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    Clinical Trial Results:
    The HYPO-AVOID STUDY: Low-dose Glucagon and Advanced Hybrid Closed-loop System for Prevention of Exercise-Induced Hypoglycaemia in People with Type 1 Diabetes

    Summary
    EudraCT number
    		 2021-004993-68
    Trial protocol
    		 DK  
    Global end of trial date
    01 Nov 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Jul 2025
    First version publication date
    09 Jul 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    85256
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Steno Diabetes Center Copenhagen
    Sponsor organisation address
    Borgmester Ib Juuls Vej 89, Købehavn, Denmark, 2730
    Public contact
    Sissel Lundemose, Steno Diabetes Center Copenhagen, +45 23742764, sissel.lundemose@regionh.dk
    Scientific contact
    Sissel Lundemose, Steno Diabetes Center Copenhagen, +45 23742764, sissel.lundemose@regionh.dk
    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
    01 Oct 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Oct 2024
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Nov 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the effect of low-dose glucagon (single 150 µg dose) administered immediately before aerobic exercise (visit B) versus a control trial without glucagon (visit C) on glucose responses during and after exercise in individuals with AHCL-treated T1D.
    Protection of trial subjects
    Visual analog scale 1-100 (VAS) was used to trace adverse events.
    Background therapy
    		 All participants with type 1 diabetes (T1D) were treated with a Minimed Medtronic 780G insulin pump (Automated Insulin Delivery (AID) system)
    Evidence for comparator
    		 We hypothesize that low-dose glucagon administered s.c. before aerobic exercise is superior to no glucagon regarding glucose control around exercise in people with T1D using AID therapy. The objective wast o compare the effect of low-dose glucagon (single 150 µg dose) administered immediately before aerobic exercise versus a control trial without glucagon on glucose responses during and after exercise in individuals with AID-treated T1D.
    Actual start date of recruitment
    01 Jan 2022
    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
    Denmark: 10
    Worldwide total number of subjects
    10
    EEA total number of subjects
    10
    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)
    9
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The HYPO-AVOID study will include individuals with AID-treated (Minimed Medtronic 780G) T1D, and the participants will be recruited from the clinic at Steno Diabetes Center Copenhagen.

    Pre-assignment
    Screening details
    		 Inclusion criteria • Age ≥ 18 years • Type 1 diabetes ≥ 2 years • Using the AHCL system MiniMed 780G ≥ 4 weeks • Novorapid use ≥1 week

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

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Glucagon (Visit 1)
    Arm description
    		 Immediately before exercise start (t = 0), 150 µg s.c. glucagon will be administrated in the abdominal area
    Arm type
    		 Experimental

    Investigational medicinal product name
    glucagon
    Investigational medicinal product code
    SUB02347MIG
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection
    Routes of administration
    Injection
    Dosage and administration details
    150 micrograms

    Arm title
    		 No glucagon (Visit 2)
    Arm description
    		 • Immediately before exercise start (t = 0), no glucagon will be administrated.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Glucagon (Visit 1) No glucagon (Visit 2)
    Started
    10
    10
    Completed
    10
    10

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall Trial Total
    Number of subjects
    		 10 10
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 9 9
        From 65-84 years
    		 1 1
    Age continuous
    Units: years
        median (full range (min-max))
    		 50 (42 to 67) -
    Gender categorical
    Units: Subjects
        Female
    		 4 4
        Male
    		 6 6
    BMI
    (kg/m2)
    Units: kg/m2
        median (full range (min-max))
    		 26 (21 to 29) -
    Type 1 duration
    Units: years
        median (full range (min-max))
    		 22 (14 to 44) -
    HbA1c
    Units: mmol/mol
        median (full range (min-max))
    		 55 (47 to 69) -
    Time in Range
    Percentage
    Units: 0-100
        median (full range (min-max))
    		 77 (69 to 79) -
    Time below range
    Percentage
    Units: 0-100
        median (full range (min-max))
    		 1 (1 to 10) -

    End points

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    End points reporting groups
    Reporting group title
    Glucagon (Visit 1)
    Reporting group description
    		 Immediately before exercise start (t = 0), 150 µg s.c. glucagon will be administrated in the abdominal area

    Reporting group title
    No glucagon (Visit 2)
    Reporting group description
    		 • Immediately before exercise start (t = 0), no glucagon will be administrated.

    Primary: • Difference in percentage of time in target glucose range (PG: 3.9 - 10.0 mmol/l) during and for 1-hour after dynamic physical exercise (0 min to +105min) between visits 1 and 2

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    End point title
    		 • Difference in percentage of time in target glucose range (PG: 3.9 - 10.0 mmol/l) during and for 1-hour after dynamic physical exercise (0 min to +105min) between visits 1 and 2
    End point description
    End point type
    Primary
    End point timeframe
    From 0-105 min.
    End point values
    		 Glucagon (Visit 1) No glucagon (Visit 2)
    Number of subjects analysed
    10
    10
    Units: %
        median (inter-quartile range (Q1-Q3))
    100 (91 to 100)
    100 (100 to 100)
    Statistical analysis title
    		 Wilcoxon Rank Test
    Comparison groups
    No glucagon (Visit 2) v Glucagon (Visit 1)
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.18
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: • Difference in incidence rate of hypoglycemic events (PG<3.9 mmol/l) (0 min to +105min) between visits 1 and 2

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    End point title
    		 • Difference in incidence rate of hypoglycemic events (PG<3.9 mmol/l) (0 min to +105min) between visits 1 and 2
    End point description
    End point type
    Secondary
    End point timeframe
    From 0 to 105 min
    End point values
    		 Glucagon (Visit 1) No glucagon (Visit 2)
    Number of subjects analysed
    10
    10
    Units: Number
        number (not applicable)
    0
    0
    No statistical analyses for this end point

    Secondary: • Difference in percentage of time below target glucose range (PG<3.9 mmol/l) (0 min to +105min) between visits 1 and 2

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    End point title
    		 • Difference in percentage of time below target glucose range (PG<3.9 mmol/l) (0 min to +105min) between visits 1 and 2
    End point description
    End point type
    Secondary
    End point timeframe
    From 0 to 105 min
    End point values
    		 Glucagon (Visit 1) No glucagon (Visit 2)
    Number of subjects analysed
    10
    10
    Units: %
        median (inter-quartile range (Q1-Q3))
    0 (0 to 0)
    0 (0 to 0)
    Statistical analysis title
    		 Wilcoxon Rank Test
    Comparison groups
    Glucagon (Visit 1) v No glucagon (Visit 2)
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: • Difference in percentage of time above target glucose range (PG>10.0 mmol/l) (0 min to +105min) between visits 1 and 2

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    End point title
    		 • Difference in percentage of time above target glucose range (PG>10.0 mmol/l) (0 min to +105min) between visits 1 and 2
    End point description
    End point type
    Secondary
    End point timeframe
    From 0 to 105 min
    End point values
    		 Glucagon (Visit 1) No glucagon (Visit 2)
    Number of subjects analysed
    10
    10
    Units: %
        median (inter-quartile range (Q1-Q3))
    0 (0 to 0)
    0 (0 to 0)
    Statistical analysis title
    		 Wilcoxon Rank Test
    Comparison groups
    Glucagon (Visit 1) v No glucagon (Visit 2)
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.37
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: • Difference in nadir PG concentration (0 min to +105min) between visits 1 and 2

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    End point title
    		 • Difference in nadir PG concentration (0 min to +105min) between visits 1 and 2
    End point description
    End point type
    Secondary
    End point timeframe
    From 0 to 105 min
    End point values
    		 Glucagon (Visit 1) No glucagon (Visit 2)
    Number of subjects analysed
    10
    10
    Units: mmol/l
        median (inter-quartile range (Q1-Q3))
    5.8 (5.2 to 6.9)
    5.8 (4.9 to 6.5)
    Statistical analysis title
    		 Wilcoxon Rank Test
    Comparison groups
    Glucagon (Visit 1) v No glucagon (Visit 2)
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.41
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: • Difference in peak PG concentration (0 min to +105min) between visits 1 and 2

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    End point title
    		 • Difference in peak PG concentration (0 min to +105min) between visits 1 and 2
    End point description
    End point type
    Secondary
    End point timeframe
    From 0 to 105 min
    End point values
    		 Glucagon (Visit 1) No glucagon (Visit 2)
    Number of subjects analysed
    10
    10
    Units: mmol/l
        arithmetic mean (standard error)
    9.3 ( 1.8 )
    7.4 ( 1.4 )
    Statistical analysis title
    		 TTEST
    Comparison groups
    Glucagon (Visit 1) v No glucagon (Visit 2)
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.01
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: • Difference in mean PG concentration (0 min to +105min) between visits 1 and 2

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    End point title
    		 • Difference in mean PG concentration (0 min to +105min) between visits 1 and 2
    End point description
    End point type
    Secondary
    End point timeframe
    From min0 to 105 min
    End point values
    		 Glucagon (Visit 1) No glucagon (Visit 2)
    Number of subjects analysed
    10
    10
    Units: mmol/l
        median (standard deviation)
    8.3 ( 1.8 )
    6.7 ( 1.3 )
    Statistical analysis title
    		 TTEST
    Comparison groups
    Glucagon (Visit 1) v No glucagon (Visit 2)
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.01
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: • Difference in PG Area Under the Curve (AUC) (0 min to +105min) between visits 1 and 2

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    End point title
    		 • Difference in PG Area Under the Curve (AUC) (0 min to +105min) between visits 1 and 2
    End point description
    End point type
    Secondary
    End point timeframe
    From min 0 to min 105.
    End point values
    		 Glucagon (Visit 1) No glucagon (Visit 2)
    Number of subjects analysed
    10
    10
    Units: mmol/l*min
        log mean (inter-quartile range (Q1-Q3))
    824.2 (782.3 to 941.2)
    686.2 (612.2 to 821.1)
    Statistical analysis title
    		 log TTEST
    Comparison groups
    Glucagon (Visit 1) v No glucagon (Visit 2)
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.01
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: • Difference in standard deviation in PG concentrations (0 min to +105min) between visits 1 and 2

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    End point title
    		 • Difference in standard deviation in PG concentrations (0 min to +105min) between visits 1 and 2
    End point description
    End point type
    Secondary
    End point timeframe
    From min 0 to min 150
    End point values
    		 Glucagon (Visit 1) No glucagon (Visit 2)
    Number of subjects analysed
    10
    10
    Units: mmol/l
        median (inter-quartile range (Q1-Q3))
    1.0 (0.7 to 1.2)
    0.5 (0.3 to 0.5)
    Statistical analysis title
    		 Wilcoxon Rank Test
    Comparison groups
    Glucagon (Visit 1) v No glucagon (Visit 2)
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.01
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: • Difference in coefficient of variation in PG concentrations (0 min to +105min) between visits 1 and 2

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    End point title
    		 • Difference in coefficient of variation in PG concentrations (0 min to +105min) between visits 1 and 2
    End point description
    End point type
    Secondary
    End point timeframe
    From min 0 to min 105.
    End point values
    		 Glucagon (Visit 1) No glucagon (Visit 2)
    Number of subjects analysed
    10
    10
    Units: mmol/l
        median (standard error)
    12.3 ( 4.3 )
    7.3 ( 2.5 )
    Statistical analysis title
    		 TTEST
    Comparison groups
    Glucagon (Visit 1) v No glucagon (Visit 2)
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.01
    Method
    		 t-test, 2-sided
    Confidence interval

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    From min 0 to min 105
    Adverse event reporting additional description
    Adverse events (nausea, stomach-ache, injections site pain, headache, and palpitation) were assessed using a 0-100 visual analogue score (VAS) before (baseline), after exercise, and at the end of the trial to evaluate the occurrence of any adverse events.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 VAS
    Dictionary version
    1
    Reporting groups
    Reporting group title
    Entire trial
    Reporting group description
    		 For the entire trial. No adverse events were reported.

    Serious adverse events
    		 Entire trial
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 10 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Entire trial
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 10 (0.00%)
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: No adverse events were recorded during the trial.

    More information

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

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    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
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