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    Clinical Trial Results:
    A double blind, randomized, placebo-controlled, adaptive 14-week Phase IIb trial to evaluate the efficacy and safety of vafidemstat in an adult borderline personality disorder (BPD) population (PORTICO)

    Summary
    EudraCT number
    		 2020-003469-20
    Trial protocol
    		 ES   DE   BG  
    Global end of trial date
    13 Nov 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Jan 2025
    First version publication date
    02 Jan 2025
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CL07-ORY-2001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04932291
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Oryzon Genomics
    Sponsor organisation address
    Sant Ferrán 74, Cornellà de Llobregat, Spain, 08940
    Public contact
    Clinical Operations, Oryzon Genomics S.A., 34 93 515 1313, sgutierrez@oryzon.com
    Scientific contact
    Chief Medical Officer, Oryzon Genomics S.A., 34 93 515 1313, mropacki@oryzon.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    27 Jun 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    13 Nov 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Nov 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    • To investigate the efficacy of vafidemstat in the treatment of agitation and aggression in adult BPD patients • To investigate the efficacy of vafidemstat in the treatment of adult BPD patients
    Protection of trial subjects
    No specific protection of trial subjects was put in place
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 Mar 2021
    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
    Spain: 17
    Country: Number of subjects enrolled
    Bulgaria: 28
    Country: Number of subjects enrolled
    Germany: 37
    Country: Number of subjects enrolled
    United States: 116
    Country: Number of subjects enrolled
    Serbia: 13
    Worldwide total number of subjects
    211
    EEA total number of subjects
    82
    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)
    211
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Main selection criteria: adult men/ women 18-65 years; DSM-5 diagnostic criteria for BPD met at least 3 months before Screening; AAPI-CR A/A subscale score ≥16 (severity X frequency); sum of A/A subscale severity scores ≥6; mantain pre-screening psychotherapy and permitted concomitant medications, should not initiate them during the trial.

    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, Data analyst

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Full analysis set population
    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
    During the 12-week, double-blind, randomized, placebo-controlled Treatment period, from Visit 2 to Visit 8, participants were randomized to: • Vafidemstat: participants received 1 capsule with 1.2 mg/day of vafidemstat from Monday to Friday and 1 capsule of placebo from Saturday to Sunday. • Placebo: participants received 1 capsule of placebo per day. During the 2-week, participant-blind, run-out safety follow-up period, from Visit 8 to Visit 9, all participants received 1 capsule of placebo per day.

    Arm title
    		 Vafidemstat 1.2 mgr
    Arm description
    		 Full analysis set population
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vafidemstat
    Investigational medicinal product code
    ORY-2001
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    During the 12-week, double-blind, randomized, placebo-controlled Treatment period, from Visit 2 to Visit 8, participants were randomized to: • Vafidemstat: participants received 1 capsule with 1.2 mg/day of vafidemstat from Monday to Friday and 1 capsule of placebo from Saturday to Sunday. • Placebo: participants received 1 capsule of placebo per day. During the 2-week, participant-blind, run-out safety follow-up period, from Visit 8 to Visit 9, all participants received 1 capsule of placebo per day.

    Number of subjects in period 1
    		Placebo Vafidemstat 1.2 mgr
    Started
    105
    106
    Completed
    79
    76
    Not completed
    26
    30
         Consent withdrawn by subject
    8
    10
         Physician decision
    -
    3
         Adverse event, non-fatal
    1
    4
         Pregnancy
    1
    -
         Subject has Covid-19
    -
    1
         Lost to follow-up
    9
    9
         Lack of efficacy
    1
    -
         Protocol deviation
    6
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Full analysis set population

    Reporting group title
    Vafidemstat 1.2 mgr
    Reporting group description
    		 Full analysis set population

    Reporting group values
    		 Placebo Vafidemstat 1.2 mgr Total
    Number of subjects
    		 105 106 211
    Age categorical
    Full analysis set population
    Units: Subjects
        Adults (18-64 years)
    		 105 106 211
    Age continuous
    Full analysis set population
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 29 (23 to 37) 31 (23 to 40) -
    Gender categorical
    Full analysis set population
    Units: Subjects
        Female
    		 80 78 158
        Male
    		 25 28 53

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Full analysis set population

    Reporting group title
    Vafidemstat 1.2 mgr
    Reporting group description
    		 Full analysis set population

    Primary: Difference in the CGI-S A/A from Baseline to average of Weeks 8 to 12

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    End point title
    		 Difference in the CGI-S A/A from Baseline to average of Weeks 8 to 12
    End point description
    Change on the Clinical Global Impression-Severity focused on Agitation/Aggression (CGI-S A/A) from Baseline to average of Weeks 8 to 12, between the active treatment arm (Vafidemstat 1.2 mgr) and the placebo arm (full analysis set population)
    End point type
    Primary
    End point timeframe
    From Baseline-Week 0 to average of Weeks 8 to 12
    End point values
    		 Placebo Vafidemstat 1.2 mgr
    Number of subjects analysed
    105
    106
    Units: Arbitary unit
        least squares mean (standard error)
    -1.31 ( 0.111 )
    -1.47 ( 0.111 )
    Statistical analysis title
    		 1ary endpoint: CGI-Severity Agitation/Aggression
    Comparison groups
    Placebo v Vafidemstat 1.2 mgr
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.2266
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.42
         upper limit
    		 0.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.133

    Primary: Difference in the BPDCL-Total Score from Baseline to average of Weeks 8 to 12

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    End point title
    		 Difference in the BPDCL-Total Score from Baseline to average of Weeks 8 to 12
    End point description
    Change on the Borderline Personality Disorder Checklist (BPDL) - Total Score from Baseline to average of Weeks 8 to 12, between the active treatment arm (Vafidemstat 1.2 mgr) and the placebo arm (full analysis set population)
    End point type
    Primary
    End point timeframe
    From Baseline-Week 0 to average of Weeks 8 to 12
    End point values
    		 Placebo Vafidemstat 1.2 mgr
    Number of subjects analysed
    105
    106
    Units: Arbitary unit
        least squares mean (standard error)
    -30.6 ( 3.449 )
    -34.0 ( 3.428 )
    Statistical analysis title
    		 1ary endpoint: BPDCL-Total Score
    Comparison groups
    Vafidemstat 1.2 mgr v Placebo
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.3839
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.2
         upper limit
    		 4.34
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.941

    Secondary: Difference in the BEST-Total Score from Baseline to average of Weeks 8 to 12

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    End point title
    		 Difference in the BEST-Total Score from Baseline to average of Weeks 8 to 12
    End point description
    Change on the Borderline Evaluation of Severity Over Time (BEST) - Total Score from Baseline to average of Weeks 8 to 12, between the active treatment arm (Vafidemstat 1.2 mgr) and the Placebo arm (full analysis set population)
    End point type
    Secondary
    End point timeframe
    From Baseline-Week 0 to average of Weeks 8 to 12
    End point values
    		 Placebo Vafidemstat 1.2 mgr
    Number of subjects analysed
    105
    106
    Units: Arbitary unit
        least squares mean (standard error)
    -8.64 ( 1.053 )
    -11.3 ( 1.047 )
    Statistical analysis title
    		 2ary endpoint: BEST-Total Score
    Comparison groups
    Placebo v Vafidemstat 1.2 mgr
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.026
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.02
         upper limit
    		 -0.32
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.189

    Secondary: Difference in the BDI-II Total Score from Baseline to average of Weeks 8 to 12

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    End point title
    		 Difference in the BDI-II Total Score from Baseline to average of Weeks 8 to 12
    End point description
    Change on the Beck Depression Inventory – II (BDI-II) - Total Score from Baseline to average of Weeks 8 to 12, between the active treatment arm (Vafidemstat 1.2 mgr) and the Placebo arm (full analysis set population)
    End point type
    Secondary
    End point timeframe
    From Baseline-Week 0 to average of Weeks 8 to 12
    End point values
    		 Placebo Vafidemstat 1.2 mgr
    Number of subjects analysed
    105
    106
    Units: Arbitary unit
        least squares mean (standard error)
    -6.18 ( 1.366 )
    -8.79 ( 1.354 )
    Statistical analysis title
    		 2ary endpoint: BDI-II Total Score
    Comparison groups
    Vafidemstat 1.2 mgr v Placebo
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0944
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.68
         upper limit
    		 0.45
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.552

    Secondary: Difference in the STAXI-2-Anger Expression Index Raw Score from Baseline to average of Weeks 8 to 12

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    End point title
    		 Difference in the STAXI-2-Anger Expression Index Raw Score from Baseline to average of Weeks 8 to 12
    End point description
    Change on the State-Trait Anger Expression Inventory 2 (STAXI-2) - Anger Expression Index Raw Score from Baseline to average of Weeks 8 to 12, between the active treatment arm (Vafidemstat 1.2 mgr) and the Placebo arm (full analysis set population)
    End point type
    Secondary
    End point timeframe
    From Baseline-Week 0 to average of Weeks 8 to 12
    End point values
    		 Placebo Vafidemstat 1.2 mgr
    Number of subjects analysed
    105
    106
    Units: Arbitary unit
        least squares mean (standard error)
    -6.36 ( 1.355 )
    -8.98 ( 1.345 )
    Statistical analysis title
    		 2ary endpoint: STAXI-2-Anger Expression Index Raw
    Comparison groups
    Placebo v Vafidemstat 1.2 mgr
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0966
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.72
         upper limit
    		 0.48
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.569

    Secondary: Difference in the STAXI-2-State Anger Scale Raw Score from Baseline to average of Weeks 8 to 12

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    End point title
    		 Difference in the STAXI-2-State Anger Scale Raw Score from Baseline to average of Weeks 8 to 12
    End point description
    Change on the State-Trait Anger Expression Inventory 2 (STAXI-2) - State Anger Scale Raw Score from Baseline to average of Weeks 8 to 12, between the active treatment arm (Vafidemstat 1.2 mgr) and the Placebo arm (full analysis set population)
    End point type
    Secondary
    End point timeframe
    From Baseline-Week 0 to average of Weeks 8 to 12
    End point values
    		 Placebo Vafidemstat 1.2 mgr
    Number of subjects analysed
    105
    106
    Units: Arbitary unit
        least squares mean (standard error)
    -4.30 ( 0.882 )
    -4.87 ( 0.879 )
    Statistical analysis title
    		 2ary endpoint: STAXI-2-State Anger Scale Raw Score
    Comparison groups
    Placebo v Vafidemstat 1.2 mgr
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.5684
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.53
         upper limit
    		 1.39
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.991

    Secondary: Difference in the STAXI-2-Trait Anger Scale Raw Score from Baseline to average of Weeks 8 to 12

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    End point title
    		 Difference in the STAXI-2-Trait Anger Scale Raw Score from Baseline to average of Weeks 8 to 12
    End point description
    Change on the State-Trait Anger Expression Inventory 2 (STAXI-2) - Trait Anger Scale Raw Score from Baseline to average of Weeks 8 to 12, between the active treatment arm (Vafidemstat 1.2 mgr) and the Placebo arm (full analysis set population)
    End point type
    Secondary
    End point timeframe
    From Baseline-Week 0 to average of Weeks 8 to 12
    End point values
    		 Placebo Vafidemstat 1.2 mgr
    Number of subjects analysed
    105
    106
    Units: Arbitary unit
        least squares mean (standard error)
    -3.45 ( 0.643 )
    -5.47 ( 0.638 )
    Statistical analysis title
    		 2ary endpoint: STAXI-2-Trait Anger Scale Raw Score
    Comparison groups
    Placebo v Vafidemstat 1.2 mgr
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0071
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.49
         upper limit
    		 -0.56
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.742

    Secondary: Difference in the STAI-State Anxiety Raw Score from Baseline to average of Weeks 8 to 12

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    End point title
    		 Difference in the STAI-State Anxiety Raw Score from Baseline to average of Weeks 8 to 12
    End point description
    Change on the State-Trait Anxiety Inventory (STAI) - State Anxiety Raw Score from Baseline to average of Weeks 8 to 12, between the active treatment arm (Vafidemstat 1.2 mgr) and the Placebo arm (full analysis set population)
    End point type
    Secondary
    End point timeframe
    From Baseline-Week 0 to average of Weeks 8 to 12
    End point values
    		 Placebo Vafidemstat 1.2 mgr
    Number of subjects analysed
    105
    106
    Units: Arbitary unit
        least squares mean (standard error)
    -6.06 ( 1.281 )
    -7.61 ( 1.281 )
    Statistical analysis title
    		 2ary endpoint: STAI-State Anxiety Raw Score
    Comparison groups
    Placebo v Vafidemstat 1.2 mgr
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.2901
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.41
         upper limit
    		 1.33
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.453

    Secondary: Difference in the CGI-S A/A over time (from Baseline to Week 12)

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    End point title
    		 Difference in the CGI-S A/A over time (from Baseline to Week 12)
    End point description
    Change over time on the Clinical Global Impression-Severity focused on Agitation/Aggression (CGI-S A/A) , from Baseline to Week 12, between the active treatment arm (Vafidemstat 1.2 mgr) and the Placebo arm (full analysis set population)
    End point type
    Secondary
    End point timeframe
    Over time: from Baseline-Week 0 to Week 12
    End point values
    		 Placebo Vafidemstat 1.2 mgr
    Number of subjects analysed
    105
    106
    Units: Arbitary unit
        least squares mean (standard error)
    -1.55 ( 0.138 )
    -1.76 ( 0.139 )
    Statistical analysis title
    		 2ary endpoint: CGI-Severity Agitation/Aggression
    Comparison groups
    Placebo v Vafidemstat 1.2 mgr
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.2142
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -4.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.8
         upper limit
    		 4.36
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.34

    Secondary: Difference in the BPDCL-Total Score over time (from Baseline to Week 12)

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    End point title
    		 Difference in the BPDCL-Total Score over time (from Baseline to Week 12)
    End point description
    Change over time on the Borderline Personality Disorder Checklist (BPDCL), from Baseline to Week 12, between the active treatment arm (Vafidemstat 1.2 mgr) and the Placebo arm (full analysis set population)
    End point type
    Secondary
    End point timeframe
    Over time: from Baseline-Week 0 to Week 12
    End point values
    		 Placebo Vafidemstat 1.2 mgr
    Number of subjects analysed
    105
    106
    Units: Arbitary unit
        least squares mean (standard error)
    -31.6 ( 3.724 )
    -35.8 ( 3.729 )
    Statistical analysis title
    		 2ary endpoint: BPDCL-Total Score
    Comparison groups
    Placebo v Vafidemstat 1.2 mgr
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.3333
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -4.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.8
         upper limit
    		 4.36
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.34

    Secondary: Difference in the BEST-Total Score over time (from Baseline to Week 12)

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    End point title
    		 Difference in the BEST-Total Score over time (from Baseline to Week 12)
    End point description
    Change over time on the Borderline Evaluation of Severity Over Time (BEST)-Total Score, from Baseline to Week 12, between the active treatment arm (Vafidemstat 1.2 mgr) and the Placebo arm (full analysis set population)
    End point type
    Secondary
    End point timeframe
    Over time: from Baseline-Week 0 to Week 12
    End point values
    		 Placebo Vafidemstat 1.2 mgr
    Number of subjects analysed
    105
    106
    Units: Arbitary unit
        least squares mean (standard error)
    -9.16 ( 1.128 )
    -11.9 ( 1.130 )
    Statistical analysis title
    		 2ary endpoint: BEST-Total Score
    Comparison groups
    Placebo v Vafidemstat 1.2 mgr
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0384
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.27
         upper limit
    		 -0.15
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.296

    Secondary: Difference in the BDI-II Total Score over time (from Baseline to Week 12)

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    End point title
    		 Difference in the BDI-II Total Score over time (from Baseline to Week 12)
    End point description
    Change over time on the Beck Depression Inventory – II (BDI-II) Total Score, from Baseline to Week 12, between the active treatment arm (Vafidemstat 1.2 mgr) and the Placebo arm (full analysis set population)
    End point type
    Secondary
    End point timeframe
    Over time: from Baseline-Week 0 to Week 12
    End point values
    		 Placebo Vafidemstat 1.2 mgr
    Number of subjects analysed
    105
    106
    Units: Arbitary unit
        least squares mean (standard error)
    -6.43 ( 1.459 )
    -8.88 ( 1.456 )
    Statistical analysis title
    		 2ary endpoint: BDI-II Total Score
    Comparison groups
    Placebo v Vafidemstat 1.2 mgr
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1473
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.78
         upper limit
    		 0.87
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.684

    Secondary: Difference in the STAXI-2-Anger Expression Index Raw Score over time (from Baseline to Week 12)

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    End point title
    		 Difference in the STAXI-2-Anger Expression Index Raw Score over time (from Baseline to Week 12)
    End point description
    Change over time on the State-Trait Anger Expression Inventory 2 (STAXI-2)-Anger Expression Index Raw Score, from Baseline to Week 12, between the active treatment arm (Vafidemstat 1.2 mgr) and the Placebo arm (full analysis set population)
    End point type
    Secondary
    End point timeframe
    Over time: from Baseline-Week 0 to Week 12
    End point values
    		 Placebo Vafidemstat 1.2 mgr
    Number of subjects analysed
    105
    106
    Units: Arbitary unit
        least squares mean (standard error)
    -6.72 ( 1.497 )
    -9.77 ( 1.491 )
    Statistical analysis title
    		 2ary endpoint: STAXI-2-Anger Expression Index Raw
    Comparison groups
    Placebo v Vafidemstat 1.2 mgr
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0851
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.53
         upper limit
    		 0.43
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.761

    Secondary: Difference in the STAXI-2-State Anger Scale Raw Score over time (from Baseline to Week 12)

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    End point title
    		 Difference in the STAXI-2-State Anger Scale Raw Score over time (from Baseline to Week 12)
    End point description
    Change over time on the State-Trait Anger Expression Inventory 2 (STAXI-2)-State Anger Scale Raw Score, from Baseline to Week 12, between the active treatment arm (Vafidemstat 1.2 mgr) and the Placebo arm (full analysis set population)
    End point type
    Secondary
    End point timeframe
    Over time: from Baseline-Week 0 to Week 12
    End point values
    		 Placebo Vafidemstat 1.2 mgr
    Number of subjects analysed
    105
    106
    Units: Arbitary unit
        least squares mean (standard error)
    -5.41 ( 0.903 )
    -6.25 ( 0.910 )
    Statistical analysis title
    		 2ary endpoint: STAXI-2-State Anger Scale Raw Score
    Comparison groups
    Placebo v Vafidemstat 1.2 mgr
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.4157
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.88
         upper limit
    		 1.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.03

    Secondary: Difference in the STAXI-2-Trait Anger Scale Raw Score over time (from Baseline to Week 12)

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    End point title
    		 Difference in the STAXI-2-Trait Anger Scale Raw Score over time (from Baseline to Week 12)
    End point description
    Change over time on the State-Trait Anger Expression Inventory 2 (STAXI-2)-Trait Anger Scale Raw Score, from Baseline to Week 12, between the active treatment arm (Vafidemstat 1.2 mgr) and the Placebo arm (full analysis set population)
    End point type
    Secondary
    End point timeframe
    Over time: from Baseline-Week 0 to Week 12
    End point values
    		 Placebo Vafidemstat 1.2 mgr
    Number of subjects analysed
    105
    106
    Units: Arbitary unit
        least squares mean (standard error)
    -3.80 ( 0.751 )
    -5.96 ( 0.750 )
    Statistical analysis title
    		 2ary endpoint: STAXI-2-Trait Anger Scale Raw Score
    Comparison groups
    Placebo v Vafidemstat 1.2 mgr
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0158
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.92
         upper limit
    		 -0.41
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.889

    Secondary: Difference in the STAI-State Anxiety Raw Score over time (from Baseline to Week 12)

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    End point title
    		 Difference in the STAI-State Anxiety Raw Score over time (from Baseline to Week 12)
    End point description
    Change over time on the State-Trait Anxiety Inventory (STAI) State Anxiety Raw Score, from Baseline to Week 12, between the active treatment arm (Vafidemstat 1.2 mgr) and the Placebo arm (full analysis set population)
    End point type
    Secondary
    End point timeframe
    Over time: from Baseline-Week 0 to Week 12
    End point values
    		 Placebo Vafidemstat 1.2 mgr
    Number of subjects analysed
    105
    106
    Units: Arbitary unit
        least squares mean (standard error)
    -7.21 ( 1.490 )
    -8.41 ( 1.507 )
    Statistical analysis title
    		 2ary endpoint: STAI-State Anxiety Raw Score
    Comparison groups
    Placebo v Vafidemstat 1.2 mgr
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.4942
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.64
         upper limit
    		 2.25
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.745

    Secondary: Difference in the STAI-Trait Anxiety Raw Score over time (from Baseline to Week 12)

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    End point title
    		 Difference in the STAI-Trait Anxiety Raw Score over time (from Baseline to Week 12)
    End point description
    Change over time on the State-Trait Anxiety Inventory (STAI) -Trait Anxiety Raw Score from Baseline to Week 12, between the active treatment arm (Vafidemstat 1.2 mgr) and the Placebo arm (full analysis set population)
    End point type
    Secondary
    End point timeframe
    Over time: from Baseline-Week 0 to Week 12
    End point values
    		 Placebo Vafidemstat 1.2 mgr
    Number of subjects analysed
    105
    106
    Units: Arbitary unit
        least squares mean (standard error)
    -4.41 ( 1.186 )
    -5.46 ( 1.142 )
    Statistical analysis title
    		 2ary endpoint: STAI-Trait Anxiety Raw Score
    Comparison groups
    Placebo v Vafidemstat 1.2 mgr
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.4057
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.54
         upper limit
    		 1.44
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.262

    Secondary: Number of subjects experiencing treatment-emergent adverse events (TEAEs)

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    End point title
    		 Number of subjects experiencing treatment-emergent adverse events (TEAEs)
    End point description
    Number of subjects experiencing treatment-emergent adverse events (TEAEs) in the active treatment arm (Vafidemstat 1.2 mgr) and the placebo arm (safety analysis set population). Study discontinuation and study drug withdrawal are equivalent: all subjects withdrawn from study drug were discontinued from the study. AESI: TEAEs of Special Interest.
    End point type
    Secondary
    End point timeframe
    From Baseline-Week 0 to Week 14
    End point values
    		 Placebo Vafidemstat 1.2 mgr
    Number of subjects analysed
    104
    106
    Units: Subjects
        Treatment-Emergent SAEs (TESAEs)
    0
    1
        Treatment-Related TEAEs
    33
    36
        Treatment-Related TESAEs
    0
    0
        TEAEs leading to discontinuation/ drug withdrawal
    1
    5
        TEAEs leading to drug interruption
    3
    5
        TEAEs by severity
    68
    61
        Mild
    60
    51
        Moderate
    35
    29
        Severe
    4
    5
        TEAEs by outcome
    68
    61
        Recovered/ Resolved
    66
    56
        Not Recovered/ Not Resolved
    17
    14
        Recovering/ Resolving
    9
    8
        Recovered/ Resolved with Sequelae
    1
    0
        Death
    0
    0
        Unknown
    0
    0
        Any TEAEs of Special Interest
    1
    9
        Platelet count decreased
    1
    8
        Neutrophil count decreased
    0
    2
        Intentional self-injury
    6
    1
        COVID-19 TEAEs
    6
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment-emergent adverse events reported from Baseline-Week 0 to Week 14
    Adverse event reporting additional description
    Safety set population
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Safety set population

    Reporting group title
    Vafidemstat 1.2 mgr
    Reporting group description
    		 Safety set population

    Serious adverse events
    		 Placebo Vafidemstat 1.2 mgr
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 106 (0.94%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Infections and infestations
    Kidney infection
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Vafidemstat 1.2 mgr
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    40 / 104 (38.46%)
    27 / 106 (25.47%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    17 / 104 (16.35%)
    13 / 106 (12.26%)
         occurrences all number
    18
    16
    Tension headache
         subjects affected / exposed
    6 / 104 (5.77%)
    5 / 106 (4.72%)
         occurrences all number
    17
    11
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    18 / 104 (17.31%)
    9 / 106 (8.49%)
         occurrences all number
    22
    11

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Feb 2021
    Modification of study endpoints’ evaluation times. Reason: changes on statistical methods. Sample size increased. Reason: changes in study statistical considerations. Amendments to Statistical Methods section. Reason: changes in study statistical considerations. Other minor changes and clarifications in different protocol sections.
    12 Jul 2021
    Addition of a paragraph on reproductive and developmental toxicology in Section 1.3. Reason: to provide a more accurate dose justification. Addition of the CSSRS to the list of safety assessments in Section 7.3 (Safety Assessments). Reason: clarification of its safety purpose. Addition of “Overdose should be reported as an adverse event” in Section 8.5. Reason: safety reporting clarification. Amendments to the Statistical Methods section. Reason: to implement a more precise and appropriate statistical methodology. Other minor changes and clarifications added to different protocol sections.
    28 Sep 2021
    Update of Concomitant Medication section and addition of new text informing participants of serotoninergic syndrome. Reason: to adhere with regulatory requirements. Update of the Laboratory Safety Assessments section. Reason: to provide clarity on safety requirements. Modification of Statistical Analysis section. Reason: to adhere with regulatory requirements. Update of Study Procedures to include qualitative research data obtention and update of Pharmacokinetic Assessment, only for the US sites. Reason: to adhere with regulatory requirements.
    08 Aug 2022
    Changes on several includion and exclusion criteria. Reason: flexibilization of the conditions for participant inclusion. Update of Concomitant Medication section. Reason: to account for the potential addiction to benzodiazepines. Update of Statistical Methods and Study Design sections to further detail the Interim analysis strategy. Reason: to implement regulatory suggestions.
    24 May 2023
    Update of Statistical Analysis & Determination of Sample Size sections regarding effect size and sample size: increase of sample size. Reason: to implement regulatory suggestions. Modifications in the Concomitant Medication and Follow-up of Participants after AEs sections. Reason: to provide clarity on participants safety.

    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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