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    Clinical Trial Results:
    A Two-Period, Open-label Trial Evaluating the Efficacy and Safety of Dasiglucagon for the Treatment of Children with Congenital Hyperinsulinism

    Summary
    EudraCT number
    2017-004547-21
    Trial protocol
    GB   DE  
    Global end of trial date
    05 Oct 2020

    Results information
    Results version number
    v1(current)
    This version publication date
    04 Aug 2021
    First version publication date
    04 Aug 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ZP4207-17109
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03777176
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Zealand Pharma A/S
    Sponsor organisation address
    Sydmarken 11, Søborg, Denmark, 2860
    Public contact
    Sune Birch, Principal Biostatistician, Zealand Pharma A/S, 45 88 77 36 00, SBirch@zealandpharma.com
    Scientific contact
    Sune Birch, Principal Biostatistician, Zealand Pharma A/S, 45 88 77 36 00, SBirch@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
    28 May 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Oct 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Oct 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of dasiglucagon administered as a subcutaneous (SC) infusion in reducing hypoglycemia in children with Congenital Hyperinsulinism.
    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
    07 Jan 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Israel: 3
    Country: Number of subjects enrolled
    United States: 14
    Country: Number of subjects enrolled
    United Kingdom: 9
    Country: Number of subjects enrolled
    Germany: 6
    Worldwide total number of subjects
    32
    EEA total number of subjects
    6
    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)
    9
    Children (2-11 years)
    23
    Adolescents (12-17 years)
    0
    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
    This trial was conducted at a total of 11 sites in the USA (4 sites), UK (4 sites), Germany (2 sites), and Israel (1 site).

    Pre-assignment
    Screening details
    A total of 37 patients were screened of which 32 patients were randomized.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Dasiglucagon + standard of care
    Arm description
    In Treatment Period 1, patients received standard of care + dasiglucagon or standard of care only for 4 weeks based on their treatment assignment. Standard of care treatment could include most drugs commonly used and/or recommended in treatment of congenital hyperinsulinism (CHI) including, but not limited to: application of carbohydrate-rich liquids mainly via nasogastric-tube or gastric infusions, carbohydrate fortification of other feeds (including oral), diazoxide treatment, and somatostatin analogues (e.g., octreotide, octreotide LAR, or lanreotide). Other CHI-specific treatment, either prior to patient’s enrolment or during their participation in the trial, could be added upon discussion with the medical monitor. In Treatment Period 2, all patients received standard of care + dasiglucagon for 4 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Dasiglucagon
    Investigational medicinal product code
    ZP4207
    Other name
    Pharmaceutical forms
    Solution for solution for infusion
    Routes of administration
    Infusion , Subcutaneous use
    Dosage and administration details
    Dosing of dasiglucagon was via an infusion pump with small doses at frequent intervals to approximate continuous infusion. Dasiglucagon injection 4 mg/mL was supplied in a 3 mL vial containing 1 mL, at a concentration of 4 mg/mL. A 2-hour dose-adjustment interval allowed plasma drug levels to approach approximately steady state before the dose was further increased. The maximum cumulative dose over the first 24 hours was 1.26 mg.

    Arm title
    Standard of care only
    Arm description
    In Treatment Period 1, patients received standard of care + dasiglucagon or standard of care only for 4 weeks based on their treatment assignment. Standard of care treatment could include most drugs commonly used and/or recommended in treatment of congenital hyperinsulinism (CHI) including, but not limited to: application of carbohydrate-rich liquids mainly via nasogastric-tube or gastric infusions, carbohydrate fortification of other feeds (including oral), diazoxide treatment, and somatostatin analogues (e.g., octreotide, octreotide LAR, or lanreotide). Other CHI-specific treatment, either prior to patient’s enrolment or during their participation in the trial, could be added upon discussion with the medical monitor. In Treatment Period 2, all patients received standard of care + dasiglucagon for 4 weeks.
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    Dasiglucagon + standard of care Standard of care only
    Started
    16
    16
    Entered treatment period 2
    16
    16
    Completed
    16
    15
    Not completed
    0
    1
         Adverse event, non-fatal
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Dasiglucagon + standard of care
    Reporting group description
    In Treatment Period 1, patients received standard of care + dasiglucagon or standard of care only for 4 weeks based on their treatment assignment. Standard of care treatment could include most drugs commonly used and/or recommended in treatment of congenital hyperinsulinism (CHI) including, but not limited to: application of carbohydrate-rich liquids mainly via nasogastric-tube or gastric infusions, carbohydrate fortification of other feeds (including oral), diazoxide treatment, and somatostatin analogues (e.g., octreotide, octreotide LAR, or lanreotide). Other CHI-specific treatment, either prior to patient’s enrolment or during their participation in the trial, could be added upon discussion with the medical monitor. In Treatment Period 2, all patients received standard of care + dasiglucagon for 4 weeks.

    Reporting group title
    Standard of care only
    Reporting group description
    In Treatment Period 1, patients received standard of care + dasiglucagon or standard of care only for 4 weeks based on their treatment assignment. Standard of care treatment could include most drugs commonly used and/or recommended in treatment of congenital hyperinsulinism (CHI) including, but not limited to: application of carbohydrate-rich liquids mainly via nasogastric-tube or gastric infusions, carbohydrate fortification of other feeds (including oral), diazoxide treatment, and somatostatin analogues (e.g., octreotide, octreotide LAR, or lanreotide). Other CHI-specific treatment, either prior to patient’s enrolment or during their participation in the trial, could be added upon discussion with the medical monitor. In Treatment Period 2, all patients received standard of care + dasiglucagon for 4 weeks.

    Reporting group values
    Dasiglucagon + standard of care Standard of care only Total
    Number of subjects
    16 16 32
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    3.55 ± 2.592 5.00 ± 2.892 -
    Gender categorical
    Units: Subjects
        Female
    6 10 16
        Male
    10 6 16
    Race
    Units: Subjects
        White
    13 9 22
        Black or African American
    2 1 3
        Asian
    1 2 3
        Other
    0 2 2
        More than 1 race
    0 2 2
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    4 0 4
        Not Hispanic or Latino
    12 16 28
    Pancreatectomy
    Units: Subjects
        Near total (> 95%)
    1 3 4
        Not Near total (<= 95%)
    3 4 7
        No Pancreatectomy
    12 9 21
    Gastrostomy/nasogastric-tube
    Units: Subjects
        Gastrostomy
    9 12 21
        Nasogastric-tube
    2 1 3
        None
    5 3 8
    Length/height
    Units: cm
        arithmetic mean (standard deviation)
    94.76 ± 18.805 105.62 ± 20.534 -
    Length/height Z-score
    Z-scores (based on the WHO growth charts) were derived using a patient's age and sex.
    Units: ratio
        arithmetic mean (standard deviation)
    -0.51 ± 1.756 -0.32 ± 1.043 -
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    17.16 ± 6.974 22.79 ± 12.688 -
    Weight Z-score
    Z-scores (based on the WHO growth charts) were derived using a patient's age and sex.
    Units: ratio
        arithmetic mean (standard deviation)
    0.74 ± 1.725 0.82 ± 1.412 -

    End points

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    End points reporting groups
    Reporting group title
    Dasiglucagon + standard of care
    Reporting group description
    In Treatment Period 1, patients received standard of care + dasiglucagon or standard of care only for 4 weeks based on their treatment assignment. Standard of care treatment could include most drugs commonly used and/or recommended in treatment of congenital hyperinsulinism (CHI) including, but not limited to: application of carbohydrate-rich liquids mainly via nasogastric-tube or gastric infusions, carbohydrate fortification of other feeds (including oral), diazoxide treatment, and somatostatin analogues (e.g., octreotide, octreotide LAR, or lanreotide). Other CHI-specific treatment, either prior to patient’s enrolment or during their participation in the trial, could be added upon discussion with the medical monitor. In Treatment Period 2, all patients received standard of care + dasiglucagon for 4 weeks.

    Reporting group title
    Standard of care only
    Reporting group description
    In Treatment Period 1, patients received standard of care + dasiglucagon or standard of care only for 4 weeks based on their treatment assignment. Standard of care treatment could include most drugs commonly used and/or recommended in treatment of congenital hyperinsulinism (CHI) including, but not limited to: application of carbohydrate-rich liquids mainly via nasogastric-tube or gastric infusions, carbohydrate fortification of other feeds (including oral), diazoxide treatment, and somatostatin analogues (e.g., octreotide, octreotide LAR, or lanreotide). Other CHI-specific treatment, either prior to patient’s enrolment or during their participation in the trial, could be added upon discussion with the medical monitor. In Treatment Period 2, all patients received standard of care + dasiglucagon for 4 weeks.

    Primary: Hypoglycaemia episode rate

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    End point title
    Hypoglycaemia episode rate
    End point description
    Hypoglycaemia episode rate was defined as average weekly number of hypoglycaemic episodes (PG <70 mg/dL or 3.9 mmol/L) during Weeks 2-4, as detected by self-monitored plasma glucose (SMPG)
    End point type
    Primary
    End point timeframe
    Weeks 2-4
    End point values
    Dasiglucagon + standard of care Standard of care only
    Number of subjects analysed
    16
    16
    Units: Average weekly episode rate
    arithmetic mean (standard deviation)
        Observed mean values
    5.29 ± 5.256
    5.85 ± 2.767
        Change from baseline
    -3.05 ± 4.343
    -3.15 ± 4.753
    Statistical analysis title
    Primary analysis
    Statistical analysis description
    The primary analysis was performed as negative binominal regression analysis comparing the SMPG-detected hypoglycaemia episode rate between treatment groups over weeks 2-4.
    Comparison groups
    Dasiglucagon + standard of care v Standard of care only
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5028
    Method
    Generalised linear regression
    Parameter type
    Mean difference (net)
    Point estimate
    0.85
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.54
         upper limit
    1.36

    Secondary: Fasting tolerance

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    End point title
    Fasting tolerance
    End point description
    Fasting tolerance was defined as time from beginning of meal to the first continuous 15-minute continuous glucose monitoring (CGM) reading <70 mg/dL, or the time the test ended if a continuous 15-minute CGM reading <70 mg/dL was not reached. A number of procedural issues with the test precluded a meaningful interpretation of the results.
    End point type
    Secondary
    End point timeframe
    Weeks 2-4
    End point values
    Dasiglucagon + standard of care Standard of care only
    Number of subjects analysed
    14
    16
    Units: hours
    arithmetic mean (standard deviation)
        Observed mean values
    6.13 ± 5.335
    4.22 ± 4.222
        Change from baseline
    1.20 ± 5.908
    1.27 ± 3.836
    Statistical analysis title
    Fasting tolerance
    Statistical analysis description
    Increase in fasting tolerance (i.e., change from baseline in time from meal to plasma glucose <70 mg/dL) was analyzed using an ANCOVA, with treatment group and region as fixed effects and baseline fasting tolerance as a covariate.
    Comparison groups
    Standard of care only v Dasiglucagon + standard of care
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6433
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.84
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.71
         upper limit
    4.39

    Secondary: CGM percent time in range

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    End point title
    CGM percent time in range
    End point description
    The continuous glucose monitoring (CGM) percent time in range 70-180 mg/dL (3.9-10.0 mmol/L) during weeks 2-4 was analysed.
    End point type
    Secondary
    End point timeframe
    Weeks 2-4
    End point values
    Dasiglucagon + standard of care Standard of care only
    Number of subjects analysed
    16 [1]
    16
    Units: Average weekly percent time in range
    arithmetic mean (standard deviation)
        Observed mean value
    75.10 ± 11.821
    72.65 ± 7.313
        Change from baseline
    -0.97 ± 11.837
    2.44 ± 9.584
    Notes
    [1] - Change from baseline was analysed for 15 subjects
    Statistical analysis title
    CGM percent time in range
    Statistical analysis description
    Percent time in range (i.e., the percent time between 70 mg/dL [3.9 mmol] and 180 mg/dL [10.0 mmol], inclusive), as measured by CGM, was analyzed by using an ANCOVA, with treatment group and region as fixed effects and baseline time in range as a covariate.
    Comparison groups
    Dasiglucagon + standard of care v Standard of care only
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9653
    Method
    ANCOVA
    Parameter type
    Least-square means
    Point estimate
    0.15
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.48
         upper limit
    6.78

    Secondary: Clinically significant SMPG-detected hypoglycaemia episodes

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    End point title
    Clinically significant SMPG-detected hypoglycaemia episodes
    End point description
    The clinically significant self-monitored plasma glucose (SMPG)-detected hypoglycaemia episodes (PG <54 mg/dL) were analysed.
    End point type
    Secondary
    End point timeframe
    Weeks 2-4
    End point values
    Dasiglucagon + standard of care Standard of care only
    Number of subjects analysed
    16
    16
    Units: Average weekly number of episodes
    arithmetic mean (standard deviation)
        Observed mean values
    1.77 ± 1.857
    1.90 ± 1.407
        Change from baseline
    -0.51 ± 2.798
    -0.35 ± 1.446
    Statistical analysis title
    Clinically significant hypoglycaemia
    Statistical analysis description
    Analysis of SMPG-detected clinically significant hypoglycaemia (<54 mg/dL [3.0 mmol/L]) episode rate was based on the hypoglycaemia episodes reported with at least 1 SMPG measurement <54 mg/dL. The endpoint was analyzed using a negative binomial regression, with treatment group and region as fixed effects and baseline hypoglycemia rate as a covariate.
    Comparison groups
    Dasiglucagon + standard of care v Standard of care only
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8114
    Method
    Negative binomial regression
    Parameter type
    Event rate ratio
    Point estimate
    0.93
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.49
         upper limit
    1.74

    Secondary: Total amount of gastric carbohydrates administered per week

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    End point title
    Total amount of gastric carbohydrates administered per week
    End point description
    Total amount of gastric carbohydrates administered (via nasogastric-tube or gastrostomy) per week to treat hypoglycaemia during weeks 2-4.
    End point type
    Secondary
    End point timeframe
    Weeks 2-4
    End point values
    Dasiglucagon + standard of care Standard of care only
    Number of subjects analysed
    11
    13
    Units: Grams
    arithmetic mean (standard deviation)
        Observed mean values
    22.89 ± 31.415
    37.66 ± 57.998
        Change from baseline
    -33.66 ± 82.767
    -19.74 ± 64.082
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    4 weeks
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Dasiglucagon + standard of care
    Reporting group description
    In Treatment Period 1, patients received standard of care + dasiglucagon or standard of care only for 4 weeks based on their treatment assignment.

    Reporting group title
    Standard of care only
    Reporting group description
    In Treatment Period 1, patients received standard of care + dasiglucagon or standard of care only for 4 weeks based on their treatment assignment.

    Reporting group title
    Treatment Period 2
    Reporting group description
    In Treatment Period 2, all patients received standard of care + dasiglucagon for 4 weeks.

    Reporting group title
    Treatment Period 1 + 2
    Reporting group description
    Dasiglucagon + standard of care treatment group for periods 1 and 2

    Serious adverse events
    Dasiglucagon + standard of care Standard of care only Treatment Period 2 Treatment Period 1 + 2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 16 (12.50%)
    1 / 16 (6.25%)
    2 / 32 (6.25%)
    3 / 32 (9.38%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 32 (3.13%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Localised infection
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular device infection
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Folliculitis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 32 (3.13%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    H1N1 influenza
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 32 (3.13%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Dasiglucagon + standard of care Standard of care only Treatment Period 2 Treatment Period 1 + 2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    14 / 16 (87.50%)
    8 / 16 (50.00%)
    24 / 32 (75.00%)
    27 / 32 (84.38%)
    General disorders and administration site conditions
    Medical device site irritation
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    1
    0
    0
    1
    Pyrexia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    1
    0
    0
    1
    Psychiatric disorders
    Irritability
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    1
    0
    0
    1
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    2 / 32 (6.25%)
    2 / 32 (6.25%)
         occurrences all number
    0
    0
    2
    2
    Investigations
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    1
    0
    0
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    2 / 32 (6.25%)
    2 / 32 (6.25%)
         occurrences all number
    0
    0
    2
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    1
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 32 (3.13%)
    1 / 32 (3.13%)
         occurrences all number
    2
    1
    1
    3
    Drooling
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    1
    0
    0
    1
    Seizure
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    1
    0
    0
    1
    Loss of consciousness
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Eye disorders
    Eye movement disorder
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    1
    0
    0
    1
    Ear and labyrinth disorders
    Otorrhoea
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    5 / 16 (31.25%)
    1 / 16 (6.25%)
    2 / 32 (6.25%)
    7 / 32 (21.88%)
         occurrences all number
    7
    1
    5
    12
    Diarrhoea
         subjects affected / exposed
    2 / 16 (12.50%)
    1 / 16 (6.25%)
    0 / 32 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    2
    1
    0
    2
    Teething
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 16 (0.00%)
    0 / 32 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    2
    0
    0
    2
    Nausea
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    1 / 32 (3.13%)
    1 / 32 (3.13%)
         occurrences all number
    2
    0
    1
    3
    Constipation
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    1
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    5 / 16 (31.25%)
    0 / 16 (0.00%)
    1 / 32 (3.13%)
    6 / 32 (18.75%)
         occurrences all number
    5
    0
    1
    6
    Rash
         subjects affected / exposed
    3 / 16 (18.75%)
    0 / 16 (0.00%)
    2 / 32 (6.25%)
    5 / 32 (15.63%)
         occurrences all number
    4
    0
    2
    6
    Rash maculo-papular
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    2 / 32 (6.25%)
    3 / 32 (9.38%)
         occurrences all number
    1
    0
    2
    3
    Dermatitis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    1 / 32 (3.13%)
    1 / 32 (3.13%)
         occurrences all number
    1
    0
    1
    2
    Erythema
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    1
    0
    0
    1
    Miliaria
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    1
    0
    0
    1
    Urticaria
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    1
    0
    0
    1
    Dermatitis diaper
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    2 / 32 (6.25%)
    2 / 32 (6.25%)
         occurrences all number
    0
    0
    2
    2
    Necrolytic migratory erythema
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    2 / 32 (6.25%)
    2 / 32 (6.25%)
         occurrences all number
    0
    0
    2
    2
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    4 / 32 (12.50%)
    4 / 32 (12.50%)
         occurrences all number
    0
    0
    16
    16
    Ketosis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    2 / 32 (6.25%)
    2 / 32 (6.25%)
         occurrences all number
    0
    0
    2
    2
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 16 (0.00%)
    2 / 32 (6.25%)
    4 / 32 (12.50%)
         occurrences all number
    2
    0
    2
    4
    Localised infection
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Folliculitis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    1
    0
    0
    1
    Candida nappy rash
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    1
    0
    0
    1
    Ear infection
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    1
    0
    0
    1
    Gastritis viral
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    1
    0
    0
    1
    Herpangina
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    1
    0
    0
    1
    Hordeolum
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    1
    0
    0
    1
    Influenza
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    1
    0
    0
    1
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    1
    0
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    1 / 32 (3.13%)
    1 / 32 (3.13%)
         occurrences all number
    0
    1
    2
    2
    Gastroenteritis Viral
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hand-foot-and-mouth disease
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Eczema infected
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    3 / 32 (9.38%)
    3 / 32 (9.38%)
         occurrences all number
    0
    0
    3
    3

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Mar 2019
    Amendment 5 (Germany). Device adapted protocol to fulfil the requirements from BfArM MPG. New section 19 added + additional device-related safety reporting added in section 11.
    03 Jun 2019
    Amendment 6 (all countries, except Germany). Main changes: Primary analysis changed (FDA request). Endpoints aligned to trial ZP4207-17103. Clarifications to hypoglycaemia reporting and electronic SMPG data. Clarified that standard of care open-label CGM is not allowed. Immunogenicity strategy updated.
    05 Jul 2019
    Amendment 7 (Germany). Local German protocol combining protocol versions 6.0 and 7.0.
    19 Sep 2019
    Amendment 8 (all countries, except Germany). Additional electrocardiogram and vital signs assessments (FDA request). Immunogenicity strategy updated (FDA).
    11 Oct 2019
    Amendment 9 (Germany). Local German protocol combining protocol versions 8.0 and 9.0.
    06 Mar 2020
    Amendment 10 (all countries, except Germany). Interim analyses removed. Immunogenicity section updated.
    11 Mar 2020
    Amendment 11 (Germany). Local German protocol combining protocol version 10.0 and changes according to protocol version 11.0.
    05 Oct 2020
    Amendment 12 (all countries, except Germany). Second key secondary efficacy endpoint related to assessment of gastric carbohydrates moved to be a secondary efficacy endpoint. All endpoints related to intake of gastric carbohydrates only to be described in the subgroup of patients who have a gastrostomy/nasogastric-tube at screening. Amendment finalized 12-Nov-2020, after LPLV but prior to DBL.
    05 Oct 2020
    Amendment 13 (Germany). Local German protocol combining protocol versions 12.0 and 13.0. Amendment finalized 12-Nov-2020, after LPLV but prior to DBL.

    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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