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    Clinical Trial Results:
    Dual-Hormone Closed-Loop Glucose Control in Type 1 Diabetes

    Summary
    EudraCT number
    		 2019-001631-31
    Trial protocol
    		 DK  
    Global end of trial date
    19 Mar 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Mar 2023
    First version publication date
    15 Mar 2023
    Other versions
    Summary report(s)
    		 Oral_presentation_ADA2021

    Trial information

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    Trial identification
    Sponsor protocol code
    DHCL2019
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04053712
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Former EUDRA-CT: 2014-003261-20, Former Protocol code number: DHCL2014
    Sponsors
    Sponsor organisation name
    Steno Diabetes Center Copenhagen
    Sponsor organisation address
    Niels Steensens Vej 2, Gentofte, Denmark, 2820
    Public contact
    Ajenthen Ranjan, Steno Diabetes Center Copenhagen, +45 26196604, ajenthen.ranjan@regionh.dk
    Scientific contact
    Ajenthen Ranjan, Steno Diabetes Center Copenhagen, +45 26196604, ajenthen.ranjan@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
    27 Feb 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Mar 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Mar 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The aims of this two-phase project are to 1) demonstrate proof-of-concept and 2) to compare dual-hormone with single-hormone closed-loop glucose control.
    Protection of trial subjects
    Participants experiencing symptomatic hypoglycemia or a plasmaglucose (PG) <3.0 mmol/L (54 mg/dL) received 15 g oral glucose (dextrose tablets) rescue treatment and received another if not resolved after 15 minutes. In contrast, if PG remained > 16.0 mmol/L (288 mg/dL) for two hours despite solving any closed-system malfunctions, an insulin bolus was administered based on the participant’s insulin sensitivity factor (ISF) to aim for a PG of 7.0 mmol/L (126 mg/dL). Side effects to glucagon (nausea, headache, stomachache, and palpitations) were scored using a 0–100 visual analog scale (VAS) every four hours from 7AM to 11PM. Regardless of the mode of closed-loop control, the study visit lasted for 33 hours. The study pumps and the continuos glucose monitors (CGMs) were then disconnected and the participants were allowed to reconnect their own pump and CGM.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Jun 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
    Denmark: 13
    Worldwide total number of subjects
    13
    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)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    13
    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 at Steno Diabetes Center Copenhagen, Denmark, from August 2019 to December 2020.

    Pre-assignment
    Screening details
    		 Inclusion criteria were age ≥18 years, T1D duration > 2 years, use of insulin pumps for ≥ 1 years, glycated hemoglobin (HbA1c) level ≤ 8.5% (69 mmol/mol), and current use of faster insulin aspart (Novo Nordisk, Bagsværd, Denmark).

    Pre-assignment period milestones
    Number of subjects started
    		 13
    Number of subjects completed
    		 13

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Subject
    Blinding implementation details
    The pumps were filled with FiAsp® and GlucaGen® during the DHCL visit or filled with FiAsp® and isotonic saline during SHCL, respectively. Participants were masked for the contents in the pumps.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Dual-hormone --> Single hormone
    Arm description
    		 Participants went through Dual-hormone and then Single-hormone treatment
    Arm type
    		 Experimental

    Investigational medicinal product name
    GlucaGen
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Variable dose between 0-1mg given based on an algorithm for the treatment and prevention of hypoglycemia.

    Investigational medicinal product name
    Fiasp
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Injection
    Dosage and administration details
    Variable dose given by the insulin pump

    Investigational medicinal product name
    Saline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Injection
    Dosage and administration details
    Saline was stored in an insulin pump but did not deliver any saline during the trials (e.g. functioned as a dummy-pump)

    Arm title
    		 Single-hormone --> Dual-hormone
    Arm description
    		 Participants went through single-hormone and then dual-hormone treatment
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fiasp
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Injection
    Dosage and administration details
    Variable dose given by the insulin pump

    Investigational medicinal product name
    Saline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Injection
    Dosage and administration details
    Saline was stored in an insulin pump but did not deliver any saline during the trials (e.g. functioned as a dummy-pump)

    Investigational medicinal product name
    GlucaGen
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Variable dose between 0-1mg given based on an algorithm for the treatment and prevention of hypoglycemia.

    Number of subjects in period 1
    		Dual-hormone --> Single hormone Single-hormone --> Dual-hormone
    Started
    7
    6
    Completed
    7
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Dual-hormone --> Single hormone
    Reporting group description
    		 Participants went through Dual-hormone and then Single-hormone treatment

    Reporting group title
    Single-hormone --> Dual-hormone
    Reporting group description
    		 Participants went through single-hormone and then dual-hormone treatment

    Reporting group values
    		 Dual-hormone --> Single hormone Single-hormone --> Dual-hormone Total
    Number of subjects
    		 7 6 13
    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
        median (full range (min-max))
    		 57 (26 to 64) 47 (35 to 60) -
    Gender categorical
    Units: Subjects
        Female
    		 3 4 7
        Male
    		 4 2 6
    Diabetes duration
    Units: year
        median (full range (min-max))
    		 30.5 (17 to 40) 25 (19 to 45) -
    Body mass index
    Units: kilogram(s)/square metre
        median (full range (min-max))
    		 27.8 (22.2 to 36.6) 28.9 (22.2 to 36.5) -
    Subject analysis sets

    Subject analysis set title
    DHCL
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Data were analyzed in an intention-to-treat approach including periods with any malfunction of the infusion set (e.g. occlusions, kinking of the tube), missing CGM values, and loss of connectivity between study devices to run the closed-loop systems . Repeated-measures ANOVA with a compound symmetry covariance structure was used to test the differences between the two study visits, adjusting for the study order. If data had a skewed distribution, logarithmic transformations were used. If the transformations could not normalize the distribution, nonparametric Wilcoxon signed rank tests were used. Spearman correlations were used to determine relationships. The difference of the time course of PG, insulin and glucagon was tested with a linear mixed model with random effects. A P value of <0.05 was considered statistically significant. Non-predefined outcomes were Bonferroni adjusted for multiple comparisons within each parameter.

    Subject analysis set title
    SHCL
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Completers of SIngle-hormone

    Subject analysis sets values
    		 DHCL SHCL
    Number of subjects
    13
    13
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        median (full range (min-max))
    50 (26 to 64)
    50 (26 to 64)
    Gender categorical
    Units: Subjects
        Female
    7
    7
        Male
    6
    6
    Diabetes duration
    Units: year
        median (full range (min-max))
    26 (17 to 45)
    26 (17 to 45)
    Body mass index
    Units: kilogram(s)/square metre
        median (full range (min-max))
    27.8 (22.2 to 36.6)
    27.8 (22.2 to 36.6)

    End points

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    End points reporting groups
    Reporting group title
    Dual-hormone --> Single hormone
    Reporting group description
    		 Participants went through Dual-hormone and then Single-hormone treatment

    Reporting group title
    Single-hormone --> Dual-hormone
    Reporting group description
    		 Participants went through single-hormone and then dual-hormone treatment

    Subject analysis set title
    DHCL
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Data were analyzed in an intention-to-treat approach including periods with any malfunction of the infusion set (e.g. occlusions, kinking of the tube), missing CGM values, and loss of connectivity between study devices to run the closed-loop systems . Repeated-measures ANOVA with a compound symmetry covariance structure was used to test the differences between the two study visits, adjusting for the study order. If data had a skewed distribution, logarithmic transformations were used. If the transformations could not normalize the distribution, nonparametric Wilcoxon signed rank tests were used. Spearman correlations were used to determine relationships. The difference of the time course of PG, insulin and glucagon was tested with a linear mixed model with random effects. A P value of <0.05 was considered statistically significant. Non-predefined outcomes were Bonferroni adjusted for multiple comparisons within each parameter.

    Subject analysis set title
    SHCL
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Completers of SIngle-hormone

    Primary: Percentage of time in CGM-range below 3.9 mmol/l

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    End point title
    		 Percentage of time in CGM-range below 3.9 mmol/l
    End point description
    End point type
    Primary
    End point timeframe
    0-33 hours
    End point values
    		 DHCL SHCL
    Number of subjects analysed
    13
    13
    Units: percent
        arithmetic mean (standard deviation)
    3.7 ± 2.5
    3.9 ± 3.1
    Statistical analysis title
    		 Wilcoxon Signed Rank Test
    Comparison groups
    DHCL v SHCL
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.26
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Primary: Number of carbohydrate interventions to treat hypoglycemia

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    End point title
    		 Number of carbohydrate interventions to treat hypoglycemia
    End point description
    End point type
    Primary
    End point timeframe
    0-33 hours
    End point values
    		 DHCL SHCL
    Number of subjects analysed
    13
    13
    Units: number of rescues
    7
    12
    Statistical analysis title
    		 McNemar
    Comparison groups
    DHCL v SHCL
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.03
    Method
    		 Mcnemar
    Confidence interval

    Secondary: Mean glucose

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    End point title
    		 Mean glucose
    End point description
    End point type
    Secondary
    End point timeframe
    0-33 hours
    End point values
    		 DHCL SHCL
    Number of subjects analysed
    13
    13
    Units: millimole(s)/litre
        arithmetic mean (standard deviation)
    8.32 ± 1.0
    8.62 ± 1.0
    Statistical analysis title
    		 Mixed Model analysis
    Statistical analysis description
    Repeated-measures ANOVA with a compound symmetry covariance structure was used to test the differences between the two study visits, adjusting for the study order. If data had a skewed distribution, logarithmic transformations were used
    Comparison groups
    DHCL v SHCL
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3
    Method
    		 Mixed models analysis
    Confidence interval

    Secondary: Number of events below 3.9 mmol/L

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    End point title
    		 Number of events below 3.9 mmol/L
    End point description
    End point type
    Secondary
    End point timeframe
    0-33 hours
    End point values
    		 DHCL SHCL
    Number of subjects analysed
    13
    13
    Units: Numbers of events
    29
    33
    Statistical analysis title
    		 McNemar
    Comparison groups
    DHCL v SHCL
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.13
    Method
    		 Mcnemar
    Confidence interval

    Secondary: Percentage of time in CGM-range between 3.9 and 10 mmol/l

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    End point title
    		 Percentage of time in CGM-range between 3.9 and 10 mmol/l
    End point description
    End point type
    Secondary
    End point timeframe
    0-33 hours
    End point values
    		 DHCL SHCL
    Number of subjects analysed
    13
    13
    Units: percent
        arithmetic mean (standard deviation)
    66.9 ± 15.1
    64.9 ± 12.1
    Statistical analysis title
    		 Mixed Model analysis
    Statistical analysis description
    Repeated-measures ANOVA with a compound symmetry covariance structure was used to test the differences between the two study visits, adjusting for the study order. If data had a skewed distribution, logarithmic transformations were used
    Comparison groups
    DHCL v SHCL
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.36
    Method
    		 Mixed models analysis
    Confidence interval

    Secondary: Percentage of time in CGM-range above 10.0 mmol/l

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    End point title
    		 Percentage of time in CGM-range above 10.0 mmol/l
    End point description
    End point type
    Secondary
    End point timeframe
    0-33 hours
    End point values
    		 DHCL SHCL
    Number of subjects analysed
    13
    13
    Units: percent
        arithmetic mean (standard deviation)
    27.5 ± 14.8
    29.2 ± 10.4
    Statistical analysis title
    		 Mixed Model analysis
    Statistical analysis description
    Repeated-measures ANOVA with a compound symmetry covariance structure was used to test the differences between the two study visits, adjusting for the study order. If data had a skewed distribution, logarithmic transformations were used
    Comparison groups
    DHCL v SHCL
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.46
    Method
    		 Mixed models analysis
    Confidence interval

    Secondary: Percentage of time in CGM-range below 3.0 mmol/l

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    End point title
    		 Percentage of time in CGM-range below 3.0 mmol/l
    End point description
    End point type
    Secondary
    End point timeframe
    0-33 hours
    End point values
    		 DHCL SHCL
    Number of subjects analysed
    13
    13
    Units: percent
        arithmetic mean (standard deviation)
    0.6 ± 0.7
    0.6 ± 0.5
    Statistical analysis title
    		 Wilcoxon Signed Rank Test
    Comparison groups
    DHCL v SHCL
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.46
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Coefficient of variation for sensor glucose

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    End point title
    		 Coefficient of variation for sensor glucose
    End point description
    End point type
    Secondary
    End point timeframe
    0-33 hours
    End point values
    		 DHCL SHCL
    Number of subjects analysed
    13
    13
    Units: percent
        arithmetic mean (standard deviation)
    39 ± 5
    39 ± 9
    Statistical analysis title
    		 Mixed Model analysis
    Statistical analysis description
    Repeated-measures ANOVA with a compound symmetry covariance structure was used to test the differences between the two study visits, adjusting for the study order. If data had a skewed distribution, logarithmic transformations were used
    Comparison groups
    DHCL v SHCL
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3
    Method
    		 Mixed models analysis
    Confidence interval

    Secondary: Mean insulin bolus dose

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    End point title
    		 Mean insulin bolus dose
    End point description
    End point type
    Secondary
    End point timeframe
    0-33 hours
    End point values
    		 DHCL SHCL
    Number of subjects analysed
    13
    13
    Units: unit(s)
        arithmetic mean (standard deviation)
    12.2 ± 6.2
    14.5 ± 5.9
    Statistical analysis title
    		 Mixed Model analysis
    Comparison groups
    DHCL v SHCL
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.17
    Method
    		 Mixed models analysis
    Confidence interval

    Secondary: Mean insulin basal dose

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    End point title
    		 Mean insulin basal dose
    End point description
    End point type
    Secondary
    End point timeframe
    0-33 hours
    End point values
    		 DHCL SHCL
    Number of subjects analysed
    13
    13
    Units: unit(s)
        arithmetic mean (standard deviation)
    28.8 ± 9.5
    31.0 ± 8.3
    Statistical analysis title
    		 Mixed Model analysis
    Comparison groups
    DHCL v SHCL
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.18
    Method
    		 Mixed models analysis
    Confidence interval

    Secondary: Mean glucagon dose

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    End point title
    		 Mean glucagon dose
    End point description
    End point type
    Secondary
    End point timeframe
    0-33 hours
    End point values
    		 DHCL SHCL
    Number of subjects analysed
    13
    13
    Units: unit(s)
        arithmetic mean (standard deviation)
    379 ± 13.8
    0 ± 0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were only reported while using the closed-loop systems, e.g. 0-33 hours during each study visit.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 RedCap
    Dictionary version
    12.03.02
    Reporting groups
    Reporting group title
    SHCL: Single-hormone
    Reporting group description
    		 -

    Reporting group title
    DHCL: Dual-hormone
    Reporting group description
    		 -

    Serious adverse events
    		 SHCL: Single-hormone DHCL: Dual-hormone
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 SHCL: Single-hormone DHCL: Dual-hormone
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 13 (100.00%)
    12 / 13 (92.31%)
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    5 / 13 (38.46%)
    1 / 13 (7.69%)
         occurrences all number
    5
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 13 (30.77%)
    5 / 13 (38.46%)
         occurrences all number
    4
    5
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Hunger
         subjects affected / exposed
    13 / 13 (100.00%)
    12 / 13 (92.31%)
         occurrences all number
    37
    35
    Endocrine disorders
    Nausea
         subjects affected / exposed
    4 / 13 (30.77%)
    5 / 13 (38.46%)
         occurrences all number
    4
    5

    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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