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    Clinical Trial Results:
    A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Cross-Over Study to Evaluate Pharmacodynamic Effects, Safety, Tolerability, and Pharmacokinetics of Multiple Oral Doses of TAK-831 in Adult Subjects With Schizophrenia

    Summary
    EudraCT number
    		 2017-001739-38
    Trial protocol
    		 GB  
    Global end of trial date
    21 Dec 2020

    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-831-2001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03359785
    WHO universal trial number (UTN)
    		 U1111-1197-9766
    Other trial identifiers
    		 NRES number: 17/YH/0196
    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
    Takeda Development Centre Europe Ltd
    Sponsor organisation address
    61 Aldwych, London, United Kingdom, WC2B 4AE
    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
    21 Dec 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Dec 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine whether luvadaxistat (TAK-831) is superior to placebo in improving cerebellar function as measured with the average percentage of conditioned responses during the eyeblink conditioning (EBC) test.
    Protection of trial subjects
    The study was conducted in accordance with Takeda 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
    10 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
    United States: 31
    Worldwide total number of subjects
    31
    EEA total number of subjects
    0
    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)
    31
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 This 2-period cross-over study assessed the pharmacodynamic (PD) effects, safety, tolerability and pharmacokinetics (PK) of multiple oral doses of luvadaxistat given once daily (QD) in adult subjects with schizophrenia. Effects of 2 dose levels of luvadaxistat (500 milligrams [mg] and 50 mg) or placebo were assessed.

    Pre-assignment
    Screening details
    		 The study consisted of a screening period (30 days), treatment period 1 (8 days), washout (14 to 21 days), treatment period 2 (8 days) and a safety follow-up visit. 17 subjects were randomized to 1 of 2 sequences comparing luvadaxistat 500 mg to placebo and 14 subjects were randomized to 1 of 2 sequences comparing luvadaxistat 50 mg to placebo.

    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
    		 Luvadaxistat 500 mg, then Placebo
    Arm description
    		 Subjects first received luvadaxistat 500 mg orally QD for 8 days during treatment period 1. After a washout of 14 to 21 days, subjects then received matching placebo orally QD for 8 days during treatment period 2. Also referred to as treatment sequence 1.
    Arm type
    		 Cross-over (experimental & placebo)

    Investigational medicinal product name
    Luvadaxistat
    Investigational medicinal product code
    TAK-831
    Other name
    NBI-1065844
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    In treatment period 1, subjects received luvadaxistat QD, administered as 5 oral tablets of 100 mg each.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    In treatment period 2, subjects received placebo QD, administered as 5 oral placebo (matching luvadaxistat) tablets.

    Arm title
    		 Placebo, then Luvadaxistat 500 mg
    Arm description
    		 Subjects first received matching placebo orally QD for 8 days during treatment period 1. After a washout of 14 to 21 days, subjects then received luvadaxistat 500 mg orally QD for 8 days during treatment period 2. Also referred to as treatment sequence 2.
    Arm type
    		 Cross-over (experimental & placebo)

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    In treatment period 1, subjects received placebo QD, administered as 5 oral placebo (matching luvadaxistat) tablets.

    Investigational medicinal product name
    Luvadaxistat
    Investigational medicinal product code
    TAK-831
    Other name
    NBI-1065844
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    In treatment period 2, subjects received luvadaxistat QD, administered as 5 oral tablets of 100 mg each.

    Arm title
    		 Luvadaxistat 50 mg, then Placebo
    Arm description
    		 Subjects first received luvadaxistat 50 mg orally QD for 8 days during treatment period 1. After a washout of 14 to 21 days, subjects then received matching placebo orally QD for 8 days during treatment period 2. Also referred to as treatment sequence 3.
    Arm type
    		 Cross-over (experimental & placebo)

    Investigational medicinal product name
    Luvadaxistat
    Investigational medicinal product code
    TAK-831
    Other name
    NBI-1065844
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    In treatment period 1, subjects received luvadaxistat QD, administered as 5 oral tablets of 10 mg each.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    In treatment period 2, subjects received placebo QD, administered as 5 oral placebo (matching luvadaxistat) tablets.

    Arm title
    		 Placebo, then Luvadaxistat 50 mg
    Arm description
    		 Subjects first received matching placebo orally QD for 8 days during treatment period 1. After a washout of 14 to 21 days, subjects then received luvadaxistat 50 mg orally QD for 8 days during treatment period 2. Also referred to as treatment sequence 4.
    Arm type
    		 Cross-over (experimental & placebo)

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    In treatment period 1, subjects received placebo QD, administered as 5 oral placebo (matching luvadaxistat) tablets.

    Investigational medicinal product name
    Luvadaxistat
    Investigational medicinal product code
    TAK-831
    Other name
    NBI-1065844
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    In treatment period 2, subjects received luvadaxistat QD, administered as 5 oral tablets of 10 mg each.

    Number of subjects in period 1
    		Luvadaxistat 500 mg, then Placebo Placebo, then Luvadaxistat 500 mg Luvadaxistat 50 mg, then Placebo Placebo, then Luvadaxistat 50 mg
    Started
    8
    9
    7
    7
    Completed
    6
    6
    5
    7
    Not completed
    2
    3
    2
    0
         Consent withdrawn by subject
    2
    2
    -
    -
         Early study termination due to study pause
    -
    -
    2
    -
         Protocol deviation
    -
    1
    -
    -

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Luvadaxistat 500 mg, then Placebo
    Reporting group description
    		 Subjects first received luvadaxistat 500 mg orally QD for 8 days during treatment period 1. After a washout of 14 to 21 days, subjects then received matching placebo orally QD for 8 days during treatment period 2. Also referred to as treatment sequence 1.

    Reporting group title
    Placebo, then Luvadaxistat 500 mg
    Reporting group description
    		 Subjects first received matching placebo orally QD for 8 days during treatment period 1. After a washout of 14 to 21 days, subjects then received luvadaxistat 500 mg orally QD for 8 days during treatment period 2. Also referred to as treatment sequence 2.

    Reporting group title
    Luvadaxistat 50 mg, then Placebo
    Reporting group description
    		 Subjects first received luvadaxistat 50 mg orally QD for 8 days during treatment period 1. After a washout of 14 to 21 days, subjects then received matching placebo orally QD for 8 days during treatment period 2. Also referred to as treatment sequence 3.

    Reporting group title
    Placebo, then Luvadaxistat 50 mg
    Reporting group description
    		 Subjects first received matching placebo orally QD for 8 days during treatment period 1. After a washout of 14 to 21 days, subjects then received luvadaxistat 50 mg orally QD for 8 days during treatment period 2. Also referred to as treatment sequence 4.

    Reporting group values
    		 Luvadaxistat 500 mg, then Placebo Placebo, then Luvadaxistat 500 mg Luvadaxistat 50 mg, then Placebo Placebo, then Luvadaxistat 50 mg Total
    Number of subjects
    		 8 9 7 7 31
    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)
    		 8 9 7 7 31
        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)
    		 33.3 ± 6.41 36.0 ± 7.30 41.6 ± 12.08 44.3 ± 10.24 -
    Gender categorical
    Units: Subjects
        Female
    		 0 2 1 2 5
        Male
    		 8 7 6 5 26
    Race
    Units: Subjects
        Asian
    		 0 0 0 1 1
        Black or African American
    		 8 8 6 4 26
        White
    		 0 1 0 2 3
        Unknown
    		 0 0 1 0 1
    Ethnicity
    Units: Subjects
        Not Hispanic or Latino
    		 8 9 6 7 30
        Hispanic or Latino
    		 0 0 1 0 1

    End points

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    End points reporting groups
    Reporting group title
    Luvadaxistat 500 mg, then Placebo
    Reporting group description
    		 Subjects first received luvadaxistat 500 mg orally QD for 8 days during treatment period 1. After a washout of 14 to 21 days, subjects then received matching placebo orally QD for 8 days during treatment period 2. Also referred to as treatment sequence 1.

    Reporting group title
    Placebo, then Luvadaxistat 500 mg
    Reporting group description
    		 Subjects first received matching placebo orally QD for 8 days during treatment period 1. After a washout of 14 to 21 days, subjects then received luvadaxistat 500 mg orally QD for 8 days during treatment period 2. Also referred to as treatment sequence 2.

    Reporting group title
    Luvadaxistat 50 mg, then Placebo
    Reporting group description
    		 Subjects first received luvadaxistat 50 mg orally QD for 8 days during treatment period 1. After a washout of 14 to 21 days, subjects then received matching placebo orally QD for 8 days during treatment period 2. Also referred to as treatment sequence 3.

    Reporting group title
    Placebo, then Luvadaxistat 50 mg
    Reporting group description
    		 Subjects first received matching placebo orally QD for 8 days during treatment period 1. After a washout of 14 to 21 days, subjects then received luvadaxistat 50 mg orally QD for 8 days during treatment period 2. Also referred to as treatment sequence 4.

    Subject analysis set title
    Luvadaxistat 50 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects who received luvadaxistat 50 mg orally QD for 8 days during either treatment periods 1 or 2 of the study.

    Subject analysis set title
    Placebo (reference for luvadaxistat 50 mg)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects who received matching placebo orally QD for 8 days during either treatment periods 1 or 2 of the study. Placebo treatment in this arm corresponds to subjects who received 50 mg luvadaxistat in the alternative treatment period (ie, subjects receiving 50 mg and 500 mg luvadaxistat were analyzed separately and placebo treatment was not pooled).

    Subject analysis set title
    Luvadaxistat 500 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects who received luvadaxistat 500 mg orally QD for 8 days during either treatment periods 1 or 2 of the study.

    Subject analysis set title
    Placebo (reference for luvadaxistat 500 mg)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects who received matching placebo orally QD for 8 days during either treatment periods 1 or 2 of the study. Placebo treatment in this arm corresponds to subjects who received 500 mg luvadaxistat in the alternative treatment period (ie, subjects receiving 50 mg and 500 mg luvadaxistat were analyzed separately and placebo treatment was not pooled).

    Primary: Change From Baseline in Average Percent of Conditioned Responses During the EBC Test at Day 8

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    End point title
    		 Change From Baseline in Average Percent of Conditioned Responses During the EBC Test at Day 8
    End point description
    EBC is a method used to investigate cerebellar-dependent learning. In EBC, a conditioned stimulus, a tone precedes but co-terminates with an unconditioned stimulus, an airpuff to the eyelid. Learning is demonstrated when an eyeblink (the conditioned response) occurs prior to the onset of the unconditioned stimulus. The percentage can range from 0% (no conditioned learning has occurred) to 100% (all responses are conditioned). Baseline was defined as the last observation prior to the dose of study treatment in the corresponding period. Results are reported as least squares (LS) mean change from baseline at Day 8, determined using an analysis of variance (ANOVA). The PD set consisted of all randomized subjects who received at least 1 dose of study treatment and had at least 1 post-dose PD result.
    End point type
    Primary
    End point timeframe
    Baseline and Day 8 of each treatment period
    End point values
    		 Luvadaxistat 50 mg Placebo (reference for luvadaxistat 50 mg) Luvadaxistat 500 mg Placebo (reference for luvadaxistat 500 mg)
    Number of subjects analysed
    10
    12
    11
    11
    Units: percent change
        least squares mean (standard error)
    0.597 ± 0.459
    0.319 ± 0.432
    0.578 ± 0.444
    1.344 ± 0.428
    Statistical analysis title
    		 Luvadaxistat 50 mg Compared with Placebo
    Statistical analysis description
    Change from baseline in percent of conditioned responses during the EBC test at Day 8.
    Comparison groups
    Luvadaxistat 50 mg v Placebo (reference for luvadaxistat 50 mg)
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2401
    Method
    		 ANOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.278
    Confidence interval
         level
    		 90%
         sides
    1-sided
         lower limit
    		 -0.246
         upper limit
    		 -
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.376
    Statistical analysis title
    		 Luvadaxistat 500 mg Compared with Placebo
    Statistical analysis description
    Change from baseline in percent of conditioned responses during the EBC test at Day 8.
    Comparison groups
    Luvadaxistat 500 mg v Placebo (reference for luvadaxistat 500 mg)
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9053
    Method
    		 ANOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.766
    Confidence interval
         level
    		 90%
         sides
    1-sided
         lower limit
    		 -1.513
         upper limit
    		 -
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.547

    Secondary: Change From Baseline in the Mean Mismatch Negativity (MMN) at Day 8

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    End point title
    		 Change From Baseline in the Mean Mismatch Negativity (MMN) at Day 8
    End point description
    MMN is an event related potential (ERP) evoked in response to unattended changes in background stimulation. MMN reflects an automatic process of detecting a mismatch between a deviant stimulus and a sensory-memory trace. Smaller amplitudes of MMN have been consistently identified in schizophrenia subjects. MMN amplitude was measured at midline frontal electrode (Fz) of electroencephalogram (EEG). Baseline was defined as the last observation prior to the dose of study treatment in the corresponding period. Results are reported as LS mean change from baseline at Day 8, determined using an ANOVA. The PD set consisted of all randomized subjects who received at least 1 dose of study treatment and had at least 1 post-dose PD result.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 8 of each treatment period
    End point values
    		 Luvadaxistat 50 mg Placebo (reference for luvadaxistat 50 mg) Luvadaxistat 500 mg Placebo (reference for luvadaxistat 500 mg)
    Number of subjects analysed
    13
    12
    15
    15
    Units: normalized arbitrary unit
        least squares mean (standard error)
    -0.239 ± 0.363
    0.669 ± 0.382
    0.594 ± 0.492
    -0.154 ± 0.501
    Statistical analysis title
    		 Luvadaxistat 50 mg Compared with Placebo
    Statistical analysis description
    Change from baseline in MMN amplitude at Day 8.
    Comparison groups
    Luvadaxistat 50 mg v Placebo (reference for luvadaxistat 50 mg)
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0497
    Method
    		 ANOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.908
    Confidence interval
         level
    		 90%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 -0.211
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.527
    Statistical analysis title
    		 Luvadaxistat 500 mg Compared with Placebo
    Statistical analysis description
    Change from baseline in MMN amplitude at Day 8.
    Comparison groups
    Luvadaxistat 500 mg v Placebo (reference for luvadaxistat 500 mg)
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8517
    Method
    		 ANOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.748
    Confidence interval
         level
    		 90%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 1.67
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.702

    Secondary: Change From Baseline in the Mean P300 Amplitude at Day 8

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    End point title
    		 Change From Baseline in the Mean P300 Amplitude at Day 8
    End point description
    The P300 wave is an ERP component that is elicited by the presentation of a novel, behaviorally relevant target stimulus embedded among irrelevant stimuli in a manner similar to MMN but requiring active listening and responding from subjects. Auditory stimuli are presented in an oddball paradigm consisting of 1 standard tone and 1 target tone. Subjects are instructed to push a button as quickly as possible when they hear the target tone but not when they hear the standard tone. P300 reflects allocation of attention and activation of immediate memory. P300 amplitude was measured at midline parietal electrode (Pz) of EEG. Baseline was defined as the last observation prior to the dose of study treatment in the corresponding period. Results are reported as LS mean change from baseline at Day 8, determined using an ANOVA. The PD set consisted of all randomized subjects who received at least 1 dose of study treatment and had at least 1 post-dose PD result.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 8 of each treatment period
    End point values
    		 Luvadaxistat 50 mg Placebo (reference for luvadaxistat 50 mg) Luvadaxistat 500 mg Placebo (reference for luvadaxistat 500 mg)
    Number of subjects analysed
    12
    12
    14
    14
    Units: normalized arbitrary unit
        least squares mean (standard error)
    -2.019 ± 1.68
    0.608 ± 1.68
    1.102 ± 1.77
    2.595 ± 1.86
    Statistical analysis title
    		 Luvadaxistat 50 mg Compared with Placebo
    Statistical analysis description
    Change from baseline in P300 target amplitude at Day 8.
    Comparison groups
    Luvadaxistat 50 mg v Placebo (reference for luvadaxistat 50 mg)
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9185
    Method
    		 ANOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -2.627
    Confidence interval
         level
    		 90%
         sides
    1-sided
         lower limit
    		 -5.02
         upper limit
    		 -
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.74
    Statistical analysis title
    		 Luvadaxistat 500 mg Compared with Placebo
    Statistical analysis description
    Change from baseline in P300 target amplitude at Day 8.
    Comparison groups
    Luvadaxistat 500 mg v Placebo (reference for luvadaxistat 500 mg)
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7193
    Method
    		 ANOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.493
    Confidence interval
         level
    		 90%
         sides
    1-sided
         lower limit
    		 -4.878
         upper limit
    		 -
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.5

    Secondary: Change From Baseline in the Mean Auditory Steady State Response (ASSR) at Day 8

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    End point title
    		 Change From Baseline in the Mean Auditory Steady State Response (ASSR) at Day 8
    End point description
    ASSRs are evoked oscillatory responses that are entrained to the frequency and phase of temporally modulated stimuli. Individuals with schizophrenia experience subjective sensory anomalies and objective deficits on assessment of sensory function. These deficits can be produced by abnormal signaling in the sensory pathways and sensory cortex or by later-stage disturbances in the cognitive processing of such inputs. ASSR can be used to assess the integrity of sensory pathways including cortical processing. The ASSR applied a frequency stimulus of 40 hertz (Hz) and was measured at midline central electrode (Cz) of EEG. Baseline was defined as the last observation prior to the dose of study treatment in the corresponding period. Results are reported as LS mean change from baseline at Day 8, determined using an ANOVA. The PD set consisted of all randomized subjects who received at least 1 dose of study treatment and had at least 1 post-dose PD result.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 8 of each treatment period
    End point values
    		 Luvadaxistat 50 mg Placebo (reference for luvadaxistat 50 mg) Luvadaxistat 500 mg Placebo (reference for luvadaxistat 500 mg)
    Number of subjects analysed
    13
    12
    15
    14
    Units: normalized arbitrary unit
        least squares mean (standard error)
    2.135 ± 8.83
    -16.282 ± 9.31
    9.411 ± 20.4
    9.203 ± 20.9
    Statistical analysis title
    		 Luvadaxistat 50 mg Compared with Placebo
    Statistical analysis description
    Change from baseline in ASSR at 40 Hz stimulation at Day 8.
    Comparison groups
    Luvadaxistat 50 mg v Placebo (reference for luvadaxistat 50 mg)
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0561
    Method
    		 ANOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    18.417
    Confidence interval
         level
    		 90%
         sides
    1-sided
         lower limit
    		 3.87
         upper limit
    		 -
    Variability estimate
    Standard error of the mean
    Dispersion value
    10.7
    Statistical analysis title
    		 Luvadaxistat 500 mg Compared with Placebo
    Statistical analysis description
    Change from baseline in ASSR at 40 Hz stimulation at Day 8.
    Comparison groups
    Luvadaxistat 500 mg v Placebo (reference for luvadaxistat 500 mg)
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4954
    Method
    		 ANOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.208
    Confidence interval
         level
    		 90%
         sides
    1-sided
         lower limit
    		 -24.409
         upper limit
    		 -
    Variability estimate
    Standard error of the mean
    Dispersion value
    17.6

    Secondary: Change from Baseline on the Brief Assessment of Cognition in Schizophrenia (BACS) Composite Score at Day 7

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    End point title
    		 Change from Baseline on the Brief Assessment of Cognition in Schizophrenia (BACS) Composite Score at Day 7
    End point description
    BACS is a cognition assessment battery and includes brief assessments of reasoning and problem solving, verbal fluency, attention, verbal memory, working memory and motor speed. The primary measure from each test 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 score was calculated by averaging the 4 measures from the BACS used in the study and then calculating a z-score of the composite. 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 observation prior to the dose of study treatment in the corresponding period. Results are reported as LS mean change from baseline at Day 7, determined using an ANOVA. The PD set consisted of all randomized subjects who received at least 1 dose of study treatment and had at least 1 post-dose PD result.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 7 of each treatment period
    End point values
    		 Luvadaxistat 50 mg Placebo (reference for luvadaxistat 50 mg) Luvadaxistat 500 mg Placebo (reference for luvadaxistat 500 mg)
    Number of subjects analysed
    12
    12
    15
    15
    Units: z-score
        least squares mean (standard error)
    2.574 ± 2.51
    5.070 ± 2.55
    5.696 ± 1.41
    -0.075 ± 1.43
    Statistical analysis title
    		 Luvadaxistat 50 mg Compared with Placebo
    Statistical analysis description
    Change from baseline on the BACS composite score at Day 7.
    Comparison groups
    Luvadaxistat 50 mg v Placebo (reference for luvadaxistat 50 mg)
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.799
    Method
    		 ANOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -2.495
    Confidence interval
         level
    		 90%
         sides
    1-sided
         lower limit
    		 -6.426
         upper limit
    		 -
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.83
    Statistical analysis title
    		 Luvadaxistat 500 mg Compared with Placebo
    Statistical analysis description
    Change from baseline on the BACS composite score at Day 7.
    Comparison groups
    Luvadaxistat 500 mg v Placebo (reference for luvadaxistat 500 mg)
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.004
    Method
    		 ANOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    5.771
    Confidence interval
         level
    		 90%
         sides
    1-sided
         lower limit
    		 3.132
         upper limit
    		 -
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.01

    Secondary: Change From Baseline in the Mean Plasma Concentrations of D-serine and L-serine at Day 8

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    End point title
    		 Change From Baseline in the Mean Plasma Concentrations of D-serine and L-serine at Day 8
    End point description
    Blood samples were collected at pre-specified timepoints and plasma concentrations of D-serine and L-serine were measured. Results are reported as LS mean change from baseline at Day 8, determined using a mixed model for repeated measures (MMRM). The PK analysis set included all randomized subjects who received at least 1 dose of study treatment and who had any available plasma concentration data.
    End point type
    Secondary
    End point timeframe
    Samples were collected on Day 1 (pre-dose and 3 to 6 hours post-dose), Day 7 (pre-dose and 3 to 6 hours post-dose) and Day 8 (pre-dose).
    End point values
    		 Luvadaxistat 50 mg Placebo (reference for luvadaxistat 50 mg) Luvadaxistat 500 mg Placebo (reference for luvadaxistat 500 mg)
    Number of subjects analysed
    12
    12
    15
    15
    Units: mg / liter
    least squares mean (standard error)
        D-serine
    0.0402 ± 0.00632
    -0.000892 ± 0.00637
    0.0398 ± 0.00710
    0.00212 ± 0.00712
        L-serine
    0.669 ± 0.479
    -0.543 ± 0.483
    -1.09 ± 0.514
    -0.304 ± 0.516
    Statistical analysis title
    		 Luvadaxistat 50 mg Compared with Placebo
    Statistical analysis description
    Change from baseline in plasma concentrations of D-serine at Day 8.
    Comparison groups
    Luvadaxistat 50 mg v Placebo (reference for luvadaxistat 50 mg)
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.0411
    Confidence interval
         level
    		 90%
         sides
    1-sided
         lower limit
    		 0.03
         upper limit
    		 -
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.00836
    Statistical analysis title
    		 Luvadaxistat 500 mg Compared with Placebo
    Statistical analysis description
    Change from baseline in plasma concentrations of D-serine at Day 8.
    Comparison groups
    Luvadaxistat 500 mg v Placebo (reference for luvadaxistat 500 mg)
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.0377
    Confidence interval
         level
    		 90%
         sides
    1-sided
         lower limit
    		 0.0264
         upper limit
    		 -
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.00861
    Statistical analysis title
    		 Luvadaxistat 50 mg Compared with Placebo
    Statistical analysis description
    Change from baseline in plasma concentrations of L-serine at Day 8.
    Comparison groups
    Luvadaxistat 50 mg v Placebo (reference for luvadaxistat 50 mg)
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0219
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    1.21
    Confidence interval
         level
    		 90%
         sides
    1-sided
         lower limit
    		 0.466
         upper limit
    		 -
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.562
    Statistical analysis title
    		 Luvadaxistat 500 mg Compared with Placebo
    Statistical analysis description
    Change from baseline in plasma concentrations of L-serine at Day 8.
    Comparison groups
    Luvadaxistat 500 mg v Placebo (reference for luvadaxistat 500 mg)
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8782
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.784
    Confidence interval
         level
    		 90%
         sides
    1-sided
         lower limit
    		 -1.65
         upper limit
    		 -
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.658

    Secondary: Change From Baseline in the Mean Plasma D-serine to Total Serine Ratio at Day 8

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    End point title
    		 Change From Baseline in the Mean Plasma D-serine to Total Serine Ratio at Day 8
    End point description
    Blood samples were collected at pre-specified timepoints and plasma concentrations of D-serine and total serine were measured. Plasma D-serine to total serine ratios were then calculated. Results are reported as LS mean change from baseline at Day 8, determined using a MMRM. The PK analysis set included all randomized subjects who received at least 1 dose of study treatment and who had any available plasma concentration data.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 8 of each treatment period
    End point values
    		 Luvadaxistat 50 mg Placebo (reference for luvadaxistat 50 mg) Luvadaxistat 500 mg Placebo (reference for luvadaxistat 500 mg)
    Number of subjects analysed
    12
    12
    15
    15
    Units: ratio
        least squares mean (standard error)
    0.00293 ± 0.000855
    0.000590 ± 0.000863
    0.00561 ± 0.000994
    0.000620 ± 0.000997
    Statistical analysis title
    		 Luvadaxistat 50 mg Compared with Placebo
    Statistical analysis description
    Change from baseline in plasma D-serine to total serine ratio at Day 8.
    Comparison groups
    Luvadaxistat 50 mg v Placebo (reference for luvadaxistat 50 mg)
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0206
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.00234
    Confidence interval
         level
    		 90%
         sides
    1-sided
         lower limit
    		 0.000925
         upper limit
    		 -
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.00107
    Statistical analysis title
    		 Luvadaxistat 500 mg Compared with Placebo
    Statistical analysis description
    Change from baseline in plasma D-serine to total serine ratio at Day 8.
    Comparison groups
    Luvadaxistat 500 mg v Placebo (reference for luvadaxistat 500 mg)
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0006
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.00499
    Confidence interval
         level
    		 90%
         sides
    1-sided
         lower limit
    		 0.00321
         upper limit
    		 -
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.00135

    Secondary: Mean Plasma Concentration of Luvadaxistat

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    End point title
    		 Mean Plasma Concentration of Luvadaxistat
    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 study treatment and who had any available luvadaxistat plasma concentration data. Here 'n' refers to number of subjects analyzed at each timepoint.
    End point type
    Secondary
    End point timeframe
    Samples were collected on Day 1 (pre-dose and at 0.25 to 2 hours and 3 to 6 hours post-dose), Day 7 (pre-dose and at 0.25 to 2 hours and 3 to 6 hours post-dose) and Day 8 (pre-dose).
    End point values
    		 Luvadaxistat 50 mg Luvadaxistat 500 mg
    Number of subjects analysed
    14
    15
    Units: nanograms / milliliter
    arithmetic mean (standard deviation)
        Day 1 - Post-dose (0.25 to 2 hours) (n = 14, 15)
    253.4 ± 199.3
    700.4 ± 783.0
        Day 1 - Post-dose (3 to 6 hours) (n = 14, 15)
    47.66 ± 35.64
    671.1 ± 473.1
        Day 7 - Pre-dose (n = 14, 15)
    8.749 ± 19.212
    78.92 ± 229.90
        Day 7 - Post-dose (0.25 to 2 hours) (n = 13, 15)
    203.5 ± 199.6
    1184 ± 482
        Day 7 - Post-dose (3 to 6 hours) (n = 13, 15)
    38.94 ± 26.23
    301.5 ± 177.2
        Day 8 - Pre-dose (n = 12, 15)
    3.366 ± 2.726
    21.61 ± 14.65
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    8-day treatment period for each of treatment periods 1 and 2 (separated by washout of up to 21 days) and up to 30 days follow-up after last dose of study treatment. Up to a maximum of 67 days for overall timeframe.
    Adverse event reporting additional description
    Treatment-emergent adverse events were defined as adverse events that occurred after the first dose of study treatment and up to 30 days after the last dose or early termination. The safety analysis set included all randomized subjects who received at least 1 dose of 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 who received matching placebo orally QD for 8 days during either treatment periods 1 or 2 of the study. Placebo treatment was pooled for subjects receiving 50 mg and 500 mg luvadaxistat.

    Reporting group title
    Luvadaxistat 500 mg
    Reporting group description
    		 Subjects who received luvadaxistat 500 mg orally QD for 8 days during either treatment periods 1 or 2 of the study.

    Reporting group title
    Luvadaxistat 50 mg
    Reporting group description
    		 Subjects who received luvadaxistat 50 mg orally QD for 8 days during either treatment periods 1 or 2 of the study.

    Serious adverse events
    		 Placebo Luvadaxistat 500 mg Luvadaxistat 50 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Placebo Luvadaxistat 500 mg Luvadaxistat 50 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 15 (0.00%)
    1 / 14 (7.14%)
    Gastrointestinal disorders
    Dyspepsia
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 15 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Sep 2017
    • The primary reason for this amendment was to revise pregnancy avoidance and contraception requirements.
    11 Oct 2017
    • The primary reason for this amendment was to revise luvadaxistat doses to be administered (from 400 mg and 40 mg to 500 mg and 50 mg) and procedures, dose justification and update clinical experience.
    30 May 2018
    • The primary reason for this amendment was to eliminate the functional magnetic resonance imaging blood oxygen level-dependent imaging component. In addition to the change in study design, inclusion/exclusion criteria were modified, study treatment distribution, including subject randomization process was modified to include interactive response technology and changes were made in the schedule of assessments. The clinical site in the UK where the study was initiated (Amendment 11 October 2017) was chosen based on its imaging capabilities. Since imaging was no longer to be conducted, a new study site (in the US) with an appropriate subject population and expertise for the modified study protocol was chosen to conduct the study. The study was initiated (Amendment 11 October 2017) at the previous site and 1 subject was enrolled and completed all assessments. The data from this subject was excluded from the current analysis as only those subjects participating in this study at the site in the US under Amendment 30 May 2018 were included.
    17 Dec 2018
    • The primary reason for this amendment was to modify exclusion criterion 17 to separate the prespecified exclusion criteria from those based on investigator opinion. Those exclusion which were subject to investigator opinion remained in exclusion criterion 17, while those that were measurable were moved to exclusion criteria 18 through 23. • In addition, an exploratory objective that did not have a corresponding endpoint was removed, revised the exclusion duration for any investigational drug to be consistent with the relevant exclusion criterion, clarified study design and added guidance for rescreening subjects, corrected inconsistency in randomization description and updated time of 12-lead electrocardiogram collection for ease of collection.
    19 Sep 2019
    • The primary reasons for this amendment were to modify inclusion criterion 10 to revise the maximum dose of quetiapine as add-on hypnotic from 100 mg to 300 mg as this increased dose was not expected to interfere with the primary and secondary endpoints and modify exclusion criterion 6 to allow rescreening of marijuana positive subjects at screening and to allow for increasing subject recruitment. • In addition, exclusion criteria were updated to capture corrections in Amendment 17 December 2018 informed to the sites via administrative letters and statistical procedure gave precedence to the statistical analysis plan over protocol to correct the inconsistencies.
    09 Jan 2020
    • The primary reason for this amendment was to modify inclusion criterion 3 to revise the maximum subject age from 50 to 60 years of age, to allow for increasing subject recruitment.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    01 Mar 2020
    This study was paused in March 2020 due to Coronavirus Disease 2019 (COVID-19) site restrictions, but was able to restart in September 2020 and complete enrollment of 31 subjects. Due to this pause, there was a higher number of early terminations than planned; however, the integrity of the study, the ability to achieve the objectives, and the outcome of the study results were not impacted by COVID-19.
    01 Sep 2020

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    One subject was excluded from the study entirely (enrolled at a site in the UK), due to a new version of the protocol being used (Amendment 30 May 2018). Thus, only data from the site in the US were included in the current analysis.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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