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    Clinical Trial Results:
    Efficacy and safety of tianeptine oral administration (25 to 50 mg/day) in elderly patients suffering from Major Depressive Disorder. A 8-week, randomized, double-blind, flexible-dose, parallel groups, placebo-controlled, international, multicentre study with escitalopram as active control, followed by an optional double-blind extension treatment period of 16 weeks.

    Summary
    EudraCT number
    		 2012-005612-26
    Trial protocol
    		 SK   FI   EE   BG  
    Global end of trial date
    13 Jan 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Oct 2016
    First version publication date
    15 Oct 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CL3-01574-237
    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,
    Public contact
    Clinical Studies Department, Institut de Recherches Internationales Servier (I.R.I.S.), +33 1 55 72 43 66, clinicaltrials@servier.com
    Scientific contact
    Clinical Studies Department, Institut de Recherches Internationales Servier (I.R.I.S.), +33 1 55 72 43 66, clinicaltrials@servier.com
    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 (I.R.I.S.), 33 1 55724366, clinicaltrials@servier.com
    Scientific contact
    Clinical Studies Department, Institut de Recherches Internationales Servier (I.R.I.S.), 33 1 55724366, 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
    13 Jan 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    13 Jan 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Jan 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the antidepressant efficacy of an 8-week tianeptine oral administration in elderly out-patients suffering from Major Depressive Disorder compared to placebo. The assay sensitivity will be evaluated comparing escitalopram to placebo.
    Protection of trial subjects
    This study was conducted in accordance with Good Clinical Practice standards, ethical principles stated in the Declaration of Helsinki and applicable regulatory requirements. After the subject has ended his/her participation in the trial, the investigator provided appropriate medication and/or arranged access to appropriate care for the patient.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 Oct 2013
    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
    France: 12
    Country: Number of subjects enrolled
    Romania: 39
    Country: Number of subjects enrolled
    Malaysia: 3
    Country: Number of subjects enrolled
    Mexico: 43
    Country: Number of subjects enrolled
    Korea, Republic of: 23
    Country: Number of subjects enrolled
    Poland: 10
    Country: Number of subjects enrolled
    Slovakia: 37
    Country: Number of subjects enrolled
    Bulgaria: 26
    Country: Number of subjects enrolled
    Estonia: 29
    Country: Number of subjects enrolled
    Finland: 89
    Worldwide total number of subjects
    311
    EEA total number of subjects
    242
    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)
    0
    From 65 to 84 years
    310
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Investigators were General Practitioners, specialists in psychiatry.

    Pre-assignment
    Screening details
    		 Male or female out-patients, ≥ 65-year old, fulfilling DSM-IV-TR criteria for a moderate to severe episode of a recurrent major depressive disorder, with Hamilton depression rating scale 17 items (HAM-D) total score ≥ 22 and clinical global impression (CGI) severity of illness score ≥ 4.

    Period 1
    Period 1 title
    Double-blind treatment period of 8 weeks
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Tianeptine
    Arm description
    		 All patients received 25 mg/day of tianeptine during the first 2 weeks of treatment. At W2, patients with insufficient clinical improvement according to a blind pre-determined clinical improvement criterion received 50 mg/day. After W2, the 25 mg or 50 mg dose was maintained up to W8.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tianeptine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Capsules of 12.5 or 25 mg of tianeptine, taken orally twice daily (one capsule in the morning and one capsule in the evening before meals). For patients receiving tianeptine 25 mg daily at inclusion (W0), a potential adjustment to 50 mg daily might occur at Week-2 (W2) using pre-determined fixed criterion, in double-blind conditions (neither the investigator, neither the sponsor staff, nor the patients knew whether the dose had been increased) in case of insufficient improvement of depressive symptoms. Patients with sufficient improvement remained on tianeptine 25 mg daily. During tapering period, dose of tianeptine was unchanged.

    Arm title
    		 Escitalopram
    Arm description
    		 All patients received a starting dosage of 5 mg/day during the first 2 weeks of treatment. At W2, all patients increased to 10 mg/day (mandatory adjustment). At the end of the study or in case of premature study withdrawal after W2, all patients received 5 mg/day for the last week (tapering period).
    Arm type
    		 Active control to assay sensitivity

    Investigational medicinal product name
    Escitalopram
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Capsule of 5 mg or 10 mg of escitalopram or placebo, taken orally twice daily (one escitalopram capsule in the morning and one placebo capsule in the evening before meals). Patients received 5 mg daily from W0 to W2, then 10 mg daily from W2. A one-week tapering period at 5 mg/day was planned to avoid possible withdrawal reactions.

    Arm title
    		 Placebo
    Arm description
    		 Potential or mandatory dose increase (tianeptine and escitalopram groups, respectively) and dose decrease (escitalopram group) were in blind condition.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    One capsule taken orally twice daily (one capsule in the morning and one capsule in the evening before meals).

    Number of subjects in period 1
    		Tianeptine Escitalopram Placebo
    Started
    105
    99
    107
    Completed
    97
    88
    91
    Not completed
    8
    11
    16
         Adverse event, non-fatal
    3
    6
    6
         Lack of efficacy
    2
    2
    5
         Non medical reasons
    3
    2
    5
         Protocol deviation
    -
    1
    -
    Period 2
    Period 2 title
    Optional extension period of 16 weeks
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Tianeptine
    Arm description
    		 To continue in the optional extension period, patients had to be responder to treatment according to HAM-D total score at W8 (decrease from baseline in HAM-D total score of at least 50%). At W12, only patients with a Clinical Global Impression (CGI) global improvement (item 2) ≤ 2 could continue in the optional extension period up to W24.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tianeptine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Capsules of 12.5 or 25 mg of tianeptine, taken orally twice daily (one capsule in the morning and one capsule in the evening before meals). The tianeptine dose fixed in blind condition at W2 according to clinical improvement (25 mg/day or 50 mg/day)remained unchanged during the optional extension period. The dose of tianeptine was unchanged during the tapering period (end of the study or in case of premature study discontinuation).

    Arm title
    		 Escitalopram
    Arm description
    		 To continue in the optional extension period, patients had to be responder to treatment according to HAM-D total score at W8 (decrease from baseline in HAM-D total score of at least 50%). At W12, only patients with a Clinical Global Impression (CGI) global improvement (item 2) ≤ 2 could continue in the optional extension period up to W24.
    Arm type
    		 Active control to assay sensitivity

    Investigational medicinal product name
    Escitalopram
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Capsule of 5 mg or 10 mg of escitalopram or placebo, taken orally twice daily (one escitalopram capsule in the morning and one placebo capsule in the evening before meals). During the optional extension period, the patients received 10 mg/day. A one-week tapering period at 5 mg/day was planned to avoid possible withdrawal reactions at the end of the study or in case of premature study discontinuation.

    Arm title
    		 Placebo
    Arm description
    		 To continue in the optional extension period, patients had to be responder to treatment according to HAM-D total score at W8 (decrease from baseline in HAM-D total score of at least 50%). At W12, only patients with a Clinical Global Impression (CGI) global improvement (item 2) ≤ 2 could continue in the optional extension period up to W24.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    One capsule taken orally twice daily (one capsule in the morning and one capsule in the evening before meals).

    Number of subjects in period 2 [1]
    		Tianeptine Escitalopram Placebo
    Started
    77
    75
    57
    Completed
    71
    69
    48
    Not completed
    6
    6
    9
         Adverse event, non-fatal
    1
    2
    2
         Lack of efficacy
    4
    1
    5
         Protocol deviation
    1
    -
    -
         Non medical reasons
    -
    3
    2
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: To continue in the optional extension period, patients had to be responder to treatment according to HAM-D total score at W8 (decrease from baseline in HAM-D total score of at least 50%). At W12, only patients with a Clinical Global Impression (CGI) global improvement (item 2) ≤ 2 could continue in the optional extension period up to W24. 20 patients in the tianeptine group, 13 patients in the escitalopram group and 34 patients in the placebo group did not enter the optional extension period.
    Period 3
    Period 3 title
    Tapering period of 1 week
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Tianeptine
    Arm description
    		 During tapering period, dose of tianeptine was unchanged. The tapering period was planned after W2 to avoid discontinuation symptoms of escitalopram as recommended in the SmPC of escitalopram.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tianeptine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Capsules of 12.5 or 25 mg of tianeptine, taken orally twice daily (one capsule in the morning and one capsule in the evening before meals). The tianeptine dose fixed in blind condition at W2 according to clinical improvement (25 mg/day or 50 mg/day) remained unchanged during the tapering period (end of the study or in case of premature study discontinuation).

    Arm title
    		 Escitalopram
    Arm description
    		 The tapering period was planned after W2 to avoid discontinuation symptoms of escitalopram as recommended in the SmPC of escitalopram. Only escitalopram dose was decreased during this period.
    Arm type
    		 Active control to assay sensitivity

    Investigational medicinal product name
    Escitalopram
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Capsule of 5 mg or 10 mg of escitalopram or placebo, taken orally twice daily (one escitalopram capsule in the morning and one placebo capsule in the evening before meals). From W2, all patients received 10 mg/day. After W2, a one-week tapering period at 5 mg/day was planned to avoid possible withdrawal reactions.

    Arm title
    		 Placebo
    Arm description
    		 The tapering period planned to follow the SmPC of escitalopram was in blind condition.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    One capsule taken orally twice daily (one capsule in the morning and one capsule in the evening before meals).

    Number of subjects in period 3
    		Tianeptine Escitalopram Placebo
    Started
    71
    69
    48
    Completed
    71
    69
    47
    Not completed
    0
    0
    1
         Lack of efficacy
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Tianeptine
    Reporting group description
    		 All patients received 25 mg/day of tianeptine during the first 2 weeks of treatment. At W2, patients with insufficient clinical improvement according to a blind pre-determined clinical improvement criterion received 50 mg/day. After W2, the 25 mg or 50 mg dose was maintained up to W8.

    Reporting group title
    Escitalopram
    Reporting group description
    		 All patients received a starting dosage of 5 mg/day during the first 2 weeks of treatment. At W2, all patients increased to 10 mg/day (mandatory adjustment). At the end of the study or in case of premature study withdrawal after W2, all patients received 5 mg/day for the last week (tapering period).

    Reporting group title
    Placebo
    Reporting group description
    		 Potential or mandatory dose increase (tianeptine and escitalopram groups, respectively) and dose decrease (escitalopram group) were in blind condition.

    Reporting group values
    		 Tianeptine Escitalopram Placebo Total
    Number of subjects
    		 105 99 107 311
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 0 0 0 0
        From 65-84 years
    		 105 98 107 310
        85 years and over
    		 0 1 0 1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 70.2 ± 4.3 70.3 ± 4.9 70.8 ± 5.1 -
    Gender categorical
    Units: Subjects
        Female
    		 71 74 80 225
        Male
    		 34 25 27 86

    End points

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    End points reporting groups
    Reporting group title
    Tianeptine
    Reporting group description
    		 All patients received 25 mg/day of tianeptine during the first 2 weeks of treatment. At W2, patients with insufficient clinical improvement according to a blind pre-determined clinical improvement criterion received 50 mg/day. After W2, the 25 mg or 50 mg dose was maintained up to W8.

    Reporting group title
    Escitalopram
    Reporting group description
    		 All patients received a starting dosage of 5 mg/day during the first 2 weeks of treatment. At W2, all patients increased to 10 mg/day (mandatory adjustment). At the end of the study or in case of premature study withdrawal after W2, all patients received 5 mg/day for the last week (tapering period).

    Reporting group title
    Placebo
    Reporting group description
    		 Potential or mandatory dose increase (tianeptine and escitalopram groups, respectively) and dose decrease (escitalopram group) were in blind condition.
    Reporting group title
    Tianeptine
    Reporting group description
    		 To continue in the optional extension period, patients had to be responder to treatment according to HAM-D total score at W8 (decrease from baseline in HAM-D total score of at least 50%). At W12, only patients with a Clinical Global Impression (CGI) global improvement (item 2) ≤ 2 could continue in the optional extension period up to W24.

    Reporting group title
    Escitalopram
    Reporting group description
    		 To continue in the optional extension period, patients had to be responder to treatment according to HAM-D total score at W8 (decrease from baseline in HAM-D total score of at least 50%). At W12, only patients with a Clinical Global Impression (CGI) global improvement (item 2) ≤ 2 could continue in the optional extension period up to W24.

    Reporting group title
    Placebo
    Reporting group description
    		 To continue in the optional extension period, patients had to be responder to treatment according to HAM-D total score at W8 (decrease from baseline in HAM-D total score of at least 50%). At W12, only patients with a Clinical Global Impression (CGI) global improvement (item 2) ≤ 2 could continue in the optional extension period up to W24.
    Reporting group title
    Tianeptine
    Reporting group description
    		 During tapering period, dose of tianeptine was unchanged. The tapering period was planned after W2 to avoid discontinuation symptoms of escitalopram as recommended in the SmPC of escitalopram.

    Reporting group title
    Escitalopram
    Reporting group description
    		 The tapering period was planned after W2 to avoid discontinuation symptoms of escitalopram as recommended in the SmPC of escitalopram. Only escitalopram dose was decreased during this period.

    Reporting group title
    Placebo
    Reporting group description
    		 The tapering period planned to follow the SmPC of escitalopram was in blind condition.

    Primary: HAM-D total score (main analysis)

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    End point title
    		 HAM-D total score (main analysis)
    End point description
    The treatment difference between tianeptine and placebo was studied in the FAS from the HAM-D total score expressed in terms of change from baseline to W8, using a two-way analysis of covariance (ANCOVA) model (including the three treatment groups). Analysis include the fixed, categorical effects of treatment, the random categorical effect of centre as well as the continuous, fixed covariate of baseline HAM-D total score. Missing data at W8 were imputed using LOCF approach.
    End point type
    Primary
    End point timeframe
    The primary efficacy criterion was the HAM-D 17 total score expressed mainly in term of change from baseline to W8.
    End point values
    		 Tianeptine Escitalopram Placebo
    Number of subjects analysed
    105 [1]
    98 [2]
    106 [3]
    Units: score
        arithmetic mean (standard deviation)
    -13.4 ± 7.4
    -13.6 ± 7.2
    -9.5 ± 6.9
    Notes
    [1] - Full analysis Set Missing data at W8 were imputed using the Last Observation Carried Forward (LOCF)
    [2] - Full Analysis Set Missing data at W8 were imputed using the Last Observation Carried Forward (LOCF)
    [3] - Full Analysis Set Missing data at W8 were imputed using the Last Observation Carried Forward (LOCF)
    Statistical analysis title
    		 Main analysis (Tianeptine versus placebo)
    Statistical analysis description
    Analysis of covariance model on factors treatment and centre (random effect) with baseline HAM-D total score as covariate.
    Comparison groups
    Tianeptine v Placebo
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    3.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.17
         upper limit
    		 5.51
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.85
    Statistical analysis title
    		 Assay sensitivity (escitalopram vs placebo)
    Statistical analysis description
    Escitalopram was compared to placebo using strictly the same strategy as for the comparison between tianeptine and placebo
    Comparison groups
    Escitalopram v Placebo
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    4.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.39
         upper limit
    		 5.79
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.86
    Notes
    [4] - Analysis of covariance model on factors treatment and centre (random effect) with baseline HAM-D total score as covariate.

    Primary: HAM-D total score (sensitivity analysis)

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    End point title
    		 HAM-D total score (sensitivity analysis)
    End point description
    Sensitivity analysis to the method of handling missing data: MMRM analysis in all patients of the FAS. Tianeptine and escitalopram were compared to placebo in the FAS on the change from baseline to W8 of HAM-D total score, using a restricted maximum likelihood (REML)-based, mixed-effects repeated measures approach (MMRM) using all the longitudinal observations at each post-baseline visit (W2, W4, W6 and W8) expressed as change from baseline. Analysis included the fixed, categorical effects of treatment, visit and treatment-by-visit interaction, the random categorical effect of centre as well as the continuous, fixed covariate of baseline.
    End point type
    Primary
    End point timeframe
    The primary efficacy criterion was the HAM-D 17 total score expressed mainly in term of change from baseline to W8.
    End point values
    		 Tianeptine Escitalopram Placebo
    Number of subjects analysed
    99 [5]
    90 [6]
    96 [7]
    Units: score
        arithmetic mean (standard deviation)
    -13.9 ± 7.4
    -14.5 ± 6.4
    -10.4 ± 6.4
    Notes
    [5] - FAS patients with HAM-D total score both at baseline and W8
    [6] - FAS patients with HAM-D total score both at baseline and W8
    [7] - FAS patients with HAM-D total score both at baseline and W8
    Statistical analysis title
    		 Sensitivity analysis (Tianeptine vs placebo)
    Statistical analysis description
    Maximum likelihood (REML)-based, mixed-effects repeated measures approach (MMRM) using all the longitudinal observations at each post-baseline visit (W2, W4, W6 and W8) expressed as change from baseline. Analysis included the fixed, categorical effects of treatment, visit and treatment-by-visit interaction, the random categorical effect of centre as well as the continuous, fixed covariate of baseline.
    Comparison groups
    Tianeptine v Placebo
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    3.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.84
         upper limit
    		 5.47
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.92
    Statistical analysis title
    		 Sensitivity analysis (escitalopram vs placebo)
    Comparison groups
    Escitalopram v Placebo
    Number of subjects included in analysis
    186
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    4.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.67
         upper limit
    		 6.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.95

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were reported at each visit over the whole duration of the study. Adverse events presented here are those reported during the W0-W25 treatment period.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Tianeptine
    Reporting group description
    		 -

    Reporting group title
    Escitalopram
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Tianeptine Escitalopram Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 105 (1.90%)
    2 / 98 (2.04%)
    3 / 107 (2.80%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 98 (1.02%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 98 (1.02%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    1 / 105 (0.95%)
    0 / 98 (0.00%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Paraesthesia
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 98 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 98 (1.02%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 98 (1.02%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Panic attack
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 98 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 98 (1.02%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bradyphrenia
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 98 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 98 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 98 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    1 / 105 (0.95%)
    0 / 98 (0.00%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3.5%
    Non-serious adverse events
    		 Tianeptine Escitalopram Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    51 / 105 (48.57%)
    63 / 98 (64.29%)
    53 / 107 (49.53%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 105 (0.00%)
    5 / 98 (5.10%)
    2 / 107 (1.87%)
         occurrences all number
    0
    5
    3
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    3 / 105 (2.86%)
    9 / 98 (9.18%)
    12 / 107 (11.21%)
         occurrences all number
    3
    9
    14
    Headache
         subjects affected / exposed
    13 / 105 (12.38%)
    17 / 98 (17.35%)
    6 / 107 (5.61%)
         occurrences all number
    17
    18
    10
    Somnolence
         subjects affected / exposed
    1 / 105 (0.95%)
    4 / 98 (4.08%)
    0 / 107 (0.00%)
         occurrences all number
    1
    4
    0
    Tremor
         subjects affected / exposed
    0 / 105 (0.00%)
    5 / 98 (5.10%)
    2 / 107 (1.87%)
         occurrences all number
    0
    5
    2
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    4 / 105 (3.81%)
    4 / 98 (4.08%)
    1 / 107 (0.93%)
         occurrences all number
    4
    4
    1
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    3 / 105 (2.86%)
    1 / 98 (1.02%)
    5 / 107 (4.67%)
         occurrences all number
    4
    1
    5
    Diarrhoea
         subjects affected / exposed
    0 / 105 (0.00%)
    4 / 98 (4.08%)
    3 / 107 (2.80%)
         occurrences all number
    0
    4
    3
    Dry mouth
         subjects affected / exposed
    3 / 105 (2.86%)
    8 / 98 (8.16%)
    5 / 107 (4.67%)
         occurrences all number
    3
    8
    5
    Flatulence
         subjects affected / exposed
    4 / 105 (3.81%)
    4 / 98 (4.08%)
    2 / 107 (1.87%)
         occurrences all number
    4
    4
    2
    Nausea
         subjects affected / exposed
    10 / 105 (9.52%)
    12 / 98 (12.24%)
    6 / 107 (5.61%)
         occurrences all number
    10
    13
    6
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    1 / 105 (0.95%)
    5 / 98 (5.10%)
    1 / 107 (0.93%)
         occurrences all number
    1
    5
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    3 / 105 (2.86%)
    4 / 98 (4.08%)
    1 / 107 (0.93%)
         occurrences all number
    3
    4
    1
    Insomnia
         subjects affected / exposed
    1 / 105 (0.95%)
    4 / 98 (4.08%)
    2 / 107 (1.87%)
         occurrences all number
    1
    4
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 105 (2.86%)
    1 / 98 (1.02%)
    4 / 107 (3.74%)
         occurrences all number
    3
    1
    5
    Back pain
         subjects affected / exposed
    1 / 105 (0.95%)
    4 / 98 (4.08%)
    0 / 107 (0.00%)
         occurrences all number
    1
    4
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    4 / 105 (3.81%)
    1 / 98 (1.02%)
    2 / 107 (1.87%)
         occurrences all number
    4
    1
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Dec 2013
    Applicable to all countries. It mainly concerned the implementation of the changes related to the revision (dated 02 October 2013) of escitalopram SmPC. According to this revision, one non selection or non-inclusion criterion was added for patients with angle-close glaucoma or history of glaucoma and a caution was warranted for concomitant use of medicinal products inducing hypokalaemia/hypomagnesaemia as these conditions increased the risk of malignant arrhythmias with study drugs. One other change implemented with this amendment was the update of the Declaration of Helsinki to be in accordance with the revised version of Fortaleza, October 2013. Secondary objectives of this amendment were to complete or correct the following information: - Conditions of storage of the treatments. - Antihistamines with central effects in the list of forbidden treatments due to their possible action on the central nervous system. - Doses of the benzodiazepines authorized as concomitant medications (equivalent to 10 mg of diazepam). - Collected blood volumes and interpretation of hepatitis B serology status. - Use of the computerized medical file. - MINI and CGI scales according to the final e-CRF format.
    22 Oct 2014
    Three countries participating to the study were added (Bulgaria, Poland and South Africa) and one country was removed (Argentina).

    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
    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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