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    Clinical Trial Results:
    Glimepiride monotherapy vs. combination of glimepiride and linagliptin therapy in patients with HNF1A-diabetes.

    Summary
    EudraCT number
    		 2017-000204-15
    Trial protocol
    		 DK  
    Global end of trial date
    26 Apr 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Oct 2020
    First version publication date
    08 Oct 2020
    Other versions
    Summary report(s)
    		 Full article

    Trial information

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    Trial identification
    Sponsor protocol code
    060286
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Steno Diabetes Center Copenhagen
    Sponsor organisation address
    Gentofte Hospitals Vej 7, 3. sal, Hellerup, Denmark, 2900
    Public contact
    Type 2 Biology, Steno Diabetes Center Copenhagen, Gentofte Hospital, 0045 40940825, tina.vilsboell.lauritsen.01@regionh.dk
    Scientific contact
    Type 2 Biology, Steno Diabetes Center Copenhagen, Gentofte Hospital, 0045 40940825, tina.vilsboell.lauritsen.01@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 Feb 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Apr 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of this trial is to investigate the effect of glimepiride + linagliptin vs. glimepiride + placebo on glycaemic variability in patients with hepatocyte nuclear factor 1-alpha (HNF1A) diabetes in a double-blind, randomised, cross-over trial. HNF1A-diabetes is also known as maturity onset diabetes of the young type 3 (MODY3). All data is available in Diabetes Care (https://care.diabetesjournals.org/content/early/2020/07/10/dc20-0408) or follow link (Pubmed-identifier: PMID: 32661107).
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki and ICH Good Clinical Practice Guidelines.
    Background therapy
    		 Subject were enrolled on either glimepiride monotherapy (19 subjects) or diet (1 subject). Pre-trial treatment with glimepiride continued throughout the trial. The glimepiride dose was either increased or decreased during treatment with linagliptin/placebo according to fasting plasma glucose levels (target mean of 4.5 to 6.0 mmol/L) and without episodes of hypoglycaemia.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Sep 2017
    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
    Denmark: 19
    Worldwide total number of subjects
    19
    EEA total number of subjects
    19
    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
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Two sites were used for recruitment: 1) Steno Diabetes Center Copenhagen, Gentofte Hospital, Hellerup, Denmark; and 2) Steno Diabetes Center Aarhus, Aarhus, Denmark

    Pre-assignment
    Screening details
    		 Twenty patients were screened. One dropped out before randomisation and is thus not part of the analysis.

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    This is a randomised, double-blind, placebo controlled cross-over trial.

    Arms
    Arm title
    		 Baseline
    Arm description
    		 All patients at baseline.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Glimepiride
    Investigational medicinal product code
    Other name
    Glimepiride (R)
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Flexible dosing according to titration ranging from 0.5 mg to 6.0 mg. The dose was once daily (0.5 mg) or twice daily (dose>0.5 mg)

    Number of subjects in period 1
    		Baseline
    Started
    19
    Completed
    19
    Period 2
    Period 2 title
    Experimental period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    Patients exposed for glimepiride + linagliptin Trial design: Patients were exposed to either: 1) 16 weeks with glimepiride + linagliptin 5 mg, a four-week wash-out and then 16 weeks with glimepiride + placebo, or 2) 1) 16 weeks with glimepiride + placebo, a four-week wash-out and then 16 weeks with glimepiride + linagliptin

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Glimepiride + placebo
    Arm description
    		 Patients exposed for glimepiride + placebo. Trial design: Subjects when through a baseline evaluation (mixed meal test and continuous glucose monitoring for six days). After baseline evaluation subjects were treated with either: 1) 16 weeks with glimepiride + linagliptin 5 mg, a four-week wash-out and then 16 weeks with glimepiride + placebo 2) 1) 16 weeks with glimepiride + placebo, a four-week wash-out and then 16 weeks with glimepiride + linagliptin Linagliptin/placebo dose was fixed. Glimepiride dose was titrated (up or down 0.5 mg) in the first four week of each treatment period. Treatment target was mean fasting plasma glucose levels of 4.5-6.0 mmol/L without episodes of hypoglycaemia. If a subject had recurrent episodes of hypoglycaemia after the titration period glimepiride dose was reduced 0.5 mg.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Glimepiride
    Investigational medicinal product code
    Other name
    Glimepiride (R)
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Flexible dosing according to titration ranging from 0.5 mg to 6.0 mg. The dose was once daily (0.5 mg) or twice daily (dose>0.5 mg)

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Once daily

    Arm title
    		 Glimepiride + linagliptin 5 mg
    Arm description
    		 Patients exposed for glimepiride + linagliptin. Trial design: Subjects when through a baseline evaluation (mixed meal test and continuous glucose monitoring for six days). After baseline evaluation subjects were treated with either: 1) 16 weeks with glimepiride + linagliptin 5 mg, a four-week wash-out and then 16 weeks with glimepiride + placebo 2) 1) 16 weeks with glimepiride + placebo, a four-week wash-out and then 16 weeks with glimepiride + linagliptin Linagliptin/placebo dose was fixed. Glimepiride dose was titrated (up or down 0.5 mg) in the first four week of each treatment period. Treatment target was mean fasting plasma glucose levels of 4.5-6.0 mmol/L without episodes of hypoglycaemia. If a subject had recurrent episodes of hypoglycaemia after the titration period glimepiride dose was reduced 0.5 mg.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Linagliptin
    Investigational medicinal product code
    Other name
    Trajenta (R)
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    5 mg tablet

    Investigational medicinal product name
    Glimepiride
    Investigational medicinal product code
    Other name
    Glimepiride (R)
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Flexible dosing according to titration ranging from 0.5 mg to 6.0 mg. The dose was once daily (0.5 mg) or twice daily (dose>0.5 mg)

    Number of subjects in period 2
    		Glimepiride + placebo Glimepiride + linagliptin 5 mg
    Started
    19
    19
    Completed
    19
    19

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Baseline
    Reporting group description
    		 All patients at baseline.

    Reporting group values
    		 Baseline Total
    Number of subjects
    		 19 19
    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
    Age
    Units: years
        arithmetic mean (standard deviation)
    		 43 ± 13 -
    Gender categorical
    Units: Subjects
        Female
    		 11 11
        Male
    		 8 8
    Subject analysis sets

    Subject analysis set title
    Baseline
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All subjects at baseline

    Subject analysis sets values
    		 Baseline
    Number of subjects
    19
    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
    Age
    Units: years
        arithmetic mean (standard deviation)
    43 ± 14
    Gender categorical
    Units: Subjects
        Female
    11
        Male
    8

    End points

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    End points reporting groups
    Reporting group title
    Baseline
    Reporting group description
    		 All patients at baseline.
    Reporting group title
    Glimepiride + placebo
    Reporting group description
    		 Patients exposed for glimepiride + placebo. Trial design: Subjects when through a baseline evaluation (mixed meal test and continuous glucose monitoring for six days). After baseline evaluation subjects were treated with either: 1) 16 weeks with glimepiride + linagliptin 5 mg, a four-week wash-out and then 16 weeks with glimepiride + placebo 2) 1) 16 weeks with glimepiride + placebo, a four-week wash-out and then 16 weeks with glimepiride + linagliptin Linagliptin/placebo dose was fixed. Glimepiride dose was titrated (up or down 0.5 mg) in the first four week of each treatment period. Treatment target was mean fasting plasma glucose levels of 4.5-6.0 mmol/L without episodes of hypoglycaemia. If a subject had recurrent episodes of hypoglycaemia after the titration period glimepiride dose was reduced 0.5 mg.

    Reporting group title
    Glimepiride + linagliptin 5 mg
    Reporting group description
    		 Patients exposed for glimepiride + linagliptin. Trial design: Subjects when through a baseline evaluation (mixed meal test and continuous glucose monitoring for six days). After baseline evaluation subjects were treated with either: 1) 16 weeks with glimepiride + linagliptin 5 mg, a four-week wash-out and then 16 weeks with glimepiride + placebo 2) 1) 16 weeks with glimepiride + placebo, a four-week wash-out and then 16 weeks with glimepiride + linagliptin Linagliptin/placebo dose was fixed. Glimepiride dose was titrated (up or down 0.5 mg) in the first four week of each treatment period. Treatment target was mean fasting plasma glucose levels of 4.5-6.0 mmol/L without episodes of hypoglycaemia. If a subject had recurrent episodes of hypoglycaemia after the titration period glimepiride dose was reduced 0.5 mg.

    Subject analysis set title
    Baseline
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All subjects at baseline

    Primary: Mean amplitude of glycemic excursions (MAGE)

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    End point title
    		 Mean amplitude of glycemic excursions (MAGE)
    End point description
    End point type
    Primary
    End point timeframe
    Difference between glimepiride + linagliptin vs. glimepiride + placebo at the end of each treatment period based on continuous glucose measurements
    End point values
    		 Glimepiride + placebo Glimepiride + linagliptin 5 mg
    Number of subjects analysed
    19
    19
    Units: mmol/L
    least squares mean (confidence interval 0.05%)
        Glycaemic variability
    5.8 (5.0 to 6.4)
    5.1 (4.2 to 6.1)
    Statistical analysis title
    		 Glimepiride + linagliptin vs. glimepiride + placeb
    Comparison groups
    Glimepiride + linagliptin 5 mg v Glimepiride + placebo
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1907
    Method
    		 Linear Mixed Model
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.9
         upper limit
    		 0.4

    Primary: Coefficient of variation (CV)

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    End point title
    		 Coefficient of variation (CV)
    End point description
    End point type
    Primary
    End point timeframe
    Difference between glimepiride + linagliptin vs. glimepiride + placebo at the end of each treatment period based on continuous glucose measurements
    End point values
    		 Glimepiride + placebo Glimepiride + linagliptin 5 mg
    Number of subjects analysed
    19
    19
    Units: percent
    least squares mean (confidence interval 95%)
        Glycaemic variability
    31.4 (28.3 to 34.4)
    27.7 (24.9 to 30.7)
    Statistical analysis title
    		 Coefficient of variation
    Comparison groups
    Glimepiride + placebo v Glimepiride + linagliptin 5 mg
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0401
    Method
    		 Linear Mixed Model
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7
         upper limit
    		 0

    Primary: Standard deviation (SD)

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    End point title
    		 Standard deviation (SD)
    End point description
    End point type
    Primary
    End point timeframe
    Difference between glimepiride + linagliptin vs. glimepiride + placebo at the end of each treatment period based on continuous glucose measurements
    End point values
    		 Glimepiride + placebo Glimepiride + linagliptin 5 mg
    Number of subjects analysed
    19
    19
    Units: mmol/mol
    least squares mean (confidence interval 95%)
        Glycaemic variability
    2.8 (2.4 to 3.2)
    2.3 (1.9 to 2.7)
    Statistical analysis title
    		 Standard deviation
    Statistical analysis description
    Difference between glimepiride + linagliptin vs. glimepiride + placebo at the end of each treatment period based on continuous glucose measurements
    Comparison groups
    Glimepiride + placebo v Glimepiride + linagliptin 5 mg
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.021
    Method
    		 Linear Mixed Model
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.8
         upper limit
    		 -0.1

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From randomisation to end of study visit
    Adverse event reporting additional description
    Information about adverse events were collected both during routinely scheduled visits as well when subjects opportunistically contacted the investigators.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23
    Reporting groups
    Reporting group title
    Glimepiride + linagliptin
    Reporting group description
    		 -

    Reporting group title
    Glimepiride + placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Glimepiride + linagliptin Glimepiride + placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 19 (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: 5%
    Non-serious adverse events
    		 Glimepiride + linagliptin Glimepiride + placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 19 (31.58%)
    8 / 19 (42.11%)
    Infections and infestations
    Gastroenteritis
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 19 (10.53%)
    4 / 19 (21.05%)
         occurrences all number
    2
    4
    Upper Airway Infection
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 19 (10.53%)
    3 / 19 (15.79%)
         occurrences all number
    2
    3
    Acute Rhinitis
         subjects affected / exposed
    2 / 19 (10.53%)
    1 / 19 (5.26%)
         occurrences all number
    2
    1

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/32661107
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