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    Clinical Trial Results:
    A Phase 2, 12-Week, Randomized, Double-Blind, Placebo-Controlled, Parallel Study to Evaluate Efficacy, Safety, Tolerability, and Pharmacokinetics of 3 Dose Levels of TAK-831 in Adjunctive Treatment of Adult Subjects With Negative Symptoms of Schizophrenia

    Summary
    EudraCT number
    		 2017-003471-54
    Trial protocol
    		 ES   CZ   DE   BG   IT  
    Global end of trial date
    12 Jan 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 May 2022
    First version publication date
    25 May 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    TAK-831-2002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03382639
    WHO universal trial number (UTN)
    		 U1111-1201-2722
    Sponsors
    Sponsor organisation name
    Neurocrine Biosciences, Inc.
    Sponsor organisation address
    12780 El Camino Real, San Diego, United States, CA 92130
    Public contact
    Neurocrine Medical Information, Neurocrine Biosciences, Inc., medinfo@neurocrine.com
    Scientific contact
    Neurocrine Medical Information, Neurocrine Biosciences, Inc., medinfo@neurocrine.com
    Sponsor organisation name
    Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda Pharmaceutical Company, Ltd
    Sponsor organisation address
    40 Landsdowne Street, Cambridge, United States, MA 02139
    Public contact
    For contact information, see Neurocrine Biosciences, Inc., medinfo@neurocrine.com
    Scientific contact
    For contact information, see Neurocrine Biosciences, Inc., medinfo@neurocrine.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
    12 Jan 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Jan 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to determine whether add-on luvadaxistat (TAK-831) is superior to placebo on the Positive and Negative Syndrome Scale Negative Symptom Factor Score (PANSS NSFS).
    Protection of trial subjects
    The study was conducted in accordance with Takeda and Neurocrine Biosciences, Inc. standards that meet regulations relating to Good Clinical Practice (GCP). The study was conducted in full compliance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use GCP guidelines and with the laws and regulations of the countries in which the study was conducted.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 Jan 2018
    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
    Bulgaria: 54
    Country: Number of subjects enrolled
    Czechia: 14
    Country: Number of subjects enrolled
    Italy: 23
    Country: Number of subjects enrolled
    Poland: 6
    Country: Number of subjects enrolled
    Russian Federation: 22
    Country: Number of subjects enrolled
    Serbia: 12
    Country: Number of subjects enrolled
    Spain: 9
    Country: Number of subjects enrolled
    Ukraine: 51
    Country: Number of subjects enrolled
    United States: 65
    Worldwide total number of subjects
    256
    EEA total number of subjects
    106
    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)
    256
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This multicenter study assessed efficacy, safety, tolerability and pharmacokinetics (PK) of adjunctive treatment with luvadaxistat when given once daily (QD) in adult subjects with negative symptoms of schizophrenia. Effects of 3 dose levels of luvadaxistat (50 milligrams [mg], 125 mg and 500 mg) or placebo were assessed.

    Pre-assignment
    Screening details
    		 The study consisted of a screening period of up to 28 days, a 14-day single-blind placebo run-in period, a 12-week double-blind treatment period and a safety follow-up visit. Randomization was stratified by age at screening (<35 and ≥35 years). The allocation ratio was 2:2:2:3 to the 3 luvadaxistat groups and placebo group, respectively.

    Period 1
    Period 1 title
    Overall study (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
    		 Placebo
    Arm description
    		 Subjects received placebo (matching luvadaxistat) orally QD for 12 weeks (Days 1 to 84).
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received placebo QD, administered as 5 oral placebo (matching luvadaxistat) tablets.

    Arm title
    		 Luvadaxistat 50 mg
    Arm description
    		 Subjects received luvadaxistat 50 mg orally QD for 12 weeks (Days 1 to 84).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Luvadaxistat
    Investigational medicinal product code
    TAK-831
    Other name
    NBI-1065844
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received luvadaxistat 50 mg QD, administered as 5 oral tablets of 10 mg each (T2 tablet formulation).

    Arm title
    		 Luvadaxistat 125 mg
    Arm description
    		 Subjects received luvadaxistat 125 mg orally QD for 12 weeks (Days 1 to 84).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Luvadaxistat
    Investigational medicinal product code
    TAK-831
    Other name
    NBI-1065844
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received luvadaxistat 125 mg QD, administered as 5 oral tablets of 25 mg each (T2 tablet formulation).

    Arm title
    		 Luvadaxistat 500 mg
    Arm description
    		 Subjects received luvadaxistat 500 mg orally QD for 12 weeks (Days 1 to 84).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Luvadaxistat
    Investigational medicinal product code
    TAK-831
    Other name
    NBI-1065844
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received luvadaxistat 500 mg QD, administered as 5 oral tablets of 100 mg each (T2 tablet formulation).

    Number of subjects in period 1
    		Placebo Luvadaxistat 50 mg Luvadaxistat 125 mg Luvadaxistat 500 mg
    Started
    87
    58
    56
    55
    Completed
    76
    53
    52
    47
    Not completed
    11
    5
    4
    8
         Consent withdrawn by subject
    4
    3
    2
    3
         Adverse event, non-fatal
    2
    -
    1
    1
         Unsatisfactory therapeutic response
    1
    -
    -
    -
         Noncompliance with study drug
    1
    2
    1
    1
         Unspecified
    2
    -
    -
    3
         Lost to follow-up
    1
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo (matching luvadaxistat) orally QD for 12 weeks (Days 1 to 84).

    Reporting group title
    Luvadaxistat 50 mg
    Reporting group description
    		 Subjects received luvadaxistat 50 mg orally QD for 12 weeks (Days 1 to 84).

    Reporting group title
    Luvadaxistat 125 mg
    Reporting group description
    		 Subjects received luvadaxistat 125 mg orally QD for 12 weeks (Days 1 to 84).

    Reporting group title
    Luvadaxistat 500 mg
    Reporting group description
    		 Subjects received luvadaxistat 500 mg orally QD for 12 weeks (Days 1 to 84).

    Reporting group values
    		 Placebo Luvadaxistat 50 mg Luvadaxistat 125 mg Luvadaxistat 500 mg Total
    Number of subjects
    		 87 58 56 55 256
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0
        Adults (18-64 years)
    		 87 58 56 55 256
        From 65-84 years
    		 0 0 0 0 0
        85 years and over
    		 0 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 39.9 ± 11.11 39.9 ± 10.96 40.1 ± 9.80 40.1 ± 11.79 -
    Gender categorical
    Units: Subjects
        Female
    		 24 20 22 22 88
        Male
    		 63 38 34 33 168
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 2 0 1 0 3
        Asian
    		 2 0 3 0 5
        Black or African American
    		 10 9 9 5 33
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0
        White
    		 70 46 42 50 208
        Multiracial
    		 0 0 0 0 0
        Not reported
    		 3 3 1 0 7
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 3 2 2 1 8
        Not Hispanic and Latino
    		 19 12 18 8 57
        Not reported
    		 65 44 36 46 191

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo (matching luvadaxistat) orally QD for 12 weeks (Days 1 to 84).

    Reporting group title
    Luvadaxistat 50 mg
    Reporting group description
    		 Subjects received luvadaxistat 50 mg orally QD for 12 weeks (Days 1 to 84).

    Reporting group title
    Luvadaxistat 125 mg
    Reporting group description
    		 Subjects received luvadaxistat 125 mg orally QD for 12 weeks (Days 1 to 84).

    Reporting group title
    Luvadaxistat 500 mg
    Reporting group description
    		 Subjects received luvadaxistat 500 mg orally QD for 12 weeks (Days 1 to 84).

    Primary: Change From Baseline on the PANSS NSFS at Week 12

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    End point title
    		 Change From Baseline on the PANSS NSFS at Week 12
    End point description
    PANSS assesses the positive symptoms, negative symptoms and general psychopathology associated with schizophrenia. The scale consists of 30 items. Each item is rated on a scale from 1 (symptom not present) to 7 (symptoms extremely severe). Here, the PANSS NSFS subscale consists of 7 items which assess the negative symptoms with subscale score ranging from 7 to 49, where a higher score indicates greater severity. Baseline was defined as the last observed value before the first dose of study treatment. Results are reported as least squares (LS) mean change from baseline at Week 12, determined using a mixed model for repeated measures (MMRM). A negative change from baseline indicates improvement. The full analysis set (FAS) included all randomized subjects who received at least 1 dose of double-blind study treatment.
    End point type
    Primary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Placebo Luvadaxistat 50 mg Luvadaxistat 125 mg Luvadaxistat 500 mg
    Number of subjects analysed
    87
    58
    56
    55
    Units: scores on a scale
        least squares mean (standard error)
    -3.1 ± 0.44
    -3.3 ± 0.52
    -3.4 ± 0.51
    -2.5 ± 0.55
    Statistical analysis title
    		 Luvadaxistat 50 mg Compared to Placebo
    Statistical analysis description
    Change from baseline on the PANSS NSFS at Week 12.
    Comparison groups
    Luvadaxistat 50 mg v Placebo
    Number of subjects included in analysis
    145
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.426
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.4
         upper limit
    		 1.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.66
    Statistical analysis title
    		 Luvadaxistat 125 mg Compared to Placebo
    Statistical analysis description
    Change from baseline on the PANSS NSFS at Week 12.
    Comparison groups
    Luvadaxistat 125 mg v Placebo
    Number of subjects included in analysis
    143
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.725 [1]
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.5
         upper limit
    		 1.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.66
    Notes
    [1] - Adjusted p-value.
    Statistical analysis title
    		 Luvadaxistat 500 mg Compared to Placebo
    Statistical analysis description
    Change from baseline on the PANSS NSFS at Week 12.
    Comparison groups
    Luvadaxistat 500 mg v Placebo
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.808 [2]
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.7
         upper limit
    		 1.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.68
    Notes
    [2] - Adjusted p-value.

    Secondary: Change from Baseline on the PANSS NSFS at Week 4 and Week 8

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    End point title
    		 Change from Baseline on the PANSS NSFS at Week 4 and Week 8
    End point description
    PANSS assesses the positive symptoms, negative symptoms and general psychopathology associated with schizophrenia. The scale consists of 30 items. Each item is rated on a scale from 1 (symptom not present) to 7 (symptoms extremely severe). Here, the PANSS NSFS subscale consists of 7 items which assess the negative symptoms with subscale score ranging from 7 to 49, where a higher score indicates greater severity. Baseline was defined as the last observed value before the first dose of study treatment. Results are reported as LS mean change from baseline at Weeks 4 and 8, determined using a MMRM. A negative change from baseline indicates improvement. The FAS included all randomized subjects who received at least 1 dose of double-blind study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 4 and 8
    End point values
    		 Placebo Luvadaxistat 50 mg Luvadaxistat 125 mg Luvadaxistat 500 mg
    Number of subjects analysed
    87
    58
    56
    55
    Units: scores on a scale
    least squares mean (standard error)
        Change at Week 4
    -1.7 ± 0.32
    -1.6 ± 0.39
    -1.8 ± 0.38
    -1.4 ± 0.40
        Change at Week 8
    -2.8 ± 0.39
    -2.2 ± 0.46
    -2.6 ± 0.45
    -2.3 ± 0.49
    Statistical analysis title
    		 Week 4: Luvadaxistat 50 mg Compared to Placebo
    Statistical analysis description
    Change from baseline on the PANSS NSFS at Week 4.
    Comparison groups
    Luvadaxistat 50 mg v Placebo
    Number of subjects included in analysis
    145
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.593
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.8
         upper limit
    		 1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.47
    Statistical analysis title
    		 Week 4: Luvadaxistat 125 mg Compared to Placebo
    Statistical analysis description
    Change from baseline on the PANSS NSFS at Week 4.
    Comparison groups
    Luvadaxistat 125 mg v Placebo
    Number of subjects included in analysis
    143
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.428
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 0.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.48
    Statistical analysis title
    		 Week 4: Luvadaxistat 500 mg Compared to Placebo
    Statistical analysis description
    Change from baseline on the PANSS NSFS at Week 4.
    Comparison groups
    Luvadaxistat 500 mg v Placebo
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.696
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.7
         upper limit
    		 1.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.48
    Statistical analysis title
    		 Week 8: Luvadaxistat 50 mg Compared to Placebo
    Statistical analysis description
    Change from baseline on the PANSS NSFS at Week 8.
    Comparison groups
    Luvadaxistat 50 mg v Placebo
    Number of subjects included in analysis
    145
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.87
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.5
         upper limit
    		 1.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.58
    Statistical analysis title
    		 Week 8: Luvadaxistat 125 mg Compared to Placebo
    Statistical analysis description
    Change from baseline on the PANSS NSFS at Week 8.
    Comparison groups
    Luvadaxistat 125 mg v Placebo
    Number of subjects included in analysis
    143
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.679
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.9
         upper limit
    		 1.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.58
    Statistical analysis title
    		 Week 8: Luvadaxistat 500 mg Compared to Placebo
    Statistical analysis description
    Change from baseline on the PANSS NSFS at Week 8.
    Comparison groups
    Luvadaxistat 500 mg v Placebo
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.794
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.7
         upper limit
    		 1.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.6

    Secondary: Change from Baseline on the Brief Negative Symptom Scale (BNSS) Total Score (12-item) at Week 12

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    End point title
    		 Change from Baseline on the Brief Negative Symptom Scale (BNSS) Total Score (12-item) at Week 12
    End point description
    The BNSS is a 13-item instrument that measures 5 domains of negative symptoms: blunted affect, alogia, asociality, anhedonia and avolition. All items in the BNSS are rated on a 7-point (0-6) scale, with anchor points generally ranging from symptoms being absent (0) to severe (6). Here, the BNSS total score (12-item, excluding item 4) was calculated by summing the 12 individual items; total score range of 0 to 72, where a higher score indicates higher severity of negative symptoms. Subjects required a BNSS total score ≥28 to be eligible for the study (excluding item 4). Baseline was defined as the last observed value before the first dose of study treatment. Results are reported as LS mean change from baseline at Week 12, determined using a MMRM. A negative change from baseline indicates improvement. The FAS included all randomized subjects who received at least 1 dose of double-blind study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Placebo Luvadaxistat 50 mg Luvadaxistat 125 mg Luvadaxistat 500 mg
    Number of subjects analysed
    87
    58
    56
    55
    Units: scores on a scale
        least squares mean (standard error)
    -7.1 ± 1.04
    -8.9 ± 1.22
    -8.0 ± 1.22
    -6.0 ± 1.30
    Statistical analysis title
    		 Luvadaxistat 50 mg Compared to Placebo
    Statistical analysis description
    Change from baseline on the BNSS total score (12-item) at Week 12.
    Comparison groups
    Luvadaxistat 50 mg v Placebo
    Number of subjects included in analysis
    145
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.122
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.9
         upper limit
    		 1.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.56
    Statistical analysis title
    		 Luvadaxistat 125 mg Compared to Placebo
    Statistical analysis description
    Change from baseline on the BNSS total score (12-item) at Week 12.
    Comparison groups
    Luvadaxistat 125 mg v Placebo
    Number of subjects included in analysis
    143
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.273
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4
         upper limit
    		 2.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.57
    Statistical analysis title
    		 Luvadaxistat 500 mg Compared to Placebo
    Statistical analysis description
    Change from baseline on the BNSS total score (12-item) at Week 12.
    Comparison groups
    Luvadaxistat 500 mg v Placebo
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.742
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.1
         upper limit
    		 4.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.61

    Secondary: Change from Baseline on the Brief Assessment of Cognition in Schizophrenia (BACS) Composite Score at Week 12

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    End point title
    		 Change from Baseline on the Brief Assessment of Cognition in Schizophrenia (BACS) Composite Score at Week 12
    End point description
    BACS is a reliable and sensitive measure of cognitive function in schizophrenia. It is a cognition assessment battery that measures 6 domains of cognitive function found to be consistently impaired in schizophrenia: verbal memory, working memory, motor speed, attention, executive functions and verbal fluency. The primary measure from each test of the BACS is standardized by creating z-scores whereby the mean of the test session of a healthy person is set to 0 and the standard deviation set to 1. A composite z-score is calculated by averaging the 6 standardized primary measures. The composite z-score indicates how much higher or lower the subject’s cognition is compared to a healthy person. Baseline was defined as the last observed value before the first dose of study treatment. Results are reported as LS mean change from baseline at Week 12, determined using a MMRM. The FAS included all randomized subjects who received at least 1 dose of double-blind study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Placebo Luvadaxistat 50 mg Luvadaxistat 125 mg Luvadaxistat 500 mg
    Number of subjects analysed
    87
    58
    56
    55
    Units: z-score
        least squares mean (standard error)
    2.3 ± 0.83
    4.6 ± 0.97
    3.5 ± 0.96
    2.3 ± 1.04
    Statistical analysis title
    		 Luvadaxistat 50 mg Compared to Placebo
    Statistical analysis description
    Change from baseline on the BACS composite score at Week 12.
    Comparison groups
    Luvadaxistat 50 mg v Placebo
    Number of subjects included in analysis
    145
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.031
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    2.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1
         upper limit
    		 4.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.22
    Statistical analysis title
    		 Luvadaxistat 125 mg Compared to Placebo
    Statistical analysis description
    Change from baseline on the BACS composite score at Week 12.
    Comparison groups
    Luvadaxistat 125 mg v Placebo
    Number of subjects included in analysis
    143
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.17
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.2
         upper limit
    		 3.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.23
    Statistical analysis title
    		 Luvadaxistat 500 mg Compared to Placebo
    Statistical analysis description
    Change from baseline on the BACS composite score at Week 12.
    Comparison groups
    Luvadaxistat 500 mg v Placebo
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.519
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.5
         upper limit
    		 2.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.26

    Secondary: Change from Baseline on the Clinical Global Impression-Schizophrenia-Severity (CGI-SCH-S) Negative Symptoms Score at Week 12

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    End point title
    		 Change from Baseline on the Clinical Global Impression-Schizophrenia-Severity (CGI-SCH-S) Negative Symptoms Score at Week 12
    End point description
    The CGI-SCH scale is an adapted version of the CGI scale that is designed to assess global illness status in patients with schizophrenia. CGI-SCH-S is a 7-point scale that requires the investigator to rate the severity of the subject’s illness at the time of assessment. Here, CGI-SCH-S negative symptoms score assesses the severity of illness for negative symptoms on the following 7-point scale: 1. normal, not at all ill; 2. borderline mentally ill; 3. mildly ill; 4. moderately ill; 5. markedly ill; 6. severely ill; or 7. among the most extremely ill. Baseline was defined as the last observed value before the first dose of study treatment. The number of subjects with each CGI-SCH-S negative symptoms score at baseline and at Week 12 is reported. The FAS included all randomized subjects who received at least 1 dose of double-blind study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Placebo Luvadaxistat 50 mg Luvadaxistat 125 mg Luvadaxistat 500 mg
    Number of subjects analysed
    71
    51
    49
    45
    Units: subjects
        Baseline: Normal, not at all ill (1)
    0
    0
    0
    0
        Baseline: Borderline mentally ill (2)
    0
    0
    1
    0
        Baseline: Mildly ill (3)
    3
    3
    1
    3
        Baseline: Moderately ill (4)
    36
    28
    25
    22
        Baseline: Markedly ill (5)
    26
    18
    20
    18
        Baseline: Severely ill (6)
    6
    2
    2
    2
        Baseline: Among the most extremely ill (7)
    0
    0
    0
    0
        Week 12: Normal, not at all ill (1)
    0
    0
    0
    0
        Week 12: Borderline mentally ill (2)
    1
    3
    2
    3
        Week 12: Mildly ill (3)
    13
    14
    12
    11
        Week 12: Moderately ill (4)
    34
    22
    21
    18
        Week 12: Markedly ill (5)
    20
    11
    13
    12
        Week 12: Severely ill (6)
    3
    1
    1
    1
        Week 12: Among the most extremely ill (7)
    0
    0
    0
    0
    Statistical analysis title
    		 Luvadaxistat 50 mg Compared to Placebo
    Statistical analysis description
    Change from baseline on the CGI-SCH-S negative symptoms score at Week 12.
    Comparison groups
    Luvadaxistat 50 mg v Placebo
    Number of subjects included in analysis
    122
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.182 [3]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [3] - The 1-sided p-values were obtained using the Cochran-Mantel-Haenszel row mean score test for comparison of the shift from baseline to Week 12.
    Statistical analysis title
    		 Luvadaxistat 125 mg Compared to Placebo
    Statistical analysis description
    Change from baseline on the CGI-SCH-S negative symptoms score at Week 12.
    Comparison groups
    Luvadaxistat 125 mg v Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.255 [4]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [4] - The 1-sided p-values were obtained using the Cochran-Mantel-Haenszel row mean score test for comparison of the shift from baseline to Week 12.
    Statistical analysis title
    		 Luvadaxistat 500 mg Compared to Placebo
    Statistical analysis description
    Change from baseline on the CGI-SCH-S negative symptoms score at Week 12.
    Comparison groups
    Luvadaxistat 500 mg v Placebo
    Number of subjects included in analysis
    116
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.173 [5]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [5] - The 1-sided p-values were obtained using the Cochran-Mantel-Haenszel row mean score test for comparison of the shift from baseline to Week 12.

    Secondary: Clinical Global Impression Schizophrenia Improvement (CGI-SCH-I) Negative Symptoms Score at Week 12

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    End point title
    		 Clinical Global Impression Schizophrenia Improvement (CGI-SCH-I) Negative Symptoms Score at Week 12
    End point description
    The CGI-SCH-I assesses the subject’s improvement (or worsening). CGI-SCH-I requires the investigator to assess the subject’s condition relative to baseline on a 7-point scale. Here, CGI-SCH-I negative symptoms score assesses the improvement for negative symptoms on the following scale: very much improved; 2. much improved; 3. minimally improved; 4. no change; 5. minimally worse; 6. much worse; or 7. very much worse. Baseline was defined as the last observed value before the first dose of study treatment. The number of subjects with each CGI-SCH-I negative symptoms score at Week 12 is reported. The FAS included all randomized subjects who received at least 1 dose of double-blind study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 12
    End point values
    		 Placebo Luvadaxistat 50 mg Luvadaxistat 125 mg Luvadaxistat 500 mg
    Number of subjects analysed
    71
    51
    49
    45
    Units: subjects
        1 - Very much improved
    0
    0
    0
    0
        2 - Much improved
    10
    13
    12
    5
        3 - Minimally improved
    29
    19
    19
    21
        4 - No change
    32
    19
    16
    18
        5 - Minimally worse
    0
    0
    2
    1
        6 - Much worse
    0
    0
    0
    0
        7 - Very much worse
    0
    0
    0
    0
    Statistical analysis title
    		 Luvadaxistat 50 mg Compared to Placebo
    Statistical analysis description
    Analysis of CGI-SCH-I negative symptoms score at Week 12.
    Comparison groups
    Luvadaxistat 50 mg v Placebo
    Number of subjects included in analysis
    122
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.097 [6]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [6] - The 1-sided p-values were obtained using the Cochran-Mantel-Haenszel row mean score test.
    Statistical analysis title
    		 Luvadaxistat 125 mg Compared to Placebo
    Statistical analysis description
    Analysis of CGI-SCH-I negative symptoms score at Week 12.
    Comparison groups
    Luvadaxistat 125 mg v Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.179 [7]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [7] - The 1-sided p-values were obtained using the Cochran-Mantel-Haenszel row mean score test.
    Statistical analysis title
    		 Luvadaxistat 500 mg Compared to Placebo
    Statistical analysis description
    Analysis of CGI-SCH-I negative symptoms score at Week 12.
    Comparison groups
    Luvadaxistat 500 mg v Placebo
    Number of subjects included in analysis
    116
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.623 [8]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [8] - The 1-sided p-values were obtained using the Cochran-Mantel-Haenszel row mean score test.

    Secondary: Change from Baseline on the Schizophrenia Cognition Rating Scale (SCoRS) Interviewer Total Score at Week 12

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    End point title
    		 Change from Baseline on the Schizophrenia Cognition Rating Scale (SCoRS) Interviewer Total Score at Week 12
    End point description
    The SCoRS is an interview-based measure of cognitive functioning that is developed to specifically assess aspects of cognitive functioning in subjects with schizophrenia. The items assess the 7 cognitive domains of attention, memory, reasoning and problem solving, working memory, processing speed, language functions and social cognition. The SCoRS total score is the sum of the 20 items and varies from 20 to 80 with 20 being the best outcome and 80 being the worst. Baseline was defined as the last observed value before the first dose of study treatment. Results are reported as LS mean change from baseline at Week 12, determined using a MMRM. The FAS included all randomized subjects who received at least 1 dose of double-blind study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Placebo Luvadaxistat 50 mg Luvadaxistat 125 mg Luvadaxistat 500 mg
    Number of subjects analysed
    87
    58
    56
    55
    Units: scores on a scale
        least squares mean (standard error)
    -1.6 ± 0.66
    -3.8 ± 0.77
    -2.3 ± 0.77
    -1.8 ± 0.83
    Statistical analysis title
    		 Luvadaxistat 50 mg Compared to Placebo
    Statistical analysis description
    Change from baseline on the SCoRS interviewer total score at Week 12.
    Comparison groups
    Luvadaxistat 50 mg v Placebo
    Number of subjects included in analysis
    145
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.011
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -2.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.1
         upper limit
    		 -0.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.95
    Statistical analysis title
    		 Luvadaxistat 125 mg Compared to Placebo
    Statistical analysis description
    Change from baseline on the SCoRS interviewer total score at Week 12.
    Comparison groups
    Luvadaxistat 125 mg v Placebo
    Number of subjects included in analysis
    143
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.257
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.5
         upper limit
    		 1.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.96
    Statistical analysis title
    		 Luvadaxistat 500 mg Compared to Placebo
    Statistical analysis description
    Change from baseline on the SCoRS interviewer total score at Week 12.
    Comparison groups
    Luvadaxistat 500 mg v Placebo
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.436
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.1
         upper limit
    		 1.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.98

    Secondary: Change from Baseline on the PANSS Total Score at Week 12

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    End point title
    		 Change from Baseline on the PANSS Total Score at Week 12
    End point description
    PANSS assesses the positive symptoms, negative symptoms and general psychopathology associated with schizophrenia. The scale consists of 30 items. Each item is rated on a scale from 1 (symptom not present) to 7 (symptoms extremely severe). The sum of the 30 items is defined as the PANSS total score and ranges from 30 to 210, where a higher score indicates greater severity. Baseline was defined as the last observed value before the first dose of study treatment. Results are reported as LS mean change from baseline at Week 12, determined using a MMRM. A negative change from baseline indicates improvement. The FAS included all randomized subjects who received at least 1 dose of double-blind study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Placebo Luvadaxistat 50 mg Luvadaxistat 125 mg Luvadaxistat 500 mg
    Number of subjects analysed
    87
    58
    56
    55
    Units: scores on a scale
        least squares mean (standard error)
    -6.2 ± 1.00
    -7.2 ± 1.19
    -6.8 ± 1.18
    -5.0 ± 1.26
    Statistical analysis title
    		 Luvadaxistat 50 mg Compared to Placebo
    Statistical analysis description
    Change from baseline on the PANSS total score at Week 12.
    Comparison groups
    Luvadaxistat 50 mg v Placebo
    Number of subjects included in analysis
    145
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.24
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4
         upper limit
    		 1.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.5
    Statistical analysis title
    		 Luvadaxistat 125 mg Compared to Placebo
    Statistical analysis description
    Change from baseline on the PANSS total score at Week 12.
    Comparison groups
    Luvadaxistat 125 mg v Placebo
    Number of subjects included in analysis
    143
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.345
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.6
         upper limit
    		 2.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.5
    Statistical analysis title
    		 Luvadaxistat 500 mg Compared to Placebo
    Statistical analysis description
    Change from baseline on the PANSS total score at Week 12.
    Comparison groups
    Luvadaxistat 500 mg v Placebo
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.775
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.9
         upper limit
    		 4.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.54

    Secondary: Change from Baseline on the PANSS Positive Symptom Factor Score (PSFS) at Week 12

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    End point title
    		 Change from Baseline on the PANSS Positive Symptom Factor Score (PSFS) at Week 12
    End point description
    PANSS assesses the positive symptoms, negative symptoms and general psychopathology associated with schizophrenia. The scale consists of 30 items. Each item is rated on a scale from 1 (symptom not present) to 7 (symptoms extremely severe). Here, the PANSS PSFS subscale consists of 7 items which assess the positive symptoms with subscale score ranging from 7 to 49, where a higher score indicates greater severity. Baseline was defined as the last observed value before the first dose of study treatment. Results are reported as LS mean change from baseline at Week 12, determined using a MMRM. A negative change from baseline indicates improvement. The FAS included all randomized subjects who received at least 1 dose of double-blind study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Placebo Luvadaxistat 50 mg Luvadaxistat 125 mg Luvadaxistat 500 mg
    Number of subjects analysed
    87
    58
    56
    55
    Units: scores on a scale
        least squares mean (standard error)
    -0.8 ± 0.33
    -1.3 ± 0.39
    -1.3 ± 0.39
    -0.6 ± 0.42
    Statistical analysis title
    		 Luvadaxistat 50 mg Compared to Placebo
    Statistical analysis description
    Change from baseline on the PANSS PSFS at Week 12.
    Comparison groups
    Luvadaxistat 50 mg v Placebo
    Number of subjects included in analysis
    145
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.181
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.4
         upper limit
    		 0.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.49
    Statistical analysis title
    		 Luvadaxistat 125 mg Compared to Placebo
    Statistical analysis description
    Change from baseline on the PANSS PSFS at Week 12.
    Comparison groups
    Luvadaxistat 125 mg v Placebo
    Number of subjects included in analysis
    143
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.182
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.4
         upper limit
    		 0.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.49
    Statistical analysis title
    		 Luvadaxistat 500 mg Compared to Placebo
    Statistical analysis description
    Change from baseline on the PANSS PSFS at Week 12.
    Comparison groups
    Luvadaxistat 500 mg v Placebo
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.639
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.8
         upper limit
    		 1.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.5

    Secondary: Luvadaxistat Plasma Concentrations

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    End point title
    		 Luvadaxistat Plasma Concentrations [9]
    End point description
    Blood samples were collected at pre-specified timepoints and plasma concentrations of luvadaxistat were measured. The PK analysis set included all randomized subjects who received at least 1 dose of double-blind study treatment and who had any available luvadaxistat plasma concentration data. Here 'n' refers to number of subjects analyzed at each time point. Note however that at Week 4, assessments were categorized as pre-dose or post-dose according to actual sampling time and due to this, some subjects may have had more than 1 record summarized for Week 4 pre-dose or Week 4 post-dose.
    End point type
    Secondary
    End point timeframe
    Samples were collected pre-dose on Day 1 and Week 4 and post-dose on Weeks 4, 6, 8 and 12.
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Plasma concentrations of luvadaxistat were determined for the luvadaxistat treatment groups only and not for the placebo treatment group.
    End point values
    		 Luvadaxistat 50 mg Luvadaxistat 125 mg Luvadaxistat 500 mg
    Number of subjects analysed
    58
    56
    55
    Units: nanograms / milliliter
    arithmetic mean (standard deviation)
        Day 1 - Pre-dose (n = 56, 55, 53)
    0.0 ± 0.00
    0.0 ± 0.00
    0.0 ± 0.00
        Week 4 - Pre-dose (n = 45, 31, 42)
    22.5 ± 44.44
    106.5 ± 197.61
    345.2 ± 653.08
        Week 4 - Post-dose (n = 64, 72, 53)
    79.0 ± 115.75
    229.8 ± 368.27
    480.2 ± 717.15
        Week 6 (n = 55, 53, 47)
    83.6 ± 123.38
    183.6 ± 257.44
    409.3 ± 502.26
        Week 8 (n = 54, 53, 46)
    109.3 ± 144.76
    202.1 ± 294.60
    366.8 ± 473.74
        Week 12 (n = 51, 48, 44)
    61.5 ± 113.94
    185.62 ± 258.73
    356.0 ± 461.42
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    12-week double-blind treatment period and up to 30 days follow-up: Day 1 up to Day 114.
    Adverse event reporting additional description
    Treatment-emergent adverse events were defined as adverse events that occurred after the first dose of double-blind study treatment and up to 30 days after the last dose or early termination. The safety analysis set included all subjects who were randomized and received at least 1 dose of double-blind study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo (matching luvadaxistat) orally QD for 12 weeks (Days 1 to 84).

    Reporting group title
    Luvadaxistat 50 mg
    Reporting group description
    		 Subjects received luvadaxistat 50 mg orally QD for 12 weeks (Days 1 to 84).

    Reporting group title
    Luvadaxistat 125 mg
    Reporting group description
    		 Subjects received luvadaxistat 125 mg orally QD for 12 weeks (Days 1 to 84).

    Reporting group title
    Luvadaxistat 500 mg
    Reporting group description
    		 Subjects received luvadaxistat 500 mg orally QD for 12 weeks (Days 1 to 84).

    Serious adverse events
    		 Placebo Luvadaxistat 50 mg Luvadaxistat 125 mg Luvadaxistat 500 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 87 (4.60%)
    0 / 58 (0.00%)
    1 / 56 (1.79%)
    0 / 55 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Psychiatric disorders
    Psychotic disorder
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 58 (0.00%)
    0 / 56 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Schizophrenia
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 58 (0.00%)
    1 / 56 (1.79%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Rhabdomyolysis
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 58 (0.00%)
    0 / 56 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 58 (0.00%)
    0 / 56 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tooth abscess
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 58 (0.00%)
    0 / 56 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Luvadaxistat 50 mg Luvadaxistat 125 mg Luvadaxistat 500 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 87 (4.60%)
    0 / 58 (0.00%)
    5 / 56 (8.93%)
    2 / 55 (3.64%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 87 (4.60%)
    0 / 58 (0.00%)
    5 / 56 (8.93%)
    2 / 55 (3.64%)
         occurrences all number
    6
    0
    7
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Jun 2018
    • The primary reason for this amendment was to revise elements of the study design. • In addition, inclusion/exclusion criteria, randomization criteria, excluded medications, criteria for discontinuation or withdrawal of a subject to include deterioration of the underlying illness, companion medications, monitoring of plasma levels of antipsychotic medication, contraception procedures, poststudy care, clarification of study procedures, and updating acceptable contraception options were revised for clarification or optimization of the prior protocol content. The number of subjects and statistical methods were revised to optimize the study efficacy analysis based on re-evaluation of the relevant scientific contingencies.
    13 Mar 2019
    • The primary reason for this amendment was to revise the assessments to reduce subject and site burden, revise inclusion/exclusion criteria to provide appropriate flexibility to the subject and site, revise concomitant medication requirements, and update recommendations for the management of pregnancy and lactation based on the relevant luvadaxistat nonclinical studies. • Additional clarifications were provided in study design, inclusion/exclusion criteria, randomization criteria, excluded medications, criteria for discontinuation or withdrawal of a subject, video monitoring for assessments, monitoring of plasma levels of antipsychotic medication, and rater monitoring.
    08 Jun 2020
    • The primary reason for this amendment was to describe management of study procedures (eg, alternative strategies for collecting data, conducting study visits, and distributing investigational product) during unexpected, unavoidable circumstances (eg, a widespread disease outbreak or natural disaster) such as the COVID-19 pandemic.

    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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