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    Clinical Trial Results:
    A Phase 2, Randomized, Double-blind, Placebo-controlled Trial to Evaluate the Efficacy, Safety, and Tolerability of Two Fixed Doses (10 mg and 30 mg QD) of CVL-231 (Emraclidine) in Participants With Schizophrenia Experiencing an Acute Exacerbation of Psychosis

    Summary
    EudraCT number
    		 2022-000580-52
    Trial protocol
    		 BG  
    Global end of trial date
    26 Aug 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Aug 2025
    First version publication date
    29 Aug 2025
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CVL-231-2001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT05227690
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AbbVie Deutschland GmbH & Co. KG
    Sponsor organisation address
    AbbVie House, Vanwall Business Park, Vanwall Road, Maidenhead, Berkshire, United Kingdom, SL6 4UB
    Public contact
    Global Medical Services, AbbVie, 001 8006339110, abbvieclinicaltrials@abbvie.com
    Scientific contact
    Global Medical Services, AbbVie, 001 8006339110, abbvieclinicaltrials@abbvie.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
    26 Aug 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Aug 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This is a Phase 2, multicenter, randomized, double-blind, placebo-controlled, parallel-group, 6-week trial to evaluate the efficacy, safety, and tolerability of 2 fixed doses of CVL-231 (Emraclidine) (10 mg QD and 30 mg QD) in male and female participants who have schizophrenia and are experiencing an acute exacerbation of psychosis.
    Protection of trial subjects
    The investigator or his/her representative will explain the nature of the trial to the participant and answer all questions regarding the trial. Participants must be informed that their participation is voluntary. Participants will be required to agree to (eg, provide electronic agreement or written signature) a statement of informed consent that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, privacy and data protection requirements, where applicable, and the IRB/IEC or trial center.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Jun 2022
    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: 29
    Country: Number of subjects enrolled
    United States: 356
    Worldwide total number of subjects
    385
    EEA total number of subjects
    29
    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)
    385
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Participants will enter a Screening Period up to 15 days (up to a maximum of 21 days allowed with approval of the medical monitor) to assess eligibility criteria and washout from prior antipsychotic medications and other prohibited medications.

    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
    		 Participants received placebo tablets orally once daily (QD) through Day 45 of Week 6.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo, oral (tablet), once per day for 6 weeks

    Arm title
    		 Emraclidine 10 mg, Once Daily (QD)
    Arm description
    		 Participants received emraclidine 10 mg tablets orally once daily (QD) through Day 45 of Week 6.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Emraclidine 10 mg
    Investigational medicinal product code
    Other name
    CVL-231, ABBV-1231
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Emraclidine 10 mg, oral (tablet), once per day for 6 weeks

    Arm title
    		 Emraclidine 30 mg, Once Daily (QD)
    Arm description
    		 Participants received emraclidine 30 mg tablets orally once daily (QD) through Day 45 of Week 6.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Emraclidine 30 mg
    Investigational medicinal product code
    Other name
    CVL-231, ABBV-1231
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Emraclidine 30 mg, oral (tablet), once per day for 6 weeks

    Number of subjects in period 1
    		Placebo Emraclidine 10 mg, Once Daily (QD) Emraclidine 30 mg, Once Daily (QD)
    Started
    128
    128
    129
    Completed
    85
    89
    92
    Not completed
    43
    39
    37
         Physician decision
    6
    -
    4
         Adverse event, non-fatal
    5
    6
    10
         Other, not specified
    2
    2
    1
         Withdrawal of consent
    28
    27
    21
         Lack of efficacy
    2
    4
    1

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo tablets orally once daily (QD) through Day 45 of Week 6.

    Reporting group title
    Emraclidine 10 mg, Once Daily (QD)
    Reporting group description
    		 Participants received emraclidine 10 mg tablets orally once daily (QD) through Day 45 of Week 6.

    Reporting group title
    Emraclidine 30 mg, Once Daily (QD)
    Reporting group description
    		 Participants received emraclidine 30 mg tablets orally once daily (QD) through Day 45 of Week 6.

    Reporting group values
    		 Placebo Emraclidine 10 mg, Once Daily (QD) Emraclidine 30 mg, Once Daily (QD) Total
    Number of subjects
    		 128 128 129 385
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 42.9 ( 11.46 ) 40.6 ( 11.28 ) 42.5 ( 12.23 ) -
    Gender categorical
    Units: Subjects
        Female
    		 31 31 27 89
        Male
    		 97 97 102 296
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 21 20 9 50
        Not Hispanic or Latino
    		 107 105 118 330
        Unknown or Not Reported
    		 0 3 2 5
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 3 3
        Asian
    		 0 0 2 2
        Native Hawaiian or Other Pacific Islander
    		 0 0 1 1
        Black or African American
    		 89 88 87 264
        White
    		 37 39 33 109
        More than one race
    		 2 1 3 6
        Unknown or Not Reported
    		 0 0 0 0

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo tablets orally once daily (QD) through Day 45 of Week 6.

    Reporting group title
    Emraclidine 10 mg, Once Daily (QD)
    Reporting group description
    		 Participants received emraclidine 10 mg tablets orally once daily (QD) through Day 45 of Week 6.

    Reporting group title
    Emraclidine 30 mg, Once Daily (QD)
    Reporting group description
    		 Participants received emraclidine 30 mg tablets orally once daily (QD) through Day 45 of Week 6.

    Primary: Change From Baseline at Week 6 in the Positive and Negative Syndrome Scale (PANSS) Total Score

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    End point title
    		 Change From Baseline at Week 6 in the Positive and Negative Syndrome Scale (PANSS) Total Score
    End point description
    The PANSS measures symptom severity of participants with schizophrenia and contains 7 positive symptom scales, 7 negative system scales, and 16 general psychopathology symptom scales. Participants are rated from 1 to 7 on each symptom scale with a total minimum score of 30 and a maximum score of 210. A decrease in PANSS total score correlates with an improvement in schizophrenia symptoms. Analysis population: Modified Intent-to-Treat population (mITT): All randomized participants who received at least 1 dose of investigational medicinal product (IMP) and have both a Baseline and at least 1 post-Baseline PANSS assessment; participants with available data
    End point type
    Primary
    End point timeframe
    Baseline through Week 6
    End point values
    		 Placebo Emraclidine 10 mg, Once Daily (QD) Emraclidine 30 mg, Once Daily (QD)
    Number of subjects analysed
    87
    90
    93
    Units: units on a scale
        least squares mean (confidence interval 95%)
    -13.5 (-17.0 to -10.0)
    -14.7 (-18.1 to -11.2)
    -16.5 (-20.0 to -13.1)
    Statistical analysis title
    		 Emraclidine 30 mg versus Placebo
    Statistical analysis description
    Least-squares mean difference from Placebo and CIs were estimated using a mixed effects repeated measures model with fixed effects for treatment group, geographic region, visit, and treatment-by-visit interaction and Baseline value as a covariate. Participant was included as a random effect. An unstructured covariance structure was used.
    Comparison groups
    Placebo v Emraclidine 30 mg, Once Daily (QD)
    Number of subjects included in analysis
    180
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1765 [1]
    Method
    		 Mixed Model for Repeated Measures (MMRM)
    Parameter type
    		 LS Mean Difference
    Point estimate
    -3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.5
         upper limit
    		 1.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.24
    Notes
    [1] - Emraclidine 30 mg - Placebo
    Statistical analysis title
    		 Emraclidine 10 mg versus Placebo
    Statistical analysis description
    Least-squares mean difference from Placebo and CIs were estimated using a mixed effects repeated measures model with fixed effects for treatment group, geographic region, visit, and treatment-by-visit interaction and Baseline value as a covariate. Participant was included as a random effect. An unstructured covariance structure was used.
    Comparison groups
    Emraclidine 10 mg, Once Daily (QD) v Placebo
    Number of subjects included in analysis
    177
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6007 [2]
    Method
    		 Mixed Model for Repeated Measures (MMRM)
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.6
         upper limit
    		 3.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.26
    Notes
    [2] - Emraclidine 10 mg - Placebo

    Secondary: Change From Baseline at Week 6 in the Clinical Global Impression - Severity (CGI-S) Score

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    End point title
    		 Change From Baseline at Week 6 in the Clinical Global Impression - Severity (CGI-S) Score
    End point description
    The CGI-S captures clinician’s response to: "Considering your total clinical experience, how mentally ill is the participant at this time?" The clinician's answer was based on the following scale: 0 = not assessed; 1 = normal, not at all ill; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; 7 = among the most extremely ill participants. Negative changes from Baseline indicate less mental illness. Analysis population: Modified Intent-to-Treat population (mITT): All randomized participants who received at least 1 dose of investigational medicinal product (IMP) and have both a Baseline and at least 1 post-Baseline PANSS assessment; participants with available data
    End point type
    Secondary
    End point timeframe
    Baseline through Week 6
    End point values
    		 Placebo Emraclidine 10 mg, Once Daily (QD) Emraclidine 30 mg, Once Daily (QD)
    Number of subjects analysed
    87
    90
    93
    Units: units on a scale
        least squares mean (confidence interval 95%)
    -0.70 (-0.89 to -0.51)
    -0.75 (-0.94 to -0.56)
    -0.84 (-1.03 to -0.65)
    Statistical analysis title
    		 Emraclidine 30 mg versus Placebo
    Statistical analysis description
    Least-squares mean difference from Placebo and CIs were estimated using a mixed effects repeated measures model with fixed effects for treatment group, geographic region, visit, and treatment-by-visit interaction and Baseline value as a covariate. Participant was included as a random effect. An unstructured covariance structure was used.
    Comparison groups
    Placebo v Emraclidine 30 mg, Once Daily (QD)
    Number of subjects included in analysis
    180
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2534 [3]
    Method
    		 Mixed Model for Repeated Measures (MMRM)
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.39
         upper limit
    		 0.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.124
    Notes
    [3] - Emraclidine 30 mg - Placebo
    Statistical analysis title
    		 Emraclidine 10 mg versus Placebo
    Statistical analysis description
    Least-squares mean difference from Placebo and CIs were estimated using a mixed effects repeated measures model with fixed effects for treatment group, geographic region, visit, and treatment-by-visit interaction and Baseline value as a covariate. Participant was included as a random effect. An unstructured covariance structure was used.
    Comparison groups
    Placebo v Emraclidine 10 mg, Once Daily (QD)
    Number of subjects included in analysis
    177
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6774 [4]
    Method
    		 Mixed Model for Repeated Measures (MMRM)
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3
         upper limit
    		 0.19
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.125
    Notes
    [4] - Emraclidine 10 mg - Placebo

    Secondary: Change From Baseline at All Time Points in Positive and Negative Syndrome Scale (PANSS) Total Score

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    End point title
    		 Change From Baseline at All Time Points in Positive and Negative Syndrome Scale (PANSS) Total Score
    End point description
    The PANSS measures symptom severity of participants with schizophrenia and contains 7 positive symptom scales, 7 negative system scales, and 16 general psychopathology symptom scales. Participants are rated from 1 to 7 on each symptom scale with a total minimum score of 30 and a maximum score of 210. A decrease in PANSS total score correlates with an improvement in schizophrenia symptoms. Analysis population: Modified Intent-to-Treat population (mITT): All randomized participants who received at least 1 dose of investigational medicinal product (IMP) and have both a Baseline and at least 1 post-Baseline PANSS assessment; participants with available data
    End point type
    Secondary
    End point timeframe
    Baseline; Weeks 1, 2, 3, 4, 5, and 6
    End point values
    		 Placebo Emraclidine 10 mg, Once Daily (QD) Emraclidine 30 mg, Once Daily (QD)
    Number of subjects analysed
    127
    124
    127
    Units: units on a scale
    least squares mean (confidence interval 95%)
        Week 1 (n=127, 124, 127)
    -5.2 (-7.3 to -3.0)
    -5.7 (-7.8 to -3.6)
    -6.2 (-8.3 to -4.1)
        Week 2 (n=113, 114, 118)
    -8.7 (-11.3 to -6.1)
    -8.8 (-11.4 to -6.3)
    -9.0 (-11.6 to -6.5)
        Week 3 (n=108, 106, 110)
    -10.3 (-13.1 to -7.5)
    -10.0 (-12.8 to -7.2)
    -11.3 (-14.1 to -8.6)
        Week 4 (n=99, 102, 104)
    -12.1 (-15.3 to -9.0)
    -12.8 (-15.9 to -9.6)
    -13.3 (-16.4 to -10.2)
        Week 5 (n=93, 96, 97)
    -13.2 (-16.5 to -9.9)
    -14.0 (-17.3 to -10.7)
    -14.7 (-18.0 to -11.4)
        Week 6 (n=87, 90, 93)
    -13.5 (-17.0 to -10.0)
    -14.7 (-18.1 to -11.2)
    -16.5 (-20.0 to -13.1)
    Statistical analysis title
    		 Week 1-- Emraclidine 30 mg versus Placebo
    Statistical analysis description
    Least-squares mean difference from Placebo and CIs were estimated using a mixed effects repeated measures model with fixed effects for treatment group, geographic region, visit, and treatment-by-visit interaction and Baseline value as a covariate. Participant was included as a random effect. An unstructured covariance structure was used.
    Comparison groups
    Placebo v Emraclidine 30 mg, Once Daily (QD)
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3596 [5]
    Method
    		 Mixed Model for Repeated Measures (MMRM)
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.2
         upper limit
    		 1.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.1
    Notes
    [5] - Emraclidine 30 mg - Placebo
    Statistical analysis title
    		 Week 1-- Emraclidine 10 mg versus Placebo
    Statistical analysis description
    Least-squares mean difference from Placebo and CIs were estimated using a mixed effects repeated measures model with fixed effects for treatment group, geographic region, visit, and treatment-by-visit interaction and Baseline value as a covariate. Participant was included as a random effect. An unstructured covariance structure was used.
    Comparison groups
    Placebo v Emraclidine 10 mg, Once Daily (QD)
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6053 [6]
    Method
    		 Mixed Model for Repeated Measures (MMRM)
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.7
         upper limit
    		 1.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.1
    Notes
    [6] - Emraclidine 10 mg - Placebo
    Statistical analysis title
    		 Week 2-- Emraclidine 30 mg versus Placebo
    Statistical analysis description
    Least-squares mean difference from Placebo and CIs were estimated using a mixed effects repeated measures model with fixed effects for treatment group, geographic region, visit, and treatment-by-visit interaction and Baseline value as a covariate. Participant was included as a random effect. An unstructured covariance structure was used.
    Comparison groups
    Placebo v Emraclidine 30 mg, Once Daily (QD)
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8149 [7]
    Method
    		 Mixed Model for Repeated Measures (MMRM)
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.4
         upper limit
    		 2.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.54
    Notes
    [7] - Emraclidine 30 mg - Placebo
    Statistical analysis title
    		 Week 2-- Emraclidine 10 mg versus Placebo
    Statistical analysis description
    Least-squares mean difference from Placebo and CIs were estimated using a mixed effects repeated measures model with fixed effects for treatment group, geographic region, visit, and treatment-by-visit interaction and Baseline value as a covariate. Participant was included as a random effect. An unstructured covariance structure was used.
    Comparison groups
    Emraclidine 10 mg, Once Daily (QD) v Placebo
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9058 [8]
    Method
    		 Mixed Model for Repeated Measures (MMRM)
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.2
         upper limit
    		 2.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.55
    Notes
    [8] - Emraclidine 10 mg - Placebo
    Statistical analysis title
    		 Week 3-- Emraclidine 30 mg versus Placebo
    Statistical analysis description
    Least-squares mean difference from Placebo and CIs were estimated using a mixed effects repeated measures model with fixed effects for treatment group, geographic region, visit, and treatment-by-visit interaction and Baseline value as a covariate. Participant was included as a random effect. An unstructured covariance structure was used.
    Comparison groups
    Placebo v Emraclidine 30 mg, Once Daily (QD)
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5419 [9]
    Method
    		 Mixed Model for Repeated Measures (MMRM)
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.4
         upper limit
    		 2.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.71
    Notes
    [9] - Emraclidine 30 mg - Placebo
    Statistical analysis title
    		 Week 3-- Emraclidine 10 mg versus Placebo
    Statistical analysis description
    Least-squares mean difference from Placebo and CIs were estimated using a mixed effects repeated measures model with fixed effects for treatment group, geographic region, visit, and treatment-by-visit interaction and Baseline value as a covariate. Participant was included as a random effect. An unstructured covariance structure was used.
    Comparison groups
    Placebo v Emraclidine 10 mg, Once Daily (QD)
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8585 [10]
    Method
    		 Mixed Model for Repeated Measures (MMRM)
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.1
         upper limit
    		 3.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.72
    Notes
    [10] - Emraclidine 10 mg - Placebo
    Statistical analysis title
    		 Week 4-- Emraclidine 30 mg versus Placebo
    Statistical analysis description
    Least-squares mean difference from Placebo and CIs were estimated using a mixed effects repeated measures model with fixed effects for treatment group, geographic region, visit, and treatment-by-visit interaction and Baseline value as a covariate. Participant was included as a random effect. An unstructured covariance structure was used.
    Comparison groups
    Placebo v Emraclidine 30 mg, Once Daily (QD)
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5521 [11]
    Method
    		 Mixed Model for Repeated Measures (MMRM)
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.1
         upper limit
    		 2.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.99
    Notes
    [11] - Emraclidine 30 mg - Placebo
    Statistical analysis title
    		 Week 4-- Emraclidine 10 mg versus Placebo
    Statistical analysis description
    Least-squares mean difference from Placebo and CIs were estimated using a mixed effects repeated measures model with fixed effects for treatment group, geographic region, visit, and treatment-by-visit interaction and Baseline value as a covariate. Participant was included as a random effect. An unstructured covariance structure was used.
    Comparison groups
    Placebo v Emraclidine 10 mg, Once Daily (QD)
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.754 [12]
    Method
    		 Mixed Model for Repeated Measures (MMRM)
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.6
         upper limit
    		 3.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    2
    Notes
    [12] - Emraclidine 10 mg - Placebo
    Statistical analysis title
    		 Week 5-- Emraclidine 30 mg versus Placebo
    Statistical analysis description
    Least-squares mean difference from Placebo and CIs were estimated using a mixed effects repeated measures model with fixed effects for treatment group, geographic region, visit, and treatment-by-visit interaction and Baseline value as a covariate. Participant was included as a random effect. An unstructured covariance structure was used.
    Comparison groups
    Placebo v Emraclidine 30 mg, Once Daily (QD)
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4842 [13]
    Method
    		 Mixed Model for Repeated Measures (MMRM)
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.7
         upper limit
    		 2.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.12
    Notes
    [13] - Emraclidine 30 mg - Placebo
    Statistical analysis title
    		 Week 5-- Emraclidine 10 mg versus Placebo
    Statistical analysis description
    Least-squares mean difference from Placebo and CIs were estimated using a mixed effects repeated measures model with fixed effects for treatment group, geographic region, visit, and treatment-by-visit interaction and Baseline value as a covariate. Participant was included as a random effect. An unstructured covariance structure was used.
    Comparison groups
    Placebo v Emraclidine 10 mg, Once Daily (QD)
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6999 [14]
    Method
    		 Mixed Model for Repeated Measures (MMRM)
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5
         upper limit
    		 3.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.13
    Notes
    [14] - Emraclidine 10 mg - Placebo
    Statistical analysis title
    		 Week 6-- Emraclidine 30 mg versus Placebo
    Statistical analysis description
    Least-squares mean difference from Placebo and CIs were estimated using a mixed effects repeated measures model with fixed effects for treatment group, geographic region, visit, and treatment-by-visit interaction and Baseline value as a covariate. Participant was included as a random effect. An unstructured covariance structure was used.
    Comparison groups
    Placebo v Emraclidine 30 mg, Once Daily (QD)
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1765 [15]
    Method
    		 Mixed Model for Repeated Measures (MMRM)
    Parameter type
    		 LS Mean Difference
    Point estimate
    -3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.5
         upper limit
    		 1.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.24
    Notes
    [15] - Emraclidine 30 mg - Placebo
    Statistical analysis title
    		 Week 6-- Emraclidine 10 mg versus Placebo
    Statistical analysis description
    Least-squares mean difference from Placebo and CIs were estimated using a mixed effects repeated measures model with fixed effects for treatment group, geographic region, visit, and treatment-by-visit interaction and Baseline value as a covariate. Participant was included as a random effect. An unstructured covariance structure was used.
    Comparison groups
    Placebo v Emraclidine 10 mg, Once Daily (QD)
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6007 [16]
    Method
    		 Mixed Model for Repeated Measures (MMRM)
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.6
         upper limit
    		 3.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.26
    Notes
    [16] - Emraclidine 10 mg - Placebo

    Secondary: Change From Baseline at All Time Points in the Clinical Global Impression - Severity (CGI-S) Score

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    End point title
    		 Change From Baseline at All Time Points in the Clinical Global Impression - Severity (CGI-S) Score
    End point description
    The CGI-S captures clinician’s response to: "Considering your total clinical experience, how mentally ill is the participant at this time?" The clinician's answer was based on the following scale: 0 = not assessed; 1 = normal, not at all ill; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; 7 = among the most extremely ill participants. Negative changes from Baseline indicate less mental illness. Analysis population: Modified Intent-to-Treat population (mITT): All randomized participants who received at least 1 dose of investigational medicinal product (IMP) and have both a Baseline and at least 1 post-Baseline PANSS assessment; participants with available data
    End point type
    Secondary
    End point timeframe
    Baseline; Weeks 1, 2, 3, 4, 5, and 6
    End point values
    		 Placebo Emraclidine 10 mg, Once Daily (QD) Emraclidine 30 mg, Once Daily (QD)
    Number of subjects analysed
    127
    124
    127
    Units: units on a scale
    least squares mean (confidence interval 95%)
        Week 1 (n=127, 124, 127)
    -0.18 (-0.29 to -0.06)
    -0.17 (-0.29 to -0.05)
    -0.21 (-0.32 to -0.09)
        Week 2 (n=114, 114, 118)
    -0.36 (-0.50 to -0.21)
    -0.39 (-0.54 to -0.25)
    -0.35 (-0.50 to -0.21)
        Week 3 (n=108, 107, 110)
    -0.48 (-0.64 to -0.32)
    -0.42 (-0.58 to -0.26)
    -0.52 (-0.67 to -0.36)
        Week 4 (n=99, 102, 104)
    -0.54 (-0.71 to -0.36)
    -0.53 (-0.70 to -0.36)
    -0.70 (-0.87 to -0.53)
        Week 5 (n=92, 96, 97)
    -0.67 (-0.85 to -0.49)
    -0.64 (-0.82 to -0.46)
    -0.74 (-0.92 to -0.56)
        Week 6 (n=87, 90, 93)
    -0.70 (-0.89 to -0.51)
    -0.75 (-0.94 to -0.56)
    -0.84 (-1.03 to -0.65)
    Statistical analysis title
    		 Week 1-- Emraclidine 30 mg versus Placebo
    Statistical analysis description
    Least-squares mean difference from Placebo and CIs were estimated using a mixed effects repeated measures model with fixed effects for treatment group, geographic region, visit, and treatment-by-visit interaction and Baseline value as a covariate. Participant was included as a random effect. An unstructured covariance structure was used.
    Comparison groups
    Placebo v Emraclidine 30 mg, Once Daily (QD)
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5822 [17]
    Method
    		 Mixed Model for Repeated Measures (MMRM)
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.15
         upper limit
    		 0.09
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.061
    Notes
    [17] - Emraclidine 30 mg - Placebo
    Statistical analysis title
    		 Week 1-- Emraclidine 10 mg versus Placebo
    Statistical analysis description
    Least-squares mean difference from Placebo and CIs were estimated using a mixed effects repeated measures model with fixed effects for treatment group, geographic region, visit, and treatment-by-visit interaction and Baseline value as a covariate. Participant was included as a random effect. An unstructured covariance structure was used.
    Comparison groups
    Placebo v Emraclidine 10 mg, Once Daily (QD)
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9244 [18]
    Method
    		 Mixed Model for Repeated Measures (MMRM)
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.11
         upper limit
    		 0.13
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.061
    Notes
    [18] - Emraclidine 10 mg - Placebo
    Statistical analysis title
    		 Week 2-- Emraclidine 30 mg versus Placebo
    Statistical analysis description
    Least-squares mean difference from Placebo and CIs were estimated using a mixed effects repeated measures model with fixed effects for treatment group, geographic region, visit, and treatment-by-visit interaction and Baseline value as a covariate. Participant was included as a random effect. An unstructured covariance structure was used.
    Comparison groups
    Placebo v Emraclidine 30 mg, Once Daily (QD)
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9348 [19]
    Method
    		 Mixed Model for Repeated Measures (MMRM)
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.17
         upper limit
    		 0.18
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.088
    Notes
    [19] - Emraclidine 30 mg - Placebo
    Statistical analysis title
    		 Week 2-- Emraclidine 10 mg versus Placebo
    Statistical analysis description
    Least-squares mean difference from Placebo and CIs were estimated using a mixed effects repeated measures model with fixed effects for treatment group, geographic region, visit, and treatment-by-visit interaction and Baseline value as a covariate. Participant was included as a random effect. An unstructured covariance structure was used.
    Comparison groups
    Emraclidine 10 mg, Once Daily (QD) v Placebo
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.716 [20]
    Method
    		 Mixed Model for Repeated Measures (MMRM)
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.21
         upper limit
    		 0.14
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.089
    Notes
    [20] - Emraclidine 10 mg - Placebo
    Statistical analysis title
    		 Week 3-- Emraclidine 30 mg versus Placebo
    Statistical analysis description
    Least-squares mean difference from Placebo and CIs were estimated using a mixed effects repeated measures model with fixed effects for treatment group, geographic region, visit, and treatment-by-visit interaction and Baseline value as a covariate. Participant was included as a random effect. An unstructured covariance structure was used.
    Comparison groups
    Placebo v Emraclidine 30 mg, Once Daily (QD)
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6883 [21]
    Method
    		 Mixed Model for Repeated Measures (MMRM)
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.24
         upper limit
    		 0.16
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1
    Notes
    [21] - Emraclidine 30 mg - Placebo
    Statistical analysis title
    		 Week 3-- Emraclidine 10 mg versus Placebo
    Statistical analysis description
    Least-squares mean difference from Placebo and CIs were estimated using a mixed effects repeated measures model with fixed effects for treatment group, geographic region, visit, and treatment-by-visit interaction and Baseline value as a covariate. Participant was included as a random effect. An unstructured covariance structure was used.
    Comparison groups
    Placebo v Emraclidine 10 mg, Once Daily (QD)
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5973 [22]
    Method
    		 Mixed Model for Repeated Measures (MMRM)
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.14
         upper limit
    		 0.25
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1
    Notes
    [22] - Emraclidine 10 mg - Placebo
    Statistical analysis title
    		 Week 4-- Emraclidine 30 mg versus Placebo
    Statistical analysis description
    Least-squares mean difference from Placebo and CIs were estimated using a mixed effects repeated measures model with fixed effects for treatment group, geographic region, visit, and treatment-by-visit interaction and Baseline value as a covariate. Participant was included as a random effect. An unstructured covariance structure was used.
    Comparison groups
    Placebo v Emraclidine 30 mg, Once Daily (QD)
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1392 [23]
    Method
    		 Mixed Model for Repeated Measures (MMRM)
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.38
         upper limit
    		 0.05
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.11
    Notes
    [23] - Emraclidine 30 mg - Placebo
    Statistical analysis title
    		 Week 4-- Emraclidine 10 mg versus Placebo
    Statistical analysis description
    Least-squares mean difference from Placebo and CIs were estimated using a mixed effects repeated measures model with fixed effects for treatment group, geographic region, visit, and treatment-by-visit interaction and Baseline value as a covariate. Participant was included as a random effect. An unstructured covariance structure was used.
    Comparison groups
    Placebo v Emraclidine 10 mg, Once Daily (QD)
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9421 [24]
    Method
    		 Mixed Model for Repeated Measures (MMRM)
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.21
         upper limit
    		 0.23
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.111
    Notes
    [24] - Emraclidine 10 mg - Placebo
    Statistical analysis title
    		 Week 5-- Emraclidine 30 mg versus Placebo
    Statistical analysis description
    Least-squares mean difference from Placebo and CIs were estimated using a mixed effects repeated measures model with fixed effects for treatment group, geographic region, visit, and treatment-by-visit interaction and Baseline value as a covariate. Participant was included as a random effect. An unstructured covariance structure was used.
    Comparison groups
    Placebo v Emraclidine 30 mg, Once Daily (QD)
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5431 [25]
    Method
    		 Mixed Model for Repeated Measures (MMRM)
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3
         upper limit
    		 0.16
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.116
    Notes
    [25] - Emraclidine 30 mg - Placebo
    Statistical analysis title
    		 Week 5-- Emraclidine 10 mg versus Placebo
    Statistical analysis description
    Least-squares mean difference from Placebo and CIs were estimated using a mixed effects repeated measures model with fixed effects for treatment group, geographic region, visit, and treatment-by-visit interaction and Baseline value as a covariate. Participant was included as a random effect. An unstructured covariance structure was used.
    Comparison groups
    Placebo v Emraclidine 10 mg, Once Daily (QD)
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.816 [26]
    Method
    		 Mixed Model for Repeated Measures (MMRM)
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.2
         upper limit
    		 0.26
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.117
    Notes
    [26] - Emraclidine 10 mg - Placebo
    Statistical analysis title
    		 Week 6-- Emraclidine 30 mg versus Placebo
    Statistical analysis description
    Least-squares mean difference from Placebo and CIs were estimated using a mixed effects repeated measures model with fixed effects for treatment group, geographic region, visit, and treatment-by-visit interaction and Baseline value as a covariate. Participant was included as a random effect. An unstructured covariance structure was used.
    Comparison groups
    Placebo v Emraclidine 30 mg, Once Daily (QD)
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2534 [27]
    Method
    		 Mixed Model for Repeated Measures (MMRM)
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.39
         upper limit
    		 0.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.124
    Notes
    [27] - Emraclidine 30 mg - Placebo
    Statistical analysis title
    		 Week 6-- Emraclidine 10 mg versus Placebo
    Statistical analysis description
    Least-squares mean difference from Placebo and CIs were estimated using a mixed effects repeated measures model with fixed effects for treatment group, geographic region, visit, and treatment-by-visit interaction and Baseline value as a covariate. Participant was included as a random effect. An unstructured covariance structure was used.
    Comparison groups
    Placebo v Emraclidine 10 mg, Once Daily (QD)
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6774 [28]
    Method
    		 Mixed Model for Repeated Measures (MMRM)
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3
         upper limit
    		 0.19
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.125
    Notes
    [28] - Emraclidine 10 mg - Placebo

    Secondary: Percentage of Responders at Week 6 (Responders Defined as ≥30% Reduction From Baseline in Positive and Negative Syndrome Scale [PANSS] Total Score)

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    End point title
    		 Percentage of Responders at Week 6 (Responders Defined as ≥30% Reduction From Baseline in Positive and Negative Syndrome Scale [PANSS] Total Score)
    End point description
    The PANSS measures symptom severity of participants with schizophrenia and contains 7 positive symptom scales, 7 negative system scales, and 16 general psychopathology symptom scales. Participants are rated from 1 to 7 on each symptom scale with a total minimum score of 30 and a maximum score of 210. A decrease in PANSS total score correlates with an improvement in schizophrenia symptoms. A PANSS responder is defined as a participant with at least a 30% decrease in PANSS total score compared to Baseline at Week 6 visit or the early termination visit. If a participant discontinued and did not have an early termination visit, the participant’s last assessment was considered. Analysis population: Modified Intent-to-Treat population (mITT): All randomized participants who received at least 1 dose of investigational medicinal product (IMP) and have both a Baseline and at least 1 post-Baseline PANSS assessment; participants with available data
    End point type
    Secondary
    End point timeframe
    Baseline through Week 6
    End point values
    		 Placebo Emraclidine 10 mg, Once Daily (QD) Emraclidine 30 mg, Once Daily (QD)
    Number of subjects analysed
    127
    125
    127
    Units: percentage of participants
        number (not applicable)
    10.2
    17.6
    17.3
    Statistical analysis title
    		 Emraclidine 30 mg versus Placebo
    Statistical analysis description
    Odds ratio, 95% confidence interval, and p-value were from a logistic regression with treatment group, geographic region and Baseline value as a covariate.
    Comparison groups
    Placebo v Emraclidine 30 mg, Once Daily (QD)
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0904
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.9
         upper limit
    		 3.99
    Statistical analysis title
    		 Emraclidine 10 mg versus Placebo
    Statistical analysis description
    Odds ratio, 95% confidence interval, and p-value were from a logistic regression with treatment group, geographic region and Baseline value as a covariate.
    Comparison groups
    Placebo v Emraclidine 10 mg, Once Daily (QD)
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0756
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.93
         upper limit
    		 4.13

    Secondary: Number of Participants With Treatment Emergent Adverse Event (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)

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    End point title
    		 Number of Participants With Treatment Emergent Adverse Event (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)
    End point description
    An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product which does not necessarily have a causal relationship with this treatment. The investigator assesses the relationship of each event to the use of study drug. A serious adverse event (SAE) is an event that results in death, is life-threatening, requires or prolongs hospitalization, results in a congenital anomaly, persistent or significant disability/incapacity or is an important medical event that, based on medical judgment, may jeopardize the participant and may require medical or surgical intervention to prevent any of the outcomes listed above. Treatment-emergent adverse events/treatment-emergent serious adverse events (TEAEs/TESAEs) are defined as any event that began or worsened in severity on or after the first dose of study drug. Analysis population: Full analysis set: All randomized subjects who rcvd ≥ 1 dose of IMP
    End point type
    Secondary
    End point timeframe
    From first dose of study drug until 28 days following last dose of study drug (up to Week 10)
    End point values
    		 Placebo Emraclidine 10 mg, Once Daily (QD) Emraclidine 30 mg, Once Daily (QD)
    Number of subjects analysed
    128
    128
    129
    Units: participants
        Any TEAE
    73
    78
    82
        TESAE
    2
    4
    1
    No statistical analyses for this end point

    Secondary: Number of Participants With Clinically Significant Changes in Electrocardiogram (ECGs)

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    End point title
    		 Number of Participants With Clinically Significant Changes in Electrocardiogram (ECGs)
    End point description
    12-lead electrocardiogram (ECG) recordings were obtained after the participant had been supine and at rest for at least 3 minutes. Analysis population: Full analysis set: All randomized participants who received at least 1 dose of investigational medicinal product (IMP)
    End point type
    Secondary
    End point timeframe
    Baseline; from first dose of study drug up to Week 6
    End point values
    		 Placebo Emraclidine 10 mg, Once Daily (QD) Emraclidine 30 mg, Once Daily (QD)
    Number of subjects analysed
    128
    128
    129
    Units: participants
        QTcF value > 450 - 480 msec
    5
    3
    1
        QTcF value > 480 - 500 msec
    0
    0
    0
        QTcF value > 500 msec
    0
    0
    0
        QTcF increase from Baseline > 30 - 60 msec
    13
    8
    8
        QTcF increase from Baseline > 60 msec
    1
    1
    0
    No statistical analyses for this end point

    Secondary: Number of Participants with Clinically Significant Changes in Clinical Laboratory Assessments

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    End point title
    		 Number of Participants with Clinically Significant Changes in Clinical Laboratory Assessments
    End point description
    Clinical laboratory tests were performed at scheduled study visits, and the investigator recorded any clinically significant changes. Analysis population: Full analysis set: All randomized participants who received at least 1 dose of investigational medicinal product (IMP)
    End point type
    Secondary
    End point timeframe
    Baseline; from first dose of study drug up to Week 6
    End point values
    		 Placebo Emraclidine 10 mg, Once Daily (QD) Emraclidine 30 mg, Once Daily (QD)
    Number of subjects analysed
    128
    128
    129
    Units: participants
    3
    4
    4
    No statistical analyses for this end point

    Secondary: Number of Participants With Clinically Significant Changes in Vital Sign Measurements

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    End point title
    		 Number of Participants With Clinically Significant Changes in Vital Sign Measurements
    End point description
    Vital signs were obtained after the participant had been supine and at rest for 3 minutes and included temperature, systolic and diastolic blood pressure, respiratory rate, and heart rate. Participants’ body weights were also measured and recorded. Analysis population: Full analysis set: All randomized participants who received at least 1 dose of investigational medicinal product (IMP)
    End point type
    Secondary
    End point timeframe
    Baseline; from first dose of study drug up to Week 6
    End point values
    		 Placebo Emraclidine 10 mg, Once Daily (QD) Emraclidine 30 mg, Once Daily (QD)
    Number of subjects analysed
    128
    128
    129
    Units: participants
        Supine Systolic Blood Pressure < 90 mmHg
    0
    0
    0
        Supine Systolic BP > 140 mmHg and ≤ 160 mmHg
    15
    9
    11
        Supine Systolic BP > 160 mmHg and ≤ 200 mmHg
    0
    0
    1
        Supine Systolic Blood Pressure > 200 mmHg
    0
    0
    0
        Orthostatic Change in Systolic BP ≥ 20 mmHg down
    4
    2
    5
        Supine Diastolic Blood Pressure < 50 mmHg
    0
    0
    0
        Supine Diastolic BP > 90 mmHg and ≤ 100 mmHg
    10
    9
    19
        Supine Diastolic BP > 100 mmHg and ≤ 120 mmHg
    0
    0
    3
        Supine Diastolic Blood Pressure > 120 mmHg
    0
    0
    0
        Orthostatic Change in Diastolic BP ≥ 10 mmHg down
    9
    7
    14
        Supine Heart Rate < 50 bpm
    1
    0
    0
        Supine Heart Rate ≥ 50 bpm and < 60 bpm
    17
    6
    6
        Supine Heart Rate > 100 bpm and ≤ 120 bpm
    8
    18
    24
        Supine Heart Rate > 120 bpm
    0
    0
    3
        Temperature < 36 °C
    1
    3
    5
        Temperature > 38 °C
    1
    0
    0
        Respiratory Rate < 12 breaths/min
    0
    0
    0
        Respiratory Rate > 20 breaths/min
    3
    5
    6
        Body Weight ≥ 7% decrease
    1
    1
    1
        Body Weight ≥ 7% increase
    16
    24
    14
    No statistical analyses for this end point

    Secondary: Number of Participants With Clinically Significant Changes in Physical and Neurological Examination Results

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    End point title
    		 Number of Participants With Clinically Significant Changes in Physical and Neurological Examination Results
    End point description
    The number of participants with clinically significant changes in physical and neurological examination results was documented. Analysis population: Full analysis set: All randomized participants who received at least 1 dose of investigational medicinal product (IMP)
    End point type
    Secondary
    End point timeframe
    Baseline; from first dose of study drug up to Week 6
    End point values
    		 Placebo Emraclidine 10 mg, Once Daily (QD) Emraclidine 30 mg, Once Daily (QD)
    Number of subjects analysed
    128
    128
    129
    Units: participants
        Clinically Significant Changes: Physical Exam
    1
    1
    3
        Clinically Significant Changes: Neurological Exam
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With Suicide-Related Treatment-Emergent Events assessed using the Columbia Suicide-Severity Rating Scale (C-SSRS)

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    End point title
    		 Number of Participants With Suicide-Related Treatment-Emergent Events assessed using the Columbia Suicide-Severity Rating Scale (C-SSRS)
    End point description
    The C-SSRS rates an individual's degree of suicidal ideation (SI) on a scale, ranging from "wish to be dead" to "active suicidal ideation with specific plan and intent." The scale identifies SI severity and intensity, which may be indicative of an individual's intent to commit suicide. C-SSRS SI severity subscale ranges from 0 (no SI) to 5 (active SI with plan and intent). Analysis population: Full analysis set: All randomized participants who received at least 1 dose of investigational medicinal product (IMP)
    End point type
    Secondary
    End point timeframe
    Baseline; from first dose of study drug up to Week 6
    End point values
    		 Placebo Emraclidine 10 mg, Once Daily (QD) Emraclidine 30 mg, Once Daily (QD)
    Number of subjects analysed
    128
    128
    129
    Units: participants
        Tx-Emergent Suicidal Ideation (Recently)
    1
    2
    7
        Tx-Emergent Serious Suicidal Ideation (Recently)
    0
    0
    0
        Emergence of Serious Suicidal Ideation (Recently)
    0
    0
    0
        Emergence of Suicidal Behavior (Present vs Past)
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Change from Baseline in Simpson Angus Scale (SAS) Total Score

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    End point title
    		 Change from Baseline in Simpson Angus Scale (SAS) Total Score
    End point description
    The SAS consists of a list of 10 symptoms of Parkinsonism. Each item is rated on a 5-point scale, with a score of 0 representing absence of symptoms and a score of 4 representing a severe condition. The SAS total score is the sum of the scores for all 10 items. Negative changes from Baseline indicate an improvement in symptoms. Analysis population: Full analysis set: All randomized participants who received at least 1 dose of investigational medicinal product (IMP); participants with available data
    End point type
    Secondary
    End point timeframe
    Baseline; Weeks 3 and 6
    End point values
    		 Placebo Emraclidine 10 mg, Once Daily (QD) Emraclidine 30 mg, Once Daily (QD)
    Number of subjects analysed
    119
    119
    125
    Units: units on a scale
    least squares mean (confidence interval 95%)
        Week 3 (n=119, 119, 125)
    0.0 (-0.1 to 0.1)
    0.0 (0.0 to 0.1)
    0.1 (0.0 to 0.2)
        Week 6 (n=89, 90, 95)
    0.0 (-0.1 to 0.1)
    0.0 (-0.1 to 0.1)
    0.0 (-0.1 to 0.1)
    Statistical analysis title
    		 Week 3-- Emraclidine 30 mg versus Placebo
    Statistical analysis description
    Least-squares mean difference from Placebo and CIs were estimated using a mixed effects repeated measures model with fixed effects for treatment group, geographic region, visit, and treatment-by-visit interaction and Baseline value as a covariate. Participant was included as a random effect. An unstructured covariance structure was used.
    Comparison groups
    Placebo v Emraclidine 30 mg, Once Daily (QD)
    Number of subjects included in analysis
    244
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2418 [29]
    Method
    		 Mixed Model for Repeated Measures (MMRM)
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.05
    Notes
    [29] - Emraclidine 30 mg - Placebo
    Statistical analysis title
    		 Week 3-- Emraclidine 10 mg versus Placebo
    Statistical analysis description
    Least-squares mean difference from Placebo and CIs were estimated using a mixed effects repeated measures model with fixed effects for treatment group, geographic region, visit, and treatment-by-visit interaction and Baseline value as a covariate. Participant was included as a random effect. An unstructured covariance structure was used.
    Comparison groups
    Placebo v Emraclidine 10 mg, Once Daily (QD)
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.572 [30]
    Method
    		 Mixed Model for Repeated Measures (MMRM)
    Parameter type
    		 LS Mean Difference
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1
         upper limit
    		 0.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.05
    Notes
    [30] - Emraclidine 10 mg - Placebo
    Statistical analysis title
    		 Week 6-- Emraclidine 30 mg versus Placebo
    Statistical analysis description
    Least-squares mean difference from Placebo and CIs were estimated using a mixed effects repeated measures model with fixed effects for treatment group, geographic region, visit, and treatment-by-visit interaction and Baseline value as a covariate. Participant was included as a random effect. An unstructured covariance structure was used.
    Comparison groups
    Placebo v Emraclidine 30 mg, Once Daily (QD)
    Number of subjects included in analysis
    244
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7459 [31]
    Method
    		 Mixed Model for Repeated Measures (MMRM)
    Parameter type
    		 LS Mean Difference
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1
         upper limit
    		 0.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.06
    Notes
    [31] - Emraclidine 30 mg - Placebo
    Statistical analysis title
    		 Week 6-- Emraclidine 10 mg versus Placebo
    Statistical analysis description
    Least-squares mean difference from Placebo and CIs were estimated using a mixed effects repeated measures model with fixed effects for treatment group, geographic region, visit, and treatment-by-visit interaction and Baseline value as a covariate. Participant was included as a random effect. An unstructured covariance structure was used.
    Comparison groups
    Placebo v Emraclidine 10 mg, Once Daily (QD)
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6729 [32]
    Method
    		 Mixed Model for Repeated Measures (MMRM)
    Parameter type
    		 LS Mean Difference
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1
         upper limit
    		 0.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.06
    Notes
    [32] - Emraclidine 10 mg - Placebo

    Secondary: Change from Baseline in Abnormal Involuntary Movement Scale (AIMS) Movement Rating Score

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    End point title
    		 Change from Baseline in Abnormal Involuntary Movement Scale (AIMS) Movement Rating Score
    End point description
    The AIMS assessment consists of 10 items describing symptoms of dyskinesia. Each item is rated on a 5-point scale, with a score of 0 representing absence of symptoms (for item 10, no awareness), and a score of 4 indicating a severe condition (for item 10, awareness, severe distress). In addition, the AIMS includes 2 yes/no questions that address the subject's dental status. Negative changes from Baseline indicate an improvement in symptoms. Analysis population: Full analysis set: All randomized participants who received at least 1 dose of investigational medicinal product (IMP); participants with available data
    End point type
    Secondary
    End point timeframe
    Baseline; Weeks 3 and 6
    End point values
    		 Placebo Emraclidine 10 mg, Once Daily (QD) Emraclidine 30 mg, Once Daily (QD)
    Number of subjects analysed
    119
    119
    125
    Units: units on a scale
    least squares mean (confidence interval 95%)
        Week 3 (n=119, 119, 125)
    0.0 (-0.1 to 0.1)
    -0.1 (-0.2 to 0.0)
    0.1 (0.0 to 0.2)
        Week 6 (n=89, 90, 95)
    0.0 (-0.1 to 0.1)
    0.0 (-0.1 to 0.1)
    0.0 (-0.1 to 0.1)
    Statistical analysis title
    		 Week 3-- Emraclidine 30 mg versus Placebo
    Statistical analysis description
    Least-squares mean difference from Placebo and CIs were estimated using a mixed effects repeated measures model with fixed effects for treatment group, geographic region, visit, and treatment-by-visit interaction and Baseline value as a covariate. Participant was included as a random effect. An unstructured covariance structure was used.
    Comparison groups
    Placebo v Emraclidine 30 mg, Once Daily (QD)
    Number of subjects included in analysis
    244
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3783 [33]
    Method
    		 Mixed Model for Repeated Measures (MMRM)
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1
         upper limit
    		 0.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.06
    Notes
    [33] - Emraclidine 30 mg - Placebo
    Statistical analysis title
    		 Week 3-- Emraclidine 10 mg versus Placebo
    Statistical analysis description
    Least-squares mean difference from Placebo and CIs were estimated using a mixed effects repeated measures model with fixed effects for treatment group, geographic region, visit, and treatment-by-visit interaction and Baseline value as a covariate. Participant was included as a random effect. An unstructured covariance structure was used.
    Comparison groups
    Placebo v Emraclidine 10 mg, Once Daily (QD)
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2242 [34]
    Method
    		 Mixed Model for Repeated Measures (MMRM)
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.2
         upper limit
    		 0
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.06
    Notes
    [34] - Emraclidine 10 mg - Placebo
    Statistical analysis title
    		 Week 6-- Emraclidine 30 mg versus Placebo
    Statistical analysis description
    Least-squares mean difference from Placebo and CIs were estimated using a mixed effects repeated measures model with fixed effects for treatment group, geographic region, visit, and treatment-by-visit interaction and Baseline value as a covariate. Participant was included as a random effect. An unstructured covariance structure was used.
    Comparison groups
    Placebo v Emraclidine 30 mg, Once Daily (QD)
    Number of subjects included in analysis
    244
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8626 [35]
    Method
    		 Mixed Model for Repeated Measures (MMRM)
    Parameter type
    		 LS Mean Difference
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1
         upper limit
    		 0.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.05
    Notes
    [35] - Emraclidine 30 mg - Placebo
    Statistical analysis title
    		 Week 6-- Emraclidine 10 mg versus Placebo
    Statistical analysis description
    Least-squares mean difference from Placebo and CIs were estimated using a mixed effects repeated measures model with fixed effects for treatment group, geographic region, visit, and treatment-by-visit interaction and Baseline value as a covariate. Participant was included as a random effect. An unstructured covariance structure was used.
    Comparison groups
    Placebo v Emraclidine 10 mg, Once Daily (QD)
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6106 [36]
    Method
    		 Mixed Model for Repeated Measures (MMRM)
    Parameter type
    		 LS Mean Difference
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1
         upper limit
    		 0.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.05
    Notes
    [36] - Emraclidine 10 mg - Placebo

    Secondary: Change From Baseline in Barnes Akathisia Rating Scale (BARS) Global Clinical Evaluation Score

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    End point title
    		 Change From Baseline in Barnes Akathisia Rating Scale (BARS) Global Clinical Evaluation Score
    End point description
    The BARS consists of 4 items related to akathisia: The first 3 items are rated on a 4-point scale, with a score of 0 representing absence of symptoms and a score of 3 representing a severe condition. The global clinical evaluation is made on a 6-point scale, with a score of 0 representing absence of symptom and a score of 5 representing severe akathisia. Negative changes from Baseline indicate an improvement in symptoms. Analysis population: Full analysis set: All randomized participants who received at least 1 dose of investigational medicinal product (IMP); participants with available data
    End point type
    Secondary
    End point timeframe
    Baseline; Weeks 3 and 6
    End point values
    		 Placebo Emraclidine 10 mg, Once Daily (QD) Emraclidine 30 mg, Once Daily (QD)
    Number of subjects analysed
    119
    119
    125
    Units: units on a scale
    least squares mean (confidence interval 95%)
        Week 3 (n=119, 119, 125)
    0.0 (-0.1 to 0.0)
    0.0 (0.0 to 0.1)
    0.0 (0.0 to 0.1)
        Week 6 (n=89, 90, 95)
    0.0 (0.0 to 0.0)
    0.0 (-0.1 to 0.0)
    0.0 (0.0 to 0.0)
    Statistical analysis title
    		 Week 3-- Emraclidine 30 mg versus Placebo
    Statistical analysis description
    Least-squares mean difference from Placebo and CIs were estimated using a mixed effects repeated measures model with fixed effects for treatment group, geographic region, visit, and treatment-by-visit interaction and Baseline value as a covariate. Participant was included as a random effect. An unstructured covariance structure was used.
    Comparison groups
    Placebo v Emraclidine 30 mg, Once Daily (QD)
    Number of subjects included in analysis
    244
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4219 [37]
    Method
    		 Mixed Model for Repeated Measures (MMRM)
    Parameter type
    		 LS Mean Difference
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.03
    Notes
    [37] - Emraclidine 30 mg - Placebo
    Statistical analysis title
    		 Week 3-- Emraclidine 10 mg versus Placebo
    Statistical analysis description
    Least-squares mean difference from Placebo and CIs were estimated using a mixed effects repeated measures model with fixed effects for treatment group, geographic region, visit, and treatment-by-visit interaction and Baseline value as a covariate. Participant was included as a random effect. An unstructured covariance structure was used.
    Comparison groups
    Emraclidine 10 mg, Once Daily (QD) v Placebo
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3933 [38]
    Method
    		 Mixed Model for Repeated Measures (MMRM)
    Parameter type
    		 LS Mean Difference
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.03
    Notes
    [38] - Emraclidine 10 mg - Placebo
    Statistical analysis title
    		 Week 6-- Emraclidine 30 mg versus Placebo
    Statistical analysis description
    Least-squares mean difference from Placebo and CIs were estimated using a mixed effects repeated measures model with fixed effects for treatment group, geographic region, visit, and treatment-by-visit interaction and Baseline value as a covariate. Participant was included as a random effect. An unstructured covariance structure was used.
    Comparison groups
    Placebo v Emraclidine 30 mg, Once Daily (QD)
    Number of subjects included in analysis
    244
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7366 [39]
    Method
    		 Mixed Model for Repeated Measures (MMRM)
    Parameter type
    		 LS Mean Difference
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.02
    Notes
    [39] - Emraclidine 30 mg - Placebo
    Statistical analysis title
    		 Week 6-- Emraclidine 10 mg versus Placebo
    Statistical analysis description
    Least-squares mean difference from Placebo and CIs were estimated using a mixed effects repeated measures model with fixed effects for treatment group, geographic region, visit, and treatment-by-visit interaction and Baseline value as a covariate. Participant was included as a random effect. An unstructured covariance structure was used.
    Comparison groups
    Placebo v Emraclidine 10 mg, Once Daily (QD)
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4639 [40]
    Method
    		 Mixed Model for Repeated Measures (MMRM)
    Parameter type
    		 LS Mean Difference
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1
         upper limit
    		 0
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.02
    Notes
    [40] - Emraclidine 10 mg - Placebo

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All-cause mortality and adverse events reported from time informed consent was signed to end of the study. Median follow-up was 81.5 days for the Placebo group, 77 days for the Emraclidine 10 mg group, and 80 days for the Emraclidine 30 mg group.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo tablets orally once daily (QD) through Day 45 of Week 6.

    Reporting group title
    Emraclidine 30 mg, Once Daily (QD)
    Reporting group description
    		 Participants received emraclidine 30 mg tablets orally once daily (QD) through Day 45 of Week 6.

    Reporting group title
    Emraclidine 10 mg, Once Daily (QD)
    Reporting group description
    		 Participants received emraclidine 10 mg tablets orally once daily (QD) through Day 45 of Week 6.

    Serious adverse events
    		 Placebo Emraclidine 30 mg, Once Daily (QD) Emraclidine 10 mg, Once Daily (QD)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 128 (1.56%)
    1 / 129 (0.78%)
    4 / 128 (3.13%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Nervous system disorders
    DYSTONIA
         subjects affected / exposed
    0 / 128 (0.00%)
    0 / 129 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    AGGRESSION
         subjects affected / exposed
    0 / 128 (0.00%)
    1 / 129 (0.78%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    AGITATION
         subjects affected / exposed
    0 / 128 (0.00%)
    0 / 129 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SCHIZOPHRENIA
         subjects affected / exposed
    2 / 128 (1.56%)
    0 / 129 (0.00%)
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Placebo Emraclidine 30 mg, Once Daily (QD) Emraclidine 10 mg, Once Daily (QD)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    56 / 128 (43.75%)
    74 / 129 (57.36%)
    66 / 128 (51.56%)
    Investigations
    BLOOD PRESSURE INCREASED
         subjects affected / exposed
    0 / 128 (0.00%)
    4 / 129 (3.10%)
    0 / 128 (0.00%)
         occurrences all number
    0
    4
    0
    BLOOD CREATINE PHOSPHOKINASE INCREASED
         subjects affected / exposed
    3 / 128 (2.34%)
    3 / 129 (2.33%)
    4 / 128 (3.13%)
         occurrences all number
    3
    3
    4
    WEIGHT INCREASED
         subjects affected / exposed
    11 / 128 (8.59%)
    8 / 129 (6.20%)
    22 / 128 (17.19%)
         occurrences all number
    11
    8
    22
    Cardiac disorders
    SINUS TACHYCARDIA
         subjects affected / exposed
    1 / 128 (0.78%)
    6 / 129 (4.65%)
    2 / 128 (1.56%)
         occurrences all number
    1
    8
    2
    Nervous system disorders
    DIZZINESS
         subjects affected / exposed
    4 / 128 (3.13%)
    3 / 129 (2.33%)
    1 / 128 (0.78%)
         occurrences all number
    4
    4
    1
    HEADACHE
         subjects affected / exposed
    12 / 128 (9.38%)
    17 / 129 (13.18%)
    18 / 128 (14.06%)
         occurrences all number
    14
    18
    20
    SOMNOLENCE
         subjects affected / exposed
    6 / 128 (4.69%)
    9 / 129 (6.98%)
    9 / 128 (7.03%)
         occurrences all number
    6
    9
    11
    General disorders and administration site conditions
    FATIGUE
         subjects affected / exposed
    1 / 128 (0.78%)
    5 / 129 (3.88%)
    0 / 128 (0.00%)
         occurrences all number
    1
    5
    0
    Gastrointestinal disorders
    TOOTHACHE
         subjects affected / exposed
    3 / 128 (2.34%)
    3 / 129 (2.33%)
    1 / 128 (0.78%)
         occurrences all number
    3
    3
    1
    NAUSEA
         subjects affected / exposed
    2 / 128 (1.56%)
    6 / 129 (4.65%)
    3 / 128 (2.34%)
         occurrences all number
    2
    7
    4
    GASTROOESOPHAGEAL REFLUX DISEASE
         subjects affected / exposed
    2 / 128 (1.56%)
    4 / 129 (3.10%)
    3 / 128 (2.34%)
         occurrences all number
    2
    5
    3
    DYSPEPSIA
         subjects affected / exposed
    4 / 128 (3.13%)
    10 / 129 (7.75%)
    5 / 128 (3.91%)
         occurrences all number
    5
    10
    5
    DRY MOUTH
         subjects affected / exposed
    3 / 128 (2.34%)
    12 / 129 (9.30%)
    5 / 128 (3.91%)
         occurrences all number
    3
    12
    5
    CONSTIPATION
         subjects affected / exposed
    4 / 128 (3.13%)
    3 / 129 (2.33%)
    3 / 128 (2.34%)
         occurrences all number
    4
    3
    3
    ABDOMINAL PAIN
         subjects affected / exposed
    4 / 128 (3.13%)
    0 / 129 (0.00%)
    0 / 128 (0.00%)
         occurrences all number
    4
    0
    0
    Psychiatric disorders
    AGITATION
         subjects affected / exposed
    4 / 128 (3.13%)
    5 / 129 (3.88%)
    1 / 128 (0.78%)
         occurrences all number
    4
    8
    1
    ANXIETY
         subjects affected / exposed
    3 / 128 (2.34%)
    3 / 129 (2.33%)
    1 / 128 (0.78%)
         occurrences all number
    3
    3
    1
    INSOMNIA
         subjects affected / exposed
    5 / 128 (3.91%)
    3 / 129 (2.33%)
    6 / 128 (4.69%)
         occurrences all number
    5
    3
    7
    PSYCHOTIC DISORDER
         subjects affected / exposed
    4 / 128 (3.13%)
    2 / 129 (1.55%)
    3 / 128 (2.34%)
         occurrences all number
    4
    2
    3
    SCHIZOPHRENIA
         subjects affected / exposed
    2 / 128 (1.56%)
    4 / 129 (3.10%)
    1 / 128 (0.78%)
         occurrences all number
    2
    4
    1
    SUICIDAL IDEATION
         subjects affected / exposed
    1 / 128 (0.78%)
    4 / 129 (3.10%)
    1 / 128 (0.78%)
         occurrences all number
    1
    4
    1
    Musculoskeletal and connective tissue disorders
    PAIN IN EXTREMITY
         subjects affected / exposed
    0 / 128 (0.00%)
    1 / 129 (0.78%)
    4 / 128 (3.13%)
         occurrences all number
    0
    1
    5
    BACK PAIN
         subjects affected / exposed
    3 / 128 (2.34%)
    8 / 129 (6.20%)
    1 / 128 (0.78%)
         occurrences all number
    3
    8
    2
    ARTHRALGIA
         subjects affected / exposed
    1 / 128 (0.78%)
    5 / 129 (3.88%)
    3 / 128 (2.34%)
         occurrences all number
    1
    6
    3
    Infections and infestations
    TOOTH ABSCESS
         subjects affected / exposed
    1 / 128 (0.78%)
    3 / 129 (2.33%)
    0 / 128 (0.00%)
         occurrences all number
    1
    4
    0
    Metabolism and nutrition disorders
    INCREASED APPETITE
         subjects affected / exposed
    2 / 128 (1.56%)
    0 / 129 (0.00%)
    3 / 128 (2.34%)
         occurrences all number
    2
    0
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Feb 2022
    Version 2.0 - Updated drug name to newly approved official INN for CVL-231, emraclidine - Increased upper limit of age range from 55 to 65 years - Added information regarding stratification by geographic region - Added flexibility to contact medical monitor if participant unable to return to facility on the same day as a day pass was given - Provided additional text to describe that some positive urine drug screen results may not require participant discontinuation after discussion and approval of medical monitor - Provided additional details regarding MMRM model analyses for primary and secondary estimands - Provided additional details regarding sensitivity analyses for primary and secondary estimands - Revised testing procedures for SARS-CoV-2 to require negative test prior to admission and to adhere to site procedures - Updated to have triplicate rather than duplicate vital sign measurements with average of last 2 values used for assessment of eligibility - Modified wording of footnote bb regarding future biospecimen research sample to indicate only collected from participants who are enrolled in trial - Minor wording modifications for clarity in describing changes in vital sign and ECG measurements - Modified Inclusion Criterion #9 regarding contraception requirements for men - Added requirement for participants using antihypertensive medications to have been on stable dose for 3 months or more to Exclusion Criterion #7 and Table 4. Added restriction that participants cannot be receiving more than 2 medications to treat hypertension to Table 4 for consistency. - Increased the exclusionary heart rate value from 90 to 100 bpm in Exclusion Criterion #19 - Added in restriction for grapefruit- or Seville orange-containing foods and beverages while in trial - Added explanation and supporting references for the use of ALT (rather than ALT and AST) to detect and monitor liver injury
    15 Mar 2023
    Version 3.0 - In sentence referring to extending enrollment due to higher anticipated early terminations, removed language “due to COVID-19 or other reasons” - In description of statistical method, the strategies for addressing intercurrent events and missing values due to discontinuations were revised to provide further delineation of the intercurrent events of different nature - Modified language in footnotes y and z regarding PK sampling - Relaxed entry criterion (Exclusion Criterion #12) regarding COVID-19/SARS-CoV-2 testing - Removed exclusion of participants with positive result for hepatitis B core antibody at Screening and updated wording of “Note”in Exclusion Criterion #15 - Reduced washout period for depot or long-acting injectable antipsychotic agents from 2 full cycles to 1.5 cycles - Allowed enrollment of participants who were involved in a long-term follow-up period of an interventional trial with no treatment within 12 months of signing ICF upon approval of medical monitor - Added instruction and table describing CTCAE grading of blood pressure-related adverse events - Added in clarification that “additional tests”for SARS-CoV-2 can be done at investigator discretion - Modified language to specify that follow-up not required for longer than 12 weeks beyond estimated delivery date for female participants who become pregnant

    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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