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    Clinical Trial Results:
    A Randomized, Double-blind, 2x2 Cross-over Euglycemic Clamp Study in Two Parallel Cohorts to Compare the Pharmacodynamic and Pharmacokinetic Properties of 0.4 and 0.6 U/kg/day Insulin Glargine (Toujeo®) with the Same Dose Levels of Insulin Degludec (Tresiba®) in Steady State After 8 Days Multiple Dosing Regimen in Patients with Diabetes Mellitus Type 1

    Summary
    EudraCT number
    2015-004843-38
    Trial protocol
    DE  
    Global end of trial date
    09 Jul 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    23 Jul 2017
    First version publication date
    23 Jul 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    LPS14585
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Sanofi-Aventis Groupe
    Sponsor organisation address
    54, rue de la Boetie , Paris, France, 75008
    Public contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.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
    03 Aug 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Jul 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the pharmacodynamic (PD) profile of Toujeo with insulin degludec (Tresiba) in steady state in a euglycemic clamp after 8 days once-daily dosing regimen at 2 dose levels in Type 1 diabetes mellitus (T1DM) subjects. - To compare the pharmacokinetic (PK) profile of Toujeo with insulin degludec in steady state in a euglycemic clamp after 8 days once-daily dosing regimen at 2 dose levels in T1DM subjects. – To access safety and tolerability of Toujeo and insulin degludec over 8 days in once-daily dosing regimen at 2 dose levels in T1DM subjects.
    Protection of trial subjects
    Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    08 Mar 2016
    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
    Germany: 48
    Worldwide total number of subjects
    48
    EEA total number of subjects
    48
    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)
    48
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted at a single center in Germany between 08 March 2016 and 09 July 2016.

    Pre-assignment
    Screening details
    A total of 48 subjects were randomized in 2 cohorts (cohort 1 and cohort 2) and were administered 2 treatments (Insulin glargine and Insulin degludec, both at 2 dose levels [0.4 U/kg/day and 0.6 U/kg/day for cohort 1 and cohort 2 respectively]) in a 2 treatment period-2 sequences cross-over design.

    Period 1
    Period 1 title
    Overall Period (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Cohort 1:Insulin glargine 0.4 U/kg & Insulin degludec 0.4 U/Kg
    Arm description
    Subjects received once daily dose of Insulin glargine (Test treatment 1 [T1]) or Insulin degludec (Reference treatment 1 [R1]) over 8 days in each treatment period (period 1 and 2) according to the treatment sequence (T1/R1 or R1/T1). A washout phase of 8-26 days was maintained between the two treatment periods.
    Arm type
    Experimental

    Investigational medicinal product name
    Insulin glargine
    Investigational medicinal product code
    HOE901-U300
    Other name
    Toujeo®
    Pharmaceutical forms
    Solution for injection in cartridge
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Insulin glargine (300 U/mL) 0.4 U/kg (T1) as subcutaneous injection over 8 days in either treatment period (period 1 and 2) according to the treatment sequence (T1/R1 or R1/T1).

    Investigational medicinal product name
    Insulin degludec
    Investigational medicinal product code
    Other name
    Tresiba®
    Pharmaceutical forms
    Solution for injection in cartridge
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Insulin degludec (100 U/mL) 0.4 U/kg (R1) as subcutaneous injection over 8 days in either treatment period (period 1 and 2) according to the treatment sequence (T1/R1 or R1/T1).

    Arm title
    Cohort 2:Insulin glargine 0.6 U/kg & Insulin degludec 0.6 U/kg
    Arm description
    Subjects received once daily doses of Insulin glargine (Test treatment 2 [T2]) or Insulin degludec (Reference treatment 2 [R2]) over 8 days in each treatment period (period 1 and 2) according to the treatment sequence (T2/R2 or R2/T2). A washout phase of 8-26 days was maintained between the two treatment periods.
    Arm type
    Experimental

    Investigational medicinal product name
    Insulin glargine
    Investigational medicinal product code
    HOE901-U300
    Other name
    Toujeo®
    Pharmaceutical forms
    Solution for injection in cartridge
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Insulin glargine (300 U/mL) 0.6 U/kg (T2) as subcutaneous injection over 8 days in either treatment period (period 1 and 2) according to the treatment sequence (T2/R2 or R2/T2).

    Investigational medicinal product name
    Insulin degludec
    Investigational medicinal product code
    Other name
    Tresiba®
    Pharmaceutical forms
    Solution for injection in cartridge
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Insulin degludec (100 U/mL) 0.6 U/kg (R2) as subcutaneous injection over 8 days in either treatment period (period 1 and 2) according to the treatment sequence (T2/R2 or R2/T2).

    Number of subjects in period 1
    Cohort 1:Insulin glargine 0.4 U/kg & Insulin degludec 0.4 U/Kg Cohort 2:Insulin glargine 0.6 U/kg & Insulin degludec 0.6 U/kg
    Started
    24
    24
    Completed
    23
    23
    Not completed
    1
    1
         Withdrew due to adverse event
             -
             1
         Consent withdrawn by subject
             1
             -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1:Insulin glargine 0.4 U/kg & Insulin degludec 0.4 U/Kg
    Reporting group description
    Subjects received once daily dose of Insulin glargine (Test treatment 1 [T1]) or Insulin degludec (Reference treatment 1 [R1]) over 8 days in each treatment period (period 1 and 2) according to the treatment sequence (T1/R1 or R1/T1). A washout phase of 8-26 days was maintained between the two treatment periods.

    Reporting group title
    Cohort 2:Insulin glargine 0.6 U/kg & Insulin degludec 0.6 U/kg
    Reporting group description
    Subjects received once daily doses of Insulin glargine (Test treatment 2 [T2]) or Insulin degludec (Reference treatment 2 [R2]) over 8 days in each treatment period (period 1 and 2) according to the treatment sequence (T2/R2 or R2/T2). A washout phase of 8-26 days was maintained between the two treatment periods.

    Reporting group values
    Cohort 1:Insulin glargine 0.4 U/kg & Insulin degludec 0.4 U/Kg Cohort 2:Insulin glargine 0.6 U/kg & Insulin degludec 0.6 U/kg Total
    Number of subjects
    24 24 48
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    43.7 ± 10.2 41 ± 11.8 -
    Gender categorical
    Units: Subjects
        Female
    2 0 2
        Male
    22 24 46
    Body mass index (BMI)
    Units: Kg/m^2
        arithmetic mean (standard deviation)
    25.42 ± 2.54 25.99 ± 2.08 -
    Glycohemoglobin (HbA1c) %
    Units: percentage of hemoglobin
        arithmetic mean (standard deviation)
    7.43 ± 1.01 7.21 ± 0.8 -
    Average Daily Basal Insulin Dose
    Units: U/Kg
        arithmetic mean (standard deviation)
    0.34 ± 0.14 0.3 ± 0.08 -
    Average Daily Prandial Insulin Dose
    Units: U/Kg
        arithmetic mean (standard deviation)
    0.33 ± 0.11 0.29 ± 0.09 -
    Average Daily Total Insulin Dose
    Units: U/Kg
        arithmetic mean (standard deviation)
    0.67 ± 0.16 0.59 ± 0.14 -

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1:Insulin glargine 0.4 U/kg & Insulin degludec 0.4 U/Kg
    Reporting group description
    Subjects received once daily dose of Insulin glargine (Test treatment 1 [T1]) or Insulin degludec (Reference treatment 1 [R1]) over 8 days in each treatment period (period 1 and 2) according to the treatment sequence (T1/R1 or R1/T1). A washout phase of 8-26 days was maintained between the two treatment periods.

    Reporting group title
    Cohort 2:Insulin glargine 0.6 U/kg & Insulin degludec 0.6 U/kg
    Reporting group description
    Subjects received once daily doses of Insulin glargine (Test treatment 2 [T2]) or Insulin degludec (Reference treatment 2 [R2]) over 8 days in each treatment period (period 1 and 2) according to the treatment sequence (T2/R2 or R2/T2). A washout phase of 8-26 days was maintained between the two treatment periods.

    Subject analysis set title
    Insulin degludec 0.4 U/kg (R1)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Insulin degludec (100 U/mL) 0.4 U/kg once daily over 8 days .

    Subject analysis set title
    Insulin glargine 0.4 U/kg (T1)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Insulin glargine (300 U/mL) 0.4 U/kg once daily over 8 days.

    Subject analysis set title
    Insulin degludec 0.6 U/kg (R2)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Insulin degludec (100 U/mL) 0.6 U/kg once daily over 8 days.

    Subject analysis set title
    Insulin glargine 0.6 U/kg (T2)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Insulin glargine (300 U/mL) 0.6 U/kg once daily over 8 days.

    Primary: Pharmacodynamics (PD): Fluctuation of the Glucose Infusion Rate (GIR) in Steady State Over the Dosing Interval of 24 Hours (GIR-smFL0-24)

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    End point title
    Pharmacodynamics (PD): Fluctuation of the Glucose Infusion Rate (GIR) in Steady State Over the Dosing Interval of 24 Hours (GIR-smFL0-24)
    End point description
    The individual fluctuation of the smoothed GIR 0-24 in steady state (GIR-smFL 0-24) after dosing on Day 8 was reported. It was calculated as the area between the individual smoothed GIR over time curve and the individual average GIR line from investigational medicinal product (IMP) administration on Day 8 until 24 hours after (within-day variability). It was measured by euglycemic clamp procedure in steady state. Analysis was performed on PD population defined as all subjects with no important deviations related to IMP intake and/or PD measurements for whom the PD parameters were available and evaluable. Clamps with less than 85% utility, incorrect dosing or a control deviation of more than 30 mg/dl during first 24 hours were excluded from the main PD analysis. A smoothing factor of 0.15 was used.
    End point type
    Primary
    End point timeframe
    From start time of IMP administration up to 24 hours after dosing on Day 8
    End point values
    Insulin degludec 0.4 U/kg (R1) Insulin glargine 0.4 U/kg (T1) Insulin degludec 0.6 U/kg (R2) Insulin glargine 0.6 U/kg (T2)
    Number of subjects analysed
    24
    21
    21
    23
    Units: mg/min/kg
        arithmetic mean (standard deviation)
    0.46 ± 0.19
    0.38 ± 0.17
    0.48 ± 0.22
    0.45 ± 0.17
    Statistical analysis title
    Test treatment 1 vs Reference treatment 1
    Statistical analysis description
    For GIR-smFL 0-24, estimates and 90% confidence interval (CI) for the geometric means ratio of treatments (T1/R1) were obtained by computing estimate and 90% CI for the difference between treatment means within the linear mixed effects model framework, and then converting to ratio of geometric means by the antilog transformation. Total number of subjects in the analysis was 24 (21 evaluable for T1 and 24 evaluable for R1). Number of treatment ratios available for the analysis is 21.
    Comparison groups
    Insulin degludec 0.4 U/kg (R1) v Insulin glargine 0.4 U/kg (T1)
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    other [1]
    Method
    Parameter type
    Geometric mean ratio
    Point estimate
    0.8
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0.66
         upper limit
    0.96
    Notes
    [1] - PD profile of test treatment was compared to reference treatment.
    Statistical analysis title
    Test treatment 2 vs Reference treatment 2
    Statistical analysis description
    For GIR-smFL 0-24, estimates and 90% confidence interval (CI) for the geometric means ratio of treatments ( T2/R2 ) were obtained by computing estimate and 90% CI for the difference between treatment means within the linear mixed effects model framework, and then converting to ratio of geometric means by the antilog transformation. Total number of subjects in the analysis was 24 (23 evaluable for T2 and 21 evaluable for R2). Number of treatment ratios available for the analysis is 20.
    Comparison groups
    Insulin glargine 0.6 U/kg (T2) v Insulin degludec 0.6 U/kg (R2)
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    other [2]
    Method
    Parameter type
    Geometric mean ratio
    Point estimate
    0.96
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0.83
         upper limit
    1.11
    Notes
    [2] - PD profile of test treatment was compared to reference treatment.

    Secondary: PD Profile in Steady state: Area under the GIR Over Time Curve up to 24 hours (GIR-AUC0-24); Maximum Smoothed Body Weight Standardized GIR (GIRmax) and Time to 50% of GIR AUC0-24 (T50%-GIR-AUC0-24)

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    End point title
    PD Profile in Steady state: Area under the GIR Over Time Curve up to 24 hours (GIR-AUC0-24); Maximum Smoothed Body Weight Standardized GIR (GIRmax) and Time to 50% of GIR AUC0-24 (T50%-GIR-AUC0-24)
    End point description
    The amount of glucose required (GIR-AUC) was a measure of insulin-mediated glucose uptake into tissues (glucose disposal or cumulative glucose lowering activity). GIR-AUC0-24 was a measure of area under the GIR over time curve up to 24 hours after dosing or end of clamp in case of premature termination or start of rescue insulin, whatever is earlier. T50%-GIR-AUC0-24 was the time to 50% of GIR-AUC0-24 and GIRmax was the maximum smoothed body weight standardized GIR. Analysis was performed on PD population.
    End point type
    Secondary
    End point timeframe
    From start time of IMP administration up to 24 h after dosing on day 8
    End point values
    Insulin degludec 0.4 U/kg (R1) Insulin glargine 0.4 U/kg (T1) Insulin degludec 0.6 U/kg (R2) Insulin glargine 0.6 U/kg (T2)
    Number of subjects analysed
    24
    21
    21
    23
    Units: Provided in categories
    arithmetic mean (standard deviation)
        GIR-AUC0-24 (mg/kg)
    1947.12 ± 1083.07
    1676.36 ± 1083.75
    3507.23 ± 1098.28
    2731.22 ± 1121.46
        T50%-GIR-AUC0-24 (hours)
    12.79 ± 1.06
    12.6 ± 2
    12.24 ± 0.89
    11.96 ± 1.44
        GIRmax (mg/min/kg)
    2.19 ± 0.97
    1.95 ± 0.98
    3.34 ± 0.91
    2.73 ± 0.99
    No statistical analyses for this end point

    Secondary: PK Profile (at Steady State) of Insulin Glargine 0.4 and 0.6 U/kg: Cmax, AUC0-24

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    End point title
    PK Profile (at Steady State) of Insulin Glargine 0.4 and 0.6 U/kg: Cmax, AUC0-24
    End point description
    Cmax: maximum concentration observed. AUC0-24: area under the serum concentration versus time curve was calculated using the trapezoidal method from time zero to 24 hours post dosing on Day 8. Analysis was performed on PK population defined as all subjects with no important deviations related to IMP intake and/or PK sampling for whom the PK parameters were available. During analysis, subjects with missing data in 1 but not both periods were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Predose and 1, 2, 4, 6, 8, 10, 12, 14, 16, 20, and 24 hours postdose on Day 8
    End point values
    Insulin glargine 0.4 U/kg (T1) Insulin glargine 0.6 U/kg (T2)
    Number of subjects analysed
    22
    24
    Units: Provided in categories
    arithmetic mean (standard deviation)
        Cmax (µU/mL)
    13.2 ± 3.32
    19.3 ± 6.14
        AUC0-24 (μU*h/mL)
    265 ± 72.2
    391 ± 132
    No statistical analyses for this end point

    Secondary: PK Profile (at Steady State) of Insulin Degludec 0.4 and 0.6 U/kg: Cmax, AUC0-24

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    End point title
    PK Profile (at Steady State) of Insulin Degludec 0.4 and 0.6 U/kg: Cmax, AUC0-24
    End point description
    Cmax: maximum concentration observed. AUC0-24: area under the serum concentration versus time curve was calculated using the trapezoidal method from time zero to 24 hours post dosing on Day 8. Analysis was performed on PK population. During analysis, subjects with missing data in 1 but not both periods were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Predose and 1, 2, 4, 6, 8, 10, 12, 14, 16, 20, and 24 hours postdose on Day 8
    End point values
    Insulin degludec 0.4 U/kg (R1) Insulin degludec 0.6 U/kg (R2)
    Number of subjects analysed
    24
    23
    Units: specified in categories
    arithmetic mean (standard deviation)
        Cmax (µU/mL)
    627 ± 128
    891 ± 147
        AUC0-24 (μU*h/mL)
    12400 ± 2620
    17600 ± 2970
    No statistical analyses for this end point

    Secondary: PK Profile (at Steady State): T50%-AUC0-24

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    End point title
    PK Profile (at Steady State): T50%-AUC0-24
    End point description
    T50%-AUC0-24: time to reach 50% of AUC0-24. Analysis was performed on PK population. During analysis, subjects with missing data in 1 but not both periods were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Predose and 1, 2, 4, 6, 8, 10, 12, 14, 16, 20, and 24 hours postdose on Day 8
    End point values
    Insulin degludec 0.4 U/kg (R1) Insulin glargine 0.4 U/kg (T1) Insulin degludec 0.6 U/kg (R2) Insulin glargine 0.6 U/kg (T2)
    Number of subjects analysed
    24
    22
    23
    24
    Units: hours
        arithmetic mean (standard deviation)
    11.43 ± 0.43
    11.82 ± 0.63
    11.45 ± 0.54
    11.74 ± 0.59
    No statistical analyses for this end point

    Secondary: PK Profile: Relative Degree of Fluctuation (Frel)

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    End point title
    PK Profile: Relative Degree of Fluctuation (Frel)
    End point description
    Relative degree of fluctuation (percentage fluctuation) was calculated at steady state. Analysis was performed on PK population.
    End point type
    Secondary
    End point timeframe
    From start time of IMP administration up to 24 hours after dosing on day 8
    End point values
    Insulin degludec 0.4 U/kg (R1) Insulin glargine 0.4 U/kg (T1) Insulin degludec 0.6 U/kg (R2) Insulin glargine 0.6 U/kg (T2)
    Number of subjects analysed
    24
    22
    23
    24
    Units: percentage fluctuation
        arithmetic mean (standard deviation)
    48 ± 16
    44 ± 22
    49 ± 17
    42 ± 16
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All Adverse Events (AEs) were collected from signature of the informed consent form up to the final visit (follow-up visit: up to Day 18 of treatment period 2) regardless of seriousness or relationship to investigational product.
    Adverse event reporting additional description
    Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during on treatment phase, per period (time from the first IMP administration (included) until 3 days (Day 11) after the last dose of IMP). Safety population: all randomized subjects who were exposed to any IMP, regardless of the amount of treatment administered.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Insulin degludec 0.4 U/kg (R1)
    Reporting group description
    Insulin degludec (100 U/mL) 0.4 U/kg once daily over 8 days.

    Reporting group title
    Insulin glargine 0.4 U/kg (T1)
    Reporting group description
    Insulin glargine (300 U/mL) 0.4 U/kg once daily over 8 days.

    Reporting group title
    Insulin degludec 0.6 U/kg (R2)
    Reporting group description
    Insulin degludec (100 U/mL) 0.6 U/kg once daily over 8 days.

    Reporting group title
    Insulin glargine 0.6 U/kg (T2)
    Reporting group description
    Insulin glargine (300 U/mL) 0.6 U/kg once daily over 8 days.

    Serious adverse events
    Insulin degludec 0.4 U/kg (R1) Insulin glargine 0.4 U/kg (T1) Insulin degludec 0.6 U/kg (R2) Insulin glargine 0.6 U/kg (T2)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 23 (0.00%)
    0 / 23 (0.00%)
    0 / 24 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Insulin degludec 0.4 U/kg (R1) Insulin glargine 0.4 U/kg (T1) Insulin degludec 0.6 U/kg (R2) Insulin glargine 0.6 U/kg (T2)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 24 (62.50%)
    20 / 23 (86.96%)
    20 / 23 (86.96%)
    22 / 24 (91.67%)
    Vascular disorders
    Phlebitis
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 23 (0.00%)
    0 / 23 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Injury, poisoning and procedural complications
    Accident
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 23 (0.00%)
    0 / 23 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Drug Administered At Inappropriate Site
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 23 (0.00%)
    0 / 23 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    0
    0
    1
    Ligament Sprain
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 23 (0.00%)
    0 / 23 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Procedural Dizziness
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 23 (0.00%)
    0 / 23 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal Pain
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 23 (4.35%)
    0 / 23 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 24 (8.33%)
    1 / 23 (4.35%)
    0 / 23 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    4
    1
    0
    2
    General disorders and administration site conditions
    Extravasation
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 23 (0.00%)
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Fatigue
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 23 (4.35%)
    0 / 23 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Psychiatric disorders
    Apathy
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 23 (4.35%)
    0 / 23 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 23 (0.00%)
    0 / 23 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 23 (0.00%)
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 23 (0.00%)
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Pain In Extremity
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 23 (4.35%)
    0 / 23 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    14 / 24 (58.33%)
    17 / 23 (73.91%)
    20 / 23 (86.96%)
    21 / 24 (87.50%)
         occurrences all number
    74
    57
    137
    102
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    0 / 24 (0.00%)
    2 / 23 (8.70%)
    0 / 23 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    2
    0
    1
    Vestibular Neuronitis
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 23 (0.00%)
    0 / 23 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Feb 2016
    Following changes were made: The vital signs and electrocardiogram (ECG) ranges for inclusion of T1DM subjects who were “otherwise healthy for T1DM by assessment of medical history and physical examination” were adjusted to known ranges in this population for systolic blood pressure (SBP) and diastolic blood pressure (DBP): 90 to 140 mmHg for SBP and 50 to 90 mmHg for DBP, and the upper limit for the QRS duration time to 110 ms.
    21 Mar 2016
    Following changes were made: Correction of inconsistence regarding the documentation of hypoglycemia.

    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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