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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 (15mg and 30 mg QD) of CVL-231 in Participants With Schizophrenia Experiencing an Acute Exacerbation of Psychosis

Summary
EudraCT number	2022-000581-17
Trial protocol	HU BG
Global end of trial date	11 Sep 2024

Results information
Results version number	v1(current)
This version publication date	23 Oct 2025
First version publication date	23 Oct 2025
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

CVL-231-2002

ISRCTN number

US NCT number

NCT05227703

WHO universal trial number (UTN)

Other trial identifiers

IND: 144,666

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

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

11 Sep 2024

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

11 Sep 2024

Was the trial ended prematurely?

Main objective of the trial

To evaluate the efficacy of 2 fixed oral doses (15 mg QD and 30 mg QD) of emraclidine in adult participants with schizophrenia 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

05 Jul 2022

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Bulgaria: 29

Country: Number of subjects enrolled

Hungary: 14

Country: Number of subjects enrolled

United States: 348

Worldwide total number of subjects

391

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

387

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Participants were randomly assigned at a ratio of 1:1:1 to one of three treatment groups (Emraclidine 15 mg QD, Emraclidine 30 mg QD, or Placebo). Randomization was stratified by geographic region (United States or all other countries). ITT population included all randomized participants and was used for the Demographic and Baseline Characteristics

Screening details

The mITT population was used for the efficacy evaluations and included all randomized participants who received at least one dose of study drug, had a baseline assessment, and had at least 1 postbaseline PANSS assessment. FAS included all randomized participants who receive at least one dose of study drug and was used for the safety analysis.

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

Are arms mutually exclusive

Yes

Placebo

Arm description

Participants received a single daily oral dose of Placebo each morning from Day 1 (baseline) through Day 45. Participants (completers and early withdrawals) were followed for safety up to approximately 28 days after the last dose.

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

Emraclidine 15 mg QD

Arm description

Participants received a single daily oral dose of Emraclidine 15 mg each morning from Day 1 (baseline) through Day 45. Participants (completers and early withdrawals) were followed for safety up to approximately 28 days after the last dose.

Arm type

Experimental

Investigational medicinal product name

Emraclidine 15 mg

Investigational medicinal product code

Other name

CVL-231, ABBV-1231

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Emraclidine 15 mg, oral (tablet), once per day for 6 weeks

Emraclidine 30 mg QD

Arm description

Participants received a single daily oral dose of Emraclidine 30 mg each morning from Day 1 (baseline) through Day 45. Participants (completers and early withdrawals) were followed for safety up to approximately 28 days after the last dose.

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 15 mg QD	Emraclidine 30 mg QD
Started	130	130	131
Completed	102	93	93
Not completed	28	37	38
Physician decision	2	2	1
Consent withdrawn by subject	17	26	32
Adverse event, non-fatal	2	6	4
Not Specified	1	1	-
Non- Compliance with Study Schedule	-	1	-
Lack of efficacy	4	-	1
Protocol deviation	2	1	-

Baseline characteristics

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Reporting group title

Placebo

Reporting group description

Reporting group title

Emraclidine 15 mg QD

Reporting group description

Reporting group title

Emraclidine 30 mg QD

Reporting group description

Reporting group values	Placebo	Emraclidine 15 mg QD	Emraclidine 30 mg QD	Total
Number of subjects	130	130	131	391
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	42.1 ( 12.18 )	42.7 ( 11.51 )	41.5 ( 10.76 )	-
Gender categorical
Units: Subjects
Female	27	34	25	86
Male	103	96	106	305
Ethnicity
Units: Subjects
Hispanic or Latino	30	25	25	80
Not Hispanic or Latino	100	105	106	311
Unknown or Not Reported	0	0	0	0
Race
Units: Subjects
American Indian or Alaska Native	0	0	1	1
Asian	1	1	0	2
Native Hawaiian or Other Pacific Islander	0	0	1	1
Black or African American	76	83	85	244
White	53	44	44	141
More than one race	0	2	0	2
Unknown or Not Reported	0	0	0	0

End points

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Reporting group title

Placebo

Reporting group description

Reporting group title

Emraclidine 15 mg QD

Reporting group description

Reporting group title

Emraclidine 30 mg QD

Reporting group description

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. Baseline was defined as the last value obtained prior to initiation of investigational medicinal product (IMP). Change from baseline for a given endpoint was defined as the value on a given Study Day (Time Point) minus the Baseline Value. 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 receive at least 1 dose of investigational medicinal product (IMP) and have both a baseline and at least 1 postbaseline PANSS assessment. Overall Number of Participants Analyzed includes participants with a non-missing value.

End point type

Primary

End point timeframe

Baseline through Week 6

End point values	Placebo	Emraclidine 15 mg QD	Emraclidine 30 mg QD
Number of subjects analysed	104	94	96
Units: score on a scale
least squares mean (confidence interval 95%)	-16.1 (-19.4 to -12.8)	-18.5 (-22.0 to -15.0)	-14.2 (-17.5 to -10.8)

Placebo v Emraclidine 15mg QD

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 15 mg QD v Placebo

Number of subjects included in analysis

198

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2925

Method

Mixed Model for Repeated Measures (MMRM)

Parameter type

LS Mean Difference

Point estimate

-2.4

Confidence interval

level

95%

sides

2-sided

lower limit

-7

upper limit

2.1

Variability estimate

Standard error of the mean

Dispersion value

2.3

Placebo v Emraclidine 30mg QD

Statistical analysis description

Comparison groups

Placebo v Emraclidine 30 mg QD

Number of subjects included in analysis

200

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3914

Method

Mixed Model for Repeated Measures (MMRM)

Parameter type

LS Mean Difference

Point estimate

1.9

Confidence interval

level

95%

sides

2-sided

lower limit

-2.5

upper limit

6.4

Variability estimate

Standard error of the mean

Dispersion value

2.27

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 rated on the following 7-point scale: 1 = normal, not at all ill; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; 7 = among the most extremely ill participants. Baseline was defined as the last value obtained prior to initiation of investigational medicinal product (IMP). Change from baseline for a given endpoint was defined as the value on a given Study Day (Time Point) minus the Baseline Value. Negative changes from Baseline indicate less mental illness. Analysis Population Description: mITT: All randomized participants who receive at least 1 dose of investigational medicinal product (IMP) and have both a baseline and at least 1 postbaseline PANSS assessment. Overall Number of Participants Analyzed includes participants with available data.

End point type

Secondary

End point timeframe

Baseline through Week 6

End point values	Placebo	Emraclidine 15 mg QD	Emraclidine 30 mg QD
Number of subjects analysed	104	94	96
Units: score on a scale
least squares mean (confidence interval 95%)	-0.83 (-1.03 to -0.64)	-1.05 (-1.25 to -0.84)	-0.80 (-1.00 to -0.60)

Placebo v Emraclidine 15 mg QD

Statistical analysis description

Comparison groups

Placebo v Emraclidine 15 mg QD

Number of subjects included in analysis

198

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1165

Method

Mixed Model for Repeated Measures (MMRM)

Parameter type

LS Mean Difference

Point estimate

-0.21

Confidence interval

level

95%

sides

2-sided

lower limit

-0.48

upper limit

0.05

Variability estimate

Standard error of the mean

Dispersion value

0.135

Placebo v Emraclidine 30 mg QD

Statistical analysis description

Comparison groups

Placebo v Emraclidine 30 mg QD

Number of subjects included in analysis

200

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8265

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

-0.23

upper limit

0.29

Variability estimate

Standard error of the mean

Dispersion value

0.134

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. Baseline was defined as the last value obtained prior to initiation of investigational medicinal product (IMP). Change from baseline for a given endpoint was defined as the value on a given Study Day (Time Point) minus the Baseline Value. A decrease in PANSS total score correlates with an improvement in schizophrenia symptoms. Analysis Population Description: mITT: All randomized participants who receive at least 1 dose of investigational medicinal product (IMP) and have both a baseline and at least 1 postbaseline PANSS assessment. Overall Number of Participants Analyzed includes 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 15 mg QD	Emraclidine 30 mg QD
Number of subjects analysed	128	122	123
Units: score on a scale
least squares mean (confidence interval 95%)
Week 1 (n=128, 121, 123)	-5.0 (-6.9 to -3.1)	-6.8 (-8.8 to -4.8)	-4.9 (-6.8 to -2.9)
Week 2 (n=122, 107, 118)	-8.5 (-10.9 to -6.1)	-8.7 (-11.2 to -6.3)	-7.5 (-9.9 to -5.1)
Week 3 (n=119, 101, 116)	-11.2 (-13.8 to -8.5)	-12.5 (-15.3 to -9.7)	-10.0 (-12.6 to -7.3)
Week 4 (n=114, 97, 101)	-12.8 (-15.5 to -10.1)	-13.4 (-16.3 to -10.5)	-12.0 (-14.8 to -9.2)
Week 5 (n=109, 95, 98)	-14.7 (-17.7 to -11.6)	-16.5 (-19.7 to -13.2)	-12.9 (-16.0 to -9.8)
Week 6 (n=104, 94, 96)	-16.1 (-19.4 to -12.8)	-18.5 (-22.0 to -15.0)	-14.2 (-17.5 to -10.8)

Week 1-- Emraclidine 15 mg versus Placebo

Statistical analysis description

Comparison groups

Placebo v Emraclidine 15 mg QD

Number of subjects included in analysis

250

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1167

Method

Mixed Model for Repeated Measures (MMRM)

Parameter type

LS Mean Difference

Point estimate

-1.8

Confidence interval

level

95%

sides

2-sided

lower limit

-4

upper limit

0.5

Variability estimate

Standard error of the mean

Dispersion value

1.14

Week 1-- Emraclidine 30 mg versus Placebo

Statistical analysis description

Comparison groups

Placebo v Emraclidine 30 mg QD

Number of subjects included in analysis

251

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9254

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

-2.1

upper limit

2.3

Variability estimate

Standard error of the mean

Dispersion value

1.14

Week 2-- Emraclidine 15 mg versus Placebo

Statistical analysis description

Comparison groups

Placebo v Emraclidine 15 mg QD

Number of subjects included in analysis

250

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8792

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

-3.3

upper limit

2.8

Variability estimate

Standard error of the mean

Dispersion value

1.55

Week 2-- Emraclidine 30 mg versus Placebo

Statistical analysis description

Comparison groups

Placebo v Emraclidine 30 mg QD

Number of subjects included in analysis

251

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5094

Method

Mixed Model for Repeated Measures (MMRM)

Parameter type

LS Mean Difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-2

upper limit

Variability estimate

Standard error of the mean

Dispersion value

1.52

Week 3-- Emraclidine 15 mg versus Placebo

Statistical analysis description

Comparison groups

Placebo v Emraclidine 15 mg QD

Number of subjects included in analysis

250

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4487

Method

Mixed Model for Repeated Measures (MMRM)

Parameter type

LS Mean Difference

Point estimate

-1.3

Confidence interval

level

95%

sides

2-sided

lower limit

-4.8

upper limit

2.1

Variability estimate

Standard error of the mean

Dispersion value

1.76

Week 3-- Emraclidine 30 mg versus Placebo

Statistical analysis description

Comparison groups

Placebo v Emraclidine 30 mg QD

Number of subjects included in analysis

251

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4852

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

-2.2

upper limit

4.6

Variability estimate

Standard error of the mean

Dispersion value

1.72

Week 4-- Emraclidine 15 mg versus Placebo

Statistical analysis description

Comparison groups

Placebo v Emraclidine 15 mg QD

Number of subjects included in analysis

250

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7593

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

-4.2

upper limit

3.1

Variability estimate

Standard error of the mean

Dispersion value

1.86

Week 4-- Emraclidine 30 mg versus Placebo

Statistical analysis description

Comparison groups

Placebo v Emraclidine 30 mg QD

Number of subjects included in analysis

251

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6792

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

-2.8

upper limit

4.3

Variability estimate

Standard error of the mean

Dispersion value

1.82

Week 5-- Emraclidine 15 mg versus Placebo

Statistical analysis description

Comparison groups

Placebo v Emraclidine 15 mg QD

Number of subjects included in analysis

250

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3983

Method

Mixed Model for Repeated Measures (MMRM)

Parameter type

LS Mean Difference

Point estimate

-1.8

Confidence interval

level

95%

sides

2-sided

lower limit

-5.9

upper limit

2.4

Variability estimate

Standard error of the mean

Dispersion value

2.1

Week 5-- Emraclidine 30 mg versus Placebo

Statistical analysis description

Comparison groups

Placebo v Emraclidine 30 mg QD

Number of subjects included in analysis

251

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3859

Method

Mixed Model for Repeated Measures (MMRM)

Parameter type

LS Mean Difference

Point estimate

1.8

Confidence interval

level

95%

sides

2-sided

lower limit

-2.3

upper limit

5.9

Variability estimate

Standard error of the mean

Dispersion value

2.07

Week 6-- Emraclidine 15 mg versus Placebo

Statistical analysis description

Comparison groups

Placebo v Emraclidine 15 mg QD

Number of subjects included in analysis

250

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2925

Method

Mixed Model for Repeated Measures (MMRM)

Parameter type

LS Mean Difference

Point estimate

-2.4

Confidence interval

level

95%

sides

2-sided

lower limit

-7

upper limit

2.1

Variability estimate

Standard error of the mean

Dispersion value

2.3

Week 6-- Emraclidine 30 mg versus Placebo

Statistical analysis description

Comparison groups

Placebo v Emraclidine 30 mg QD

Number of subjects included in analysis

251

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3914

Method

Mixed Model for Repeated Measures (MMRM)

Parameter type

LS Mean Difference

Point estimate

1.9

Confidence interval

level

95%

sides

2-sided

lower limit

-2.5

upper limit

6.4

Variability estimate

Standard error of the mean

Dispersion value

2.27

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

Top of page

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 rated on the following 7-point scale: 1 = normal, not at all ill; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; 7 = among the most extremely ill participants. Baseline was defined as the last value obtained prior to initiation of Emraclidine. Change from baseline for a given endpoint was defined as the value on a given Study Day (Time Point) minus the Baseline Value. Negative changes from Baseline indicate less mental illness. Analysis Population Description: mITT: All randomized participants who receive at least 1 dose of investigational medicinal product (IMP) and have both a baseline and at least 1 postbaseline PANSS assessment. Overall Number of Participants Analyzed includes 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 15 mg QD	Emraclidine 30 mg QD
Number of subjects analysed	128	122	123
Units: score on a scale
least squares mean (confidence interval 95%)
Week 1 (n=128, 121, 122)	-0.21 (-0.33 to -0.09)	-0.33 (-0.46 to -0.21)	-0.21 (-0.33 to -0.09)
Week 2 (n=122, 107, 118)	-0.42 (-0.56 to -0.28)	-0.42 (-0.56 to -0.27)	-0.38 (-0.52 to -0.24)
Week 3 (n=119, 101, 116)	-0.55 (-0.70 to -0.40)	-0.64 (-0.80 to -0.48)	-0.49 (-0.64 to -0.34)
Week 4 (n=114, 97, 101)	-0.72 (-0.88 to -0.55)	-0.74 (-0.91 to -0.57)	-0.62 (-0.79 to -0.46)
Week 5 (n=109, 95, 98)	-0.78 (-0.96 to -0.60)	-0.91 (-1.10 to -0.72)	-0.69 (-0.87 to -0.51)
Week 6 (n=104, 94, 96)	-0.83 (-1.03 to -0.64)	-1.05 (-1.25 to -0.084)	-0.80 (-1.00 to -0.60)

Week 1-- Emraclidine 15 mg versus Placebo

Statistical analysis description

Comparison groups

Placebo v Emraclidine 15 mg QD

Number of subjects included in analysis

250

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0865

Method

Mixed Model for Repeated Measures (MMRM)

Parameter type

LS Mean Difference

Point estimate

-0.12

Confidence interval

level

95%

sides

2-sided

lower limit

-0.27

upper limit

0.02

Variability estimate

Standard error of the mean

Dispersion value

0.073

Week 1-- Emraclidine 30 mg versus Placebo

Statistical analysis description

Comparison groups

Placebo v Emraclidine 30 mg QD

Number of subjects included in analysis

251

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9921

Method

Mixed Model for Repeated Measures (MMRM)

Parameter type

LS Mean Difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-0.14

upper limit

0.14

Variability estimate

Standard error of the mean

Dispersion value

0.072

Week 2-- Emraclidine 15 mg versus Placebo

Statistical analysis description

Comparison groups

Placebo v Emraclidine 15 mg QD

Number of subjects included in analysis

250

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.972

Method

Mixed Model for Repeated Measures (MMRM)

Parameter type

LS Mean Difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-0.18

upper limit

0.18

Variability estimate

Standard error of the mean

Dispersion value

0.091

Week 2-- Emraclidine 30 mg versus Placebo

Statistical analysis description

Comparison groups

Placebo v Emraclidine 30 mg QD

Number of subjects included in analysis

251

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6621

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

-0.14

upper limit

0.21

Variability estimate

Standard error of the mean

Dispersion value

0.089

Week 3-- Emraclidine 15 mg versus Placebo

Statistical analysis description

Comparison groups

Placebo v Emraclidine 15 mg QD

Number of subjects included in analysis

250

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3617

Method

Mixed Model for Repeated Measures (MMRM)

Parameter type

LS Mean Difference

Point estimate

-0.09

Confidence interval

level

95%

sides

2-sided

lower limit

-0.29

upper limit

0.11

Variability estimate

Standard error of the mean

Dispersion value

0.101

Week 3-- Emraclidine 30 mg versus Placebo

Statistical analysis description

Comparison groups

Placebo v Emraclidine 30 mg QD

Number of subjects included in analysis

251

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5456

Method

Mixed Model for Repeated Measures (MMRM)

Parameter type

LS Mean Difference

Point estimate

0.06

Confidence interval

level

95%

sides

2-sided

lower limit

-0.13

upper limit

0.25

Variability estimate

Standard error of the mean

Dispersion value

0.098

Week 4-- Emraclidine 30 mg versus Placebo

Statistical analysis description

Comparison groups

Placebo v Emraclidine 30 mg QD

Number of subjects included in analysis

251

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3922

Method

Mixed Model for Repeated Measures (MMRM)

Parameter type

LS Mean Difference

Point estimate

0.09

Confidence interval

level

95%

sides

2-sided

lower limit

-0.12

upper limit

0.3

Variability estimate

Standard error of the mean

Dispersion value

0.108

Week 5-- Emraclidine 15 mg versus Placebo

Statistical analysis description

Comparison groups

Placebo v Emraclidine 15 mg QD

Number of subjects included in analysis

250

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2915

Method

Mixed Model for Repeated Measures (MMRM)

Parameter type

LS Mean Difference

Point estimate

-0.13

Confidence interval

level

95%

sides

2-sided

lower limit

-0.37

upper limit

0.11

Variability estimate

Standard error of the mean

Dispersion value

0.122

Week 5-- Emraclidine 30 mg versus Placebo

Statistical analysis description

Comparison groups

Emraclidine 30 mg QD v Placebo

Number of subjects included in analysis

251

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4425

Method

Mixed Model for Repeated Measures (MMRM)

Parameter type

LS Mean Difference

Point estimate

0.09

Confidence interval

level

95%

sides

2-sided

lower limit

-0.14

upper limit

0.33

Variability estimate

Standard error of the mean

Dispersion value

0.12

Week 4-- Emraclidine 15 mg versus Placebo

Statistical analysis description

Comparison groups

Placebo v Emraclidine 15 mg QD

Number of subjects included in analysis

250

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8459

Method

Mixed Model for Repeated Measures

Parameter type

LS Mean Difference

Point estimate

-0.02

Confidence interval

level

95%

sides

2-sided

lower limit

-0.24

upper limit

0.19

Variability estimate

Standard error of the mean

Dispersion value

0.11

Week 6-- Emraclidine 30 mg versus Placebo

Statistical analysis description

Comparison groups

Placebo v Emraclidine 30 mg QD

Number of subjects included in analysis

251

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8265

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

-0.23

upper limit

0.29

Variability estimate

Standard error of the mean

Dispersion value

0.134

Week 4-- Emraclidine 15 mg versus Placebo

Statistical analysis description

Comparison groups

Placebo v Emraclidine 15 mg QD

Number of subjects included in analysis

250

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8459

Method

Mixed Model for Repeated Measures

Parameter type

LS Mean Difference

Point estimate

-0.02

Confidence interval

level

95%

sides

2-sided

lower limit

-0.24

upper limit

0.19

Variability estimate

Standard error of the mean

Dispersion value

0.11

Secondary: Percentage of Responders at Week 6 (Responders Defined as ≥30% Reduction From Baseline in PANSS Total Score)

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End point title

Percentage of Responders at Week 6 (Responders Defined as ≥30% Reduction From Baseline in 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 PANSS responder is defined as a participant with at least a 30% change in PANSS total score compared to baseline at Week 6 or the early termination visit. If a subject discontinued and did not have an early termination visit, the subject's last assessment was considered. Analysis Population Description: mITT: All randomized participants who receive at least 1 dose of Emraclidine and have both a baseline and at least 1 postbaseline PANSS assessment. Overall Number of Participants Analyzed includes participants with a non-missing value.

End point type

Secondary

End point timeframe

Baseline through Week 6

End point values	Placebo	Emraclidine 15 mg QD	Emraclidine 30 mg QD
Number of subjects analysed	128	122	123
Units: percentage of participants
number (not applicable)	19.5	23.8	12.2

Emraclidine 15 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 15 mg QD

Number of subjects included in analysis

250

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4597

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.26

Confidence interval

level

95%

sides

2-sided

lower limit

0.68

upper limit

2.33

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 QD

Number of subjects included in analysis

251

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1205

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.57

Confidence interval

level

95%

sides

2-sided

lower limit

0.28

upper limit

1.16

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. Full analysis set: All randomized participants who received at least 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 15 mg QD	Emraclidine 30 mg QD
Number of subjects analysed	130	130	131
Units: Count of Participants
Any TEAE	69	65	65
TESAE	1	3	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

Assessment of clinically significant changes in electrocardiogram measures measured by 12-lead ECG recording after the participant has been supine and at rest for at least 3 minutes. Analysis Population Description: 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 15 mg QD	Emraclidine 30 mg QD
Number of subjects analysed	130	130	131
Units: Count of Participants
QTcF value: > 450 - 480 msec	3	1	3
QTcF value: > 480 - 500 msec	1	0	0
QTcF value: > 500 msec	0	0	0
QTcF increase from baseline: > 30 - 60 msec	7	10	10
QTcF increase from baseline: > 60 msec	1	1	1

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 Description: 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 15 mg QD	Emraclidine 30 mg QD
Number of subjects analysed	130	130	131
Units: Count of Participants	3	4	3

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 Description: 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 15 mg QD	Emraclidine 30 mg QD
Number of subjects analysed	130	130	131
Units: Count of Participants
Supine Systolic Blood Pressure (SBP): < 90 mmHg	0	0	0
Supine SBP:> 140 mmHg and ≤ 160 mmHg	10	10	19
Supine SBP:160 mmHg and ≤ 200 mmHg	0	0	0
Supine SBP:> 200 mmHg	0	0	0
Orthostatic Change in SBP:≥ 20 mmHg decrease	4	1	2
Supine Diastolic Blood Pressure (DBP): < 50 mmHg	0	0	0
Supine DBP:> 90 mmHg and ≤ 100 mmHg	5	12	19
Supine DBP:> 100 mmHg and ≤ 120 mmHg	0	1	1
Supine DBP: > 120 mmHg	0	0	0
Orthostatic Change in DBP:≥ 10 mmHg decrease	3	12	5
Supine Heart Rate: < 50 bpm	0	2	0
Supine Heart Rate: ≥ 50 bpm and < 60 bpm	19	12	8
Supine Heart Rate: > 100 bpm and ≤ 120 bpm	5	20	16
Supine Heart Rate: > 120 bpm	0	0	1
Temperature: < 36 °C	2	5	4
Temperature: > 38 °C	2	0	0
Respiratory Rate: < 12 breaths/min	0	1	0
Respiratory Rate: > 20 breaths/min	3	1	3
Weight: ≥ 7% decrease	6	0	4
Weight: ≥ 7% increase	8	13	13

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 Description: 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 15 mg QD	Emraclidine 30 mg QD
Number of subjects analysed	130	130	131
Units: Count of Participants
Clinically Significant Changes: Physical Exam	1	1	0
Clinically Significant Changes: Neurological Exam	3	3	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 Description: 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 15 mg QD	Emraclidine 30 mg QD
Number of subjects analysed	130	130	131
Units: Count of Participants
Tx-Emergent Suicidal Ideation (Recently)	3	5	2
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. Baseline was defined as the last value obtained prior to initiation of study drug. Change from baseline for a given endpoint was defined as the value on a given Study Day (Time Point) minus the Baseline Value. Negative changes from Baseline indicate an improvement in symptoms. Analysis Population Description: 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 15 mg QD	Emraclidine 30 mg QD
Number of subjects analysed	130	130	131
Units: score on a scale
least squares mean (confidence interval 95%)
Week 3 (n=123, 107, 119)	-0.1 (-0.1 to 0.0)	0.0 (-0.1 to 0.1)	0.0 (0.0 to 0.1)
Week 6 (n=105, 92, 95)	0.0 (-0.1 to 0.1)	0.0 (0.0 to 0.1)	0.0 (-0.1 to 0.1)

Week 3-- Emraclidine 15 mg versus Placebo

Comparison groups

Placebo v Emraclidine 15 mg QD

Number of subjects included in analysis

260

Analysis specification

Pre-specified

Analysis type

superiority ^[1]

P-value

= 0.0493

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

upper limit

0.2

Variability estimate

Standard error of the mean

Dispersion value

0.04

Notes
[1] - 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.

Week 3-- Emraclidine 30 mg versus Placebo

Comparison groups

Placebo v Emraclidine 30 mg QD

Number of subjects included in analysis

261

Analysis specification

Pre-specified

Analysis type

superiority ^[2]

P-value

= 0.0226

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

upper limit

0.2

Variability estimate

Standard error of the mean

Dispersion value

0.04

Notes
[2] - 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.

Week 6-- Emraclidine 15 mg versus Placebo

Comparison groups

Placebo v Emraclidine 15 mg QD

Number of subjects included in analysis

260

Analysis specification

Pre-specified

Analysis type

superiority ^[3]

P-value

= 0.6845

Method

Mixed Model for Repeated Measures (MMRM)

Parameter type

LS Mean Difference

Point estimate

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
[3] - 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.

Week 6-- Emraclidine 30 mg versus Placebo

Comparison groups

Placebo v Emraclidine 30 mg QD

Number of subjects included in analysis

261

Analysis specification

Pre-specified

Analysis type

superiority ^[4]

P-value

= 0.895

Method

Mixed Model for Repeated Measures (MMRM)

Parameter type

LS Mean Difference

Point estimate

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
[4] - 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.

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 Description: 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 15 mg QD	Emraclidine 30 mg QD
Number of subjects analysed	130	130	131
Units: score on a scale
least squares mean (confidence interval 95%)
Week 3 (n=123, 107, 119)	0.0 (0.0 to 0.1)	0.0 (-0.1 to 0.1)	0.0 (-0.1 to 0.1)
Week 6 (n=105, 92, 95)	0.0 (0.0 to 0.1)	0.0 (-0.1 to 0.0)	0.0 (0.0 to 0.1)

Week 3-- Emraclidine 15 mg versus Placebo

Comparison groups

Placebo v Emraclidine 15 mg QD

Number of subjects included in analysis

260

Analysis specification

Pre-specified

Analysis type

superiority ^[5]

P-value

= 0.5073

Method

Mixed Model for Repeated Measures (MMRM)

Parameter type

LS Mean Difference

Point estimate

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
[5] - 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.

Week 3-- Emraclidine 30 mg versus Placebo

Comparison groups

Placebo v Emraclidine 30 mg QD

Number of subjects included in analysis

261

Analysis specification

Pre-specified

Analysis type

superiority ^[6]

P-value

= 0.465

Method

Mixed Model for Repeated Measures (MMRM)

Parameter type

LS Mean Difference

Point estimate

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
[6] - 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.

Week 6-- Emraclidine 15 mg versus Placebo

Comparison groups

Placebo v Emraclidine 15 mg QD

Number of subjects included in analysis

260

Analysis specification

Pre-specified

Analysis type

superiority ^[7]

P-value

= 0.0672

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

Variability estimate

Standard error of the mean

Dispersion value

0.03

Notes
[7] - 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.

Week 6-- Emraclidine 30 mg versus Placebo

Comparison groups

Placebo v Emraclidine 30 mg QD

Number of subjects included in analysis

261

Analysis specification

Pre-specified

Analysis type

superiority ^[8]

P-value

= 0.803

Method

Mixed Model for Repeated Measures (MMRM)

Parameter type

LS Mean Difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-0.1

upper limit

0.1

Variability estimate

Standard error of the mean

Dispersion value

0.03

Notes
[8] - 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.

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

Top of page

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 Description: 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 15 mg QD	Emraclidine 30 mg QD
Number of subjects analysed	130	130	131
Units: score on a scale
least squares mean (confidence interval 95%)
Week 3 (n=123, 107, 119)	0.0 (-0.1 to 0.0)	0.0 (-0.1 to 0.0)	0.0 (-0.1 to 0.0)
Week 6 (n=105, 92, 95)	-0.1 (-0.1 to 0.0)	0.0 (0.0 to 0.1)	0.0 (-0.1 to 0.0)

Week 3-- Emraclidine 15 mg versus Placebo

Comparison groups

Placebo v Emraclidine 15 mg QD

Number of subjects included in analysis

260

Analysis specification

Pre-specified

Analysis type

superiority ^[9]

P-value

= 0.8259

Method

Mixed Model for Repeated Measures (MMRM)

Parameter type

LS Mean Difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-0.1

upper limit

0.1

Variability estimate

Standard error of the mean

Dispersion value

0.03

Notes
[9] - 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.

Week 3-- Emraclidine 30 mg versus Placebo

Comparison groups

Placebo v Emraclidine 30 mg QD

Number of subjects included in analysis

261

Analysis specification

Pre-specified

Analysis type

superiority ^[10]

P-value

= 0.5936

Method

Mixed Model for Repeated Measures (MMRM)

Parameter type

LS Mean Difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-0.1

upper limit

Variability estimate

Standard error of the mean

Dispersion value

0.03

Notes
[10] - 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.

Week 6-- Emraclidine 15 mg versus Placebo

Comparison groups

Placebo v Emraclidine 15 mg QD

Number of subjects included in analysis

260

Analysis specification

Pre-specified

Analysis type

superiority ^[11]

P-value

= 0.0253

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

upper limit

0.1

Variability estimate

Standard error of the mean

Dispersion value

0.03

Notes
[11] - 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.

Week 6-- Emraclidine 30 mg versus Placebo

Comparison groups

Placebo v Emraclidine 30 mg QD

Number of subjects included in analysis

261

Analysis specification

Pre-specified

Analysis type

superiority ^[12]

P-value

= 0.271

Method

Mixed Model for Repeated Measures (MMRM)

Parameter type

LS Mean Difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

0.1

Variability estimate

Standard error of the mean

Dispersion value

0.03

Notes
[12] - 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.

Adverse events

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Timeframe for reporting adverse events

All-cause mortality and adverse event tables include events reported from the time informed consent was signed to the end of the study. The median time on follow-up was 80, 67.5, and 64.0 days for Placebo, Emraclidine 15 mg, and Emraclidine 30 mg groups.

Adverse event reporting additional description

respectively.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

27.0

Reporting group title

Placebo

Reporting group description

Reporting group title

Emraclidine_30_mg_QD

Reporting group description

Reporting group title

Emraclidine_15_mg_QD

Reporting group description

Serious adverse events	Placebo	Emraclidine_30_mg_QD	Emraclidine_15_mg_QD
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 130 (0.77%)	1 / 131 (0.76%)	3 / 130 (2.31%)
number of deaths (all causes)	0	0	0
number of deaths resulting from adverse events	0	0	0
Nervous system disorders
HEADACHE
subjects affected / exposed	0 / 130 (0.00%)	0 / 131 (0.00%)	1 / 130 (0.77%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
NEUROLEPTIC MALIGNANT SYNDROME
subjects affected / exposed	1 / 130 (0.77%)	0 / 131 (0.00%)	0 / 130 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Eye disorders
VISION BLURRED
subjects affected / exposed	0 / 130 (0.00%)	0 / 131 (0.00%)	1 / 130 (0.77%)
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
SCHIZOPHRENIA
subjects affected / exposed	0 / 130 (0.00%)	0 / 131 (0.00%)	1 / 130 (0.77%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
AGITATION
subjects affected / exposed	0 / 130 (0.00%)	1 / 131 (0.76%)	0 / 130 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PSYCHOTIC DISORDER
subjects affected / exposed	0 / 130 (0.00%)	0 / 131 (0.00%)	1 / 130 (0.77%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ACUTE PSYCHOSIS
subjects affected / exposed	0 / 130 (0.00%)	0 / 131 (0.00%)	1 / 130 (0.77%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
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_QD	Emraclidine_15_mg_QD
Total subjects affected by non serious adverse events
subjects affected / exposed	47 / 130 (36.15%)	50 / 131 (38.17%)	47 / 130 (36.15%)
Investigations
BLOOD PRESSURE INCREASED
subjects affected / exposed	0 / 130 (0.00%)	1 / 131 (0.76%)	3 / 130 (2.31%)
occurrences all number	0	1	3
WEIGHT INCREASED
subjects affected / exposed	5 / 130 (3.85%)	4 / 131 (3.05%)	11 / 130 (8.46%)
occurrences all number	5	4	11
Cardiac disorders
SINUS TACHYCARDIA
subjects affected / exposed	0 / 130 (0.00%)	0 / 131 (0.00%)	4 / 130 (3.08%)
occurrences all number	0	0	5
Nervous system disorders
DIZZINESS
subjects affected / exposed	0 / 130 (0.00%)	3 / 131 (2.29%)	2 / 130 (1.54%)
occurrences all number	0	3	3
SOMNOLENCE
subjects affected / exposed	6 / 130 (4.62%)	4 / 131 (3.05%)	4 / 130 (3.08%)
occurrences all number	6	4	4
HEADACHE
subjects affected / exposed	14 / 130 (10.77%)	17 / 131 (12.98%)	18 / 130 (13.85%)
occurrences all number	17	19	19
Gastrointestinal disorders
ABDOMINAL DISCOMFORT
subjects affected / exposed	3 / 130 (2.31%)	0 / 131 (0.00%)	4 / 130 (3.08%)
occurrences all number	4	0	4
TOOTHACHE
subjects affected / exposed	6 / 130 (4.62%)	2 / 131 (1.53%)	3 / 130 (2.31%)
occurrences all number	6	2	3
GASTROOESOPHAGEAL REFLUX DISEASE
subjects affected / exposed	0 / 130 (0.00%)	3 / 131 (2.29%)	1 / 130 (0.77%)
occurrences all number	0	3	1
NAUSEA
subjects affected / exposed	5 / 130 (3.85%)	4 / 131 (3.05%)	6 / 130 (4.62%)
occurrences all number	5	4	6
CONSTIPATION
subjects affected / exposed	2 / 130 (1.54%)	3 / 131 (2.29%)	6 / 130 (4.62%)
occurrences all number	2	3	6
DRY MOUTH
subjects affected / exposed	1 / 130 (0.77%)	7 / 131 (5.34%)	1 / 130 (0.77%)
occurrences all number	1	7	1
DYSPEPSIA
subjects affected / exposed	2 / 130 (1.54%)	3 / 131 (2.29%)	4 / 130 (3.08%)
occurrences all number	2	3	4
Psychiatric disorders
ANXIETY
subjects affected / exposed	4 / 130 (3.08%)	4 / 131 (3.05%)	4 / 130 (3.08%)
occurrences all number	4	4	4
INSOMNIA
subjects affected / exposed	4 / 130 (3.08%)	4 / 131 (3.05%)	2 / 130 (1.54%)
occurrences all number	4	4	2
SUICIDAL IDEATION
subjects affected / exposed	3 / 130 (2.31%)	3 / 131 (2.29%)	0 / 130 (0.00%)
occurrences all number	3	3	0
Musculoskeletal and connective tissue disorders
BACK PAIN
subjects affected / exposed	3 / 130 (2.31%)	3 / 131 (2.29%)	0 / 130 (0.00%)
occurrences all number	3	3	0
PAIN IN EXTREMITY
subjects affected / exposed	0 / 130 (0.00%)	1 / 131 (0.76%)	3 / 130 (2.31%)
occurrences all number	0	1	3
Infections and infestations
TINEA PEDIS
subjects affected / exposed	0 / 130 (0.00%)	3 / 131 (2.29%)	0 / 130 (0.00%)
occurrences all number	0	3	0
TOOTH ABSCESS
subjects affected / exposed	2 / 130 (1.54%)	3 / 131 (2.29%)	0 / 130 (0.00%)
occurrences all number	2	3	0

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Were there any global substantial amendments to the protocol? Yes

23 Feb 2022

Key changes in Protocol CVL-231-2002 Version 2.0 include: updating the drug name to its International Nonproprietary Name (emraclidine); adding a EudraCT number for EU compliance; updating sponsor and signatory information; expanding the upper age limit from 55 to 65 to broaden eligibility; clarifying participant stratification by region; allowing flexibility in medical monitor contact and urine drug screen procedures; and providing more detail on statistical analyses (MMRM and sensitivity analyses). Laboratory protocols were revised for SARS-CoV-2 testing and vital signs now require triplicate measurement in line with AHA standards. Dietary restrictions were clarified to prohibit grapefruit or Seville orange products. The document also refined criteria for inclusion/exclusion (e.g., contraception for men, language modernization of disability terms, stricter antihypertensive therapy requirements, and higher threshold for exclusionary heart rate). Prohibitions on medications prolonging QT interval were lifted due to emraclidine’s profile. Other changes address biospecimen collection, nonclinical paragraph removal, language improvements for clarity, alignment with regulatory guidance (CTFG, DSM-5), and enhanced sections on liver test assessment and sample collection. Overall, these amendments aim to improve protocol clarity, increase trial inclusiveness, meet regulatory requirements, and ensure participant safety.

15 Mar 2023

Key changes in Protocol CVL-231-2002 Version 3.0 include changes and updates focusing on clarifying trial procedures. The Signature Page was updated to reflect new sponsor signatories due to changes in internal responsibilities. In the Synopsis, references to extending enrollment because of COVID-19 impacts were removed, and statistical methods were revised for clearer handling of intercurrent events. The Schedule of Assessments saw clarifications in PK sampling footnotes to aid site procedures. Exclusion Criteria were adjusted, relaxing COVID-19 testing requirements to allow site-specific procedures. The exclusion of participants with a positive hepatitis B core antibody was removed, now focusing on active hepatitis B risk. Participants from previous trials without treatment for a year can now enroll, pending medical monitor approval. For Prohibited Therapy, the washout period for specific antipsychotic agents was reduced to align with other trials for acute schizophrenia. Adverse event instructions were enhanced with guidance for grading blood pressure-related events. Clinical Laboratory Tests now allow SARS-CoV-2 tests at the investigator's discretion. The follow-up period for pregnant participants was specified not to exceed 12 weeks post-estimated delivery, aligning with guidelines for pregnant partners of male participants. The Cytochrome P450 3A Inducers/Inhibitors table was updated to reflect current medication standards. Generally, minor grammatical and wording corrections were made for clarity. Overall, the amendment streamlines processes, incorporates updated guidance, and enhances the clarity of trial procedures.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: A Phase 2, Randomized, Double-blind, Placebo-controlled Trial to Evaluate the Efficacy, Safety, and Tolerability of Two Fixed Doses (15mg and 30 mg QD) of CVL-231 in Participants With Schizophrenia Experiencing an Acute Exacerbation of Psychosis

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

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

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

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

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

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

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

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

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

Secondary: Percentage of Responders at Week 6 (Responders Defined as ≥30% Reduction From Baseline in PANSS Total Score)

Secondary: Percentage of Responders at Week 6 (Responders Defined as ≥30% Reduction From Baseline in PANSS Total Score)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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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 (15mg and 30 mg QD) of CVL-231 in Participants With Schizophrenia Experiencing an Acute Exacerbation of Psychosis