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    Clinical Trial Results:
    A single centre, double blind, non-inferiority study to evaluate the antidepressant activity of Viotra™ compared with amitriptyline in the treatment of major depressive disorder (MDD) in patients who have an unsatisfactory response / are resistant to SSRIs.

    Summary
    EudraCT number
    		 2013-000719-26
    Trial protocol
    		 GB  
    Global end of trial date
    29 Oct 2015

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

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    ETS6103-003
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02014363
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    e-Therapeutics plc
    Sponsor organisation address
    17 Blenheim Office Park, Oxfordshire, United Kingdom, OX29 8LN
    Public contact
    Clinical Operations Manager, e-Therapeutics plc, 44 1993880000, contact@etherapeutics.co.uk
    Scientific contact
    Clinical Operations Manager, e-Therapeutics plc, 44 1993880000, contact@etherapeutics.co.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    29 Oct 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Oct 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Oct 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate that the antidepressant activity of Viotra™ is not inferior to amitriptyline in subjects who have an unsatisfactory response to / are resistant to treatment with SSRIs.
    Protection of trial subjects
    Patients were assessed regularly with regards to the status of their depressive episode. Safety assessments such as blood sampling for the assessment of haematological and clinical chemistry parameters, ECG assessments and pregnancy tests were performed periodically.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    29 Oct 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 367
    Worldwide total number of subjects
    367
    EEA total number of subjects
    367
    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)
    365
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 After 6 wks treatment with citalopram, subjects who had a HAMD-17 score of ≥12 at the end of the lead-in phase were randomised to take low or high-dose tramadol or standard dose amitriptyline. The subjects visited the site at weeks 1, 2, 4, 6, and 8 for assessment of their mental state and safety and were followed up 28 days after the final visit.

    Pre-assignment
    Screening details
    		 Patients with confirmed major depressive disorder and with HAM-D score of ≥18 started 6 wk run-in with citalopram. Patients with HAM-D score ≥12 at the end of the run in were potentially eligible for randomisation.

    Period 1
    Period 1 title
    Treatment (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor
    Blinding implementation details
    All medication dispensed during the blinded randomisation phase were identical in appearance. The blinded study medication was provided to the Investigator Site and dispensed to the patients. The blinded study medication code was recorded, to enable unblinding of treatments received after database lock.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 ETS6103 low dose
    Arm description
    		 Low-dose of ETS6103
    Arm type
    		 Experimental

    Investigational medicinal product name
    ETS6103
    Investigational medicinal product code
    Other name
    Tramadol
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    8-week treatment with one low-dose ETS6103 capsule taken once daily orally with water at between 19:00h and 21:00h.

    Arm title
    		 ETS6103 high dose
    Arm description
    		 High dose of ETS6103
    Arm type
    		 Experimental

    Investigational medicinal product name
    ETS6103
    Investigational medicinal product code
    Other name
    Tramadol
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    8-week treatment with one high-dose ETS6103 capsule taken once daily orally with water at between 19:00h and 21:00h.

    Arm title
    		 Amitriptyline
    Arm description
    		 Amitriptyline
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Amitriptyline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Weeks 1 & 2: one 75 mg amitriptyline capsule taken once daily orally with water at between 7-9pm (evening). Weeks 3 - 8: one 150mg amitriptyline capsule taken once daily orally with water at between 7-9pm (evening).

    Number of subjects in period 1 [1]
    		ETS6103 low dose ETS6103 high dose Amitriptyline
    Started
    55
    54
    55
    Completed
    38
    35
    31
    Not completed
    17
    19
    24
         Consent withdrawn by subject
    3
    -
    1
         Adverse event, non-fatal
    6
    8
    12
         Other
    1
    -
    1
         Non-compliance
    1
    1
    1
         Lack of efficacy
    6
    10
    9
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The number of patients enrolled reflects the numbers of patients screened and included in the safety analysis dataset. The number of patients in the baseline period is the number of patients randomised and included in the full analysis dataset.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    ETS6103 low dose
    Reporting group description
    		 Low-dose of ETS6103

    Reporting group title
    ETS6103 high dose
    Reporting group description
    		 High dose of ETS6103

    Reporting group title
    Amitriptyline
    Reporting group description
    		 Amitriptyline

    Reporting group values
    		 ETS6103 low dose ETS6103 high dose Amitriptyline Total
    Number of subjects
    		 55 54 55 164
    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)
    		 55 54 55 164
        From 65-84 years
    		 0 0 0 0
        85 years and over
    		 0 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 39 40 36 115
        Male
    		 16 14 19 49
    Subject analysis sets

    Subject analysis set title
    Safety analysis set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects who signed an informed consent and entered the lead-in phase

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects of the SA set who received at least one dose of randomised study medication with at least one on treatment measurement of the primary variable after randomisation

    Subject analysis set title
    Per protocol set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects of the FA set for whom no relevant protocol deviations were documented

    Subject analysis sets values
    		 Safety analysis set Full analysis set Per protocol set
    Number of subjects
    367
    162
    126
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
        Adults (18-64 years)
    365
    162
    126
        From 65-84 years
    2
    0
    0
        85 years and over
    0
    0
    0
    Age continuous
    Units:
        
    ( )
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    248
    114
    86
        Male
    119
    48
    40

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    ETS6103 low dose
    Reporting group description
    		 Low-dose of ETS6103

    Reporting group title
    ETS6103 high dose
    Reporting group description
    		 High dose of ETS6103

    Reporting group title
    Amitriptyline
    Reporting group description
    		 Amitriptyline

    Subject analysis set title
    Safety analysis set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects who signed an informed consent and entered the lead-in phase

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects of the SA set who received at least one dose of randomised study medication with at least one on treatment measurement of the primary variable after randomisation

    Subject analysis set title
    Per protocol set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects of the FA set for whom no relevant protocol deviations were documented

    Primary: The mean difference in baseline-adjusted MADRS score at the end of treatment (week 8)

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    End point title
    		 The mean difference in baseline-adjusted MADRS score at the end of treatment (week 8)
    End point description
    End point type
    Primary
    End point timeframe
    Baseline (start of treatment) to week 8. For missing results for the efficacy variable MADRS, LOCF (last-observation-carried-forward) was applied.
    End point values
    		 ETS6103 low dose ETS6103 high dose Amitriptyline
    Number of subjects analysed
    44
    43
    39
    Units: Baseline-adjusted MADRS score
        least squares mean (standard error)
    -6.1396 ( 1.64423 )
    -6.0076 ( 1.65174 )
    -11.3762 ( 1.7344 )
    Statistical analysis title
    		 Non-inferiority ETS6103 high vs. amitriptyline
    Statistical analysis description
    Noninferiority test - comparison ETS6103 high dose vs. amitriptyline, PP set
    Comparison groups
    ETS6103 high dose v Amitriptyline
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.9861 [1]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [1] - One-sided p-value (Non-inferiority) 97.5% confidence interval (one-sided). Non-inferiority margin 2.5.
    Statistical analysis title
    		 Non-inferiority ETS6103 low vs. amitriptyline
    Statistical analysis description
    Noninferiority test - comparison ETS6103 low dose vs. amitriptyline, PP set
    Comparison groups
    Amitriptyline v ETS6103 low dose
    Number of subjects included in analysis
    83
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.9828 [2]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [2] - One-sided p-value (Non-inferiority) 97.5% confidence interval (one-sided). Non-inferiority margin 2.5.

    Secondary: The mean difference in baseline-adjusted MADRS score at week 1

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    End point title
    		 The mean difference in baseline-adjusted MADRS score at week 1
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline (randomisation) to week 1
    End point values
    		 ETS6103 low dose ETS6103 high dose Amitriptyline
    Number of subjects analysed
    54 [3]
    54 [4]
    54 [5]
    Units: Baseline adjusted MADRS score
        arithmetic mean (standard deviation)
    -0.87 ( 6.588 )
    -1.7 ( 7.324 )
    -3.13 ( 5.306 )
    Notes
    [3] - Full analysis dataset
    [4] - Full analysis dataset
    [5] - Full analysis dataset
    No statistical analyses for this end point

    Secondary: The mean difference in baseline-adjusted MADRS score at week 2

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    End point title
    		 The mean difference in baseline-adjusted MADRS score at week 2
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline (randomisation) to week 2
    End point values
    		 ETS6103 low dose ETS6103 high dose Amitriptyline
    Number of subjects analysed
    54 [6]
    54 [7]
    54 [8]
    Units: Baseline-adjusted MADRS score
        arithmetic mean (standard deviation)
    -2.17 ( 8.181 )
    -3.35 ( 8.175 )
    -5 ( 8.362 )
    Notes
    [6] - Full analysis dataset
    [7] - Full analysis dataset
    [8] - Full analysis dataset
    No statistical analyses for this end point

    Secondary: The mean difference in baseline-adjusted MADRS score at week 4

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    End point title
    		 The mean difference in baseline-adjusted MADRS score at week 4
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline (randomisation) to week 4
    End point values
    		 ETS6103 low dose ETS6103 high dose Amitriptyline
    Number of subjects analysed
    54 [9]
    54 [10]
    54 [11]
    Units: Baseline-adjusted MADRS score
        arithmetic mean (standard deviation)
    -3.89 ( 10.225 )
    -4.93 ( 9.206 )
    -7.09 ( 9.495 )
    Notes
    [9] - Full analysis dataset
    [10] - Full analysis dataset
    [11] - Full analysis dataset
    No statistical analyses for this end point

    Secondary: The mean difference in baseline-adjusted MADRS score at week 6

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    End point title
    		 The mean difference in baseline-adjusted MADRS score at week 6
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline (randomisation) to week 6
    End point values
    		 ETS6103 low dose ETS6103 high dose Amitriptyline
    Number of subjects analysed
    54 [12]
    54 [13]
    54 [14]
    Units: Baseline adjusted MADRS score
        arithmetic mean (standard deviation)
    -5.22 ( 11.12 )
    -5.93 ( 10.365 )
    -7.87 ( 9.798 )
    Notes
    [12] - Full analysis dataset
    [13] - Full analysis dataset
    [14] - Full analysis dataset
    No statistical analyses for this end point

    Secondary: Patients in remission

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    End point title
    		 Patients in remission
    End point description
    Patients with remission defined as ≤ 10 on the MADRS at the end of treatment (week 8).
    End point type
    Secondary
    End point timeframe
    Baseline (randomisation) to end of treatment (week 8).
    End point values
    		 ETS6103 low dose ETS6103 high dose Amitriptyline
    Number of subjects analysed
    54 [15]
    54 [16]
    54 [17]
    Units: Number of patients
    7
    11
    17
    Notes
    [15] - Full analysis dataset
    [16] - Full analysis dataset
    [17] - Full analysis dataset
    No statistical analyses for this end point

    Secondary: Patients responsing

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    End point title
    		 Patients responsing
    End point description
    Responders defined as ≥ 50% decrease from baseline in the MADRS at the end of treatment (week 8)
    End point type
    Secondary
    End point timeframe
    Baseline (randomisation) to end of treatment (week 8).
    End point values
    		 ETS6103 low dose ETS6103 high dose Amitriptyline
    Number of subjects analysed
    54 [18]
    54 [19]
    54 [20]
    Units: Number of patients
    15
    17
    22
    Notes
    [18] - Full analysis dataset
    [19] - Full analysis dataset
    [20] - Full analysis dataset
    No statistical analyses for this end point

    Secondary: Mean difference in baseline-adjusted CGI severity at week 8

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    End point title
    		 Mean difference in baseline-adjusted CGI severity at week 8
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline (week 0) to week 8.
    End point values
    		 ETS6103 low dose ETS6103 high dose Amitriptyline
    Number of subjects analysed
    50
    50
    48
    Units: Baseline-adjusted CGI
        arithmetic mean (standard deviation)
    -1 ( 1.294 )
    -0.98 ( 1.505 )
    -1.21 ( 1.458 )
    Statistical analysis title
    		 CGI-S comparison low dose ETS6103 and amitriptylin
    Statistical analysis description
    Baseline-adjusted CGI severity scores were compared between low dose ETS6103 and amitriptyline and high dose ETS6103 and amitriptyline using the ANCOVA model. The model statements were comparable to the primary efficacy parameter, whereas the test was based on superiority.
    Comparison groups
    ETS6103 low dose v Amitriptyline
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5089
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.1727
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3444
         upper limit
    		 0.6898
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.26047
    Statistical analysis title
    		 CGI-S comparison high dose ETS6103 and amitriptyli
    Statistical analysis description
    Baseline-adjusted CGI severity scores were compared between low dose ETS6103 and amitriptyline and high dose ETS6103 and amitriptyline using the ANCOVA model. The model statements were comparable to the primary efficacy parameter, whereas the test was based on superiority.
    Comparison groups
    Amitriptyline v ETS6103 high dose
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4417
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.2232
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3503
         upper limit
    		 0.7967
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.28889

    Secondary: The mean difference in CGI improvement at week 1

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    End point title
    		 The mean difference in CGI improvement at week 1
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline (week 0) to week 1.
    End point values
    		 ETS6103 low dose ETS6103 high dose Amitriptyline
    Number of subjects analysed
    48
    51
    42
    Units: CGI improvement score
        arithmetic mean (standard deviation)
    3.67 ( 0.953 )
    3.57 ( 1.153 )
    3.48 ( 1.131 )
    Statistical analysis title
    		 CGI-I low dose ETS6103 and amitriptyline wk1
    Statistical analysis description
    CGI-I analysis of absolute scales for week 1 - comparison low dose ETS6103 vs. Amitriptyline
    Comparison groups
    ETS6103 low dose v Amitriptyline
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3883
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.1905
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.2461
         upper limit
    		 0.6271
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.2197
    Statistical analysis title
    		 CGI-I high dose ETS6103 and amitriptyline wk1
    Statistical analysis description
    CGI-I analysis of absolute scales for week 1 - comparison high dose ETS6103 vs. Amitriptyline
    Comparison groups
    Amitriptyline v ETS6103 high dose
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.699
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.0924
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3808
         upper limit
    		 0.5657
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.23826

    Secondary: The mean difference in CGI improvement at week 2

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    End point title
    		 The mean difference in CGI improvement at week 2
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline (week 0) to week 2.
    End point values
    		 ETS6103 low dose ETS6103 high dose Amitriptyline
    Number of subjects analysed
    48
    51
    43
    Units: CGI improvement score
        arithmetic mean (standard deviation)
    3.46 ( 1.051 )
    3.31 ( 1.191 )
    3.26 ( 1.432 )
    Statistical analysis title
    		 CGI-I high dose ETS6103 and amitriptyline wk2
    Statistical analysis description
    CGI-I analysis of absolute scales for week 2 - comparison high dose ETS6103 vs. Amitriptyline
    Comparison groups
    ETS6103 high dose v Amitriptyline
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.831
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.0579
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.4795
         upper limit
    		 0.5954
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.2706
    Statistical analysis title
    		 CGI-I low dose ETS6103 and amitriptyline wk2
    Statistical analysis description
    CGI-I analysis of absolute scales for week 2 - comparison low dose ETS6103 vs. Amitriptyline
    Comparison groups
    Amitriptyline v ETS6103 low dose
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4408
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.2025
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3172
         upper limit
    		 0.7222
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.26156

    Secondary: The mean difference in CGI improvement at week 4

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    End point title
    		 The mean difference in CGI improvement at week 4
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline (week 0) to week 4.
    End point values
    		 ETS6103 low dose ETS6103 high dose Amitriptyline
    Number of subjects analysed
    48
    51
    43
    Units: CGI improvement
        arithmetic mean (standard deviation)
    3 ( 1.111 )
    3.08 ( 1.262 )
    2.86 ( 1.407 )
    Statistical analysis title
    		 CGI-I high dose ETS6103 and amitriptyline wk4
    Statistical analysis description
    CGI-I analysis of absolute scales for week 4 - comparison high dose ETS6103 vs. Amitriptyline
    Comparison groups
    Amitriptyline v ETS6103 high dose
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4308
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.218
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3291
         upper limit
    		 0.765
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.27545
    Statistical analysis title
    		 CGI-I low dose ETS6103 and amitriptyline wk4
    Statistical analysis description
    CGI-I analysis of absolute scales for week 4 - comparison low dose ETS6103 vs. Amitriptyline
    Comparison groups
    Amitriptyline v ETS6103 low dose
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5991
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.1395
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3859
         upper limit
    		 0.665
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.26444

    Secondary: The mean difference in CGI improvement at week 6

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    End point title
    		 The mean difference in CGI improvement at week 6
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline (week 0) to week 6.
    End point values
    		 ETS6103 low dose ETS6103 high dose Amitriptyline
    Number of subjects analysed
    48
    51
    43
    Units: CGI improvement score
        arithmetic mean (standard deviation)
    3 ( 1.305 )
    3.18 ( 1.452 )
    2.67 ( 1.393 )
    Statistical analysis title
    		 CGI-I high dose ETS6103 and amitriptyline wk6
    Statistical analysis description
    CGI-I analysis of absolute scales for week 6 - comparison high dose ETS6103 vs. Amitriptyline
    Comparison groups
    ETS6103 high dose v Amitriptyline
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0922
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.5021
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.084
         upper limit
    		 1.0881
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.29505
    Statistical analysis title
    		 CGI-I low dose ETS6103 and amitriptyline wk6
    Statistical analysis description
    CGI-I analysis of absolute scales for week 6 - comparison low dose ETS6103 vs. Amitriptyline
    Comparison groups
    Amitriptyline v ETS6103 low dose
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2527
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.3256
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.2363
         upper limit
    		 0.8875
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.2828

    Secondary: The mean difference in CGI improvement at week 8

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    End point title
    		 The mean difference in CGI improvement at week 8
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline (week 0) to week 8
    End point values
    		 ETS6103 low dose ETS6103 high dose Amitriptyline
    Number of subjects analysed
    53
    53
    52
    Units: CGI improvement score
        arithmetic mean (standard deviation)
    3.23 ( 1.625 )
    3.19 ( 1.798 )
    2.73 ( 1.773 )
    Statistical analysis title
    		 CGI-I high dose ETS6103 and amitriptyline wk8
    Statistical analysis description
    CGI-I analysis of absolute scales for week 8 - comparison high dose ETS6103 vs. Amitriptyline
    Comparison groups
    ETS6103 high dose v Amitriptyline
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1918
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.4579
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.2333
         upper limit
    		 1.1491
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.3485
    Statistical analysis title
    		 CGI-I low dose ETS6103 and amitriptyline wk8
    Statistical analysis description
    CGI-I analysis of absolute scales for week 8 - comparison low dose ETS6103 vs. Amitriptyline
    Comparison groups
    Amitriptyline v ETS6103 low dose
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1382
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.4956
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1623
         upper limit
    		 1.1536
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.33173

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Randomisation to end of 4-week follow-up visit.
    Adverse event reporting additional description
    Interventional phase.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    ETS6103 Low dose
    Reporting group description
    		 AEs occurring in ETS6103 low-dose patients, during the interventional phase (between randomisation and 4-week follow-up visit).

    Reporting group title
    ETS6103 High dose
    Reporting group description
    		 AEs occurring in ETS6103 high-dose patients, during the interventional phase (between randomisation and 4-week follow-up visit).

    Reporting group title
    Amitriptyline
    Reporting group description
    		 AEs occurring in amitriptyline patients, during the interventional phase (between randomisation and 4-week follow-up visit).

    Serious adverse events
    		 ETS6103 Low dose ETS6103 High dose Amitriptyline
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 55 (1.82%)
    1 / 54 (1.85%)
    1 / 55 (1.82%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 54 (1.85%)
    0 / 55 (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
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 54 (0.00%)
    0 / 55 (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
    Psychiatric disorders
    Alcohol abuse
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 54 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 ETS6103 Low dose ETS6103 High dose Amitriptyline
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    43 / 55 (78.18%)
    50 / 54 (92.59%)
    47 / 55 (85.45%)
    Investigations
    Electrocardiogram QT prolonged
         subjects affected / exposed
    3 / 55 (5.45%)
    1 / 54 (1.85%)
    2 / 55 (3.64%)
         occurrences all number
    3
    1
    2
    Blood pressure increased
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 54 (1.85%)
    3 / 55 (5.45%)
         occurrences all number
    0
    1
    3
    Mean cell volume increased
         subjects affected / exposed
    1 / 55 (1.82%)
    2 / 54 (3.70%)
    1 / 55 (1.82%)
         occurrences all number
    1
    2
    1
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    2 / 55 (3.64%)
    0 / 54 (0.00%)
    3 / 55 (5.45%)
         occurrences all number
    2
    0
    3
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 55 (10.91%)
    5 / 54 (9.26%)
    3 / 55 (5.45%)
         occurrences all number
    6
    5
    3
    Dizziness
         subjects affected / exposed
    2 / 55 (3.64%)
    5 / 54 (9.26%)
    4 / 55 (7.27%)
         occurrences all number
    2
    5
    4
    Tremor
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 54 (0.00%)
    8 / 55 (14.55%)
         occurrences all number
    0
    0
    8
    Somnolence
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 54 (1.85%)
    5 / 55 (9.09%)
         occurrences all number
    0
    1
    5
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 55 (5.45%)
    7 / 54 (12.96%)
    4 / 55 (7.27%)
         occurrences all number
    3
    7
    4
    Gastrointestinal disorders
    Dry mouth
         subjects affected / exposed
    3 / 55 (5.45%)
    7 / 54 (12.96%)
    26 / 55 (47.27%)
         occurrences all number
    3
    7
    26
    Vomiting
         subjects affected / exposed
    3 / 55 (5.45%)
    6 / 54 (11.11%)
    6 / 55 (10.91%)
         occurrences all number
    4
    8
    6
    Nausea
         subjects affected / exposed
    6 / 55 (10.91%)
    5 / 54 (9.26%)
    0 / 55 (0.00%)
         occurrences all number
    6
    7
    0
    Diarrhoea
         subjects affected / exposed
    1 / 55 (1.82%)
    3 / 54 (5.56%)
    4 / 55 (7.27%)
         occurrences all number
    1
    3
    4
    Dyspepsia
         subjects affected / exposed
    0 / 55 (0.00%)
    2 / 54 (3.70%)
    4 / 55 (7.27%)
         occurrences all number
    0
    2
    4
    Constipation
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 54 (0.00%)
    5 / 55 (9.09%)
         occurrences all number
    0
    0
    5
    Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 55 (3.64%)
    1 / 54 (1.85%)
    1 / 55 (1.82%)
         occurrences all number
    2
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    3 / 55 (5.45%)
    3 / 54 (5.56%)
    2 / 55 (3.64%)
         occurrences all number
    3
    3
    2
    Cough
         subjects affected / exposed
    4 / 55 (7.27%)
    1 / 54 (1.85%)
    1 / 55 (1.82%)
         occurrences all number
    4
    1
    1
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    3 / 55 (5.45%)
    7 / 54 (12.96%)
    0 / 55 (0.00%)
         occurrences all number
    3
    8
    0
    Hyperhidrosis
         subjects affected / exposed
    4 / 55 (7.27%)
    1 / 54 (1.85%)
    2 / 55 (3.64%)
         occurrences all number
    4
    1
    2
    Rash
         subjects affected / exposed
    1 / 55 (1.82%)
    5 / 54 (9.26%)
    0 / 55 (0.00%)
         occurrences all number
    1
    6
    0
    Psychiatric disorders
    Abnormal dreams
         subjects affected / exposed
    7 / 55 (12.73%)
    8 / 54 (14.81%)
    3 / 55 (5.45%)
         occurrences all number
    7
    8
    3
    Anxiety
         subjects affected / exposed
    1 / 55 (1.82%)
    1 / 54 (1.85%)
    5 / 55 (9.09%)
         occurrences all number
    1
    1
    5
    Nightmare
         subjects affected / exposed
    2 / 55 (3.64%)
    4 / 54 (7.41%)
    1 / 55 (1.82%)
         occurrences all number
    2
    4
    1
    Irritability
         subjects affected / exposed
    1 / 55 (1.82%)
    2 / 54 (3.70%)
    1 / 55 (1.82%)
         occurrences all number
    1
    2
    1
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    1 / 55 (1.82%)
    1 / 54 (1.85%)
    2 / 55 (3.64%)
         occurrences all number
    1
    1
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 55 (1.82%)
    2 / 54 (3.70%)
    1 / 55 (1.82%)
         occurrences all number
    1
    2
    1
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 55 (7.27%)
    5 / 54 (9.26%)
    0 / 55 (0.00%)
         occurrences all number
    4
    5
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 May 2013
    The MHRA guidelines on acceptable forms of effective contraception in UK clinical trials were applied. All subjects had to be fully informed about the prescribing information for citalopram, tramadol and amitriptyline.
    05 Sep 2013
    The company name was changed due to the merger of Harrison Clinical Research (HCR) with Synteract to become SynteractHCR (SHCR). Visit windows during the lead-in phase were added to allow flexibility without compromising the value of key efficacy variables and taking citalopram supply into account. Subjects who attended visit 2 early for any reason, had to complete the 2 weeks of treatment with 20mg citalopram before starting the 40mg citalopram The data documented in the Case Report Forms of lead-in subjects who were not randomised, had to be listed but not analysed. Typographical errors and inconsistencies were corrected.
    24 Apr 2014
    The recruitment period was extended to Q2 2015. Exclusion criterion 5 was amended to permit propanolol if a stable dose (minimum 30 days) had been prescribed for non-psychotropic reasons e.g. high blood pressure. Formal psychotherapy or alternative treatments was defined in exclusion criterion 7 as that administered by a specialist healthcare professional, using formal structured techniques. The exclusion of epilepsy or history of seizures in exclusion criterion 10 was clarified. Additional guidance on withdrawal criteria for subjects with a QTc interval of >500ms measured at visits 2 or 6 or >60ms increase from screening and guidance on ECG review timelines was added.
    05 Mar 2015
    Addition of LOCF (Last observation carried forward) technique for missing values of the MADRS score and CGI improvement. Revision of the classification of subsets in order to specify that subjects with at least one on treatment measurement of the primary variable after randomisation would be included in the FA set. Furthermore, all subjects of the FA set without relevant protocol deviations would be included in the PP set.

    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
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