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    Clinical Trial Results:
    Effects of agomelatine (25 to 50 mg/day) on circadian rhythms in patients with Major Depressive Disorder. An exploratory 6-week open, flexible dose, international multicentre, non comparative study.

    Summary
    EudraCT number
    2010-024191-25
    Trial protocol
    DE   AT  
    Global end of trial date
    25 Jul 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    06 Jul 2016
    First version publication date
    05 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CL3-20098-080
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Institut de Recherches Internationales Servier
    Sponsor organisation address
    50 rue Carnot, Suresnes Cedex, France, 92284
    Public contact
    Innovation Therapeutic Pole, Institut de Recherches Internationales Servier, 50 rue Carnot, Suresnes Cedex, France 92284 , +33 1 55 72 43 66, clinicaltrials@servier.com
    Scientific contact
    Innovation Therapeutic Pole, Institut de Recherches Internationales Servier, 50 rue Carnot, Suresnes Cedex, France 92284 , +33 1 55 72 43 66, clinicaltrials@servier.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
    25 Jul 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Jul 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Jul 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this exploratory study was to assess the effect of agomelatine on the circadian rhythms in Major Depressive Disorder patients by evaluating circadian parameters.
    Protection of trial subjects
    The study was performed in accordance with the ethical principles stated in the Declaration of Helsinki 1964, as revised in Fortaleza, Brazil, 2013. For MDD patients: mandatory withdrawal from the study if hospitalisation for aggravation of depression, high suicide risk or suicide attempt, occurrence of psychotic features, occurence of pre-defined laboratory criteria and / or signs or symptoms of hepatic dysfunction, pregnancy. Other criteria for premature withdrawal from the study: treatment failure, adverse event. For Healthy Volunteers: withdrawal from the study if serious adverse event or significant alteration in clinical and/or laboratory parameters.
    Background therapy
    -
    Evidence for comparator
    A cohort of Healthy Volunteers was designed to define the circadian parameters in a normal control group without treatment and to allow the comparison of the baseline circadian profile of MDD patients to the circadian profile of non depressed individuals.
    Actual start date of recruitment
    26 Jul 2012
    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
    Poland: 28
    Country: Number of subjects enrolled
    Austria: 6
    Country: Number of subjects enrolled
    Germany: 132
    Worldwide total number of subjects
    166
    EEA total number of subjects
    166
    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)
    166
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Investigators were psychiatrists.

    Pre-assignment
    Screening details
    MDD patients were male or female outpatients fulfilling DSM-IV-TR criteria for MDD, single episode or recurrent (no more than 3), with a current episode of moderate to severe intensity, with HAM-D total score >=22, sum of HAM-D items 5+6 >= 3 and HAD depression score >= 11. Healthy volunteers matched in classes of age and sex to MDD patients.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    MDD patients (agomelatine)
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    agomelatine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Agomelatine 25 mg: 1 or 2 tablets daily

    Arm title
    Healthy Volunteers (no treatment)
    Arm description
    -
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    MDD patients (agomelatine) Healthy Volunteers (no treatment)
    Started
    123
    43
    Completed
    108
    39
    Not completed
    15
    4
         Adverse event, non-fatal
    2
    -
         Non-medical reason
    8
    4
         Protocol deviation
    4
    -
         Lack of efficacy
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    MDD patients (agomelatine)
    Reporting group description
    -

    Reporting group title
    Healthy Volunteers (no treatment)
    Reporting group description
    -

    Reporting group values
    MDD patients (agomelatine) Healthy Volunteers (no treatment) Total
    Number of subjects
    123 43 166
    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
    Units: years
        arithmetic mean (standard deviation)
    44.6 ± 10.6 41.3 ± 12 -
    Gender categorical
    Units: Subjects
        Female
    63 25 88
        Male
    60 18 78
    DLMO
    For comparison at baseline, Dim Light Melatonin Onset (DLMO) was assessed the day before W0 for MDD patients and on D7 for healthy volunteers, by measuring melatonin levels in the saliva. For Healthy Volunteers, DLMO was measured only in the CAS-HV.
    Units: h.min
        arithmetic mean (standard deviation)
    20.58 ± 1.02 0 ± 0 -
    Subject analysis sets

    Subject analysis set title
    Circadian Analysis Set of MDD patients
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    The Circadian Analysis Set of MDD patients (CAS-MDD) was defined as all included patients having taken at least one dose of study medication and having at least one interpretable value at baseline and after baseline for any efficacy criterion related to circadian rhythms.

    Subject analysis set title
    Circadian Analysis Set of Healthy Volunteers
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    The Circadian Analysis Set of Healthy Volunteers (CAS-HV) was defined as all included healthy volunteers having at least one interpretable value for any criterion related to circadian rhythms.

    Subject analysis sets values
    Circadian Analysis Set of MDD patients Circadian Analysis Set of Healthy Volunteers
    Number of subjects
    117
    30
    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
    Units: years
        arithmetic mean (standard deviation)
    44.5 ± 10.8
    41.5 ± 12.7
    Gender categorical
    Units: Subjects
        Female
    59
    15
        Male
    58
    15
    DLMO
    For comparison at baseline, Dim Light Melatonin Onset (DLMO) was assessed the day before W0 for MDD patients and on D7 for healthy volunteers, by measuring melatonin levels in the saliva. For Healthy Volunteers, DLMO was measured only in the CAS-HV.
    Units: h.min
        arithmetic mean (standard deviation)
    20.58 ± 1.03
    21.29 ± 0.37

    End points

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    End points reporting groups
    Reporting group title
    MDD patients (agomelatine)
    Reporting group description
    -

    Reporting group title
    Healthy Volunteers (no treatment)
    Reporting group description
    -

    Subject analysis set title
    Circadian Analysis Set of MDD patients
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    The Circadian Analysis Set of MDD patients (CAS-MDD) was defined as all included patients having taken at least one dose of study medication and having at least one interpretable value at baseline and after baseline for any efficacy criterion related to circadian rhythms.

    Subject analysis set title
    Circadian Analysis Set of Healthy Volunteers
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    The Circadian Analysis Set of Healthy Volunteers (CAS-HV) was defined as all included healthy volunteers having at least one interpretable value for any criterion related to circadian rhythms.

    Primary: no primary criterion

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    End point title
    no primary criterion [1]
    End point description
    End point type
    Primary
    End point timeframe
    As the study was an exploratory study, no primary criterion was defined.
    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: As the study was an exploratory study, no primary criterion was defined
    End point values
    Circadian Analysis Set of MDD patients
    Number of subjects analysed
    Units: not available
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were reported all over the study.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    MDD patients (agomelatine)
    Reporting group description
    -

    Reporting group title
    Healthy Volunteers (no treatment)
    Reporting group description
    -

    Serious adverse events
    MDD patients (agomelatine) Healthy Volunteers (no treatment)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 43 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain lower
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 43 (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: 0.5%
    Non-serious adverse events
    MDD patients (agomelatine) Healthy Volunteers (no treatment)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    40 / 122 (32.79%)
    3 / 43 (6.98%)
    Vascular disorders
    Lymphoedema
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    Fatigue
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    2 / 122 (1.64%)
    0 / 43 (0.00%)
         occurrences all number
    2
    0
    Polycystic ovaries
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Sleep disorder
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 122 (0.82%)
    1 / 43 (2.33%)
         occurrences all number
    1
    1
    Weight increased
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 122 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    1
    Cardiac disorders
    Bradyarrhythmia
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    13 / 122 (10.66%)
    2 / 43 (4.65%)
         occurrences all number
    16
    2
    Paraesthesia
         subjects affected / exposed
    3 / 122 (2.46%)
    0 / 43 (0.00%)
         occurrences all number
    3
    0
    Dizziness
         subjects affected / exposed
    2 / 122 (1.64%)
    0 / 43 (0.00%)
         occurrences all number
    2
    0
    Cubital tunnel syndrome
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    Dizziness postural
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    Dysguesia
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    Orthostatic intolerance
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    Sedation
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    Somnolence
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    Tension headache
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Vision blurred
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    3 / 122 (2.46%)
    0 / 43 (0.00%)
         occurrences all number
    3
    0
    Abdominal pain upper
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    Constipation
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal motility disorder
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal tract irritation
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    Toothache
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    Myalgia
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    7 / 122 (5.74%)
    0 / 43 (0.00%)
         occurrences all number
    7
    0
    Bronchitis
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    Influenza
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Increased appetite
         subjects affected / exposed
    2 / 122 (1.64%)
    0 / 43 (0.00%)
         occurrences all number
    2
    0
    Fluid retention
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    Hypercholesterolaemia
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    Myositis
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 May 2012
    ­Concerned all countries: Modification required by the Austria’s Ethics Committees, which was to add the withdrawal criterion “CGI item 2 (global improvement) score ≥ 5 at W4”. ­Addition of a new precaution for saliva sampling (patients should not brush their teeth during salivary sampling), as recommended in literature. ­Update of non-pre-selection criteria, miscellaneous conditions and method and measurement times, notably regarding the conditions for use of the pill (new contra indications and wearing of a MRI warning wrist band) and the wearing of the belt (for 1 instead 2 days, because recording time lasted for about 21 hours). ­A footnote of the investigational schedule table was modified to get the liver function tests results before the W4 visit. ­Administrative changes. ­Update of the study drug storage conditions, according to the agomelatine SmPC.
    08 Oct 2012
    Concerned all countries: ­Inclusion of the centralised analysis of body temperature, heart rate and DLMO, to further minimise bias. ­Addition of an example “patients not having fully cooperated with baseline examinations” in the non-inclusion criteria. ­Update of the methods and measurement times, circadian parameters and minimal core body temperature by:  Adding a possible contact between investigator and the patient in order to help him to put and activate the core body temperature and heart rate kit.  Specifying the procedure for telemetric pill excretion. Administrative changes.
    20 Dec 2013
    ­Concerned all sites in Germany: Addition of efficacy measurements (maximum of core body temperature, mid-range crossing of core body temperature, maximum of heart rate and mid-range crossing of heart rate) for circadian parameters analysis. ­Update of the protocol in order to include the cohort of healthy volunteers in the main technical protocol, instead of the initially planned sub-study protocol dedicated to the description of healthy volunteers. ­Adaption of the safety measurements' description in accordance with international guidance. ­Modification of statistical methodology following the addition of healthy volunteers and the upgrade process for adverse events. The analysis of circadian rhythms in patients of the FAS was also deleted. ­Administrative changes.

    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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