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    Clinical Trial Results:
    A randomized, double-blind study comparing the efficacy and safety of trazodone OAD and venlafaxine XR in the treatment of patients with Major Depressive Disorder

    Summary
    EudraCT number
    		 2011-005878-37
    Trial protocol
    		 IT   AT   CZ   ES   SK   RO  
    Global end of trial date
    25 Apr 2014

    Results information
    Results version number
    		 v2(current)
    This version publication date
    18 Aug 2018
    First version publication date
    12 Aug 2015
    Other versions
    		 v1 (removed from public view)
    Version creation reason
    • Changes to summary attachments
    A summary of results is uploaded replacing the CSR.
    Summary report(s)
    		 Synopsis

    Trial information

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    Trial identification
    Sponsor protocol code
    039(C)SC11063
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02086929
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    ACRAF SpA
    Sponsor organisation address
    Piazzale della stazione, s.n.c., S.Palomba- Pomezia (Rome), Italy, 00071
    Public contact
    Clinical Trial Application Unit, ANGELINI ACRAF SpA, +39 0691045335, ctaunit@angelini.it
    Scientific contact
    Clinical Trial Application Unit, ANGELINI ACRAF SpA, +39 0691045432, ctaunit@angelini.it
    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
    07 Jul 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Apr 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy and safety of trazodone OAD vs venlafaxine XR after an 8-week treatment period in patients with major depressive disorder (MDD).
    Protection of trial subjects
    The study was performed in accordance with the protocol and the European Community CPMP guidelines of GCP for Trials on Medicinal Products [CPMP/ICH/135/1995] and applicable regulatory requirements. The study was in keeping with the requirements of the “Declaration of Helsinki” as adopted by the 18th World Medical Association (WMA) General Assembly in 1964 and with the subsequent revisions.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    21 Dec 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
    Slovakia: 75
    Country: Number of subjects enrolled
    Spain: 12
    Country: Number of subjects enrolled
    Austria: 15
    Country: Number of subjects enrolled
    Czech Republic: 72
    Country: Number of subjects enrolled
    Italy: 37
    Country: Number of subjects enrolled
    Romania: 110
    Worldwide total number of subjects
    321
    EEA total number of subjects
    321
    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)
    304
    From 65 to 84 years
    17
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Male and female 18-75 years, outpatients, MDD according o DMS-IV criteria, 17- item HAMD score >= 18, discontinuation of antidepressantsor proibited medications (wash out) for a period specif to taper schedule ( based on 5 elimination half-life of the used medication).

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    To maintain the blinding conditions of the study, trazodone OAD tablets and venlafaxine XR capsules were inserted into capsules having identical appearance.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Trazodone OAD
    Arm description
    		 Trazodone once a daily administration
    Arm type
    		 Experimental

    Investigational medicinal product name
    Trazodone
    Investigational medicinal product code
    039
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One trazodone OAD 150mg tablet daily for 1 week ( dose- titration) followed by one trazodone OAD 300 mg tablet daily for 8 weeks. After 3 and 5 weeks of treatment for non-responding patients dose increases (in increments of 75 mg/day) till to reach the maximum of 450 mg/day. According to the maximum dosage taken by the patients at the end of Treatment Phase, a 1 to 3 weeks of Tapering Period was planned for no responders.

    Arm title
    		 Venlafaxine
    Arm description
    		 Venlafaxine XR
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Venlafaxine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Venlafaxine XR 75 mg/die for 8 weeks. After 3 and 5 weeks of treatment for non-responding patients, dose increases (in increments of 75 mg/day) till to reach the maximum of 225 mg/day.

    Number of subjects in period 1
    		Trazodone OAD Venlafaxine
    Started
    165
    156
    Completed
    117
    121
    Not completed
    48
    35
         Consent withdrawn by subject
    15
    11
         Adverse event, non-fatal
    25
    15
         IMP not available
    1
    -
         Lack of efficacy
    2
    2
         Protocol deviation
    5
    7

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Trazodone OAD
    Reporting group description
    		 Trazodone once a daily administration

    Reporting group title
    Venlafaxine
    Reporting group description
    		 Venlafaxine XR

    Reporting group values
    		 Trazodone OAD Venlafaxine Total
    Number of subjects
    		 165 156 321
    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)
    		 157 147 304
        From 65-84 years
    		 8 9 17
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 47.8 ( 11.38 ) 47.9 ( 11.41 ) -
    Gender categorical
    Units: Subjects
        Female
    		 120 121 241
        Male
    		 45 35 80

    End points

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    End points reporting groups
    Reporting group title
    Trazodone OAD
    Reporting group description
    		 Trazodone once a daily administration

    Reporting group title
    Venlafaxine
    Reporting group description
    		 Venlafaxine XR

    Primary: Change in HAMD-17 total score frome baseline at Visit 9/ITT

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    End point title
    		 Change in HAMD-17 total score frome baseline at Visit 9/ITT
    End point description
    The primary efficacy measurement was the comparison of HAMD-17 scores reported at the Visit 9 with those reported at the baseline.
    End point type
    Primary
    End point timeframe
    At Visit 2 (baseline) and Visit 9 (Day 56).
    End point values
    		 Trazodone OAD Venlafaxine
    Number of subjects analysed
    162
    152
    Units: score on a scale
        arithmetic mean (standard deviation)
    -12.9 ( 6.82 )
    -14.7 ( 6.56 )
    Statistical analysis title
    		 Change HAMD-17 total score from baseline V9/ITT
    Statistical analysis description
    Change HAMD-17 total score from baseline and at V9 in the ITT (LOCF) population
    Comparison groups
    Trazodone OAD v Venlafaxine
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.01
    Method
    		 ANCOVA
    Confidence interval

    Primary: Change in HAMD-17 total score frome baseline at Visit 9/PP

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    End point title
    		 Change in HAMD-17 total score frome baseline at Visit 9/PP
    End point description
    The primary efficacy measurement was the comparison of HAMD-17 scores reported at the Visit 9 with those reported at the baseline
    End point type
    Primary
    End point timeframe
    At Visit 2 (baseline) and Visit 9 (Day 56).
    End point values
    		 Trazodone OAD Venlafaxine
    Number of subjects analysed
    122
    127
    Units: score on a scale
        arithmetic mean (standard deviation)
    -15.4 ( 5.32 )
    -16.4 ( 5.39 )
    Statistical analysis title
    		 Change HAMD-17 total score from baseline V9/PP
    Statistical analysis description
    Change HAMD-17 total score from baseline at V9 in the PP population
    Comparison groups
    Trazodone OAD v Venlafaxine
    Number of subjects included in analysis
    249
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.056
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Change in MADRS score frome baseline at Visit 9/ITT

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    End point title
    		 Change in MADRS score frome baseline at Visit 9/ITT
    End point description
    Mean change from baseline (Visit 2-D0) in MADRS score at Visit 9 (D56).
    End point type
    Secondary
    End point timeframe
    At Visit 2 (baseline)and Visit 9 (Day 56).
    End point values
    		 Trazodone OAD Venlafaxine
    Number of subjects analysed
    162
    151
    Units: score on a scale
        arithmetic mean (standard deviation)
    -14.4 ( 7.65 )
    -16.9 ( 7.65 )
    Statistical analysis title
    		 Change MADRS score from baseline V9/ITT
    Statistical analysis description
    Change MADRS score from baseline at V9 in the ITT population
    Comparison groups
    Trazodone OAD v Venlafaxine
    Number of subjects included in analysis
    313
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.003
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Change in MADRS score frome baseline at Visit 9/PP

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    End point title
    		 Change in MADRS score frome baseline at Visit 9/PP
    End point description
    Mean change from baseline (Visit 2-D0) in MADRS score at Visit 9 (D56).
    End point type
    Secondary
    End point timeframe
    At Visit 2 (baseline) and Visit 9 (Day 56).
    End point values
    		 Trazodone OAD Venlafaxine
    Number of subjects analysed
    122
    127
    Units: score on a scale
        arithmetic mean (standard deviation)
    -17.1 ( 6.01 )
    -18.6 ( 6.58 )
    Statistical analysis title
    		 Change MADRS score from baseline V9/PP
    Statistical analysis description
    Change MADRS score from baseline at V9 in the PP population
    Comparison groups
    Trazodone OAD v Venlafaxine
    Number of subjects included in analysis
    249
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.018
    Method
    		 ANCOVA
    Confidence interval

    Secondary: CGI-Severity of Illness/baseline-V9/ITT

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    End point title
    		 CGI-Severity of Illness/baseline-V9/ITT
    End point description
    The distribution of CGI-S (Clinical Global Impression-Severity of illness ) and the change from baseline. The CGI-S was evaluated with a seven-point scale: 1=normal, not at all ill; 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; 7=among the most extremely ill patients.
    End point type
    Secondary
    End point timeframe
    At Visit 2 (baseline) to Visit 9(Day 56).
    End point values
    		 Trazodone OAD Venlafaxine
    Number of subjects analysed
    162
    152
    Units: score on a scale
        arithmetic mean (standard deviation)
    -1.8 ( 1.16 )
    -2.1 ( 1.17 )
    Statistical analysis title
    		 Change CGI-S total score from baseline V9/ITT
    Statistical analysis description
    Change CGI-S total score from baseline at V9 in the ITT (LOCF) population
    Comparison groups
    Trazodone OAD v Venlafaxine
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.032
    Method
    		 ANCOVA
    Confidence interval

    Secondary: CGI-Severity of Illness/baseline-V9/PP

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    End point title
    		 CGI-Severity of Illness/baseline-V9/PP
    End point description
    End point type
    Secondary
    End point timeframe
    At Visit 2 (baseline) to Visit 9 (Day 56).
    End point values
    		 Trazodone OAD Venlafaxine
    Number of subjects analysed
    122
    127
    Units: score on a scale
        arithmetic mean (standard deviation)
    -2.1 ( 1.06 )
    -2.3 ( 1.02 )
    Statistical analysis title
    		 Change CGI-S total score from baseline V9/PP
    Statistical analysis description
    Change CGI-S total score from baseline at V9 in PP population
    Comparison groups
    Trazodone OAD v Venlafaxine
    Number of subjects included in analysis
    249
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.056 [1]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [1] - Not significant

    Secondary: CGI-Global improvement V9/ITT

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    End point title
    		 CGI-Global improvement V9/ITT
    End point description
    The CGI-G was evaluated with a seven-point scale: 1=very much improved; 2=much improved; 3=minimaly improved; 4=no change; 5=minimally worse; 6=much worse; 7=very much worse.
    End point type
    Secondary
    End point timeframe
    At Visit 9 (D56)
    End point values
    		 Trazodone OAD Venlafaxine
    Number of subjects analysed
    162
    152
    Units: score on a scale
        arithmetic mean (standard deviation)
    2 ( 1.12 )
    1.7 ( 0.99 )
    Statistical analysis title
    		 CGI-G total score V9/ITT
    Statistical analysis description
    CGI- Global Improvement total score at V9 in the ITT (LOCF) population
    Comparison groups
    Trazodone OAD v Venlafaxine
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.0088
    Method
    		 ANOVA
    Confidence interval

    Secondary: CGI-Global improvement V9/PP

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    End point title
    		 CGI-Global improvement V9/PP
    End point description
    End point type
    Secondary
    End point timeframe
    At Visit 9 (D56)
    End point values
    		 Trazodone OAD Venlafaxine
    Number of subjects analysed
    122
    127
    Units: score on a scale
        arithmetic mean (standard deviation)
    1.7 ( 0.82 )
    1.5 ( 0.72 )
    Statistical analysis title
    		 CGI-G total score V9/PP
    Statistical analysis description
    CGI- Global Improvement total score at V9 in the PP population
    Comparison groups
    Trazodone OAD v Venlafaxine
    Number of subjects included in analysis
    249
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.0383
    Method
    		 ANOVA
    Confidence interval

    Secondary: HAMD-17 responder rates V9/ITT

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    End point title
    		 HAMD-17 responder rates V9/ITT
    End point description
    Responders were defined as patients with at least 50% decrease with respect to baseline on the HAMD score at Visit 9 (D56).
    End point type
    Secondary
    End point timeframe
    AT visit 9 /D56)
    End point values
    		 Trazodone OAD Venlafaxine
    Number of subjects analysed
    162
    152
    Units: percent
        number (not applicable)
    65.4
    76.3
    Statistical analysis title
    		 HAMD- 17 responder rates V9/ITT
    Statistical analysis description
    HAMD-17 responder rates at V9 for ITT (LOCF) population
    Comparison groups
    Trazodone OAD v Venlafaxine
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.0396
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval

    Secondary: HAMD-17 responder rates V9/PP

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    End point title
    		 HAMD-17 responder rates V9/PP
    End point description
    End point type
    Secondary
    End point timeframe
    At Visit 2 (D0) and Visit 9 (D56)
    End point values
    		 Trazodone OAD Venlafaxine
    Number of subjects analysed
    122
    127
    Units: percent
        number (not applicable)
    82.8
    87.4
    Statistical analysis title
    		 HAMD- 17 responder rates V9/PP
    Statistical analysis description
    HAMD-17 responder rates at V9 for PP population
    Comparison groups
    Trazodone OAD v Venlafaxine
    Number of subjects included in analysis
    249
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.2097 [2]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [2] - Not significant

    Secondary: HAMD-17 remitter rates V9/ ITT

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    End point title
    		 HAMD-17 remitter rates V9/ ITT
    End point description
    Remitters were defined as patients with HAMD score ≤ 7 at Visit 9 (D56)
    End point type
    Secondary
    End point timeframe
    At the Visit 9 (D56)
    End point values
    		 Trazodone OAD Venlafaxine
    Number of subjects analysed
    162
    152
    Units: percent
        number (not applicable)
    37.7
    52
    Statistical analysis title
    		 HAMD- 17 remitter rates V9/ITT
    Statistical analysis description
    HAMD-17 remitter rates at V9 for ITT (LOCF) population
    Comparison groups
    Trazodone OAD v Venlafaxine
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.0068
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval

    Secondary: HAMD-17 remitter rates V9/ PP

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    End point title
    		 HAMD-17 remitter rates V9/ PP
    End point description
    End point type
    Secondary
    End point timeframe
    At the Visit 9 (D56)
    End point values
    		 Trazodone OAD Venlafaxine
    Number of subjects analysed
    122
    127
    Units: percent
        number (not applicable)
    48.4
    60.6
    Statistical analysis title
    		 HAMD- 17 remitter rates V9/PP
    Statistical analysis description
    HAMD- 17 remitter rates V9 in the PP population
    Comparison groups
    Trazodone OAD v Venlafaxine
    Number of subjects included in analysis
    249
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.013
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the ICF signature until 30 days after the last IMP administration.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    Venlafaxine
    Reporting group description
    		 -

    Reporting group title
    Trazodone OAD
    Reporting group description
    		 Trazodone once a day

    Serious adverse events
    		 Venlafaxine Trazodone OAD
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 156 (0.64%)
    3 / 165 (1.82%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    0
    0
    Nervous system disorders
    Mental impairment
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Psychiatric disorders
    Suicide attempt
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 165 (0.61%)
         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: 0%
    Non-serious adverse events
    		 Venlafaxine Trazodone OAD
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    73 / 156 (46.79%)
    83 / 165 (50.30%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cerebellopontine angle tumour
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 165 (0.00%)
         occurrences all number
    1
    0
    Thyroid neoplasm
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 165 (0.61%)
         occurrences all number
    0
    1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 156 (1.28%)
    0 / 165 (0.00%)
         occurrences all number
    2
    0
    Orthostatic hypotension
         subjects affected / exposed
    1 / 156 (0.64%)
    1 / 165 (0.61%)
         occurrences all number
    1
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 156 (1.92%)
    7 / 165 (4.24%)
         occurrences all number
    3
    7
    Influenza like illness
         subjects affected / exposed
    1 / 156 (0.64%)
    1 / 165 (0.61%)
         occurrences all number
    1
    1
    Oedema peripheral
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 165 (0.61%)
         occurrences all number
    0
    1
    Swelling
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 165 (0.61%)
         occurrences all number
    0
    1
    Immune system disorders
    Allergy to arthropod bite
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 165 (0.61%)
         occurrences all number
    0
    1
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 165 (0.61%)
         occurrences all number
    0
    1
    Ejaculation delayed
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 165 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 165 (0.61%)
         occurrences all number
    0
    1
    Cough
         subjects affected / exposed
    1 / 156 (0.64%)
    1 / 165 (0.61%)
         occurrences all number
    1
    1
    Dry throat
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 165 (0.61%)
         occurrences all number
    0
    1
    Epistaxis
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 165 (0.61%)
         occurrences all number
    0
    1
    Nasal congestion
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 165 (0.61%)
         occurrences all number
    0
    1
    Rhinorrhoea
         subjects affected / exposed
    3 / 156 (1.92%)
    0 / 165 (0.00%)
         occurrences all number
    3
    0
    Throat tightness
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 165 (0.00%)
         occurrences all number
    1
    0
    Yawning
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 165 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Alcohol abuse
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 165 (0.00%)
         occurrences all number
    1
    0
    Confusional state
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 165 (0.00%)
         occurrences all number
    2
    0
    Depression
         subjects affected / exposed
    2 / 156 (1.28%)
    0 / 165 (0.00%)
         occurrences all number
    2
    0
    Derealisation
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 165 (0.00%)
         occurrences all number
    1
    0
    Disturbance in sexual arousal
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 165 (0.00%)
         occurrences all number
    1
    0
    Hypersomnia
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 165 (0.00%)
         occurrences all number
    1
    0
    Initial insomnia
         subjects affected / exposed
    5 / 156 (3.21%)
    0 / 165 (0.00%)
         occurrences all number
    5
    0
    Insomnia
         subjects affected / exposed
    3 / 156 (1.92%)
    5 / 165 (3.03%)
         occurrences all number
    3
    5
    Major depression
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 165 (0.61%)
         occurrences all number
    0
    1
    Nervousness
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 165 (0.00%)
         occurrences all number
    1
    0
    Sleep disorder
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 165 (0.61%)
         occurrences all number
    0
    1
    Suicide attempt
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 165 (0.61%)
         occurrences all number
    0
    1
    Tension
         subjects affected / exposed
    5 / 156 (3.21%)
    0 / 165 (0.00%)
         occurrences all number
    6
    0
    Terminal insomnia
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 165 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 165 (0.00%)
         occurrences all number
    1
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 165 (0.00%)
         occurrences all number
    1
    0
    Blood glucose increased
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 165 (0.00%)
         occurrences all number
    1
    0
    Electrocardiogram abnormal
         subjects affected / exposed
    0 / 156 (0.00%)
    2 / 165 (1.21%)
         occurrences all number
    0
    2
    Electrocardiogram QT prolonged
         subjects affected / exposed
    6 / 156 (3.85%)
    9 / 165 (5.45%)
         occurrences all number
    6
    9
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    2 / 156 (1.28%)
    0 / 165 (0.00%)
         occurrences all number
    2
    0
    Glucose urine present
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 165 (0.00%)
         occurrences all number
    1
    0
    Urine output increased
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 165 (0.61%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Facial bones fracture
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 165 (0.00%)
         occurrences all number
    1
    0
    Medication error
         subjects affected / exposed
    3 / 156 (1.92%)
    3 / 165 (1.82%)
         occurrences all number
    3
    3
    Overdose
         subjects affected / exposed
    2 / 156 (1.28%)
    2 / 165 (1.21%)
         occurrences all number
    2
    2
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    9 / 156 (5.77%)
    3 / 165 (1.82%)
         occurrences all number
    9
    4
    Tachycardia
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 165 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Disturbance in attention
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 165 (0.61%)
         occurrences all number
    0
    1
    Dizziness
         subjects affected / exposed
    6 / 156 (3.85%)
    17 / 165 (10.30%)
         occurrences all number
    6
    18
    Dysgeusia
         subjects affected / exposed
    1 / 156 (0.64%)
    1 / 165 (0.61%)
         occurrences all number
    1
    1
    Headache
         subjects affected / exposed
    17 / 156 (10.90%)
    10 / 165 (6.06%)
         occurrences all number
    19
    11
    Hydrocephalus
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 165 (0.00%)
         occurrences all number
    1
    0
    Mental impairment
         subjects affected / exposed
    0 / 156 (0.00%)
    2 / 165 (1.21%)
         occurrences all number
    0
    2
    Sedation
         subjects affected / exposed
    0 / 156 (0.00%)
    4 / 165 (2.42%)
         occurrences all number
    0
    4
    Somnolence
         subjects affected / exposed
    0 / 156 (0.00%)
    14 / 165 (8.48%)
         occurrences all number
    0
    14
    Syncope
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 165 (0.61%)
         occurrences all number
    0
    1
    Tremor
         subjects affected / exposed
    4 / 156 (2.56%)
    0 / 165 (0.00%)
         occurrences all number
    4
    0
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 165 (0.61%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 165 (0.00%)
         occurrences all number
    1
    0
    Vertigo
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 165 (0.61%)
         occurrences all number
    0
    1
    Eye disorders
    Asthenopia
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 165 (0.61%)
         occurrences all number
    0
    1
    Diplopia
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 165 (0.00%)
         occurrences all number
    1
    0
    Mydriasis
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 165 (0.00%)
         occurrences all number
    2
    0
    Photophobia
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 165 (0.61%)
         occurrences all number
    0
    1
    Vision blurred
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 165 (0.00%)
         occurrences all number
    2
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 156 (0.00%)
    2 / 165 (1.21%)
         occurrences all number
    0
    2
    Abdominal pain upper
         subjects affected / exposed
    1 / 156 (0.64%)
    2 / 165 (1.21%)
         occurrences all number
    1
    2
    Breath odour
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 165 (0.00%)
         occurrences all number
    1
    0
    Constipation
         subjects affected / exposed
    3 / 156 (1.92%)
    2 / 165 (1.21%)
         occurrences all number
    3
    2
    Dental caries
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 165 (0.61%)
         occurrences all number
    0
    1
    Diarrhoea
         subjects affected / exposed
    4 / 156 (2.56%)
    3 / 165 (1.82%)
         occurrences all number
    5
    3
    Dry mouth
         subjects affected / exposed
    3 / 156 (1.92%)
    11 / 165 (6.67%)
         occurrences all number
    3
    11
    Dyspepsia
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 165 (0.61%)
         occurrences all number
    0
    1
    Gastritis
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 165 (0.61%)
         occurrences all number
    0
    1
    Nausea
         subjects affected / exposed
    22 / 156 (14.10%)
    10 / 165 (6.06%)
         occurrences all number
    23
    10
    Vomiting
         subjects affected / exposed
    2 / 156 (1.28%)
    2 / 165 (1.21%)
         occurrences all number
    2
    2
    Hepatobiliary disorders
    Hepatitis
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 165 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    5 / 156 (3.21%)
    3 / 165 (1.82%)
         occurrences all number
    5
    3
    Psoriasis
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 165 (0.61%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Pollakiuria
         subjects affected / exposed
    0 / 156 (0.00%)
    2 / 165 (1.21%)
         occurrences all number
    0
    2
    Urinary retention
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 165 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 165 (0.61%)
         occurrences all number
    0
    1
    Back pain
         subjects affected / exposed
    1 / 156 (0.64%)
    1 / 165 (0.61%)
         occurrences all number
    1
    1
    Musculoskeletal pain
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 165 (0.61%)
         occurrences all number
    0
    1
    Myalgia
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 165 (0.00%)
         occurrences all number
    1
    0
    Sensation of heaviness
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 165 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 165 (0.61%)
         occurrences all number
    0
    1
    Chronic hepatitis C
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 165 (0.61%)
         occurrences all number
    0
    1
    Gastroenteritis
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 165 (0.61%)
         occurrences all number
    0
    1
    Influenza
         subjects affected / exposed
    1 / 156 (0.64%)
    2 / 165 (1.21%)
         occurrences all number
    1
    2
    Nasopharyngitis
         subjects affected / exposed
    1 / 156 (0.64%)
    1 / 165 (0.61%)
         occurrences all number
    1
    1
    Pyelonephritis
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 165 (0.61%)
         occurrences all number
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 156 (1.28%)
    0 / 165 (0.00%)
         occurrences all number
    2
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 156 (0.64%)
    1 / 165 (0.61%)
         occurrences all number
    1
    1
    Vaginal infection
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 165 (0.61%)
         occurrences all number
    0
    2
    Viral infection
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 165 (0.00%)
         occurrences all number
    2
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 165 (0.61%)
         occurrences all number
    0
    1
    Hyperglycaemia
         subjects affected / exposed
    2 / 156 (1.28%)
    0 / 165 (0.00%)
         occurrences all number
    2
    0
    Increased appetite
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 165 (0.61%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Jun 2012
    The substantial amendment no. 1/0 (June 28th, 2012) proposed changes as requested by the Voluntary Harmonized Procedure (VHP). It aimed to introduce further safety precautions in terms of study procedures and selection of study population. Additional procedures (haematology and serum chemistry tests) for the safety monitoring of the patients were implemented at visit 4 and visit 6. A new inclusion criteria limiting the enrolment to patients ≤75 years and a new exclusion criteria avoiding the enrolment of subjects with high blood pressure were introduced.
    10 Oct 2012
    The substantial amendment no. 2 (October 10th, 2012) was made to submit an updated version of the IMPD (Investigational Medicianl Product Dossier). The new IMPD (Ver. 2.0 of October 9th, 2012) included new stability data on the IMPs derived from previously planned stability studies.
    07 Jun 2013
    The amendment no. 3/0 (June 7th, 2013) proposed changes regarding the IMPD and IB. The new IMPD (Ver. 3.0 of June 3rd, 2013) included changes related to IMPs storage condition, Marketing Authorization status of trazodone OAD in Europe and long term stability studies. The new IB (ver. 7.0 of March 26th, 2013) included changes related to non-clinical pharmacological data and post-marketing experience in USA. The new data did not impact on the safety profile of the trazodone and on the information to be given to the patients..
    10 Jun 2013
    The Amendment no. 4/0 (June 10th, 2013) proposed changes to the Study Protocol, Study Synopsis, Information sheet/Informed Consent, Letter to the General Practitioner. Relevant sections of these documents included changes regarding Sponsor Personnel, contact details of a vendor, side effects, special warnings and precautions for use of the reference product (venlafaxine) accordingly to the new SPC approved in April 2013 in Italy. The amendment included also an updated version of the IB (ver. 7.0 of March 26th, 2013).
    24 Feb 2014
    The Amendment no. 5/0 (February 24th, 2014) proposed to replace the Principal Investigator of an Italian site. This Amendment was applied only to the Italian site which it refers to.

    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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