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    Clinical Trial Results:
    Post-marketing study of Amaryl ® (Glimepiride) in patients with type 2 diabetes to investigate pediatric and adult population pharmacokinetics [multicenter, non-comparative, 12-28 weeks, non-blind titration (0.5-6 mg/day) study].

    Summary
    EudraCT number
    		 2014-004643-12
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    13 May 2008

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Apr 2016
    First version publication date
    18 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    POP6739
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Sanofi-aventis K.K.
    Sponsor organisation address
    Tokyo Opera City Tower, 3-20-2, Nishi Shinjuku, Shinjuku-ku, Tokyo, Japan, 163-1488
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    13 Aug 2008
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 May 2008
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the pharmacokinetics of Amaryl® in pediatric subjects (8 to 16 years of age) with type 2 diabetes in comparison with adults subjects (17 years or older of age) with type 2 diabetes under steady state
    Protection of trial subjects
    For paediatric subjects, the parent(s) or guardian(s) as well as the children were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time. In addition to the consent form for the parent(s)/guardian(s), an assent form in child-appropriate language was provided and explained to the child. Repeated invasive procedures were minimized. For the population with pharmacokinetic analysis a minimum number of blood sampling was performed. A topical anesthesia may have been used to minimize distress and discomfort. Adult 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
    19 Jul 2006
    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
    Japan: 141
    Worldwide total number of subjects
    141
    EEA total number of subjects
    0
    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)
    4
    Adolescents (12-17 years)
    33
    Adults (18-64 years)
    61
    From 65 to 84 years
    42
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 34 sites in Japan. A total of 142 subjects were enrolled between 19 July 2006 and 07 November 2007.

    Pre-assignment
    Screening details
    		 Of 142 enrolled subjects, 141 subjects were treated.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Amaryl - Pediatric
    Arm description
    		 Amaryl in children (8-16 years) for 12-28 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Glimepiride
    Investigational medicinal product code
    HOE490
    Other name
    Amaryl ®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    0.5 or 1 mg/day (once daily, before or after meal in morning) or 2 to 6 mg/day (once or twice daily, before or after meal in morning or morning and evening).

    Arm title
    		 Amaryl - Adult
    Arm description
    		 Amaryl in adults (years >= 17 ) for 12-28 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Glimepiride
    Investigational medicinal product code
    HOE490
    Other name
    Amaryl ®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    0.5 or 1 mg/day (once daily, before or after meal in morning) or 2 to 6 mg/day (once or twice daily, before or after meal in morning or morning and evening).

    Number of subjects in period 1
    		Amaryl - Pediatric Amaryl - Adult
    Started
    35
    106
    Completed
    32
    105
    Not completed
    3
    1
         Poor treatment compliance
    1
    -
         Subjects did not Wish to Continue
    2
    -
         Adverse event
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Amaryl - Pediatric
    Reporting group description
    		 Amaryl in children (8-16 years) for 12-28 weeks.

    Reporting group title
    Amaryl - Adult
    Reporting group description
    		 Amaryl in adults (years >= 17 ) for 12-28 weeks.

    Reporting group values
    		 Amaryl - Pediatric Amaryl - Adult Total
    Number of subjects
    		 35 106 141
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 13.4 ± 1.8 62.1 ± 12.4 -
    Gender categorical
    Units: Subjects
        Female
    		 17 40 57
        Male
    		 18 66 84

    End points

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    End points reporting groups
    Reporting group title
    Amaryl - Pediatric
    Reporting group description
    		 Amaryl in children (8-16 years) for 12-28 weeks.

    Reporting group title
    Amaryl - Adult
    Reporting group description
    		 Amaryl in adults (years >= 17 ) for 12-28 weeks.

    Primary: Apparent Clearance (CL/F)

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    End point title
    		 Apparent Clearance (CL/F) [1]
    End point description
    Apparent clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. Full analysis set/pharmacokinetic (FAS/PK) included all subjects (excluding 4 subjects in pediatric arm and 2 subjects in adult arm of the enrolled subjects) for whom pharmacokinetic parameters were analysed.
    End point type
    Primary
    End point timeframe
    Visit 8 (or one of Visit 2-7) - up to 28 weeks
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This is a population PK analysis - Statistical analysis results are the estimates obtained from the one-compartment model as are provided in below table
    End point values
    		 Amaryl - Pediatric Amaryl - Adult
    Number of subjects analysed
    31
    105
    Units: L/h
        arithmetic mean (standard deviation)
    1.79 ± 0.77
    1.64 ± 0.59
    No statistical analyses for this end point

    Primary: Apparent Volume of Distribution (Vss /F)

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    End point title
    		 Apparent Volume of Distribution (Vss /F) [2]
    End point description
    Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a study drug. Analysis was performed on FAS/PK population.
    End point type
    Primary
    End point timeframe
    Visit 8 (or one of Visit 2-7) - up to 28 weeks
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This is a population PK analysis - Statistical analysis results are the estimates obtained from the one-compartment model as are provided in below table
    End point values
    		 Amaryl - Pediatric Amaryl - Adult
    Number of subjects analysed
    31
    105
    Units: litre(s)
        arithmetic mean (standard deviation)
    6.84 ± 0.09
    6.83 ± 0.11
    No statistical analyses for this end point

    Primary: Half-Life (t1/2)

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    End point title
    		 Half-Life (t1/2) [3]
    End point description
    Half-life is the time measured for the plasma concentration of the drug to decrease by one half. Analysis was performed on FAS/PK population.
    End point type
    Primary
    End point timeframe
    Visit 8 (or one of Visit 2-7) - up to 28 weeks
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This is a population PK analysis - Statistical analysis results are the estimates obtained from the one-compartment model as are provided in below table
    End point values
    		 Amaryl - Pediatric Amaryl - Adult
    Number of subjects analysed
    31
    105
    Units: hours
        arithmetic mean (standard deviation)
    3.15 ± 1.38
    3.3 ± 1.6
    No statistical analyses for this end point

    Secondary: Change from Baseline in Hemoglobin A1C (HbA1C) at Endpoints

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    End point title
    		 Change from Baseline in Hemoglobin A1C (HbA1C) at Endpoints
    End point description
    Intent-to-treat (ITT) population included all treated subjects.
    End point type
    Secondary
    End point timeframe
    (Visit 1 -8) - from baseline up to last observation max of 28 weeks
    End point values
    		 Amaryl - Pediatric Amaryl - Adult
    Number of subjects analysed
    35
    106
    Units: percentage of Hb
    arithmetic mean (standard deviation)
        Baseline (n= 35, 105)
    8.26 ± 1.98
    8.7 ± 1.37
        Endpoint (n= 35, 106)
    7.85 ± 2.04
    7.18 ± 0.85
        Change from baseline (n= 35, 105)
    -0.41 ± 1.9
    -1.5 ± 1.08
    No statistical analyses for this end point

    Secondary: Change from Baseline in Fasting plasma glucose (FPG) at Endpoints

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    End point title
    		 Change from Baseline in Fasting plasma glucose (FPG) at Endpoints
    End point description
    Analysis was peformed on ITT population.
    End point type
    Secondary
    End point timeframe
    (Visit 1 -8) - from baseline up to last observation max of 28 weeks
    End point values
    		 Amaryl - Pediatric Amaryl - Adult
    Number of subjects analysed
    35
    106
    Units: mg/dL
    arithmetic mean (standard deviation)
        Baseline
    159.6 ± 64
    166.7 ± 37.2
        Endpoint
    155.9 ± 61.3
    134.7 ± 22.6
        Change from baseline
    -3.7 ± 60.6
    -32 ± 34.4
    No statistical analyses for this end point

    Secondary: Change from Baseline in Fasting Blood Glucose by Self-monitoring of Blood Glucose (SMBG) at Endpoints

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    End point title
    		 Change from Baseline in Fasting Blood Glucose by Self-monitoring of Blood Glucose (SMBG) at Endpoints
    End point description
    Analysis was perfomed on ITT population.
    End point type
    Secondary
    End point timeframe
    (Visit 1 -8) - from baseline up to last observation max of 28 weeks
    End point values
    		 Amaryl - Pediatric Amaryl - Adult
    Number of subjects analysed
    35
    106
    Units: mg/dL
    arithmetic mean (standard deviation)
        Baseline (n= 24, 63)
    158.9 ± 69
    156.9 ± 44.4
        Endpoint (n= 26, 64)
    140.8 ± 50
    123.8 ± 26.9
        Change from baseline (n= 24, 63)
    -18.4 ± 70.5
    -32.8 ± 44.8
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All Adverse Events (AE) were collected from signature of the informed consent form up to the final visit (Week 12-28) regardless of seriousness or relationship to investigational product.
    Adverse event reporting additional description
    Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the ‘on treatment period’ (the time between first and the last administration of the investigational product).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    11.0
    Reporting groups
    Reporting group title
    Amaryl - Pediatric
    Reporting group description
    		 Amaryl in children (8-16 years) for 12-28 weeks.

    Reporting group title
    Amaryl - Adult
    Reporting group description
    		 Amaryl in adult (years >= 17) for 12-28 weeks.

    Serious adverse events
    		 Amaryl - Pediatric Amaryl - Adult
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 106 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Psychiatric disorders
    Mental Disorder
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Amaryl - Pediatric Amaryl - Adult
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    22 / 35 (62.86%)
    39 / 106 (36.79%)
    Investigations
    Blood Creatine Phosphokinase Increased
         subjects affected / exposed
    3 / 35 (8.57%)
    1 / 106 (0.94%)
         occurrences all number
    3
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 35 (8.57%)
    0 / 106 (0.00%)
         occurrences all number
    3
    0
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 106 (0.00%)
         occurrences all number
    2
    0
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 106 (0.00%)
         occurrences all number
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Rhinitis Allergic
         subjects affected / exposed
    3 / 35 (8.57%)
    1 / 106 (0.94%)
         occurrences all number
    3
    1
    Upper Respiratory Tract Inflammation
         subjects affected / exposed
    6 / 35 (17.14%)
    5 / 106 (4.72%)
         occurrences all number
    6
    5
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    2 / 35 (5.71%)
    4 / 106 (3.77%)
         occurrences all number
    2
    4
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    3 / 35 (8.57%)
    0 / 106 (0.00%)
         occurrences all number
    3
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    3 / 35 (8.57%)
    13 / 106 (12.26%)
         occurrences all number
    4
    17
    Influenza
         subjects affected / exposed
    2 / 35 (5.71%)
    1 / 106 (0.94%)
         occurrences all number
    2
    1
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    3 / 35 (8.57%)
    20 / 106 (18.87%)
         occurrences all number
    3
    60

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Jul 2007
    In this amendment the number of sites (35 sites) was changed to approximately 50 sites.
    10 Aug 2007
    Concomitant drugs with precaution to potentiate the hyperglycemic action was changed ( that is Ciprofloxacin and Levofloxacin were added) due to amendment of the package insert.
    24 Aug 2007
    Minor administrative changes were made due to the changes on the administrative structure.
    10 Apr 2008
    Minor administrative changes and editorial changes were made due to the changes on the administrative structure.

    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
    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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