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    Clinical Trial Results:
    D-cycloserine augmented exposure therapy in patients with agoraphobia

    Summary
    EudraCT number
    		 2011-001398-19
    Trial protocol
    		 DE  
    Global end of trial date
    25 Apr 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 May 2022
    First version publication date
    14 May 2022
    Other versions
    Summary report(s)
    		 2018_LearnToForget-DoesPost-exposureAdministrationOfD-cycloserineEnhanceFearExtinctionInAgoraphobia

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    Exposition-DCS
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01928823
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Charité - Universitätsmedizin Berlin
    Sponsor organisation address
    Charitéplatz 1, Berlin, Germany, 10117
    Public contact
    Dipl.-Psych. Lena Pyrkosch, Charité - Universitätsmedizin Berlin Klinik für Psychiatrie und Psychotherapie, +49 30 450517214, lena.pyrkosch@charite.de
    Scientific contact
    Prof. Dr. Andreas Ströhle, Charité - Universitätsmedizin Berlin Klinik für Psychiatrie und Psychotherapie, +49 30 450517034 , andreas.stroehle@charite.de
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    25 Apr 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Apr 2014
    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
    Aim of the trial is to investigate if d-cycloserine augmented exposure therapy reduces agoraphobic symptomatology to a greater extend than placebo augmented exposure therapy.
    Protection of trial subjects
    Safty/Data- Committees and Evaluation- Comitte: 2 external Monitoring appointments (12.12.2012, 07.03.2014) fallowed by a continuous monitoring by a project-external employee .
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    09 Nov 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy, Scientific research
    Long term follow-up duration
    		 1 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 73
    Worldwide total number of subjects
    73
    EEA total number of subjects
    73
    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)
    71
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Clinical and diagnosic sessions were held -56 to -1 days before the first therapy session.

    Pre-assignment
    Screening details
    		 Screening: 145 Informed Consent: 94 Study inclusion: 78 Randomization: 73 Dropouts: 4 For participating in the study inclusion and exclusion criteria according to AMG §40 had to be confirmed.

    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 DCS Arm
    Arm description
    		 Patients underwent 3 exposure sessions with two rounds respectively. Within 30 min after the second round of exposure patients were given double blind and randomized 50 mg of DCS by oral administration.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Seromycin
    Investigational medicinal product code
    Other name
    CYCLOSERINE
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Each capsule contains 50mg Cycloserin. Subjects received one caspule after therapy session: 3, 4 and 5.

    Arm title
    		 PBO Arm
    Arm description
    		 Patients underwent 3 exposure sessions with two rounds respectively. Within 30 min after the second round of exposure patients were given double blind and randomized the PBO.
    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
    each capsule contains 50mg of placebo (DAC NRF :99,5% Mannitol, 0,5% highly dispersed Siliciumdioxid). Subjects received a capsule after the session 3,4 and 5.

    Number of subjects in period 1
    		DCS Arm PBO Arm
    Started
    36
    37
    Completed
    36
    33
    Not completed
    0
    4
         Protocol deviation
    -
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    DCS Arm
    Reporting group description
    		 Patients underwent 3 exposure sessions with two rounds respectively. Within 30 min after the second round of exposure patients were given double blind and randomized 50 mg of DCS by oral administration.

    Reporting group title
    PBO Arm
    Reporting group description
    		 Patients underwent 3 exposure sessions with two rounds respectively. Within 30 min after the second round of exposure patients were given double blind and randomized the PBO.

    Reporting group values
    		 DCS Arm PBO Arm Total
    Number of subjects
    		 36 37 73
    Age categorical
    Units: Subjects
        Adults (18-75 years)
    		 36 37 73
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 34.10 ± 10.37 40.86 ± 12.94 -
    Gender categorical
    Units: Subjects
        Female
    		 14 11 25
        Male
    		 22 26 48
    Diagnosis
    F40.00: No indication of panic disorder F40.01: With panic disorder
    Units: Subjects
        F40.00
    		 10 10 20
        F40.01
    		 26 27 53
    Axis I comorbidities
    Units: Subjects
        none
    		 24 25 49
        >= one
    		 12 12 24
    Axis II personality disorders
    Units: Subjects
        none
    		 24 25 49
        >= one
    		 12 12 24
    Ongoing psychopharmacotherapy
    Units: Subjects
        No
    		 24 18 42
        Yes
    		 12 19 31
    Family status
    Units: Subjects
        Single
    		 16 16 32
        Stable relationship
    		 20 21 41
    Living situation
    Units: Subjects
        Alone
    		 14 8 22
        With family/ friends
    		 22 29 51
    Education
    Units: Subjects
        No high school diploma
    		 13 11 24
        High school diploma or higher
    		 23 26 49
    Occupational status
    Units: Subjects
        None
    		 8 7 15
        Part time or other
    		 15 7 22
        Full time
    		 13 22 35
        N/A
    		 0 1 1
    PAS observer-rated sum score
    The Panic and Agoraphobia Scale (PAS): The PAS is a reliable, valid and internationally used scale for the determination of severity of disease in patients with agoraphobia and/ or panic disorder (Bandelow, 1995). In many therapy studies also its sensitivity for measuring change or improvement of symptomatology was demonstrated (Bandelow, 1995). For the present trial, the PAS was used in the self-rated and observer-rated (by therapist) version.
    Units: Scale
        arithmetic mean (standard deviation)
    		 24.74 ± 8.96 22.03 ± 7.77 -
    PAS self-rated sum score
    The Panic and Agoraphobia Scale (PAS): The PAS is a reliable, valid and internationally used scale for the determination of severity of disease in patients with agoraphobia and/ or panic disorder (Bandelow, 1995). In many therapy studies also its sensitivity for measuring change or improvement of symptomatology was demonstrated (Bandelow, 1995). For the present trial, the PAS was used in the self-rated and observer-rated (by therapist) version.
    Units: Scale
        arithmetic mean (standard deviation)
    		 20.68 ± 10.31 19.20 ± 9.69 -
    ACQ mean
    Agoraphobic Cognitions Questionnaire (ACQ): The ACQ consists of 14 items measuring the patients central phobic cognitions, e. g. “I am going to pass out”. It may be scored as a total scale or according to its two subscales (loss of control and physical concerns).
    Units: Scale
        arithmetic mean (standard deviation)
    		 2.11 ± 0.44 2.01 ± 0.55 -
    BSQ mean
    Body Sensations Questionnaire (BSQ): The BSQ, consisting of 17 items, is a valid an reliable instrument to assess the patients phobic fear of bodily symptoms such as “heart beat” or “dizziness”.
    Units: Scale
        arithmetic mean (standard deviation)
    		 2.67 ± 0.74 2.68 ± 0.83 -
    MI alone mean
    Mobility Inventory (MI): In the MI 26 situations are rated for avoidance by the patients both when they are alone (subscale MI alone) or when they are accompanied (subscale MI accompanied).
    Units: Scale
        arithmetic mean (standard deviation)
    		 2.69 ± 0.99 2.56 ± 0.84 -
    MI accompanied mean
    Mobility Inventory (MI): In the MI 26 situations are rated for avoidance by the patients both when they are alone (subscale MI alone) or when they are accompanied (subscale MI accompanied).
    Units: Scale
        arithmetic mean (standard deviation)
    		 2.10 ± 0.79 1.88 ± 0.61 -
    ASI sum score
    Anxiety Sensitivity Index (ASI): The 16-item ASI measures the patients' fear of anxiety-related sensations and the evaluation about their harmful consequences. The ASI was shown to also display good sensitivity to change over the course of treatment.
    Units: Score
        arithmetic mean (standard deviation)
    		 27.55 ± 10.32 28.13 ± 9.17 -
    BAI sum score
    Beck Anxiety Inventory (BAI): The BAI, containing 21 items, is a valid and reliable inventory for measuring common symptoms of clinical anxiety, e. g. numbness or sweating.
    Units: Score
        arithmetic mean (standard deviation)
    		 21.44 ± 12.24 21.25 ± 12.21 -
    BDI II sum score
    Beck Depression Inventory (BDI): As for the high overlap between anxiety and depression we considered it important to also assess depressive symptoms in our patient sample with the help of the most commonly used inventory BDI II.
    Units: Score
        arithmetic mean (standard deviation)
    		 12.03 ± 8.62 10.94 ± 8.76 -
    BSI sum score
    Brief Symptom Inventory (BSI): We decided to apply the BSI in order to also have a measure for general psychopathological symptoms pertaining to different disorder-specific domains.
    Units: Score
        arithmetic mean (standard deviation)
    		 39.71 ± 26.00 35.58 ± 26.58 -
    CGI
    Clinical Global Impression (CGI): The CGI is a very easy to apply clinician rated scale measuring global severity of illness. Although short it is one of the most widely used brief assessment tools in psychiatry.
    Units: Scale
        arithmetic mean (standard deviation)
    		 5.31 ± 0.62 4.89 ± 0.61 -
    Duration of disease
    Units: Months
        arithmetic mean (standard deviation)
    		 49.91 ± 53.97 122.25 ± 111.59 -

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    DCS Arm
    Reporting group description
    		 Patients underwent 3 exposure sessions with two rounds respectively. Within 30 min after the second round of exposure patients were given double blind and randomized 50 mg of DCS by oral administration.

    Reporting group title
    PBO Arm
    Reporting group description
    		 Patients underwent 3 exposure sessions with two rounds respectively. Within 30 min after the second round of exposure patients were given double blind and randomized the PBO.

    Primary: PAS observer-rated sum score

    		 Close Top of page
    End point title
    		 PAS observer-rated sum score
    End point description
    The Panic and Agoraphobia Scale (PAS): The PAS is a reliable, valid and internationally used scale for the determination of severity of disease in patients with agoraphobia and/ or panic disorder (Bandelow, 1995). In many therapy studies also its sensitivity for measuring change or improvement of symptomatology was demonstrated (Bandelow, 1995). For the present trial, the PAS was used in the self-rated and observer-rated (by therapist) version.
    End point type
    Primary
    End point timeframe
    t1 up to t11
    End point values
    		 DCS Arm PBO Arm
    Number of subjects analysed
    36
    37
    Units: Scale
        arithmetic mean (standard deviation)
    7.69 ± 6.30
    6.61 ± 7.96
    Attachments
    		 Untitled (Filename: ANOVA Rep Meas_primary endpoints.pdf)
    Statistical analysis title
    		 ANOVA Repeated Measures
    Statistical analysis description
    We employed for all outcome criteria repeated measures ANOVAS with one between-subject factor (group: DCS, PBO) and one within-subject factor (time: t1, t4, t10 and t11). Sphericity was analyzed by Mauchley testing and degrees of freedom were adjusted by Greenhouse-Geisser correction if p < 0.05. Effect sizes were reported as partial eta-squared (η2p). Tests were employed two-tailed and statistical significance was accepted if p < 0.05.
    Comparison groups
    DCS Arm v PBO Arm
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Parameter type
    		 F-test
    Confidence interval
    Variability estimate
    Standard error of the mean

    Primary: PAS self-rated sum score

    		 Close Top of page
    End point title
    		 PAS self-rated sum score
    End point description
    The Panic and Agoraphobia Scale (PAS): The PAS is a reliable, valid and internationally used scale for the determination of severity of disease in patients with agoraphobia and/ or panic disorder (Bandelow, 1995). In many therapy studies also its sensitivity for measuring change or improvement of symptomatology was demonstrated (Bandelow, 1995). For the present trial, the PAS was used in the self-rated and observer-rated (by therapist) version.
    End point type
    Primary
    End point timeframe
    t1 up to t11
    End point values
    		 DCS Arm PBO Arm
    Number of subjects analysed
    36
    37
    Units: Scale
        arithmetic mean (standard deviation)
    8.22 ± 6.28
    7.71 ± 8.26
    Attachments
    		 Untitled (Filename: ANOVA Rep Meas_primary endpoints.pdf)
    Statistical analysis title
    		 ANOVA Repeated Measures
    Statistical analysis description
    We employed for all outcome criteria repeated measures ANOVAS with one between-subject factor (group: DCS, PBO) and one within-subject factor (time: t1, t4, t10 and t11). Sphericity was analyzed by Mauchley testing and degrees of freedom were adjusted by Greenhouse-Geisser correction if p < 0.05. Effect sizes were reported as partial eta-squared (η2p). Tests were employed two-tailed and statistical significance was accepted if p < 0.05.
    Comparison groups
    DCS Arm v PBO Arm
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Parameter type
    		 F-test
    Confidence interval
    Variability estimate
    Standard error of the mean

    Secondary: ACQ mean

    		 Close Top of page
    End point title
    		 ACQ mean
    End point description
    Agoraphobic Cognitions Questionnaire (ACQ): The ACQ consists of 14 items measuring the patients central phobic cognitions, e. g. “I am going to pass out”. It may be scored as a total scale or according to its two subscales (loss of control and physical concerns).
    End point type
    Secondary
    End point timeframe
    t1 up to t11
    End point values
    		 DCS Arm PBO Arm
    Number of subjects analysed
    36
    37
    Units: Scale
        arithmetic mean (standard deviation)
    1.46 ± 0.45
    1.43 ± 0.42
    Attachments
    		 Untitled (Filename: ANOVA Rep Meas_secondary endpoints.pdf)
    Statistical analysis title
    		 ANOVA Repeated Measures
    Statistical analysis description
    We employed for all outcome criteria repeated measures ANOVAS with one between-subject factor (group: DCS, PBO) and one within-subject factor (time: t1, t4, t10 and t11). Sphericity was analyzed by Mauchley testing and degrees of freedom were adjusted by Greenhouse-Geisser correction if p < 0.05. Effect sizes were reported as partial eta-squared (η2p). Tests were employed two-tailed and statistical significance was accepted if p < 0.05.
    Comparison groups
    DCS Arm v PBO Arm
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Parameter type
    		 F-test
    Confidence interval
    Variability estimate
    Standard error of the mean

    Secondary: BSQ mean

    		 Close Top of page
    End point title
    		 BSQ mean
    End point description
    Body Sensations Questionnaire (BSQ): The BSQ, consisting of 17 items, is a valid an reliable instrument to assess the patients phobic fear of bodily symptoms such as “heart beat” or “dizziness”.
    End point type
    Secondary
    End point timeframe
    t1 up to t11
    End point values
    		 DCS Arm PBO Arm
    Number of subjects analysed
    36
    37
    Units: Scale
        arithmetic mean (standard deviation)
    1.83 ± 0.62
    1.83 ± 0.61
    Attachments
    		 Untitled (Filename: ANOVA Rep Meas_secondary endpoints.pdf)
    Statistical analysis title
    		 ANOVA Repeated Measures
    Statistical analysis description
    We employed for all outcome criteria repeated measures ANOVAS with one between-subject factor (group: DCS, PBO) and one within-subject factor (time: t1, t4, t10 and t11). Sphericity was analyzed by Mauchley testing and degrees of freedom were adjusted by Greenhouse-Geisser correction if p < 0.05. Effect sizes were reported as partial eta-squared (η2p). Tests were employed two-tailed and statistical significance was accepted if p < 0.05.
    Comparison groups
    DCS Arm v PBO Arm
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Parameter type
    		 F-test
    Confidence interval
    Variability estimate
    Standard error of the mean

    Secondary: MI alone mean

    		 Close Top of page
    End point title
    		 MI alone mean
    End point description
    Mobility Inventory (MI): In the MI 26 situations are rated for avoidance by the patients both when they are alone (subscale MI alone) or when they are accompanied (subscale MI accompanied).
    End point type
    Secondary
    End point timeframe
    t1 up to t11
    End point values
    		 DCS Arm PBO Arm
    Number of subjects analysed
    36
    37
    Units: Scale
        arithmetic mean (standard deviation)
    1.58 ± 0.60
    1.59 ± 0.69
    Attachments
    		 Untitled (Filename: ANOVA Rep Meas_secondary endpoints.pdf)
    Statistical analysis title
    		 ANOVA Repeated Measures
    Statistical analysis description
    We employed for all outcome criteria repeated measures ANOVAS with one between-subject factor (group: DCS, PBO) and one within-subject factor (time: t1, t4, t10 and t11). Sphericity was analyzed by Mauchley testing and degrees of freedom were adjusted by Greenhouse-Geisser correction if p < 0.05. Effect sizes were reported as partial eta-squared (η2p). Tests were employed two-tailed and statistical significance was accepted if p < 0.05.
    Comparison groups
    DCS Arm v PBO Arm
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Parameter type
    		 F-test
    Confidence interval
    Variability estimate
    Standard error of the mean

    Secondary: Mi accompanied mean

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    End point title
    		 Mi accompanied mean
    End point description
    Mobility Inventory (MI): In the MI 26 situations are rated for avoidance by the patients both when they are alone (subscale MI alone) or when they are accompanied (subscale MI accompanied).
    End point type
    Secondary
    End point timeframe
    t1 up to t11
    End point values
    		 DCS Arm PBO Arm
    Number of subjects analysed
    36
    37
    Units: Scale
        arithmetic mean (standard deviation)
    1.35 ± 0.40
    1.25 ± 0.32
    Attachments
    		 Untitled (Filename: ANOVA Rep Meas_secondary endpoints.pdf)
    Statistical analysis title
    		 ANOVA Repeated Measures
    Statistical analysis description
    We employed for all outcome criteria repeated measures ANOVAS with one between-subject factor (group: DCS, PBO) and one within-subject factor (time: t1, t4, t10 and t11). Sphericity was analyzed by Mauchley testing and degrees of freedom were adjusted by Greenhouse-Geisser correction if p < 0.05. Effect sizes were reported as partial eta-squared (η2p). Tests were employed two-tailed and statistical significance was accepted if p < 0.05.
    Comparison groups
    DCS Arm v PBO Arm
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Parameter type
    		 F-test
    Confidence interval
    Variability estimate
    Standard error of the mean

    Secondary: ASI sum score

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    End point title
    		 ASI sum score
    End point description
    Anxiety Sensitivity Index (ASI): The 16-item ASI measures the patients' fear of anxiety-related sensations and the evaluation about their harmful consequences. The ASI was shown to also display good sensitivity to change over the course of treatment.
    End point type
    Secondary
    End point timeframe
    t1 up to t11
    End point values
    		 DCS Arm PBO Arm
    Number of subjects analysed
    36
    37
    Units: Scale
        arithmetic mean (standard deviation)
    12.67 ± 9.18
    12.01 ± 8.36
    Attachments
    		 Untitled (Filename: ANOVA Rep Meas_secondary endpoints.pdf)
    Statistical analysis title
    		 ANOVA Repeated Measures
    Statistical analysis description
    We employed for all outcome criteria repeated measures ANOVAS with one between-subject factor (group: DCS, PBO) and one within-subject factor (time: t1, t4, t10 and t11). Sphericity was analyzed by Mauchley testing and degrees of freedom were adjusted by Greenhouse-Geisser correction if p < 0.05. Effect sizes were reported as partial eta-squared (η2p). Tests were employed two-tailed and statistical significance was accepted if p < 0.05.
    Comparison groups
    DCS Arm v PBO Arm
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Parameter type
    		 F-test
    Confidence interval
    Variability estimate
    Standard error of the mean

    Secondary: BAI sum score

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    End point title
    		 BAI sum score
    End point description
    Beck Anxiety Inventory (BAI): The BAI, containing 21 items, is a valid and reliable inventory for measuring common symptoms of clinical anxiety, e. g. numbness or sweating.
    End point type
    Secondary
    End point timeframe
    t1 up to t11
    End point values
    		 DCS Arm PBO Arm
    Number of subjects analysed
    36
    37
    Units: Scale
        arithmetic mean (standard deviation)
    8.57 ± 8.04
    8.98 ± 7.43
    Attachments
    		 Untitled (Filename: ANOVA Rep Meas_secondary endpoints.pdf)
    Statistical analysis title
    		 ANOVA Repeated Measures
    Statistical analysis description
    We employed for all outcome criteria repeated measures ANOVAS with one between-subject factor (group: DCS, PBO) and one within-subject factor (time: t1, t4, t10 and t11). Sphericity was analyzed by Mauchley testing and degrees of freedom were adjusted by Greenhouse-Geisser correction if p < 0.05. Effect sizes were reported as partial eta-squared (η2p). Tests were employed two-tailed and statistical significance was accepted if p < 0.05.
    Comparison groups
    DCS Arm v PBO Arm
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Parameter type
    		 F-test
    Confidence interval
    Variability estimate
    Standard error of the mean

    Secondary: BDI II sum score

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    End point title
    		 BDI II sum score
    End point description
    Beck Depression Inventory (BDI): As for the high overlap between anxiety and depression we considered it important to also assess depressive symptoms in our patient sample with the help of the most commonly used inventory BDI II.
    End point type
    Secondary
    End point timeframe
    t1 up to t11
    End point values
    		 DCS Arm PBO Arm
    Number of subjects analysed
    36
    37
    Units: Scale
        arithmetic mean (standard deviation)
    4.69 ± 4.53
    4.00 ± 4.45
    Attachments
    		 Untitled (Filename: ANOVA Rep Meas_secondary endpoints.pdf)
    Statistical analysis title
    		 ANOVA Repeated Measures
    Statistical analysis description
    We employed for all outcome criteria repeated measures ANOVAS with one between-subject factor (group: DCS, PBO) and one within-subject factor (time: t1, t4, t10 and t11). Sphericity was analyzed by Mauchley testing and degrees of freedom were adjusted by Greenhouse-Geisser correction if p < 0.05. Effect sizes were reported as partial eta-squared (η2p). Tests were employed two-tailed and statistical significance was accepted if p < 0.05.
    Comparison groups
    DCS Arm v PBO Arm
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Parameter type
    		 F-test
    Confidence interval
    Variability estimate
    Standard error of the mean

    Secondary: BSI sum score

    		 Close Top of page
    End point title
    		 BSI sum score
    End point description
    Brief Symptom Inventory (BSI): We decided to apply the BSI in order to also have a measure for general psychopathological symptoms pertaining to different disorder-specific domains.
    End point type
    Secondary
    End point timeframe
    t1 up to t11
    End point values
    		 DCS Arm PBO Arm
    Number of subjects analysed
    36
    37
    Units: Scale
        arithmetic mean (standard deviation)
    12.54 ± 9.33
    13.46 ± 11.45
    Attachments
    		 Untitled (Filename: ANOVA Rep Meas_secondary endpoints.pdf)
    Statistical analysis title
    		 ANOVA Repeated Measures
    Statistical analysis description
    We employed for all outcome criteria repeated measures ANOVAS with one between-subject factor (group: DCS, PBO) and one within-subject factor (time: t1, t4, t10 and t11). Sphericity was analyzed by Mauchley testing and degrees of freedom were adjusted by Greenhouse-Geisser correction if p < 0.05. Effect sizes were reported as partial eta-squared (η2p). Tests were employed two-tailed and statistical significance was accepted if p < 0.05.
    Comparison groups
    DCS Arm v PBO Arm
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Parameter type
    		 F-test
    Confidence interval
    Variability estimate
    Standard error of the mean

    Secondary: CGI

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    End point title
    		 CGI
    End point description
    Clinical Global Impression (CGI): The CGI is a very easy to apply clinician rated scale measuring global severity of illness. Although short it is one of the most widely used brief assessment tools in psychiatry.
    End point type
    Secondary
    End point timeframe
    t1 up to t11
    End point values
    		 DCS Arm PBO Arm
    Number of subjects analysed
    36
    37
    Units: Scale
        arithmetic mean (standard deviation)
    2.98 ± 0.94
    2.46 ± 1.11
    Attachments
    		 Untitled (Filename: ANOVA Rep Meas_secondary endpoints.pdf)
    Statistical analysis title
    		 ANOVA Repeated Measures
    Statistical analysis description
    We employed for all outcome criteria repeated measures ANOVAS with one between-subject factor (group: DCS, PBO) and one within-subject factor (time: t1, t4, t10 and t11). Sphericity was analyzed by Mauchley testing and degrees of freedom were adjusted by Greenhouse-Geisser correction if p < 0.05. Effect sizes were reported as partial eta-squared (η2p). Tests were employed two-tailed and statistical significance was accepted if p < 0.05.
    Comparison groups
    DCS Arm v PBO Arm
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Parameter type
    		 F-test
    Confidence interval
    Variability estimate
    Standard error of the mean

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    57 days
    Adverse event reporting additional description
    Potential side effects of the study drug were elicited by protocol-guided questioning and monitored from therapy session t7 on.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 own
    Dictionary version
    1
    Reporting groups
    Reporting group title
    DCS Arm
    Reporting group description
    		 Patients underwent 3 exposure sessions with two rounds respectively. Within 30 minutes after the second round of exposure patients were given double blind and randomized either PBO or 50mg of DCS by oral administration. 50mg of DCS is a commonly used dosage in DCS studies with anxiety patients as clinical trials (e. g. Ressler et al., 2004) and meta-analyses (e. g. Mataix-Cols et al., 2017) could not show better efficacy with higher dosages. Study medication and the randomization list were generated by the Charité Pharmacy, Campus Virchow, with the aid of the software Randomization (version 01/08/2008) and using the method of randomly permuted blocks of pairs. The randomization list remained in the Charité Pharmacy until completion of data collection, thus assuring for blindness of patients, therapists and all study personal regarding the patients’ study condition.

    Reporting group title
    PBO Arm
    Reporting group description
    		 Patients underwent 3 exposure sessions with two rounds respectively. Within 30 minutes after the second round of exposure patients were given double blind and randomized either PBO or 50mg of DCS by oral administration. Study medication and the randomization list were generated by the Charité Pharmacy, Campus Virchow, with the aid of the software Randomization (version 01/08/2008) and using the method of randomly permuted blocks of pairs. The randomization list remained in the Charité Pharmacy until completion of data collection, thus assuring for blindness of patients, therapists and all study personal regarding the patients’ study condition.

    Serious adverse events
    		 DCS Arm PBO Arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 37 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 DCS Arm PBO Arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 36 (11.11%)
    1 / 37 (2.70%)
    Investigations
    Overall
         subjects affected / exposed
    4 / 36 (11.11%)
    1 / 37 (2.70%)
         occurrences all number
    1
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/30237105
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