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    Clinical Trial Results:
    Effects of agomelatine versus escitalopram on emotional experiences in outpatients suffering from Major Depressive Disorder. An exploratory, randomised, double-blind, international, multicentre study with parallel groups: agomelatine (25 to 50 mg/day) versus escitalopram (10 to 20 mg/day) over a 6- month period.

    Due to the EudraCT – Results system being out of service between 31 July 2015 and 12 January 2016, these results have been published in compliance with revised timelines.
    Summary
    EudraCT number
    2011-005320-17
    Trial protocol
    GB  
    Global end of trial date
    03 Oct 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    17 Mar 2016
    First version publication date
    17 Mar 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CL3-20098-060
    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, France, 92284
    Public contact
    Clinical Studies Department, Institut de Recherches Internationales Servier, 33 1 55 72 43 66, clinicaltrials@servier.com
    Scientific contact
    Clinical Studies Department, Institut de Recherches Internationales Servier, 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
    03 Oct 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Oct 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Oct 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this exploratory study is to differentiate the effect of two antidepressants, agomelatine versus escitalopram, on the emotional experiences in outpatients suffering from Major Depressive Disorder.
    Protection of trial subjects
    The study was conducted in accordance with the ethical principles stated in the Declaration of Helsinki, 1964, as revised in Seoul, 2008 and Fortaleza, 2013. Mandatory withdrawal of the trial if withdrawal of consent by the patient, hospitalisation for aggravation of depression, high suicidal risks or suicide attempt, occurrence of psychotic features, occurrence of pre-defined laboratory criteria and / or signs or symptoms of hepatic dysfunction, signs of cardiac arrhytmia, pregnancy Other criteria for premature withdrawal from the study: treatment failure, adverse event, any event or circumstances related or unrelated to the treatment justifying the discontinuation of the treatment in the investigator's opinion In order to avoid abrupt discontinuation of escitalopram and according to the investigator's opinion and the reason for withdrawal, a tapering treatment could be dispensed to the patient at the withdrawal visit for a period of 7 days.
    Background therapy
    -
    Evidence for comparator
    escitalopram
    Actual start date of recruitment
    11 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
    Australia: 25
    Country: Number of subjects enrolled
    Brazil: 73
    Country: Number of subjects enrolled
    Canada: 97
    Country: Number of subjects enrolled
    South Africa: 104
    Country: Number of subjects enrolled
    United Kingdom: 99
    Worldwide total number of subjects
    398
    EEA total number of subjects
    99
    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)
    394
    From 65 to 84 years
    4
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Investigators were psychiatrists or general practitioners.

    Pre-assignment
    Screening details
    Study population was male or female outpatients with Major Depressive Disorder. At selection, Hamilton Depression Rating Scale 17 items was to be ≥ 22, Clinical Global Impression severity of illness ≥ 4, Hospital Anxiety and Depression scale with Depression score ≥ 11 and Depression score > Anxiety score.

    Period 1
    Period 1 title
    Double-blind treatment period (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator
    Blinding implementation details
    Treatment randomisation and allocation centralized (interactive response system). Study products of identical appearance The double-blind treatment period with all subjects receiving either experimental treatment (agomelatine) or active comparator (escitalopram) is described in the document.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    agomelatine
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    agomelatine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    1 capsule daily: 25 or 50 mg agomelatine

    Arm title
    escitalopram
    Arm description
    -
    Arm type
    Active comparator

    Investigational medicinal product name
    escitalopram
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    1 capsule daily: 10 or 20 mg escitalopram

    Number of subjects in period 1
    agomelatine escitalopram
    Started
    199
    199
    Completed
    140
    135
    Not completed
    59
    64
         recovery-improvement
    -
    1
         non-medical reason
    22
    26
         Adverse event, non-fatal
    14
    26
         Protocol deviation
    6
    6
         Lack of efficacy
    17
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    agomelatine
    Reporting group description
    -

    Reporting group title
    escitalopram
    Reporting group description
    -

    Reporting group values
    agomelatine escitalopram Total
    Number of subjects
    199 199 398
    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)
    41.4 ± 12 40.8 ± 12.7 -
    Gender categorical
    Units: Subjects
        Female
    133 133 266
        Male
    66 66 132

    End points

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    End points reporting groups
    Reporting group title
    agomelatine
    Reporting group description
    -

    Reporting group title
    escitalopram
    Reporting group description
    -

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All patients of the Randomized Set having taken at least one dose of study medication and having a value at baseline and at least one post-baseline efficacy assessment

    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
    Full Analysis Set
    Number of subjects analysed
    [2]
    Units: not available
    0
    Notes
    [2] - As the study was an exploratory study, no primary criterion was defined.
    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 . Adverse events reported during the period W0 -W24 are presented here as it was the only period of the study when patients received agomelatine.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    agomelatine
    Reporting group description
    -

    Reporting group title
    escitalopram
    Reporting group description
    -

    Serious adverse events
    agomelatine escitalopram
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 199 (4.52%)
    17 / 198 (8.59%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 199 (0.00%)
    2 / 198 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Pregnancy
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicidal ideation
         subjects affected / exposed
    1 / 199 (0.50%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intentional self-injury
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depressive symptom
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hallucination, auditory
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sleep disorder
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    joint dislocation
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    accident
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    fall
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alcohol poisoning
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intentional overdose
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Sedation
         subjects affected / exposed
    0 / 199 (0.00%)
    2 / 198 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    somnolence
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    syncope
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Restless legs syndrome
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disturbance in attention
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    inguinal hernia
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis alcoholic
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal colic
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Localised infection
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    sinusitis
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Increased appetite
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 198 (0.51%)
         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: 5%
    Non-serious adverse events
    agomelatine escitalopram
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    132 / 199 (66.33%)
    142 / 198 (71.72%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    31 / 199 (15.58%)
    34 / 198 (17.17%)
         occurrences all number
    43
    40
    Dizziness
         subjects affected / exposed
    11 / 199 (5.53%)
    8 / 198 (4.04%)
         occurrences all number
    11
    9
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    14 / 199 (7.04%)
    34 / 198 (17.17%)
         occurrences all number
    14
    36
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    5 / 199 (2.51%)
    16 / 198 (8.08%)
         occurrences all number
    5
    18

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    31 Jan 2012
    Update of the phase of the study from Phase III to Phase II for all Brazilians sites, in the context of an exploratory study
    11 May 2012
    Following the update of the SmPC of escitalopram from postmarketing experience, the following points were added:  A non-selection criteria for patients with known QT interval prolongation or congenital long QT syndrome.  A mandatory withdrawal criteria for patients with signs of cardiac arrhythmia.  Clarification on forbidden treatments before and during the study for treatments known to prolong QT interval.
    08 Jun 2012
    Concerned all sites in UK: change of national coordinator (considered in UK as substantial amendment)
    29 Oct 2012
    According to this updated SmPC, a liver function test at W8 visit had been added so that when the dose was increased at the W2 visit, the liver function tests were performed at the same frequency as when initiating treatment. In addition, the follow-up of the patient in case of withdrawal from the study had been clarified: the patient was asked to come back for a follow-up visit 7 days after the withdrawal visit instead of 14 days after the study discontinuation visit.
    13 Jun 2013
     The follow-up / assessments to be performed and visits to be completed for prematurely withdrawn patients had been clarified in order to avoid any misunderstanding.  The criterion on drug screening had been clarified in order to be consistent with authorised codeine intake.  The recruitment period had been extended as the recruitment rate is slower than expected.  Fasting conditions were required only in case of lipid parameters and blood glucose assessment.
    15 Nov 2013
     The recruitment period had been extended as the recruitment rate was slower than expected.  The non-selection criteria and the treatments authorised with restriction before and during the study had been updated according to the last version of Summary of Product Characteristics (SmPC) of Escitalopram.  The withdrawal criterion “Jaundice or any other symptom suggesting hepatic dysfunction” had been updated in order to be consistent with the information reported in the SmPC of Agomelatine.  In case of any AST and/or ALT increase > 3 ULN, an adverse event had to be immediately reported without waiting for the liver function retest results in order to ensure an accurate follow-up of the event.  The new version of the Declaration of Helsinki had been integrated in this new amendment following its review at the last WMA meeting (Fortaleza, October 2013).

    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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    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
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