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    Clinical Trial Results:
    Low-dose Glibenclamide in Type 2 Diabetes Mellitus - Part A (LEGEND-A)

    Summary
    EudraCT number
    		 2015-002837-23
    Trial protocol
    		 GB  
    Global end of trial date
    19 Feb 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Aug 2019
    First version publication date
    01 Aug 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    19062015
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT19062015
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Oxford
    Sponsor organisation address
    Churchill Hospital, Oxford, United Kingdom, OX3 7LE
    Public contact
    Ioannis Spiliotis, University of Oxford, ioannis.spiliotis@ocdem.ox.ac.uk
    Scientific contact
    Ioannis Spiliotis, University of Oxford, ioannis.spiliotis@ocdem.ox.ac.uk
    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
    20 Nov 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Mar 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Feb 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To identify the dose of glibenclamide that causes a significant decrease in fasting plasma glucagon concentration.
    Protection of trial subjects
    The main serious side-effect of glibenclamide is hypoglycaemia, however the overall risk is low and is dose- dependent. Furthermore, potential participants who have significant renal or liver disease will be excluded from the trial. The doses of glibenclamide used in the trial are lower than those used in normal clinical practice for the treatment of type 2 diabetes and therefore are very unlikely to result in severe hypoglycaemia episodes. This trial will involve administration of glibenclamide at doses much lower than those used in clinical practice. There is currently no licensed formulation of glibenclamide that can easily and reproducibly deliver doses as low as 0.3mg. Therefore, an oral suspension of glibenclamide (GlibenTek), which can be titrated by volume, has been formulated by the company AmmTeK (Paris, France) and is already being used for a different clinical trial. GlibenTek will be supplied by Pharmaservices (Paris, France). The study will involve 9 visits to the clinical trials unit for fasting blood tests every 3 or 4 days for a total of 21 days. The dosing schedule has been adjusted so as to minimise the inconvenience to participants by avoiding visits on weekends. In addition, home visits for blood sampling will be organised where possible for those participants who are unable to attend all the clinical trials unit visit.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Apr 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
    United Kingdom: 16
    Worldwide total number of subjects
    16
    EEA total number of subjects
    16
    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)
    6
    From 65 to 84 years
    10
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Inclusion criteria: 1. Diagnosis of Type 2 diabetes 2. age 18 years or over 3. Diet controlled or on metformin only for diabetic control 4. HbA1c 6.0% - 9.5% (42mmol/mol to 80mmol/mol) inclusive

    Pre-assignment period milestones
    Number of subjects started
    		 19 [1]
    Number of subjects completed
    		 16

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 did not meet inclusion criteria: 3
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 19 potential participants were screened, however only 16 met the inclusion criteria for the trial.
    Period 1
    Period 1 title
    overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    n/a

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 High baseline fasting glucagon
    Arm description
    		 High baseline fasting glucagon (defined as >= 15pmol/L). Increasing doses of glibenclamide oral suspension from 0.3mg/day to 6mg/day.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Glibenclamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Oral liquid suspension at strengths of 0.6 mg/ml and 6mg/ml. Dosing schedule ranged from 0.3mg to 6mg daily, split into morning and evening.

    Arm title
    		 Normal baseline fasting glucagon
    Arm description
    		 Normal baseline fasting glucagon (defined as <15pmol/L). Increasing doses of glibenclamide oral suspension from 0.3mg/day to 6mg/day.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Glibenclamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Oral liquid suspension at strengths of 0.6mg/ml and 6mg/ml. Dosing schedule ranged from 0.3 - 6mg daily, split into morning and evening.

    Number of subjects in period 1
    		High baseline fasting glucagon Normal baseline fasting glucagon
    Started
    4
    12
    Completed
    4
    12

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    High baseline fasting glucagon
    Reporting group description
    		 High baseline fasting glucagon (defined as >= 15pmol/L). Increasing doses of glibenclamide oral suspension from 0.3mg/day to 6mg/day.

    Reporting group title
    Normal baseline fasting glucagon
    Reporting group description
    		 Normal baseline fasting glucagon (defined as <15pmol/L). Increasing doses of glibenclamide oral suspension from 0.3mg/day to 6mg/day.

    Reporting group values
    		 High baseline fasting glucagon Normal baseline fasting glucagon Total
    Number of subjects
    		 4 12 16
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
        Adults > 18
    		 4 12 16
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 52 ( 10 ) 68 ( 7 ) -
    Gender categorical
    Units: Subjects
        Female
    		 1 8 9
        Male
    		 3 4 7

    End points

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    End points reporting groups
    Reporting group title
    High baseline fasting glucagon
    Reporting group description
    		 High baseline fasting glucagon (defined as >= 15pmol/L). Increasing doses of glibenclamide oral suspension from 0.3mg/day to 6mg/day.

    Reporting group title
    Normal baseline fasting glucagon
    Reporting group description
    		 Normal baseline fasting glucagon (defined as <15pmol/L). Increasing doses of glibenclamide oral suspension from 0.3mg/day to 6mg/day.

    Primary: Concentration of plasma glucagon using fasting blood samples prior to each dose change

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    End point title
    		 Concentration of plasma glucagon using fasting blood samples prior to each dose change
    End point description
    0.3mg glibenclamide dose. See attached spreadsheet for full analysis of results of doses 0.3mg-1.8mg glibenclamide.
    End point type
    Primary
    End point timeframe
    Pre-dose blood sampling on day 3
    End point values
    		 High baseline fasting glucagon Normal baseline fasting glucagon
    Number of subjects analysed
    4
    12
    Units: pmol/L
        arithmetic mean (standard error)
    20.3 ( 2.3 )
    6.45 ( 1.1 )
    Attachments
    		 LEGEND-A glucagon analysis
    Statistical analysis title
    		 Two-way repeated measures ANOVA
    Comparison groups
    Normal baseline fasting glucagon v High baseline fasting glucagon
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events will be recorded from the baseline assessment onwards, i.e. prior to the each dose change of the trial medication.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 SNOMED CT
    Dictionary version
    1.36.4
    Reporting groups
    Reporting group title
    Hypoglycaemia
    Reporting group description
    		 Hypoglycaemia (blood glucose <4.0mmol/L)

    Reporting group title
    Dizzy/tired/headache
    Reporting group description
    		 Reported symptoms of dizziness, tiredness, or headache that were unrelated to hypoglycaemia events.

    Reporting group title
    Urinary tract infection
    Reporting group description
    		 -

    Serious adverse events
    		 Hypoglycaemia Dizzy/tired/headache Urinary tract infection
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Hypoglycaemia Dizzy/tired/headache Urinary tract infection
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 16 (62.50%)
    3 / 16 (18.75%)
    1 / 16 (6.25%)
    General disorders and administration site conditions
    Headache
    Additional description: Symptoms of dizziness, tiredness or headache unrelated to hypoglycaemia events.
         subjects affected / exposed
    7 / 16 (43.75%)
    3 / 16 (18.75%)
    1 / 16 (6.25%)
         occurrences all number
    12
    3
    1
    Endocrine disorders
    Hypoglycaemia
    Additional description: Either documented blood glucose <4.0mmol/L or symptoms consistent with hypoglycaemia in absence of blood glucose monitoring.
         subjects affected / exposed
    7 / 16 (43.75%)
    3 / 16 (18.75%)
    1 / 16 (6.25%)
         occurrences all number
    12
    3
    1
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    7 / 16 (43.75%)
    3 / 16 (18.75%)
    1 / 16 (6.25%)
         occurrences all number
    12
    3
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    31 Aug 2016
    Change to inclusion criteria from HbA1c 53-80mmol/mol inclusive, to HbA1c 42-80mmol/mol.

    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.
    Full pharmacokinetic data does not currently exist for the low doses of glibenclamide used in this trial. The sample size of the "high" baseline glucagon is small & the prevalence of baseline fasting hyperglucagonaemia in this population is unknown.
    For support, Contact us.
    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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