		 0.9614
    Notes
    [3] - Treatments may be described as comparable if the 90% CI of the respective ratio was within the interval of 0.8-1.25. A formal test of equivalence was not performed, the p-value is from an exploratory superiority test. 17 subjects were included in the analysis: 16 received dasiglucagon and 17 received GlucaGen. The group had a crossover design.
    Statistical analysis title
    		 0.6mg dasiglucagon vs 1.0mg Glucagen
    Statistical analysis description
    Analysis of variance (ANOVA) with log-transformed response, treatment, period, sequence and patient within sequence as fixed effect. The ratio of geometric LS-means of treatments (ZP4207/GlucaGen) is presented within each group. Please note that the results are of an exploratory nature since there was no formal sample size calculation and no H0-hypothesis was defined.
    Comparison groups
    Group 3 0.6 mg dasiglucagon v Group 3 1.0 mg GlucaGen
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [4]
    P-value
    		 = 0.0315
    Method
    		 ANOVA
    Parameter type
    		 least squares mean ratio
    Point estimate
    0.789
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.6628
         upper limit
    		 0.9397
    Notes
    [4] - Treatments may be described as comparable if the 90% CI of the respective ratio was within the interval of 0.8-1.25. A formal test of equivalence was not performed, the p-value is from an exploratory superiority test. 16 subjects were included in the analysis: 16 received dasiglucagon and 16 received GlucaGen. The group had a crossover design.
    Statistical analysis title
    		 1.0mg dasiglucagon vs 1.0mg Glucagen
    Statistical analysis description
    Analysis of variance (ANOVA) with log-transformed response, treatment, period, sequence and patient within sequence as fixed effect. The ratio of geometric LS-means of treatments (ZP4207/GlucaGen) is presented within each group. Please note that the results are of an exploratory nature since there was no formal sample size calculation and no H0-hypothesis was defined.
    Comparison groups
    Group 4 1.0 mg dasiglucagon v Group 3 1.0 mg GlucaGen
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [5]
    P-value
    		 = 0.0217
    Method
    		 ANOVA
    Parameter type
    		 least squares mean ratio
    Point estimate
    1.3
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.0883
         upper limit
    		 1.5577
    Notes
    [5] - Treatments may be described as comparable if the 90% CI of the respective ratio was within the interval of 0.8-1.25. A formal test of equivalence was not performed, the p-value is from an exploratory superiority test. This was actually a comparison of Group 4 1.0 mg dasiglucagon and Group 4 1.0 mg GlucaGen. Number of subjects in this analysis was 16 (16 received dasiglucagon and 15 received GlucaGen). The group had a crossover design.

    Primary: AUC(0-360min)

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    End point title
    		 AUC(0-360min) [6]
    End point description
    Area under the plasma dasiglucagon or GlucaGen concentration vs. time curve from 0 to 360 min post-dose. The GlucaGen endpoints are displayed as derived from baseline-adjusted profiles.
    End point type
    Primary
    End point timeframe
    0-360 min post dose
    Notes
    [6] - 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: GlucaGen 1.0 mg data available for Groups 1, 3 and 4 were pooled
    End point values
    		 Group 1 0.1 mg dasiglucagon Group 2 0.3 mg dasiglucagon Group 3 0.6 mg dasiglucagon Group 4 1.0 mg dasiglucagon Group 2 0.5 mg GlucaGen Group 3 1.0 mg GlucaGen
    Number of subjects analysed
    5
    16
    16
    16
    17
    16 [7]
    Units: pmol*h/L
        geometric mean (geometric coefficient of variation)
    437 ( 27.4 )
    1350 ( 12.2 )
    2610 ( 14.0 )
    4740 ( 14.5 )
    924 ( 18.8 )
    1630 ( 19.0 )
    Notes
    [7] - Number of subjects was 33 as GlucaGen 1.0 mg data available for Groups 1, 3 and 4 were pooled
    Statistical analysis title
    		 0.3mg dasiglucagon vs 0.5mg Glucagen
    Statistical analysis description
    Analysis of variance (ANOVA) with log-transformed response, treatment, period, sequence and patient within sequence as fixed effect. The ratio of geometric LS-means of treatments (ZP4207/GlucaGen) is presented within each group. Please note that the results are of an exploratory nature since there was no formal sample size calculation and no H0-hypothesis was defined.
    Comparison groups
    Group 2 0.3 mg dasiglucagon v Group 2 0.5 mg GlucaGen
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [8]
    P-value
    		 < 0.0001
    Method
    		 ANOVA
    Parameter type
    		 least squares mean ratio
    Point estimate
    1.47
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.3774
         upper limit
    		 1.575
    Notes
    [8] - Treatments may be described as comparable if the 90% CI of the respective ratio was within the interval of 0.8-1.25. A formal test of equivalence was not performed, the p-value is from an exploratory superiority test. 17 subjects were included in the analysis: 16 received dasiglucagon and 17 received GlucaGen. The group had a crossover design.
    Statistical analysis title
    		 0.6mg dasiglucagon vs 1.0mg Glucagen
    Statistical analysis description
    Analysis of variance (ANOVA) with log-transformed response, treatment, period, sequence and patient within sequence as fixed effect. The ratio of geometric LS-means of treatments (ZP4207/GlucaGen) is presented within each group. Please note that the results are of an exploratory nature since there was no formal sample size calculation and no H0-hypothesis was defined.
    Comparison groups
    Group 3 0.6 mg dasiglucagon v Group 3 1.0 mg GlucaGen
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [9]
    P-value
    		 < 0.0001
    Method
    		 ANOVA
    Parameter type
    		 least squares mean ratio
    Point estimate
    1.76
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.5774
         upper limit
    		 1.967
    Notes
    [9] - Treatments may be described as comparable if the 90% CI of the respective ratio was within the interval of 0.8-1.25. A formal test of equivalence was not performed, the p-value is from an exploratory superiority test. 16 subjects were included in the analysis: 16 received dasiglucagon and 16 received GlucaGen. The group had a crossover design.
    Statistical analysis title
    		 1.0mg dasiglucagon vs 1.0mg Glucagen
    Statistical analysis description
    Analysis of variance (ANOVA) with log-transformed response, treatment, period, sequence and patient within sequence as fixed effect. The ratio of geometric LS-means of treatments (ZP4207/GlucaGen) is presented within each group. Please note that the results are of an exploratory nature since there was no formal sample size calculation and no H0-hypothesis was defined.
    Comparison groups
    Group 3 1.0 mg GlucaGen v Group 4 1.0 mg dasiglucagon
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [10]
    P-value
    		 < 0.0001
    Method
    		 ANOVA
    Parameter type
    		 least squares mean ratio
    Point estimate
    2.66
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 2.5224
         upper limit
    		 2.8056
    Notes
    [10] - Treatments may be described as comparable if the 90% CI of the respective ratio was within the interval of 0.8-1.25. A formal test of equivalence was not performed, the p-value is from an exploratory superiority test. This was actually a comparison of Group 4 1.0 mg dasiglucagon and Group 4 1.0 mg GlucaGen. Number of subjects in this analysis was 16 (16 received dasiglucagon and 15 received GlucaGen). The group had a crossover design.

    Primary: Cmax

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    End point title
    		 Cmax [11]
    End point description
    Maximum of all valid plasma dasiglucagon or GlucaGen concentration measurements from 0 to 360 min post-dose. The GlucaGen endpoints are displayed as derived from baseline-adjusted profiles.
    End point type
    Primary
    End point timeframe
    0-360 min post dose
    Notes
    [11] - 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: GlucaGen 1.0 mg data available for Groups 1, 3 and 4 were pooled
    End point values
    		 Group 1 0.1 mg dasiglucagon Group 2 0.3 mg dasiglucagon Group 3 0.6 mg dasiglucagon Group 4 1.0 mg dasiglucagon Group 2 0.5 mg GlucaGen Group 3 1.0 mg GlucaGen
    Number of subjects analysed
    5
    16
    16
    16
    17
    16 [12]
    Units: pmol/L
        geometric mean (geometric coefficient of variation)
    320 ( 33.7 )
    954 ( 21.3 )
    1510 ( 28.2 )
    2690 ( 27.4 )
    1060 ( 28.0 )
    1650 ( 30.6 )
    Notes
    [12] - Number of subjects was 33 as GlucaGen 1.0 mg data available for Groups 1, 3 and 4 were pooled
    Statistical analysis title
    		 0.3mg dasiglucagon vs 0.5mg Glucagen
    Statistical analysis description
    Analysis of variance (ANOVA) with log-transformed response, treatment, period, sequence and patient within sequence as fixed effect. The ratio of geometric LS-means of treatments (ZP4207/GlucaGen) is presented within each group. Please note that the results are of an exploratory nature since there was no formal sample size calculation and no H0-hypothesis was defined.
    Comparison groups
    Group 2 0.3 mg dasiglucagon v Group 2 0.5 mg GlucaGen
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [13]
    P-value
    		 = 0.1217
    Method
    		 ANOVA
    Parameter type
    		 least squares mean ratio
    Point estimate
    0.907
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.8167
         upper limit
    		 1.0068
    Notes
    [13] - Treatments may be described as comparable if the 90% CI of the respective ratio was within the interval of 0.8-1.25. A formal test of equivalence was not performed, the p-value is from an exploratory superiority test. 17 subjects were included in the analysis: 16 received dasiglucagon and 17 received GlucaGen. The group had a crossover design.
    Statistical analysis title
    		 0.6mg dasiglucagon vs 1.0mg Glucagen
    Statistical analysis description
    Analysis of variance (ANOVA) with log-transformed response, treatment, period, sequence and patient within sequence as fixed effect. The ratio of geometric LS-means of treatments (ZP4207/GlucaGen) is presented within each group. Please note that the results are of an exploratory nature since there was no formal sample size calculation and no H0-hypothesis was defined.
    Comparison groups
    Group 3 0.6 mg dasiglucagon v Group 3 1.0 mg GlucaGen
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [14]
    P-value
    		 = 0.7359
    Method
    		 ANOVA
    Parameter type
    		 least squares mean ratio
    Point estimate
    1.03
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.885
         upper limit
    		 1.1991
    Notes
    [14] - Treatments may be described as comparable if the 90% CI of the respective ratio was within the interval of 0.8-1.25. A formal test of equivalence was not performed, the p-value is from an exploratory superiority test. 16 subjects were included in the analysis: 16 received dasiglucagon and 16 received GlucaGen. The group had a crossover design.
    Statistical analysis title
    		 1.0mg dasiglucagon vs 1.0mg Glucagen
    Statistical analysis description
    Analysis of variance (ANOVA) with log-transformed response, treatment, period, sequence and patient within sequence as fixed effect. The ratio of geometric LS-means of treatments (ZP4207/GlucaGen) is presented within each group. Please note that the results are of an exploratory nature since there was no formal sample size calculation and no H0-hypothesis was defined.
    Comparison groups
    Group 3 1.0 mg GlucaGen v Group 4 1.0 mg dasiglucagon
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [15]
    P-value
    		 = 0.0002
    Method
    		 ANOVA
    Parameter type
    		 least squares mean ratio
    Point estimate
    1.44
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.2679
         upper limit
    		 1.6332
    Notes
    [15] - Treatments may be described as comparable if the 90% CI of the respective ratio was within the interval of 0.8-1.25. A formal test of equivalence was not performed, the p-value is from an exploratory superiority test. This was actually a comparison of Group 4 1.0 mg dasiglucagon and Group 4 1.0 mg GlucaGen. Number of subjects in this analysis was 16 (16 received dasiglucagon and 15 received GlucaGen). The group had a crossover design.

    Primary: Tmax

    		 Close Top of page
    End point title
    		 Tmax [16]
    End point description
    Time to maximum of plasma dasiglucagon or GlucaGen concentration measurements. The GlucaGen endpoints are displayed as derived from baseline-adjusted profiles.
    End point type
    Primary
    End point timeframe
    0-360 min post dose
    Notes
    [16] - 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: GlucaGen 1.0 mg data available for Groups 1, 3 and 4 were pooled
    End point values
    		 Group 1 0.1 mg dasiglucagon Group 2 0.3 mg dasiglucagon Group 3 0.6 mg dasiglucagon Group 4 1.0 mg dasiglucagon Group 2 0.5 mg GlucaGen Group 3 1.0 mg GlucaGen
    Number of subjects analysed
    5
    16
    16
    16
    17
    16 [17]
    Units: hours
        median (full range (min-max))
    0.500 (0.500 to 0.583)
    0.625 (0.333 to 0.833)
    0.583 (0.500 to 1.67)
    0.625 (0.333 to 0.833)
    0.250 (0.167 to 0.583)
    0.333 (0.167 to 0.833)
    Notes
    [17] - Number of subjects was 33 as GlucaGen 1.0 mg data available for Groups 1, 3 and 4 were pooled
    Statistical analysis title
    		 0.3mg dasiglucagon vs 0.5mg Glucagen
    Statistical analysis description
    As tmax was a discontinuous parameter, it was analysed using Wilcoxon’s Signed Rank test for paired observations within each group in a non-parametric analysis. Point estimates of median differences between treatments were determined according to Hodges and Lehmann, together with the corresponding 90% confidence intervals. Please note that the results are of an exploratory nature since there was no formal sample size calculation and no H0-hypothesis was defined.
    Comparison groups
    Group 2 0.5 mg GlucaGen v Group 2 0.3 mg dasiglucagon
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [18]
    P-value
    		 = 0.0009
    Method
    		 Wilcoxon’s Signed Rank test
    Parameter type
    		 Median difference (final values)
    Point estimate
    0.25
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.1667
         upper limit
    		 0.4167
    Notes
    [18] - Treatments may be described as comparable if the 90% CI of the respective ratio was within the interval of 0.8-1.25. A formal test of equivalence was not performed, the p-value is from an exploratory superiority test. 17 subjects were included in the analysis: 16 received dasiglucagon and 17 received GlucaGen. The group had a crossover design.
    Statistical analysis title
    		 0.6mg dasiglucagon vs 1.0mg Glucagen
    Statistical analysis description
    As tmax was a discontinuous parameter, it was analysed using Wilcoxon’s Signed Rank test for paired observations within each group in a non-parametric analysis. Point estimates of median differences between treatments were determined according to Hodges and Lehmann, together with the corresponding 90% confidence intervals. Please note that the results are of an exploratory nature since there was no formal sample size calculation and no H0-hypothesis was defined.
    Comparison groups
    Group 3 0.6 mg dasiglucagon v Group 3 1.0 mg GlucaGen
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [19]
    P-value
    		 < 0.0001
    Method
    		 Wilcoxon’s Signed Rank test
    Parameter type
    		 Median difference (final values)
    Point estimate
    0.333
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.25
         upper limit
    		 0.5
    Notes
    [19] - Treatments may be described as comparable if the 90% CI of the respective ratio was within the interval of 0.8-1.25. A formal test of equivalence was not performed, the p-value is from an exploratory superiority test. 16 subjects were included in the analysis: 16 received dasiglucagon and 16 received GlucaGen. The group had a crossover design.
    Statistical analysis title
    		 1.0mg dasiglucagon vs 1.0mg Glucagen
    Statistical analysis description
    As tmax was a discontinuous parameter, it was analysed using Wilcoxon’s Signed Rank test for paired observations within each group in a non-parametric analysis. Point estimates of median differences between treatments were determined according to Hodges and Lehmann, together with the corresponding 90% confidence intervals. Please note that the results are of an exploratory nature since there was no formal sample size calculation and no H0-hypothesis was defined.
    Comparison groups
    Group 3 1.0 mg GlucaGen v Group 4 1.0 mg dasiglucagon
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [20]
    P-value
    		 = 0.002
    Method
    		 Wilcoxon’s Signed Rank test
    Parameter type
    		 Median difference (final values)
    Point estimate
    0.25
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.1667
         upper limit
    		 0.3333
    Notes
    [20] - Treatments may be described as comparable if the 90% CI of the respective ratio was within the interval of 0.8-1.25. A formal test of equivalence was not performed, the p-value is from an exploratory superiority test. This was actually a comparison of Group 4 1.0 mg dasiglucagon and Group 4 1.0 mg GlucaGen. Number of subjects in this analysis was 16 (16 received dasiglucagon and 15 received GlucaGen). The group had a crossover design.

    Primary: λz

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    End point title
    		 λz [21] [22]
    End point description
    Terminal elimination rate constant of plasma dasiglucagon or GlucaGen. The GlucaGen endpoints are displayed as derived from baseline-adjusted profiles.
    End point type
    Primary
    End point timeframe
    0-360 min post dose
    Notes
    [21] - 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: As there were multiple primary PK endpoints, λz was analysed using summary statistics by treatment and dose. No ANOVA was performed.
    [22] - 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: GlucaGen 1.0 mg data available for Groups 1, 3 and 4 were pooled
    End point values
    		 Group 1 0.1 mg dasiglucagon Group 2 0.3 mg dasiglucagon Group 3 0.6 mg dasiglucagon Group 4 1.0 mg dasiglucagon Group 2 0.5 mg GlucaGen Group 3 1.0 mg GlucaGen
    Number of subjects analysed
    5
    16
    16
    16
    17
    16 [23]
    Units: h-1
        geometric mean (geometric coefficient of variation)
    1.63 ( 19.6 )
    1.64 ( 18.5 )
    1.46 ( 22.2 )
    1.35 ( 30.0 )
    1.90 ( 19.2 )
    1.73 ( 26.9 )
    Notes
    [23] - Number of subjects was 33 as GlucaGen 1.0 mg data available for Groups 1, 3 and 4 were pooled
    No statistical analyses for this end point

    Primary: T½

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    End point title
    		 T½ [24] [25]
    End point description
    Terminal plasma elimination half-life of dasiglucagon or GlucaGen. The GlucaGen endpoints are displayed as derived from baseline-adjusted profiles.
    End point type
    Primary
    End point timeframe
    0-360 min post dose
    Notes
    [24] - 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: As there were multiple primary PK endpoints, T½ was analysed using summary statistics by treatment and dose. No ANOVA was performed.
    [25] - 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: GlucaGen 1.0 mg data available for Groups 1, 3 and 4 were pooled
    End point values
    		 Group 1 0.1 mg dasiglucagon Group 2 0.3 mg dasiglucagon Group 3 0.6 mg dasiglucagon Group 4 1.0 mg dasiglucagon Group 2 0.5 mg GlucaGen Group 3 1.0 mg GlucaGen
    Number of subjects analysed
    5
    16
    16
    16
    17
    16 [26]
    Units: hours
        geometric mean (geometric coefficient of variation)
    0.424 ( 20.3 )
    0.423 ( 16.9 )
    0.475 ( 27.7 )
    0.515 ( 31.4 )
    0.364 ( 18.4 )
    0.401 ( 31.4 )
    Notes
    [26] - Number of subjects was 33 as GlucaGen 1.0 mg data available for Groups 1, 3 and 4 were pooled
    No statistical analyses for this end point

    Primary: CL/f

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    End point title
    		 CL/f [27] [28]
    End point description
    Total body clearance of plasma dasiglucagon or GlucaGen. The GlucaGen endpoints are displayed as derived from baseline-adjusted profiles.
    End point type
    Primary
    End point timeframe
    0-360 min post dose
    Notes
    [27] - 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: As there were multiple primary PK endpoints, CL/f was analysed using summary statistics by treatment and dose. No ANOVA was performed.
    [28] - 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: GlucaGen 1.0 mg data available for Groups 1, 3 and 4 were pooled
    End point values
    		 Group 1 0.1 mg dasiglucagon Group 2 0.3 mg dasiglucagon Group 3 0.6 mg dasiglucagon Group 4 1.0 mg dasiglucagon Group 2 0.5 mg GlucaGen Group 3 1.0 mg GlucaGen
    Number of subjects analysed
    5
    16
    16
    16
    17
    16 [29]
    Units: L/h
        geometric mean (geometric coefficient of variation)
    67.8 ( 30.0 )
    65.6 ( 12.0 )
    68.0 ( 14.8 )
    62.2 ( 16.7 )
    163 ( 17.4 )
    180 ( 22.9 )
    Notes
    [29] - Number of subjects was 33 as GlucaGen 1.0 mg data available for Groups 1, 3 and 4 were pooled
    No statistical analyses for this end point

    Primary: Vz/f

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    End point title
    		 Vz/f [30] [31]
    End point description
    Volume of distribution of plasma dasiglucagon or GlucaGen. The GlucaGen endpoints are displayed as derived from baseline-adjusted profiles.
    End point type
    Primary
    End point timeframe
    0-360 min post dose
    Notes
    [30] - 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: As there were multiple primary PK endpoints, Vz/f was analysed using summary statistics by treatment and dose. No ANOVA was performed.
    [31] - 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: GlucaGen 1.0 mg data available for Groups 1, 3 and 4 were pooled
    End point values
    		 Group 1 0.1 mg dasiglucagon Group 2 0.3 mg dasiglucagon Group 3 0.6 mg dasiglucagon Group 4 1.0 mg dasiglucagon Group 2 0.5 mg GlucaGen Group 3 1.0 mg GlucaGen
    Number of subjects analysed
    5
    16
    16
    16
    17
    16 [32]
    Units: Litres
        geometric mean (geometric coefficient of variation)
    41.5 ( 41.8 )
    40.1 ( 21.2 )
    46.6 ( 39.5 )
    46.2 ( 36.6 )
    85.5 ( 26.6 )
    104 ( 38.0 )
    Notes
    [32] - Number of subjects was 33 as GlucaGen 1.0 mg data available for Groups 1, 3 and 4 were pooled
    No statistical analyses for this end point

    Primary: MRT

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    End point title
    		 MRT [33] [34]
    End point description
    Mean residence time of plasma dasiglucagon or GlucaGen. The GlucaGen endpoints are displayed as derived from baseline-adjusted profiles.
    End point type
    Primary
    End point timeframe
    0-360 min post dose
    Notes
    [33] - 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: As there were multiple primary PK endpoints, MRT was analysed using summary statistics by treatment and dose. No ANOVA was performed.
    [34] - 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: GlucaGen 1.0 mg data available for Groups 1, 3 and 4 were pooled
    End point values
    		 Group 1 0.1 mg dasiglucagon Group 2 0.3 mg dasiglucagon Group 3 0.6 mg dasiglucagon Group 4 1.0 mg dasiglucagon Group 2 0.5 mg GlucaGen Group 3 1.0 mg GlucaGen
    Number of subjects analysed
    5
    16
    16
    16
    17
    16 [35]
    Units: Hours
        geometric mean (geometric coefficient of variation)
    1.05 ( 12.2 )
    1.07 ( 14.1 )
    1.29 ( 23.6 )
    1.29 ( 21.5 )
    0.739 ( 13.9 )
    0.827 ( 20.4 )
    Notes
    [35] - Number of subjects was 33 as GlucaGen 1.0 mg data available for Groups 1, 3 and 4 were pooled
    No statistical analyses for this end point

    Primary: AUE0-30min

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    End point title
    		 AUE0-30min [36]
    End point description
    Area under the plasma glucose concentration vs. time curve from 0 to 30 min post-dose above baseline
    End point type
    Primary
    End point timeframe
    0-30 min post dose
    Notes
    [36] - 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: GlucaGen 1.0 mg data available for Groups 1, 3 and 4 were pooled
    End point values
    		 Group 1 0.1 mg dasiglucagon Group 2 0.3 mg dasiglucagon Group 3 0.6 mg dasiglucagon Group 4 1.0 mg dasiglucagon Group 2 0.5 mg GlucaGen Group 3 1.0 mg GlucaGen
    Number of subjects analysed
    5
    16
    17
    16
    17
    16 [37]
    Units: mg*h/dL
        arithmetic mean (standard deviation)
    12.9 ( 5.21 )
    20.9 ( 6.13 )
    21.1 ( 6.10 )
    24.1 ( 5.18 )
    22.1 ( 5.48 )
    21.9 ( 5.74 )
    Notes
    [37] - Number of subjects was 33 as GlucaGen 1.0 mg data available for Groups 1, 3 and 4 were pooled
    Statistical analysis title
    		 0.3mg dasiglucagon vs 0.5mg Glucagen
    Statistical analysis description
    Analysis of variance (ANOVA) with log-transformed response, treatment, period, sequence and patient within sequence as fixed effect. The ratio of geometric LS-means of treatments (ZP4207/GlucaGen) is presented within each group. Please note that the results are of an exploratory nature since there was no formal sample size calculation and no H0-hypothesis was defined.
    Comparison groups
    Group 2 0.3 mg dasiglucagon v Group 2 0.5 mg GlucaGen
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [38]
    P-value
    		 = 0.4396
    Method
    		 ANOVA
    Parameter type
    		 least squares mean ratio
    Point estimate
    0.934
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.8042
         upper limit
    		 1.0858
    Notes
    [38] - Treatments may be described as comparable if the 90% CI of the respective ratio was within the interval of 0.8-1.25. A formal test of equivalence was not performed, the p-value is from an exploratory superiority test. 17 subjects were included in the analysis: 16 received dasiglucagon and 17 received GlucaGen. The group had a crossover design.
    Statistical analysis title
    		 0.6mg dasiglucagon vs 1.0mg Glucagen
    Statistical analysis description
    Analysis of variance (ANOVA) with log-transformed response, treatment, period, sequence and patient within sequence as fixed effect. The ratio of geometric LS-means of treatments (ZP4207/GlucaGen) is presented within each group. Please note that the results are of an exploratory nature since there was no formal sample size calculation and no H0-hypothesis was defined.
    Comparison groups
    Group 3 0.6 mg dasiglucagon v Group 3 1.0 mg GlucaGen
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [39]
    P-value
    		 = 0.596
    Method
    		 ANOVA
    Parameter type
    		 least squares mean ratio
    Point estimate
    0.965
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.8613
         upper limit
    		 1.0822
    Notes
    [39] - Treatments may be described as comparable if the 90% CI of the respective ratio was within the interval of 0.8-1.25. A formal test of equivalence was not performed, the p-value is from an exploratory superiority test. 17 subjects were included in the analysis: 17 received dasiglucagon and 16 received GlucaGen. The group had a crossover design.
    Statistical analysis title
    		 1.0mg dasiglucagon vs 1.0mg Glucagen
    Statistical analysis description
    Analysis of variance (ANOVA) with log-transformed response, treatment, period, sequence and patient within sequence as fixed effect. The ratio of geometric LS-means of treatments (ZP4207/GlucaGen) is presented within each group. Please note that the results are of an exploratory nature since there was no formal sample size calculation and no H0-hypothesis was defined.
    Comparison groups
    Group 3 1.0 mg GlucaGen v Group 4 1.0 mg dasiglucagon
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [40]
    P-value
    		 = 0.1507
    Method
    		 ANOVA
    Parameter type
    		 least squares mean ratio
    Point estimate
    1.11
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.9833
         upper limit
    		 1.2556
    Notes
    [40] - Treatments may be described as comparable if the 90% CI of the respective ratio was within the interval of 0.8-1.25. A formal test of equivalence was not performed, the p-value is from an exploratory superiority test. This was actually a comparison of Group 4 1.0 mg dasiglucagon and Group 4 1.0 mg GlucaGen. 16 subjects were included in the analysis: 16 received dasiglucagon and 15 received GlucaGen. The group had a crossover design.

    Primary: AUE

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    End point title
    		 AUE [41]
    End point description
    Area under the plasma glucose concentration vs. time curve from 0 to last available measurement post-dose above baseline
    End point type
    Primary
    End point timeframe
    0-360 min post dose
    Notes
    [41] - 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: GlucaGen 1.0 mg data available for Groups 1, 3 and 4 were pooled
    End point values
    		 Group 1 0.1 mg dasiglucagon Group 2 0.3 mg dasiglucagon Group 3 0.6 mg dasiglucagon Group 4 1.0 mg dasiglucagon Group 2 0.5 mg GlucaGen Group 3 1.0 mg GlucaGen
    Number of subjects analysed
    5
    16
    17
    16
    17
    16 [42]
    Units: mg*h/dL
        arithmetic mean (standard deviation)
    344 ( 149 )
    666 ( 247 )
    788 ( 165 )
    895 ( 213 )
    462 ( 273 )
    566 ( 232 )
    Notes
    [42] - Number of subjects was 33 as GlucaGen 1.0 mg data available for Groups 1, 3 and 4 were pooled
    Statistical analysis title
    		 0.3mg dasiglucagon vs 0.5mg Glucagen
    Statistical analysis description
    Analysis of variance (ANOVA) with log-transformed response, treatment, period, sequence and patient within sequence as fixed effect. The ratio of geometric LS-means of treatments (ZP4207/GlucaGen) is presented within each group. Please note that the results are of an exploratory nature since there was no formal sample size calculation and no H0-hypothesis was defined.
    Comparison groups
    Group 2 0.3 mg dasiglucagon v Group 2 0.5 mg GlucaGen
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [43]
    P-value
    		 < 0.0001
    Method
    		 ANOVA
    Parameter type
    		 least squares mean ratio
    Point estimate
    1.61
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.396
         upper limit
    		 1.8564
    Notes
    [43] - Treatments may be described as comparable if the 90% CI of the respective ratio was within the interval of 0.8-1.25. A formal test of equivalence was not performed, the p-value is from an exploratory superiority test. 17 subjects were included in the analysis: 16 received dasiglucagon and 17 received GlucaGen. The group had a crossover design.
    Statistical analysis title
    		 0.6mg dasiglucagon vs 1.0mg Glucagen
    Statistical analysis description
    Analysis of variance (ANOVA) with log-transformed response, treatment, period, sequence and patient within sequence as fixed effect. The ratio of geometric LS-means of treatments (ZP4207/GlucaGen) is presented within each group. Please note that the results are of an exploratory nature since there was no formal sample size calculation and no H0-hypothesis was defined.
    Comparison groups
    Group 3 0.6 mg dasiglucagon v Group 3 1.0 mg GlucaGen
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [44]
    P-value
    		 = 0.0043
    Method
    		 ANOVA
    Parameter type
    		 least squares mean ratio
    Point estimate
    1.38
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.1676
         upper limit
    		 1.6303
    Notes
    [44] - Treatments may be described as comparable if the 90% CI of the respective ratio was within the interval of 0.8-1.25. A formal test of equivalence was not performed, the p-value is from an exploratory superiority test. 17 subjects were included in the analysis: 17 received dasiglucagon and 16 received GlucaGen. The group had a crossover design.
    Statistical analysis title
    		 1.0mg dasiglucagon vs 1.0mg Glucagen
    Statistical analysis description
    Analysis of variance (ANOVA) with log-transformed response, treatment, period, sequence and patient within sequence as fixed effect. The ratio of geometric LS-means of treatments (ZP4207/GlucaGen) is presented within each group. Please note that the results are of an exploratory nature since there was no formal sample size calculation and no H0-hypothesis was defined.
    Comparison groups
    Group 3 1.0 mg GlucaGen v Group 4 1.0 mg dasiglucagon
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [45]
    P-value
    		 < 0.0001
    Method
    		 ANOVA
    Parameter type
    		 least squares mean ratio
    Point estimate
    1.77
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.5649
         upper limit
    		 2.0043
    Notes
    [45] - Treatments may be described as comparable if the 90% CI of the respective ratio was within the interval of 0.8-1.25. A formal test of equivalence was not performed, the p-value is from an exploratory superiority test. This was actually a comparison of Group 4 1.0 mg dasiglucagon and Group 4 1.0 mg GlucaGen. 16 subjects were included in the analysis: 16 received dasiglucagon and 15 received GlucaGen. The group had a crossover design.

    Primary: CE30min

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    End point title
    		 CE30min [46]
    End point description
    Plasma glucose concentration at 30 min post-dose above baseline
    End point type
    Primary
    End point timeframe
    0-30 min post dose
    Notes
    [46] - 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: GlucaGen 1.0 mg data available for Groups 1, 3 and 4 were pooled
    End point values
    		 Group 1 0.1 mg dasiglucagon Group 2 0.3 mg dasiglucagon Group 3 0.6 mg dasiglucagon Group 4 1.0 mg dasiglucagon Group 2 0.5 mg GlucaGen Group 3 1.0 mg GlucaGen
    Number of subjects analysed
    5
    16
    17
    16
    17
    16 [47]
    Units: mg/dL
        arithmetic mean (standard deviation)
    66.1 ( 23.8 )
    93.4 ( 23.7 )
    98.2 ( 25.0 )
    100 ( 20.3 )
    93.5 ( 21.4 )
    96.5 ( 21.9 )
    Notes
    [47] - Number of subjects was 33 as GlucaGen 1.0 mg data available for Groups 1, 3 and 4 were pooled
    Statistical analysis title
    		 0.3mg dasiglucagon vs 0.5mg Glucagen
    Statistical analysis description
    Analysis of variance (ANOVA) with log-transformed response, treatment, period, sequence and patient within sequence as fixed effect. The ratio of geometric LS-means of treatments (ZP4207/GlucaGen) is presented within each group. Please note that the results are of an exploratory nature since there was no formal sample size calculation and no H0-hypothesis was defined.
    Comparison groups
    Group 2 0.3 mg dasiglucagon v Group 2 0.5 mg GlucaGen
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [48]
    P-value
    		 = 0.9195
    Method
    		 ANOVA
    Parameter type
    		 least squares mean ratio
    Point estimate
    1.01
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.8933
         upper limit
    		 1.1353
    Notes
    [48] - Treatments may be described as comparable if the 90% CI of the respective ratio was within the interval of 0.8-1.25. A formal test of equivalence was not performed, the p-value is from an exploratory superiority test. 17 subjects were included in the analysis: 16 received dasiglucagon and 17 received GlucaGen. The group had a crossover design.
    Statistical analysis title
    		 0.6mg dasiglucagon vs 1.0mg Glucagen
    Statistical analysis description
    Analysis of variance (ANOVA) with log-transformed response, treatment, period, sequence and patient within sequence as fixed effect. The ratio of geometric LS-means of treatments (ZP4207/GlucaGen) is presented within each group. Please note that the results are of an exploratory nature since there was no formal sample size calculation and no H0-hypothesis was defined.
    Comparison groups
    Group 3 0.6 mg dasiglucagon v Group 3 1.0 mg GlucaGen
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [49]
    P-value
    		 = 0.8449
    Method
    		 ANOVA
    Parameter type
    		 least squares mean ratio
    Point estimate
    1.01
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.9255
         upper limit
    		 1.102
    Notes
    [49] - Treatments may be described as comparable if the 90% CI of the respective ratio was within the interval of 0.8-1.25. A formal test of equivalence was not performed, the p-value is from an exploratory superiority test. 17 subjects were included in the analysis: 17 received dasiglucagon and 16 received GlucaGen. The group had a crossover design.
    Statistical analysis title
    		 1.0mg dasiglucagon vs 1.0mg Glucagen
    Statistical analysis description
    Analysis of variance (ANOVA) with log-transformed response, treatment, period, sequence and patient within sequence as fixed effect. The ratio of geometric LS-means of treatments (ZP4207/GlucaGen) is presented within each group. Please note that the results are of an exploratory nature since there was no formal sample size calculation and no H0-hypothesis was defined.
    Comparison groups
    Group 3 1.0 mg GlucaGen v Group 4 1.0 mg dasiglucagon
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [50]
    P-value
    		 = 0.2366
    Method
    		 ANOVA
    Parameter type
    		 least squares mean ratio
    Point estimate
    1.06
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.9767
         upper limit
    		 1.143
    Notes
    [50] - Treatments may be described as comparable if the 90% CI of the respective ratio was within the interval of 0.8-1.25. A formal test of equivalence was not performed, the p-value is from an exploratory superiority test. This was actually a comparison of Group 4 1.0 mg dasiglucagon and Group 4 1.0 mg GlucaGen. 16 subjects were included in the analysis: 16 received dasiglucagon and 15 received GlucaGen. The group had a crossover design.

    Primary: CE

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    End point title
    		 CE [51]
    End point description
    Maximum of all valid plasma glucose concentration measurements from 0 to 360 min post-dose above baseline
    End point type
    Primary
    End point timeframe
    0-360 min post dose
    Notes
    [51] - 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: GlucaGen 1.0 mg data available for Groups 1, 3 and 4 were pooled
    End point values
    		 Group 1 0.1 mg dasiglucagon Group 2 0.3 mg dasiglucagon Group 3 0.6 mg dasiglucagon Group 4 1.0 mg dasiglucagon Group 2 0.5 mg GlucaGen Group 3 1.0 mg GlucaGen
    Number of subjects analysed
    5
    16
    17
    16
    17
    16 [52]
    Units: mg/dL
        arithmetic mean (standard deviation)
    102 ( 33.7 )
    174 ( 44.6 )
    190 ( 32.2 )
    209 ( 40.2 )
    142 ( 42.6 )
    166 ( 42.5 )
    Notes
    [52] - Number of subjects was 33 as GlucaGen 1.0 mg data available for Groups 1, 3 and 4 were pooled
    Statistical analysis title
    		 0.3mg dasiglucagon vs 0.5mg Glucagen
    Statistical analysis description
    Analysis of variance (ANOVA) with log-transformed response, treatment, period, sequence and patient within sequence as fixed effect. The ratio of geometric LS-means of treatments (ZP4207/GlucaGen) is presented within each group. Please note that the results are of an exploratory nature since there was no formal sample size calculation and no H0-hypothesis was defined.
    Comparison groups
    Group 2 0.3 mg dasiglucagon v Group 2 0.5 mg GlucaGen
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [53]
    P-value
    		 < 0.0001
    Method
    		 ANOVA
    Parameter type
    		 least squares mean ratio
    Point estimate
    1.24
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.1604
         upper limit
    		 1.3242
    Notes
    [53] - Treatments may be described as comparable if the 90% CI of the respective ratio was within the interval of 0.8-1.25. A formal test of equivalence was not performed, the p-value is from an exploratory superiority test. 17 subjects were included in the analysis: 16 received dasiglucagon and 17 received GlucaGen. The group had a crossover design.
    Statistical analysis title
    		 0.6mg dasiglucagon vs 1.0mg Glucagen
    Statistical analysis description
    Analysis of variance (ANOVA) with log-transformed response, treatment, period, sequence and patient within sequence as fixed effect. The ratio of geometric LS-means of treatments (ZP4207/GlucaGen) is presented within each group. Please note that the results are of an exploratory nature since there was no formal sample size calculation and no H0-hypothesis was defined.
    Comparison groups
    Group 3 0.6 mg dasiglucagon v Group 3 1.0 mg GlucaGen
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [54]
    P-value
    		 = 0.0305
    Method
    		 ANOVA
    Parameter type
    		 least squares mean ratio
    Point estimate
    1.14
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.0353
         upper limit
    		 1.2513
    Notes
    [54] - Treatments may be described as comparable if the 90% CI of the respective ratio was within the interval of 0.8-1.25. A formal test of equivalence was not performed, the p-value is from an exploratory superiority test. 17 subjects were included in the analysis: 17 received dasiglucagon and 16 received GlucaGen. The group had a crossover design.
    Statistical analysis title
    		 1.0mg dasiglucagon vs 1.0mg Glucagen
    Statistical analysis description
    Analysis of variance (ANOVA) with log-transformed response, treatment, period, sequence and patient within sequence as fixed effect. The ratio of geometric LS-means of treatments (ZP4207/GlucaGen) is presented within each group. Please note that the results are of an exploratory nature since there was no formal sample size calculation and no H0-hypothesis was defined.
    Comparison groups
    Group 3 1.0 mg GlucaGen v Group 4 1.0 mg dasiglucagon
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [55]
    P-value
    		 < 0.0001
    Method
    		 ANOVA
    Parameter type
    		 least squares mean ratio
    Point estimate
    1.32
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.2174
         upper limit
    		 1.4271
    Notes
    [55] - Treatments may be described as comparable if the 90% CI of the respective ratio was within the interval of 0.8-1.25. A formal test of equivalence was not performed, the p-value is from an exploratory superiority test. This was actually a comparison of Group 4 1.0 mg dasiglucagon and Group 4 1.0 mg GlucaGen. 16 subjects were included in the analysis: 16 received dasiglucagon and 15 received GlucaGen. The group had a crossover design.

    Primary: Glucose tmax

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    End point title
    		 Glucose tmax [56]
    End point description
    Time to maximum of plasma glucose concentration measurements
    End point type
    Primary
    End point timeframe
    0-360 min post dose
    Notes
    [56] - 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: GlucaGen 1.0 mg data available for Groups 1, 3 and 4 were pooled
    End point values
    		 Group 1 0.1 mg dasiglucagon Group 2 0.3 mg dasiglucagon Group 3 0.6 mg dasiglucagon Group 4 1.0 mg dasiglucagon Group 2 0.5 mg GlucaGen Group 3 1.0 mg GlucaGen
    Number of subjects analysed
    5
    16
    17
    16
    17
    16 [57]
    Units: hours
        median (full range (min-max))
    1.25 (0.833 to 1.67)
    1.67 (1.00 to 2.50)
    1.67 (1.67 to 4.33)
    2.50 (1.67 to 2.50)
    1.00 (0.667 to 5.00)
    1.25 (0.833 to 6.12)
    Notes
    [57] - Number of subjects was 33 as GlucaGen 1.0 mg data available for Groups 1, 3 and 4 were pooled
    Statistical analysis title
    		 0.3mg dasiglucagon vs 0.5mg Glucagen
    Statistical analysis description
    As glucose tmax was a discontinuous parameter, it was analysed using Wilcoxon’s Signed Rank test for paired observations within each group in a non-parametric analysis. Point estimates of median differences between treatments were determined according to Hodges and Lehmann, together with the corresponding 90% confidence intervals. Please note that the results are of an exploratory nature since there was no formal sample size calculation and no H0-hypothesis was defined.
    Comparison groups
    Group 2 0.3 mg dasiglucagon v Group 2 0.5 mg GlucaGen
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [58]
    P-value
    		 = 0.0085
    Method
    		 Wilcoxon’s Signed Rank test
    Parameter type
    		 Median difference (final values)
    Point estimate
    0.667
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.4167
         upper limit
    		 0.667
    Notes
    [58] - Treatments may be described as comparable if the 90% CI of the respective ratio was within the interval of 0.8-1.25. A formal test of equivalence was not performed, the p-value is from an exploratory superiority test. 17 subjects were included in the analysis: 16 received dasiglucagon and 17 received GlucaGen. The group had a crossover design.
    Statistical analysis title
    		 0.6mg dasiglucagon vs 1.0mg Glucagen
    Statistical analysis description
    As glucose tmax was a discontinuous parameter, it was analysed using Wilcoxon’s Signed Rank test for paired observations within each group in a non-parametric analysis. Point estimates of median differences between treatments were determined according to Hodges and Lehmann, together with the corresponding 90% confidence intervals. Please note that the results are of an exploratory nature since there was no formal sample size calculation and no H0-hypothesis was defined.
    Comparison groups
    Group 3 0.6 mg dasiglucagon v Group 3 1.0 mg GlucaGen
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [59]
    P-value
    		 = 0.0508
    Method
    		 Wilcoxon’s Signed Rank test
    Parameter type
    		 Median difference (final values)
    Point estimate
    0.417
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.4167
         upper limit
    		 0.8333
    Notes
    [59] - Treatments may be described as comparable if the 90% CI of the respective ratio was within the interval of 0.8-1.25. A formal test of equivalence was not performed, the p-value is from an exploratory superiority test. 17 subjects were included in the analysis: 17 received dasiglucagon and 16 received GlucaGen. The group had a crossover design.
    Statistical analysis title
    		 1.0mg dasiglucagon vs 1.0mg Glucagen
    Statistical analysis description
    As glucose tmax was a discontinuous parameter, it was analysed using Wilcoxon’s Signed Rank test for paired observations within each group in a non-parametric analysis. Point estimates of median differences between treatments were determined according to Hodges and Lehmann, together with the corresponding 90% confidence intervals. Please note that the results are of an exploratory nature since there was no formal sample size calculation and no H0-hypothesis was defined.
    Comparison groups
    Group 3 1.0 mg GlucaGen v Group 4 1.0 mg dasiglucagon
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [60]
    P-value
    		 < 0.0001
    Method
    		 Wilcoxon’s Signed Rank test
    Parameter type
    		 Median difference (final values)
    Point estimate
    1.04
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.8333
         upper limit
    		 1.25
    Notes
    [60] - Treatments may be described as comparable if the 90% CI of the respective ratio was within the interval of 0.8-1.25. A formal test of equivalence was not performed, the p-value is from an exploratory superiority test. This was actually a comparison of Group 4 1.0 mg dasiglucagon and Group 4 1.0 mg GlucaGen. 16 subjects were included in the analysis: 16 received dasiglucagon and 15 received GlucaGen. The group had a crossover design.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from the time of the first trial related activity after the patient signed the informed consent until the follow-up visit at end of trial. Reporting will be on treatment emergent adverse events only.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    0.1 mg dasiglucagon
    Reporting group description
    		 0.1 mg dasiglucagon

    Reporting group title
    0.3 mg dasiglucagon
    Reporting group description
    		 0.3 mg dasiglucagon

    Reporting group title
    0.6 mg dasiglucagon
    Reporting group description
    		 0.6 mg dasiglucagon

    Reporting group title
    1.0 mg dasiglucagon
    Reporting group description
    		 1.0 mg dasiglucagon

    Reporting group title
    0.5 mg GlucaGen
    Reporting group description
    		 0.5 mg GlucaGen

    Reporting group title
    1.0 mg GlucaGen
    Reporting group description
    		 1.0 mg GlucaGen

    Serious adverse events
    		 0.1 mg dasiglucagon 0.3 mg dasiglucagon 0.6 mg dasiglucagon 1.0 mg dasiglucagon 0.5 mg GlucaGen 1.0 mg GlucaGen
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 34 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 0.1 mg dasiglucagon 0.3 mg dasiglucagon 0.6 mg dasiglucagon 1.0 mg dasiglucagon 0.5 mg GlucaGen 1.0 mg GlucaGen
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 6 (66.67%)
    10 / 16 (62.50%)
    11 / 17 (64.71%)
    11 / 16 (68.75%)
    10 / 17 (58.82%)
    23 / 34 (67.65%)
    Vascular disorders
    Cardiovascular insufficiency
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Orthostatic intolerance
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Head discomfort
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Headache
         subjects affected / exposed
    3 / 6 (50.00%)
    6 / 16 (37.50%)
    5 / 17 (29.41%)
    5 / 16 (31.25%)
    1 / 17 (5.88%)
    7 / 34 (20.59%)
         occurrences all number
    3
    8
    6
    5
    1
    7
    Vertigo
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    2 / 17 (11.76%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    2
    0
    0
    1
    General disorders and administration site conditions
    Burning sensation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Fatigue
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Feeling hot
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Hyperhidrosis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Injection site erythema
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    1
    1
    0
    1
    0
    1
    Injection site oedema
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    2 / 16 (12.50%)
    0 / 17 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    0
    0
    1
    2
    0
    2
    Injection site pruritus
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    Injection site urticaria
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Mucosal erosion
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Abdominal pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Dysgeusia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Flatulence
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Nausea
         subjects affected / exposed
    1 / 6 (16.67%)
    9 / 16 (56.25%)
    9 / 17 (52.94%)
    7 / 16 (43.75%)
    9 / 17 (52.94%)
    18 / 34 (52.94%)
         occurrences all number
    1
    9
    9
    7
    9
    18
    Vomiting
         subjects affected / exposed
    0 / 6 (0.00%)
    6 / 16 (37.50%)
    6 / 17 (35.29%)
    2 / 16 (12.50%)
    4 / 17 (23.53%)
    4 / 34 (11.76%)
         occurrences all number
    0
    6
    6
    2
    5
    4
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Endocrine disorders
    Hypoglycaemia
    Additional description: The values reported exclude hypoglycemia events from the start of insulin-induced hypoglycmic procedure up to dosing.
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    2 / 16 (12.50%)
    3 / 17 (17.65%)
    5 / 34 (14.71%)
         occurrences all number
    2
    0
    1
    2
    3
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Jan 2016
    Administrative changes and minor clarifcations

    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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    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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