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    Clinical Trial Results:
    The effect of lixisenatide in type 1 diabetes

    Summary
    EudraCT number
    2013-002259-14
    Trial protocol
    GB  
    Global end of trial date
    03 May 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    09 Feb 2018
    First version publication date
    09 Feb 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TRG12-05
    Additional study identifiers
    ISRCTN number
    ISRCTN00290196
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    University of Oxford
    Sponsor organisation address
    Joint Research Office, Churchill Hospital, Oxford, United Kingdom, OX3 7LE
    Public contact
    Dr Irene Kennedy, Diabetes Trials Unit, University of Oxford, +44 (0)1865857257, trg@dtu.ox.ac.uk
    Scientific contact
    Dr Irene Kennedy, Diabetes Trials Unit, University of Oxford, +44 (0)1865857257, trg@dtu.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
    03 May 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 May 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    03 May 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the main trial is to determine whether adding lixisenatide to basal bolus insulin (combination of long acting insulin once a day called basal with short acting insulin with meals, called bolus) significantly improves glycaemic (blood sugar) control during the 3 hour post prandial period (i.e. following a meal) compared to basal bolus insulin and a 'dummy' or placebo injection.
    Protection of trial subjects
    The trial was conducted in conformance with Good Clinical Practice (GCP) standards and applicable local statutes and regulations regarding ethical committee review, informed consent and the protection of human subjects participating in biomedical research. The following additional measures, defined for this individual trial, were in-place for the protection of the trial subjects: - The main trial was preceded by a preliminary safety trial which assessed the amount of meal-time insulin dose reduction that avoided hypoglycaemic episodes while maintaining blood glucose levels within an acceptable range when dual treatment with GLP-1 receptor agonist and insulin was started. - To avoid hypoglycaemia in trial participants, their usual dose of insulin was reduced at the beginning of treatment periods, and titrated to maintain blood glucose within the protocol-defined range. - In the event that a participant experienced severe hypoglycaemia (an event requiring third-party assistance) at any point during the trial, Investigational Medicinal Product (IMP) would be discontinued permanently.
    Background therapy
    Inclusion criteria for the trial specify participants must be taking a stable insulin dose (within 20%) over 3 months prior to recruitment.
    Evidence for comparator
    -
    Actual start date of recruitment
    02 May 2014
    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: 27
    Worldwide total number of subjects
    27
    EEA total number of subjects
    27
    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)
    26
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The trial was single-centre, carried out at the Clinical Research Unit (CRU), Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), UK, between 2nd May 2014 (First Patient First Visit) and 3rd May 2016 (Last Patient Last Visit)

    Pre-assignment
    Screening details
    Participants aged 18-70 years inclusive providing written informed consent were eligible if they were diagnosed with stable type 1 diabetes for at least 12 months (Stable insulin dose (within 20%) over 3 months prior to recruitment), used a Basal-Bolus insulin regimen, HbA1c between 6.5% and 10.0% (inclusive) and BMI < 35 Kg/m2.

    Pre-assignment period milestones
    Number of subjects started
    38 [1]
    Number of subjects completed
    27

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    Participants failed to meet eligibility criteria.: 11
    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: The number of participants starting the pre-assignment period are those who provided Informed Consent and were screened. The number enrolled is the number eligible who then went on to be enrolled i.e. randomised. The difference is due to those individuals who failed screening.
    Period 1
    Period 1 title
    Main trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor
    Blinding implementation details
    Participants were randomised to one of two treatment arms in a double blind cross-over trial. An independent statistician generated the randomization code list and this was added in a concealed fashion to the Trial Management System (TMS). It was blinded to all personnel apart from: The independent statistician who generated it; the IT team member who uploaded it onto the TMS; the IMP packaging team and the pharmacy team who managed the 24-hour emergency unblinding service.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Lixisenatide followed by matching placebo
    Arm description
    Lixisenatide treatment period (4 weeks) followed by a washout period (4 weeks) then matching placebo treatment period (4 weeks) followed by a final washout period (4 weeks). Participants were asked to inject the trial medication using an injection pen once each morning (between 8-10 am) in addition to their prescribed insulin medication.
    Arm type
    Cross-over design

    Investigational medicinal product name
    Lixisenatide
    Investigational medicinal product code
    AVE0010
    Other name
    Lyxumia
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Lixisenatide 10μg/day injected subcutaneously between 8-10am for 2 weeks followed by lixisenatide 20μg/day injected for a further 2 weeks then a 28-day washout period.

    Investigational medicinal product name
    Matching placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Matching placebo 10μg/day injected subcutaneously between 8-10am for 2 weeks followed by matching placebo 20μg/day injected for a further 2 weeks then a 28-day washout period leading to the closeout visit.

    Arm title
    Matching placebo followed by lixisenatide
    Arm description
    Matching placebo treatment period (4 weeks) followed by a washout period (4 weeks) then lixisenatide treatment period (4 weeks) followed by a final washout period (4 weeks). Participants were asked to inject the trial medication using an injection pen once each morning (between 8-10 am) in addition to their prescribed insulin medication.
    Arm type
    Cross-over design

    Investigational medicinal product name
    Matching placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Matching placebo 10μg/day injected subcutaneously between 8-10am for 2 weeks followed by matching placebo 20μg/day injected for a further 2 weeks then a 28-day washout period leading to the closeout visit.

    Investigational medicinal product name
    Lixisenatide
    Investigational medicinal product code
    AVE0010
    Other name
    Lyxumia
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Lixisenatide 10μg/day injected subcutaneously between 8-10am for 2 weeks followed by lixisenatide 20μg/day injected for a further 2 weeks then a 28-day washout period.

    Number of subjects in period 1
    Lixisenatide followed by matching placebo Matching placebo followed by lixisenatide
    Started
    13
    14
    Completed
    12
    13
    Not completed
    1
    1
         Subject decision to stop visits, consent unchanged
             1
             -
         Pregnancy
             -
             1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Lixisenatide followed by matching placebo
    Reporting group description
    Lixisenatide treatment period (4 weeks) followed by a washout period (4 weeks) then matching placebo treatment period (4 weeks) followed by a final washout period (4 weeks). Participants were asked to inject the trial medication using an injection pen once each morning (between 8-10 am) in addition to their prescribed insulin medication.

    Reporting group title
    Matching placebo followed by lixisenatide
    Reporting group description
    Matching placebo treatment period (4 weeks) followed by a washout period (4 weeks) then lixisenatide treatment period (4 weeks) followed by a final washout period (4 weeks). Participants were asked to inject the trial medication using an injection pen once each morning (between 8-10 am) in addition to their prescribed insulin medication.

    Reporting group values
    Lixisenatide followed by matching placebo Matching placebo followed by lixisenatide Total
    Number of subjects
    13 14 27
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    13 13 26
        From 65-84 years
    0 1 1
    Gender categorical
    Units: Subjects
        Female
    6 8 14
        Male
    7 6 13
    Smoking status
    Units: Subjects
        Current smoker
    2 1 3
        Current non-smoker
    11 13 24
    Body Mass Index (BMI)
    Units: Kg/cm2
        arithmetic mean (standard deviation)
    26.7 ± 3.5 27.0 ± 3.8 -
    Waist circumference
    Units: cm
        arithmetic mean (standard deviation)
    91.9 ± 10.1 91.6 ± 14.8 -
    HbA1c
    Units: mmol/L
        arithmetic mean (standard deviation)
    66.2 ± 9.7 64.2 ± 6.8 -
    Fasting Plasma Glucose (FPG)
    Units: mmol/L
        arithmetic mean (standard deviation)
    9.8 ± 5.4 9.9 ± 3.9 -
    C-peptide
    Units: nmol/L
        arithmetic mean (standard deviation)
    0.0 ± 0.1 0.0 ± 0.0 -
    Subject analysis sets

    Subject analysis set title
    Full analysis population
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Data for one participant was removed from the full analysis population for Arm 2 (matching placebo followed by lixisenatide) due to pregnancy post-randomisation. Twenty-six participants were therefore included in the initial full analysis data-set. Data for two of the remaining twenty-six participants was subsequently also excluded from the primary analysis because one participant dropped out of the study visits after the first treatment period and one participant was missing baseline primary endpoint data. This meant that determination of treatment affect was not possible for these two individuals' data. The primary end-point results analysis data presented in this report relates to the remaining 24 of the 27 participants randomised. The Safety Population (SP) consists of all randomised individuals who received at least one dose of the study medication, hence adverse event information in this report is presented for all 27 participants randomised.

    Subject analysis sets values
    Full analysis population
    Number of subjects
    26
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    25
        From 65-84 years
    1
    Age continuous
    Units:
        
    ±
    Gender categorical
    Units: Subjects
        Female
    13
        Male
    13
    Smoking status
    Units: Subjects
        Current smoker
    3
        Current non-smoker
    23
    Body Mass Index (BMI)
    Units: Kg/cm2
        arithmetic mean (standard deviation)
    27.01 ± 3.57
    Waist circumference
    Units: cm
        arithmetic mean (standard deviation)
    92.42 ± 12.22
    HbA1c
    Units: mmol/L
        arithmetic mean (standard deviation)
    65.58 ± 8.07
    Fasting Plasma Glucose (FPG)
    Units: mmol/L
        arithmetic mean (standard deviation)
    10.16 ± 4.38
    C-peptide
    Units: nmol/L
        arithmetic mean (standard deviation)
    0.03 ± 0.04

    End points

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    End points reporting groups
    Reporting group title
    Lixisenatide followed by matching placebo
    Reporting group description
    Lixisenatide treatment period (4 weeks) followed by a washout period (4 weeks) then matching placebo treatment period (4 weeks) followed by a final washout period (4 weeks). Participants were asked to inject the trial medication using an injection pen once each morning (between 8-10 am) in addition to their prescribed insulin medication.

    Reporting group title
    Matching placebo followed by lixisenatide
    Reporting group description
    Matching placebo treatment period (4 weeks) followed by a washout period (4 weeks) then lixisenatide treatment period (4 weeks) followed by a final washout period (4 weeks). Participants were asked to inject the trial medication using an injection pen once each morning (between 8-10 am) in addition to their prescribed insulin medication.

    Subject analysis set title
    Full analysis population
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Data for one participant was removed from the full analysis population for Arm 2 (matching placebo followed by lixisenatide) due to pregnancy post-randomisation. Twenty-six participants were therefore included in the initial full analysis data-set. Data for two of the remaining twenty-six participants was subsequently also excluded from the primary analysis because one participant dropped out of the study visits after the first treatment period and one participant was missing baseline primary endpoint data. This meant that determination of treatment affect was not possible for these two individuals' data. The primary end-point results analysis data presented in this report relates to the remaining 24 of the 27 participants randomised. The Safety Population (SP) consists of all randomised individuals who received at least one dose of the study medication, hence adverse event information in this report is presented for all 27 participants randomised.

    Primary: The change in the percentage of Continuous Glucose Monitoring (CGM) readings between 4 and 10 mmol/l (inclusive) during the 3 hour post-prandial period, before and after treatment with lixisenatide compared to matching placebo.

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    End point title
    The change in the percentage of Continuous Glucose Monitoring (CGM) readings between 4 and 10 mmol/l (inclusive) during the 3 hour post-prandial period, before and after treatment with lixisenatide compared to matching placebo.
    End point description
    The primary end-point is to determine whether adding lixisenatide to basal bolus insulin significantly improves glycaemic control during the 3 hour post prandial period compared to basal bolus insulin and a placebo injection.
    End point type
    Primary
    End point timeframe
    Up to 4 months.
    End point values
    Lixisenatide followed by matching placebo Matching placebo followed by lixisenatide
    Number of subjects analysed
    11 [1]
    13 [2]
    Units: Change in percentage of participants
        arithmetic mean (standard deviation)
    -4.70 ± 26.3
    -9.86 ± 29.75
    Notes
    [1] - One participant only completed period 1 and a second was missing baseline primary endpoint data.
    [2] - Data for one participant was removed from the analysis data-set due to pregnancy post-randomisation.
    Statistical analysis title
    The Within-subject differences
    Statistical analysis description
    The analysis was based on the means and standard deviations of the within-subject difference to reflect the resultant treatment effect and the paired nature of the design. The treatment effect was estimated based on an average of within-subject differences, after testing for the assumptions of no carryover or period effect, and that the within-subject differences were normally distributed. The estimated treatment effects are presented in means and standard deviations with 95% interval ranges.
    Comparison groups
    Matching placebo followed by lixisenatide v Lixisenatide followed by matching placebo
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    other [3]
    P-value
    < 0.05
    Method
    t-test, 2-sided
    Parameter type
    Mean difference (final values)
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -
         upper limit
    -
    Variability estimate
    Standard deviation
    Notes
    [3] - Efficacy study.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Safety was assessed from screening through to each participant's closout visit. The closeout visit took place a minimum of 28 days after last dose of trial medication.
    Adverse event reporting additional description
    All Adverse Events were documented within 24 hours of awareness with sponsor notified of Serious Adverse Events or pregnancy within 24 hours of awareness using sponsor-supplied forms.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    Events not coded
    Dictionary version
    N/A
    Reporting groups
    Reporting group title
    Lixisenatide followed by matching placebo
    Reporting group description
    Lixisenatide treatment period (4 weeks) followed by a washout period (4 weeks) then matching placebo treatment period (4 weeks) followed by a final washout period (4 weeks). Participants were asked to inject the trial medication using an injection pen once each morning (between 8-10 am) in addition to their prescribed insulin medication.

    Reporting group title
    Matching placebo followed by lixisenatide
    Reporting group description
    Matching placebo treatment period (4 weeks) followed by a washout period (4 weeks) then lixisenatide treatment period (4 weeks) followed by a final washout period (4 weeks). Participants were asked to inject the trial medication using an injection pen once each morning (between 8-10 am) in addition to their prescribed insulin medication.

    Serious adverse events
    Lixisenatide followed by matching placebo Matching placebo followed by lixisenatide
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 14 (7.14%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    General disorders and administration site conditions
    Loss of consciousness
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Lixisenatide followed by matching placebo Matching placebo followed by lixisenatide
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 13 (100.00%)
    14 / 14 (100.00%)
    Pregnancy, puerperium and perinatal conditions
    Pregnancy
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Eye disorders
    Diabetes eye complications
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 14 (14.29%)
         occurrences all number
    0
    3
    General disorders and administration site conditions
    Non-specific event
         subjects affected / exposed
    2 / 13 (15.38%)
    3 / 14 (21.43%)
         occurrences all number
    2
    3
    Headache
         subjects affected / exposed
    2 / 13 (15.38%)
    2 / 14 (14.29%)
         occurrences all number
    3
    3
    Gastrointestinal disorders
    Gastrointestinal side-effects
         subjects affected / exposed
    4 / 13 (30.77%)
    5 / 14 (35.71%)
         occurrences all number
    7
    7
    Endocrine disorders
    Hypoglycaemia
         subjects affected / exposed
    12 / 13 (92.31%)
    14 / 14 (100.00%)
         occurrences all number
    292
    511
    Infections and infestations
    Infection
         subjects affected / exposed
    5 / 13 (38.46%)
    2 / 14 (14.29%)
         occurrences all number
    5
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Mar 2014
    Substantial amendment 1.0 - summary of changes: - Amend the type of Continuous Glucose Monitoring device used during the trial. - Extend the Body Mass Index eligibility criterion from < or = 27 kg/m2 to < 30 kg/m2. - Clarify how the Part A trial results will be analysed. - Ensure that visit procedures are consistent and will permit the collection of eligibility data at screening. - To seek permission to store surplus blood samples collected during the Part B trial for up to 5 years following the end of the trial, after which time they will be destroyed.
    09 Jul 2014
    Substantial amendment 2.0 - Summary of changes: - To increase the Body Mass Index (BMI) eligibility criterion from < 30 kg/m2 to < 35 kg/m2. - To remove the following inclusion criterion: 'Insulin treatment since diabetes'. - To amend the blood collection tubes used for the following tests during the trial: Glucose-dependant insulinotropic peptide or gastric inhibitory peptide (GIP), Glucagon-Like-Peptide1 (GLP1), Glucagon and the counter-regulatory hormones, adrenaline, noradrenaline, cortisol and pancreatic polypeptide.
    05 Dec 2014
    Substantial amendment 3.0 - Summary of changes: - To increase the upper age limit eligibility criterion from aged 18-65 years to 18-70 years. - To increase the upper glycated haemoglobin (HbA1c) eligibility criterion limit from 7.0 - 9.0% inclusive to 7.0 - 10.0% inclusive. - To increase the upper C-peptide value (C-peptide negative group only) eligibility criterion from Random or fasting C-peptide <0.02 nmol/l to <0.1 nmol/l. - Include a breath test procedure to measure gastric emptying. - Clarify that the ancillary study procedures are optional and take place once during the trial. To also document separate Informed Consent for the ancillary study procedures. - Revise the length of some of the Part B trial visits. - Update the Gastric Inhibitory Peptide (GIP) and Glucagon Like Peptide-1 (GLP-1) assay names. - To update other trial documents in-line with the above protocol updates (Participant Information Leaflet, Informed Consent Form, Protocol summary and the advertising poster). - To notify that an updated version of existing Investigator Brochure is now issued (Edition 11 dated 21 April 2014).
    21 Aug 2015
    Substantial amendment 4.0 - Summary of changes: - To decrease the lower glycated haemoglobin (HbA1c) limit eligibility criterion from 7.0 - 10.0% inclusive to 6.5 - 10.0% inclusive. - To Update to the existing single-centre clinical site team (addition of one further research clinician).

    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.
    The study closed to recruitment on 5th January 2016. This deadline was fixed in-line with the expiry date of the study medication. At this point a total of 27 participants were randomised onto the main study compared to the target of 30.
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