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    Clinical Trial Results:
    A phase 3, randomized, double-blind, placebo- and active-controlled, parallel-arm trial to assess the efficacy, safety, and pharmacokinetics of dasiglucagon relative to placebo and GlucaGen® when administered as a rescue therapy for severe hypoglycemia in children with T1DM treated with insulin

    Summary
    EudraCT number
    		 2018-000892-33
    Trial protocol
    		 DE   SI  
    Global end of trial date
    28 Jun 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Apr 2020
    First version publication date
    04 Apr 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ZP4207-17086
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03667053
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Zealand Pharma A/S
    Sponsor organisation address
    Sydmarken 11, Søborg, Denmark, 2860
    Public contact
    Dorte Skydsgaard, Zealand Pharma A/S, +45 5060 3767, dsk@zealandpharma.com
    Scientific contact
    Ramin Tehranchi, Zealand Pharma A/S, +45 5060 3793, rte@zealandpharma.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-002233-PIP01-17
    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
    17 Dec 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Jun 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Jun 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to demonstrate that dasiglucagon is superior to placebo following a single injection of 0.6 mg of dasiglucagon in treating hypoglycemia in children with type 1 diabetes mellitus (T1DM).
    Protection of trial subjects
    The trial was conducted in accordance of the World Medical Association Declaration of Helsinki, current guidelines for GCP and local regulations.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 Sep 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Slovenia: 11
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    United States: 29
    Worldwide total number of subjects
    42
    EEA total number of subjects
    13
    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)
    16
    Adolescents (12-17 years)
    26
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The patients were recruited from five trial centers; 3 in the US and one each in Slovenia and Germany.

    Pre-assignment
    Screening details
    		 A total of 59 patients were screened of which 42 patients were randomized.

    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, Data analyst
    Blinding implementation details
    The subjects were randomized 2:1:1 and stratified by age intervals: 6 to <12 years, and 12 to <18 years to receive dasiglucagon, placebo, or GlucaGen. In Germany a staggered approach was used. A positive safety assessment was needed for at least 10 patients in the older age group (overall) before younger patients were allowed to be enrolled. Since the products were not identical in appearance, unblinded trial personnel were responsible for the handling, preparation and administration of IMP.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Dasiglucagon
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    dasiglucagon
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    A single dose of 0.6 mg dasiglucagon (0.6 mL).

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    A single dose of placebo (0.6 mL).

    Arm title
    		 GlucaGen
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    GlucaGen
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    A single dose of 1mg Glucagen (1mL). A half dose was recommended for children below 25kg.

    Number of subjects in period 1
    		Dasiglucagon Placebo GlucaGen
    Started
    21
    11
    10
    Treated
    20
    11
    10
    Completed
    20
    11
    10
    Not completed
    1
    0
    0
         Consent withdrawn by subject
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Dasiglucagon
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    GlucaGen
    Reporting group description
    		 -

    Reporting group values
    		 Dasiglucagon Placebo GlucaGen Total
    Number of subjects
    		 21 11 10 42
    Age categorical
    Units: Subjects
        Children (2-11 years)
    		 8 4 4 16
        Adolescents (12-17 years)
    		 13 7 6 26
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 12.3 ( 3.42 ) 12.8 ( 3.25 ) 12.4 ( 3.50 ) -
    Gender categorical
    Units: Subjects
        Female
    		 10 6 2 18
        Male
    		 11 5 8 24
    Race
    Units: Subjects
        White
    		 20 10 10 40
        Other
    		 1 0 0 1
        Missing
    		 0 1 0 1
    Height
    Units: centimeter(s)
        arithmetic mean (standard deviation)
    		 154.6 ( 18.32 ) 161.1 ( 19.45 ) 158.5 ( 20.10 ) -
    Weight
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    		 51.54 ( 22.202 ) 54.95 ( 21.404 ) 48.81 ( 14.992 ) -
    BMI
    Units: kilogram(s)/square meter
        arithmetic mean (standard deviation)
    		 20.74 ( 6.057 ) 20.39 ( 4.885 ) 18.92 ( 2.617 ) -
    Subject analysis sets

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All patients of the safety analysis set. Treatment assignment was based on the randomized treatment. Assignment to the stratification factor injection site was based on the planned and not the actual used injection site.

    Subject analysis set title
    Safety analysis set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All patients who were randomized and received at least 1 dose of IMP. Treatment assignment was based on the treatment actually received.

    Subject analysis sets values
    		 Full analysis set Safety analysis set
    Number of subjects
    41
    41
    Age categorical
    Units: Subjects
        Children (2-11 years)
    16
    16
        Adolescents (12-17 years)
    25
    25
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    12.5 ( 3.32 )
    12.5 ( 3.32 )
    Gender categorical
    Units: Subjects
        Female
    18
    18
        Male
    23
    23
    Race
    Units: Subjects
        White
    39
    39
        Other
    1
    1
        Missing
    1
    1
    Height
    Units: centimeter(s)
        arithmetic mean (standard deviation)
    157.3 ( 18.78 )
    157.3 ( 18.78 )
    Weight
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    51.79 ( 20.106 )
    51.79 ( 20.106 )
    BMI
    Units: kilogram(s)/square meter
        arithmetic mean (standard deviation)
    20.20 ( 5.050 )
    20.20 ( 5.050 )

    End points

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    End points reporting groups
    Reporting group title
    Dasiglucagon
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    GlucaGen
    Reporting group description
    		 -

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All patients of the safety analysis set. Treatment assignment was based on the randomized treatment. Assignment to the stratification factor injection site was based on the planned and not the actual used injection site.

    Subject analysis set title
    Safety analysis set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All patients who were randomized and received at least 1 dose of IMP. Treatment assignment was based on the treatment actually received.

    Primary: Time to plasma glucose recovery

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    End point title
    		 Time to plasma glucose recovery
    End point description
    Plasma glucose recovery was defined as first increase in plasma glucose of ≥20 mg/dL (1.1 mmol/L) from baseline without administration of rescue IV glucose. Patients who received rescue IV glucose before 45 minutes and patients not recovering within 45 minutes after dosing were censored at 45 minutes.
    End point type
    Primary
    End point timeframe
    Time from administration/baseline
    End point values
    		 Dasiglucagon Placebo GlucaGen
    Number of subjects analysed
    20
    11 [1]
    10
    Units: minute
        median (confidence interval 95%)
    10.00 (8.00 to 12.00)
    30.00 (20.00 to 45)
    10.00 (8.00 to 12.00)
    Notes
    [1] - Upper CL for placebo median is set to 45 minutes (censored value)
    Statistical analysis title
    		 log-rank test: Dasiglucagon versus placebo
    Statistical analysis description
    The treatment group difference between dasiglucagon and placebo was evaluated inferentially using a pairwise two-sided log rank test.
    Comparison groups
    Dasiglucagon v Placebo
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Logrank
    Confidence interval

    Secondary: Plasma glucose recovery at defined times

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    End point title
    		 Plasma glucose recovery at defined times
    End point description
    The number of subjects achieving a ≥20 mg/dL (1.1 mmol/L) increase in plasma glucose from baseline within the specified time.
    End point type
    Secondary
    End point timeframe
    time from administration/baseline
    End point values
    		 Dasiglucagon Placebo GlucaGen
    Number of subjects analysed
    20
    11
    10
    Units: subjects
        Glucose recovery at 30 minutes
    20
    6
    10
        Glucose recovery at 20 minutes
    20
    2
    10
        Glucose recovery at 15 minutes
    19
    0
    10
        Glucose recovery at 10 minutes
    13
    0
    6
    Statistical analysis title
    		 Recovery rates of dasiglucagon and placebo
    Statistical analysis description
    The recovery rates of dasiglucagon and placebo were compared at each time point using a Cochran-Mantel-Haenszel test stratified by age group and injection site.
    Comparison groups
    Dasiglucagon v Placebo
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0073 [2]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [2] - p-value = 0.0005 at 10 minutes p-value was <0.0001 at 15 and 20 minutes p-value = 0.0073 at 30 minutes

    Secondary: Plasma Glucose Change from Baseline

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    End point title
    		 Plasma Glucose Change from Baseline
    End point description
    End point type
    Secondary
    End point timeframe
    Time from administration/baseline
    End point values
    		 Dasiglucagon Placebo GlucaGen
    Number of subjects analysed
    20
    11
    10
    Units: mg/dL
    arithmetic mean (standard deviation)
        At 30 minutes
    98.459 ( 19.6527 )
    17.510 ( 15.6313 )
    85.225 ( 12.5052 )
        At 20 minutes
    65.369 ( 15.2461 )
    7.322 ( 13.3543 )
    58.000 ( 10.5297 )
        At 15 minutes
    45.342 ( 15.0860 )
    0.835 ( 11.1276 )
    40.631 ( 9.7317 )
        At 10 minutes
    27.225 ( 13.6768 )
    -3.405 ( 8.0276 )
    20.919 ( 6.7227 )
    Statistical analysis title
    		 Least squares means: Dasiglucagon versus Placebo
    Statistical analysis description
    Change from baseline in plasma glucose at 30, 20, 15, and 10 minutes after IMP injection was calculated using nominal sampling times and analyzed using an analysis of variance model with treatment, age group and injection site for each endpoint.
    Comparison groups
    Dasiglucagon v Placebo
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [3]
    Method
    		 ANOVA
    Confidence interval
    Notes
    [3] - The p-value was <0.0001 at all time points (10, 15, 20 and 30 minutes)

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from the first trial-related activity after the patient had signed the informed consent to the end of the follow-up period.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Age group 6-11 years - Dasiglucagon
    Reporting group description
    		 -

    Reporting group title
    Age group 6-11 years - Placebo
    Reporting group description
    		 -

    Reporting group title
    Age group 6-11 years - GlucaGen
    Reporting group description
    		 -

    Reporting group title
    Age group 12-17 years - Dasiglucagon
    Reporting group description
    		 -

    Reporting group title
    Age group 12-17 years - Placebo
    Reporting group description
    		 -

    Reporting group title
    Age group 12-17 years - Glucagen
    Reporting group description
    		 -

    Serious adverse events
    		 Age group 6-11 years - Dasiglucagon Age group 6-11 years - Placebo Age group 6-11 years - GlucaGen Age group 12-17 years - Dasiglucagon Age group 12-17 years - Placebo Age group 12-17 years - Glucagen
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Age group 6-11 years - Dasiglucagon Age group 6-11 years - Placebo Age group 6-11 years - GlucaGen Age group 12-17 years - Dasiglucagon Age group 12-17 years - Placebo Age group 12-17 years - Glucagen
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 8 (37.50%)
    1 / 4 (25.00%)
    4 / 4 (100.00%)
    12 / 12 (100.00%)
    6 / 7 (85.71%)
    5 / 6 (83.33%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    2 / 12 (16.67%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    2
    1
    0
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    2 / 4 (50.00%)
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    2
    0
    0
    1
    Injection site pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Injection site oedema
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Injection site induration
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Infusion site bruising
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Infusion site pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Thrombocytopenia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 4 (0.00%)
    2 / 4 (50.00%)
    11 / 12 (91.67%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    2
    0
    2
    12
    0
    1
    Vomiting
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    8 / 12 (66.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    1
    11
    0
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Renal and urinary disorders
    Urinary incontinence
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    2 / 12 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    3
    0
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Sinusitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 12 (8.33%)
    4 / 7 (57.14%)
    2 / 6 (33.33%)
         occurrences all number
    1
    0
    0
    1
    16
    2

    More information

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

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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