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    Clinical Trial Results:
    Adjustment of insulin Degludec to Reduce post-Exercise (nocturnal) hypoglycaeMia in people with diabetes – the ADREM study

    Summary
    EudraCT number
    		 2019-004222-22
    Trial protocol
    		 NL  
    Global end of trial date
    02 Sep 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Sep 2022
    First version publication date
    16 Sep 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    U1111-1235-6899
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Radboud University Medical Center
    Sponsor organisation address
    Geert Grooteplein Zuid 10, Nijmegen, Netherlands, 6525 GA
    Public contact
    research physician, Radboud University Medical Center, +31 243618819, evertine.abbink@radboudumc.nl
    Scientific contact
    research physician, Radboud University Medical Center, +31 243618819, evertine.abbink@radboudumc.nl
    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
    30 Aug 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    02 Sep 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Sep 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the effect of three degludec dosing regimens on the risk of post-exercise nocturnal hypoglycaemia (time spent in glucose range ≤3.8 mmol/l, 00:00 to 05:59h) in type 1 diabetes mellitus patients at elevated risk of hypoglycaemia.
    Protection of trial subjects
    Insulin degludec has a generally favourable safety profile. The drug is approved by the Dutch medicines evaluation board and is generally well tolerated. In total 15 blood samples will be taken. The total blood volume taken will be approximately 300 ml during a total period of 10 weeks. Needles used to draw blood may cause inconvenience or pain at the insertion site. During the screening and the long visits an intravenous cannula will be inserted to limit the number of venous punctures. The risk classification was assessed as low.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 Sep 2020
    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
    Netherlands: 18
    Worldwide total number of subjects
    18
    EEA total number of subjects
    18
    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)
    18
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were recruited from the outpatient clinic of the Radboud University Medical Center and Rijnstate hospital, via social media and websites of patient associations.

    Pre-assignment
    Screening details
    		 A total of 19 participants were screened, 18 of whom were included. One participant was withdrawn after screening because of personal reasons unrelated to the study. First inclusion: 22-9-2020. Last inclusion: 10-6-2021. After eligibility, patients not on degludec were transferred to it at least 28 days before first exercise day.

    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
    No

    Arm title
    		 ADREM-CON
    Arm description
    		 No adjustment of insulin degludec
    Arm type
    		 No adjustment

    Investigational medicinal product name
    Insulin Degludec
    Investigational medicinal product code
    EU/1/12/807/001
    Other name
    Tresiba
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Individualized dosage, administer once daily. No dose reduction on the exercise day

    Arm title
    		 ADREM-D40
    Arm description
    		 40% dose reduction of insulin degludec
    Arm type
    		 40% dose reduction

    Investigational medicinal product name
    Insulin Degludec
    Investigational medicinal product code
    EU/1/12/807/001
    Other name
    Tresiba
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Individualized dosage, administer once daily. A 40% dose reduction on the exercise day

    Arm title
    		 ADREM-D20-PP
    Arm description
    		 8h postponement and 20% dose reduction of insulin degludec
    Arm type
    		 8h postponement and 20% dose reduction

    Investigational medicinal product name
    Insulin Degludec
    Investigational medicinal product code
    EU/1/12/807/001
    Other name
    Tresiba
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Individualized dosage, administer once daily. An 8-hour postponement and 20% dose reduction on the exercise day.

    Number of subjects in period 1
    		ADREM-CON ADREM-D40 ADREM-D20-PP
    Started
    18
    18
    18
    Completed
    18
    18
    18

    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
    		 18 18
    Age categorical
    Inclusion criterium: adults aged 18-60 years
    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)
    		 18 18
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 6 6
        Male
    		 12 12

    End points

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    End points reporting groups
    Reporting group title
    ADREM-CON
    Reporting group description
    		 No adjustment of insulin degludec

    Reporting group title
    ADREM-D40
    Reporting group description
    		 40% dose reduction of insulin degludec

    Reporting group title
    ADREM-D20-PP
    Reporting group description
    		 8h postponement and 20% dose reduction of insulin degludec

    Primary: Amount of people spending time in hypoglycaemic range (i.e. glucose <3.9 mmol/l) during the night (00:00 to 05:59h) following the exercise day measured by continuous glucose monitoring

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    End point title
    		 Amount of people spending time in hypoglycaemic range (i.e. glucose <3.9 mmol/l) during the night (00:00 to 05:59h) following the exercise day measured by continuous glucose monitoring
    End point description
    End point type
    Primary
    End point timeframe
    The night (00:00 to 05:59h) following the exercise day
    End point values
    		 ADREM-CON ADREM-D40 ADREM-D20-PP
    Number of subjects analysed
    18
    18
    18
    Units: yes/no
        Yes
    3
    1
    1
        No
    15
    17
    17
    Statistical analysis title
    		 Logistic random effects model
    Statistical analysis description
    We used random effects models to account for the three measurements for each participant with period and treatment as independent variables.
    Comparison groups
    ADREM-CON v ADREM-D40 v ADREM-D20-PP
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 < 0.05
    Method
    		 Logistic random effects model
    Parameter type
    		 Count
    Confidence interval
    Notes
    [1] - Subjects in this analysis: 18

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    22-9-2020 / 2-9-2021
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25
    Reporting groups
    Reporting group title
    ADREM-CON
    Reporting group description
    		 No adjustment of insulin degludec

    Reporting group title
    ADREM-D40
    Reporting group description
    		 40% dose reduction of insulin degludec

    Reporting group title
    ADREM-D20-PP
    Reporting group description
    		 8h postponement and 20% dose reduction of insulin degludec

    Serious adverse events
    		 ADREM-CON ADREM-D40 ADREM-D20-PP
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 ADREM-CON ADREM-D40 ADREM-D20-PP
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    Infections and infestations
    COVID-19
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    Cellulitis
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0

    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
    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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