A Phase 2, Randomized, Double-blind, Placebo-controlled Trial to Evaluate the Efficacy, Safety, and Tolerability of Two Fixed Doses (15 mg and 30 mg QD) of CVL-231 (Emraclidine) in Participants With Schizophrenia Experiencing an Acute Exacerbation of Psychosis
Phase: PHASE2
Conditions: Schizophrenia
Sponsor: AbbVie

 
Protocol CVL-231-2002
Emraclidine
 
 
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CLINICAL PROTOCOL 
 
Title: 
A Phase 2, Randomized, Double-blind, Placebo-controlled 
Trial to Evaluate the Efficacy, Safety, and Tolerability of 
Two Fixed Doses (15 mg and 30 mg QD) of CVL-231 in 
Participants With Schizophrenia Experiencing an Acute 
Exacerbation of Psychosis 
Trial Number: 
CVL-231-2002 
Trial Phase: 
2 
Compound: 
Emraclidine (CVL-231) 
Sponsor Name: 
Cerevel Therapeutics, LLC 
Legal Registered 
Address: 
222 Jacobs Street, Suite 200 
Cambridge, MA 02141 
US 
Health Authority 
Identifier Numbers 
IND 144,666 
EudraCT 2022-000581-17 
 
 
Short Title: A Placebo-controlled Trial of 15 and 30 mg QD Doses of CVL-231 in 
Participants With Schizophrenia Experiencing an Acute Exacerbation of Psychosis 
 
 
MEDICAL MONITOR NAME AND CONTACT INFORMATION IS PROVIDED IN 
THE TRIAL OPERATIONS MANUAL 
 
CONFIDENTIAL – PROPRIETARY INFORMATION 
Version 3.0: 15 Mar 2023 
Version 2.0: 23 Feb 2022 
Version 1.0: 07 Dec 2021 
NCT05227703

 
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PROTOCOL VERSION 3.0 SUMMARY OF CHANGES TABLE 
Document History 
Protocol Version 
Date 
3.0 
15 Mar 2023 
2.0 
23 Feb 2022 
1.0 
07 Dec 2021 
A summary of the protocol amendment issued prior to the present amendment is provided 
in Section 10.9. 
Amendment: Protocol Version 3.0 (15 Mar 2023) 
This amendment is considered to be nonsubstantial based on the criteria set forth in 
Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union because it neither significantly impacts the safety or physical/mental 
integrity of participants nor the scientific value of the trial. 
Overall Rationale for the Amendment: 
The overall rationale for the amendment is to clarify trial procedures.  
Section # and Namea 
Description of Change 
Brief Rationale 
Signature Page 
Updated sponsor signatories 
Change in internal 
responsibilities 
1.1 Synopsis 
In sentence referring to extending 
enrollment due to higher 
anticipated early terminations, 
removed language “due to 
COVID-19 or other reasons” 
Modification due to impacts 
from COVID-19 pandemic no 
longer necessary 
1.1 Synopsis 
9.3.2 Primary 
Endpoint/Estimand 
Analyses 
9.3.3 Second 
Endpoint/Estimand 
Analyses 
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. 
  
1.3 Schedule of 
Assessments  
Modified language in footnotes y 
and z regarding PK sampling  
Clarify site procedures  
5.2 Exclusion Criteria  
Relaxed entry criterion 
(Exclusion Criterion #12) 
regarding COVID-19/ 
SARS-CoV-2 testing  
Allows flexibility to follow 
COVID-19 procedures 
employed by each individual 
site  

 
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Section # and Namea 
Description of Change 
Brief Rationale 
5.2 Exclusion Criteria  
Removed exclusion of 
participants with positive result 
for hepatitis B core antibody at 
Screening and updated wording 
of “Note” in Exclusion Criterion 
#15 
Focus on risk due to active 
hepatitis B virus rather than 
any past exposure; wording 
updated per Cerevel standard  
5.2 Exclusion Criteria 
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 
Clarify exclusion regarding 
prior trial participation in 
Exclusion Criterion #29 
6.7.2 Prohibited Therapy  
Reduced washout period for 
depot or long-acting injectable 
antipsychotic agents from 2 full 
cycles to 1.5 cycles  
Matches washout period for 
other trials in participants 
with acute schizophrenia  
8.2.3 Vital Sign 
Measurements 
10.3.3 Recording and 
Follow-Up of AEs and/or 
SAEs/AESIs  
Added instruction and table 
describing CTCAE grading of 
blood pressure-related adverse 
events  
Provide additional guidance 
and clarification for grading 
of AEs of increased blood 
pressure  
10.2 Clinical Laboratory 
Tests  
Added in clarification that 
“additional tests” for 
SARS-CoV-2 can be done at 
investigator discretion  
Clarification of trial 
procedures  
10.4.2.2 Female 
Participants Who Become 
Pregnant  
Modified language to specify that 
follow-up not required for longer 
than 12 weeks beyond estimated 
delivery date  
Match duration required for 
follow-up period for pregnant 
partners of male participants  
10.7 Moderate to Strong 
Inducers and Inhibitors of 
Cytochrome P450 3A (not 
exhaustive) 
Updated table  
Reflect current medication 
use and updates made per 
Cerevel standards  
Overall 
Minor grammatical and wording 
corrections/clarifications made 
throughout protocol 
Correct errors or provide 
further clarification  
Abbreviations: AE=adverse event; AESI=adverse event of special interest; COVID-19=coronavirus 
disease-2019; CTCAE=Common Terminology Criteria for Adverse Events; FDA= Food and Drug 
Administration; PK=pharmacokinetic; SAE=serious adverse event; SARS-CoV-2=severe acute respiratory 
virus syndrome coronavirus-2. 
a. Numbering (eg, section numbers and numbered lists) refers to current version of the protocol.  
 

 
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TABLE OF CONTENTS 
CLINICAL PROTOCOL ..................................................................................................1 
SPONSOR SIGNATORIES ..............................................................................................2 
PROTOCOL VERSION 3.0 SUMMARY OF CHANGES TABLE .............................3 
TABLE OF CONTENTS ..................................................................................................5 
TABLE OF TABLES .........................................................................................................8 
TABLE OF FIGURES .......................................................................................................9 
1 
PROTOCOL SUMMARY .......................................................................................10 
1.1 
Synopsis .................................................................................................................10 
1.2 
Schema ..................................................................................................................17 
1.3 
Schedule of Assessments ......................................................................................17 
2 
INTRODUCTION ....................................................................................................23 
2.1 
Trial Rationale .....................................................................................................23 
2.2 
Background ..........................................................................................................23 
2.2.1 
Disease Overview ...........................................................................................23 
2.2.2 
Nonclinical Experience ..................................................................................24 
2.2.3 
Clinical Experience ........................................................................................25 
2.3 
Benefit/Risk Assessment ......................................................................................26 
3 
OBJECTIVES AND ENDPOINTS .........................................................................27 
4 
TRIAL DESIGN .......................................................................................................28 
4.1 
Overall Design ......................................................................................................28 
4.1.1 
Screening Period ............................................................................................28 
4.1.2 
Treatment Period ...........................................................................................28 
4.1.3 
Follow-up Period ............................................................................................29 
4.1.4 
Definition of Completed Participant ............................................................30 
4.2 
Scientific Rationale for Trial Design ..................................................................30 
4.3 
Justification for Dose ...........................................................................................31 
4.4 
End of Trial Definition ........................................................................................31 
5 
TRIAL POPULATION ............................................................................................31 
5.1 
Inclusion Criteria .................................................................................................31 
5.2 
Exclusion Criteria ................................................................................................33 
5.3 
Lifestyle Considerations ......................................................................................37 
5.3.1 
Meals and Dietary Restrictions.....................................................................37 
5.3.2 
Caffeine, Alcohol, and Tobacco ....................................................................37 
5.3.3 
Activity ............................................................................................................37 
5.4 
Screen Failures .....................................................................................................38 
6 
TRIAL INTERVENTION AND CONCOMITANT THERAPY .........................38 
6.1 
Trial Interventions Administered .......................................................................38 
6.2 
Preparation, Handling, Storage, and Accountability .......................................39 
6.3 
Measures to Minimize Bias: Randomization and Blinding..............................39 
6.3.1 
Participant Assignment to Treatment ..........................................................39 
6.3.2 
Blinding ...........................................................................................................40 
6.4 
Trial Intervention Compliance ...........................................................................40 
6.5 
Dose Modification ................................................................................................40 
6.6 
Intervention After the End of the Trial .............................................................40 

 
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6.7 
Prior and Concomitant Therapy ........................................................................41 
6.7.1 
Time Period for Recording Prior and Concomitant Therapy ...................41 
6.7.2 
Prohibited Therapy ........................................................................................41 
6.7.3 
Benzodiazepine Use During the Trial ..........................................................43 
6.7.4 
Non-benzodiazepine Sleep Aids ....................................................................44 
6.7.5 
Psychotherapy ................................................................................................44 
7 
DISCONTINUATION OF TRIAL INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL ..................................44 
7.1 
Discontinuation of Trial Intervention ................................................................44 
7.2 
Participant Discontinuation/Withdrawal From the Trial ................................44 
7.3 
Lost to Follow-up .................................................................................................45 
8 
TRIAL ASSESSMENTS AND PROCEDURES ....................................................45 
8.1 
Efficacy Assessments ...........................................................................................46 
8.1.1 
Positive and Negative Syndrome Scale ........................................................46 
8.1.2 
Clinical Global Impression-Severity of Symptoms Scale ...........................47 
8.1.3 
Clinical Global Impression-Improvement Scale .........................................47 
8.1.4 
Brief Assessment of Cognition in Schizophrenia – Symbol Coding 
Test ..................................................................................................................48 
8.2 
Safety Assessments ...............................................................................................48 
8.2.1 
Height and Weight .........................................................................................48 
8.2.2 
Physical and Neurological Examinations.....................................................48 
8.2.3 
Vital Sign Measurements ..............................................................................49 
8.2.4 
Electrocardiograms........................................................................................50 
8.2.5 
Clinical Safety Laboratory Assessments ......................................................50 
8.2.6 
Suicidal Ideation and Behavior Risk Monitoring .......................................51 
8.2.7 
Extrapyramidal Symptoms ...........................................................................51 
8.3 
Adverse Events, Serious Adverse Events, and Other Safety Reporting .........52 
8.3.1 
Time Period and Frequency for Collecting AE and SAE/AESI 
Information .....................................................................................................53 
8.3.2 
Method of Detecting AEs and SAEs/AESIs .................................................53 
8.3.3 
Follow-up of AEs and SAEs/AESIs ..............................................................53 
8.3.4 
Regulatory Reporting Requirements for SAEs/AESIs ...............................53 
8.3.5 
Pregnancy .......................................................................................................54 
8.3.6 
Treatment of Overdose ..................................................................................54 
8.3.7 
Adverse Events of Special Interest ...............................................................55 
8.4 
Pharmacokinetics .................................................................................................56 
8.5 
Biomarkers ...........................................................................................................57 
8.6 
Future Biospecimen Research ............................................................................57 
8.7 
Health Economics and Resource Utilization .....................................................57 
8.7.1 
Short Form – 6 Dimensions Version 2.0 ......................................................57 
9 
STATISTICAL CONSIDERATIONS ....................................................................58 
9.1 
Statistical Hypotheses ..........................................................................................58 
9.2 
Analysis Sets .........................................................................................................58 
9.3 
Statistical Analyses...............................................................................................59 
9.3.1 
General Considerations .................................................................................59 
9.3.2 
Primary Endpoint/Estimand Analyses ........................................................59 

 
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9.3.3 
Secondary Endpoint/Estimand Analyses .....................................................60 
9.3.4 
Other Endpoints .............................................................................................60 
9.3.5 
Safety Analyses ...............................................................................................61 
9.3.6 
Other Analyses ...............................................................................................61 
9.4 
Interim Analyses ..................................................................................................61 
9.5 
Sample Size Determination .................................................................................61 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ................................................................................................63 
10.1 
Regulatory, Ethical, and Trial Oversight Considerations ...............................63 
10.1.1 
Regulatory and Ethical Considerations .......................................................63 
10.1.2 
Financial Disclosure .......................................................................................63 
10.1.3 
Informed Consent Process ............................................................................64 
10.1.4 
Data Protection...............................................................................................64 
10.1.5 
Dissemination of Clinical Trial Data ............................................................64 
10.1.6 
Data Quality Assurance .................................................................................65 
10.1.7 
Source Documents ..........................................................................................66 
10.1.8 
Trial and Site Closure ....................................................................................66 
10.1.9 
Publication Policy...........................................................................................67 
10.2 
Clinical Laboratory Tests....................................................................................67 
10.3 
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ...............................................................69 
10.3.1 
Definition of AE..............................................................................................69 
10.3.2 
Definition of SAE ...........................................................................................70 
10.3.3 
Recording and Follow-Up of AEs and/or SAEs/AESIs ..............................71 
10.3.4 
Reporting of SAEs/AESIs..............................................................................74 
10.4 
Contraceptive Guidance and Collection of Pregnancy Information ...............75 
10.4.1 
Definitions .......................................................................................................75 
10.4.2 
Collection of Pregnancy Information ...........................................................76 
10.5 
Future Biospecimen Research ............................................................................78 
10.6 
Liver Safety: Suggested Actions and Follow-up Assessments .........................79 
10.6.1 
Assessment of Elevations in Liver Test Results ...........................................79 
10.6.2 
Criteria for Permanent Discontinuation of IMP (Potential Hy’s 
Law Cases) ......................................................................................................79 
10.6.3 
Criteria for Temporary Withholding or Permanent 
Discontinuation of IMP .................................................................................80 
10.6.4 
Evaluation of Alternative Causes of Liver Test Result 
Abnormalities .................................................................................................81 
10.7 
Moderate to Strong Inducers and Inhibitors of Cytochrome P450 3A 
(not exhaustive) ....................................................................................................83 
10.8 
Abbreviations .......................................................................................................85 
10.9 
Protocol Amendment History .............................................................................87 
11 REFERENCES .........................................................................................................91 
PRINCIPAL INVESTIGATOR SIGNATURE PAGE ................................................95 
 
 
 

 
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TABLE OF TABLES 
Table 1 
Schedule of Assessments ..........................................................................18 
Table 2 
Objectives and Endpoints........................................................................27 
Table 3 
Investigational Medicinal Product .........................................................39 
Table 4 
List of Medications Prohibited Before Randomization ........................42 
Table 5 
List of Medications Prohibited During the Treatment Period ............42 
Table 6 
Analysis Set Descriptions ........................................................................58 
Table 7 
Protocol-Required Safety Laboratory Tests .........................................68 
Table 8 
Definition of AE........................................................................................69 
Table 9 
Events Meeting the AE Definition ..........................................................69 
Table 10 
Definition of SAE .....................................................................................70 
Table 11 
Recording of AEs and/or SAEs/AESIs ...................................................71 
Table 12 
Assessment of Severity and Causality of AEs and/or SAEs/AESIs .....72 
Table 13 
Follow-Up of AEs and SAEs/AESIs .......................................................73 
Table 14 
SAE/AESI Reporting to the Sponsor or Designee via an Electronic 
Data Collection Tool ................................................................................74 
Table 15 
SAE/AESI Reporting to the Sponsor or Designee via Paper Form (if 
needed) ......................................................................................................74 
Table 16 
Monitoring of Liver Tests .......................................................................79 
Table 17 
Criteria for Temporarily Withholding IMP in Association With 
Abnormalities in Liver Test Results .......................................................80 
Table 18 
Alternative Causes of Abnormalities in Liver Test Results .................81 
Table 19 
Investigation of Alternative Etiologies for Elevated Liver Test Results
....................................................................................................................81 
 
 

 
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TABLE OF FIGURES 
Figure 1 
Trial Schematic ........................................................................................17 
 
 

 
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1 PROTOCOL SUMMARY 
1.1 
Synopsis 
Protocol Title:  
A Phase 2, Randomized, Double-blind, Placebo-controlled Trial to Evaluate the Efficacy, 
Safety, and Tolerability of Two Fixed Doses (15 mg and 30 mg QD) of CVL-231 in 
Participants With Schizophrenia Experiencing an Acute Exacerbation of Psychosis 
Short Title:  
A Placebo-controlled Trial of 15 and 30 mg QD Doses of CVL-231 in Participants With 
Schizophrenia Experiencing an Acute Exacerbation of Psychosis 
Rationale:  
Emraclidine (previously referred to as CVL-231) is a brain penetrant muscarinic 
acetylcholine receptor (mAChR) activator that selectively binds to the M4 muscarinic 
receptor subtype while sparing other muscarinic receptor subtypes (M1, M2, M3, and 
M5). Emraclidine is being developed for treatment of psychosis in schizophrenia. 
The aim of this trial is to investigate the efficacy, safety, and tolerability of 2 fixed doses 
of emraclidine (15 mg and 30 mg once daily [QD]) in participants with schizophrenia 
who are experiencing an acute exacerbation of psychosis.  

 
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Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
• 
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 
Primary Endpoint: 
• 
Change from Baseline at Week 6 in the 
PANSS total score 
Key Secondary Endpoint: 
• 
Change from Baseline at Week 6 in the 
CGI-S score 
Secondary Endpoints: 
• 
Change from Baseline at all time points in 
PANSS total score  
• 
Change from Baseline at all time points in 
CGI-S score 
• 
Percentage of responders at Week 6 
(responders defined as ≥30% reduction from 
Baseline in PANSS total score)  
Exploratory Endpoints: 
• 
CGI-I at Weeks 3 and 6 
• 
Change from Baseline at all time points in 
PANSS positive, negative, and general 
psychopathology subscale scores 
• 
Change from Baseline at all time points in 
PANSS Marder Factor scores 
Secondary 
• 
To evaluate the safety and tolerability 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 
• 
Treatment-emergent adverse events  
• 
Clinically significant changes in 
electrocardiograms, clinical laboratory 
assessments and metabolic parameters, 
standard vital sign measurements, and 
physical and neurological examination 
results, including body weight 
• 
Clinically significant findings in suicidality 
assessed using the C-SSRS 
• 
Extrapyramidal symptoms evaluated using 
the change from Baseline in SAS, AIMS, and 
BARS assessments 

 
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Objectives 
Endpoints 
Exploratory 
• 
To evaluate the plasma pharmacokinetics of 
emraclidine and its metabolite, CV-0000364, 
following 2 fixed oral doses (15 mg QD and 
30 mg QD) of emraclidine in adult participants 
with schizophrenia experiencing an acute 
exacerbation of psychosis 
• 
Pharmacokinetic parameters for emraclidine 
and its metabolite, CV-0000364 (Cmax and 
AUCtau) 
• 
To evaluate quality of life and cognition 
following 2 fixed oral doses (15 mg QD and 
30 mg QD) of emraclidine in adult participants 
with schizophrenia experiencing an acute 
exacerbation of psychosis 
• 
Change from Baseline at Week 6 in BACS 
symbol coding test 
• 
Change from Baseline at Week 6 in SF-6D 
Abbreviations: AIMS=Abnormal Involuntary Movement Scale; AUC=area under the concentration-time 
curve; BACS=Brief Assessment of Cognition in Schizophrenia; BARS=Barnes Akathisia Rating Scale; 
CGI-I=Clinical Global Impression-Improvement of Symptoms; CGI-S=Clinical Global Impression-
Severity of Symptoms; Cmax=maximum (peak) plasma concentration; C-SSRS=Columbia-Suicide Severity 
Rating Scale; PANSS=Positive and Negative Syndrome Scale; QD=once daily; SAS=Simpson Angus 
Scale; SF-6D=Short Form-6 Dimensions. 
Brief Summary (Lay Language): 
The purpose of this trial is to measure the efficacy, safety, and tolerability of 2 fixed 
doses of emraclidine (15 mg QD and 30 mg QD) compared with placebo in participants 
with schizophrenia who are experiencing an acute exacerbation of psychosis. Trial details 
include the following:  
• Trial duration: up to approximately 13 weeks 
• Treatment duration: up to 45 days 
• Visit frequency: all eligible participants will be admitted to the inpatient facility at the 
time they sign the informed consent form (ICF) and remain in the inpatient facility for 
the duration of treatment 
Overall Design: 
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 emraclidine (15 mg QD and 30 mg QD) in male and female participants aged 18 
to 65 years, inclusive, who have schizophrenia and are experiencing an acute 
exacerbation of psychosis.  
Participants will enter a Screening Period of 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. All participants 
will be admitted to the inpatient facility at the time they sign the ICF and remain in the 
inpatient facility for the duration of treatment.  

 
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On Day 1 (Baseline), participants will be randomized in a 1:1:1 ratio to the following 
treatment groups: 
• 
Emraclidine 15 mg QD 
• 
Emraclidine 30 mg QD 
• 
Placebo QD 
The randomization will be stratified by geographic region with 2 strata: United States or 
all other countries. 
The daily dosing schedule will start on Day 1 with all participants receiving a single daily 
dose of investigational medicinal product (IMP) in the morning.  
Participants are to remain in the inpatient facility for the entire duration of the trial (ie, 
from ICF signing through Week 6/early termination [ET]); however, beginning at the 
Week 3 time point, participants who are sufficiently stable (per investigator assessment) 
may receive day passes for urgent issues. While away from the site, participants must be 
supervised by hospital/research staff (medical monitor approval for supervision by a 
family member or caregiver may be obtained). Participants are not permitted to stay away 
from the inpatient facility overnight; if, in unforeseen circumstances, the participant is 
unable to return to the facility the same day, the medical monitor should be contacted to 
discuss continuing participant eligibility. In addition, the participant must agree to submit 
to testing (ie, urine drug screen and alcohol breathalyzer test) upon return to the site. If 
the breathalyzer test is positive, the medical monitor should be contacted to determine 
continued eligibility of the participant. Participants returning from a day pass who have a 
positive urine drug screen will be discontinued from the trial. Participants with a positive 
urine drug screen resulting from use of marijuana (any tetrahydrocannabinol 
[THC]-containing product), prescription, or over-the-counter medications or products 
that, in the investigator’s documented opinion, do not signal a clinical condition that 
would impact the safety of the participant or interpretation of the trial results may 
continue in the trial following consultation and approval by the medical monitor. 
All participants will continue dosing through Day 45 of Week 6. For the Week 6 time 
point, trial assessments will be completed on 2 separate days; on Day 42, the Positive and 
Negative Syndrome Scale (PANSS), Clinical Global Impression-Severity of Symptoms 
(CGI-S), and Clinical Global Impression-Improvement of Symptoms (CGI-I) will be 
completed, and on the last day of the treatment period, Day 45, the remaining scale and 
safety assessments will be completed. A minimum of 3 days is required between the 
completion of the Day 42 assessments and the Day 45 assessments, as noted in the 
Schedule of Assessments. Participants will receive their last dose of IMP on Day 45. 
Participants who complete all trial visits, through Week 6 (Day 45), may be offered entry 
into an optional open-label rollover trial when the trial is available for rollover 
participation. 

 
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Participants may be allowed to stay in the inpatient facility up to 1 week after their last 
dose of IMP if necessary to achieve stabilization on alternate therapy with review and 
approval by the medical monitor. 
All participants (completers and early withdrawals), with the exception of those entering 
the optional open-label rollover trial, will have a follow-up safety contact at 
approximately 28 days after the last dose of IMP.  
Number of Participants:  
Approximately 600 participants will be screened to achieve approximately 
372 participants qualified to be randomized to treatment in the trial (124 per treatment 
group). 
In the event of higher than anticipated early terminations, Cerevel may extend enrollment 
in order to achieve trial objectives. 
Key Entry Criteria:  
• Men and women 18 to 65 years of age, inclusive, with a primary diagnosis of 
schizophrenia per the Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition, as confirmed by the Mini International Neuropsychiatric Interview for 
Psychotic Disorders, and experiencing an acute exacerbation or relapse of psychotic 
symptoms, with onset less than 60 days prior to signing the informed consent form 
• PANSS total score between 85 and 120, inclusive, and CGI-S ≥4 (moderately to 
severely ill) at the time of signing the informed consent form and at Baseline 
Intervention Groups and Duration: 
Participants will receive treatment with 1) emraclidine 15 mg QD, 2) emraclidine 30 mg 
QD, or 3) placebo during the Treatment Period of the trial. 
The trial will include up to a 15-day Screening Period, a 45-day Inpatient Treatment 
Period, and a 28-day Follow-up Period. Each participant will participate in the trial for up 
to approximately 13 weeks. 
Statistical Considerations: 
Sample Size Estimation: 
A sample size of approximately 93 participants in each treatment group completing the 
Week 6 assessments (approximately 279 in total) should provide at least 90% power to 
detect an effect size of 0.48 in change from Baseline in PANSS total score at Week 6 
between either active treatment group versus placebo at the =0.05 level. The effect size 
of 0.48 represents a clinically meaningful effect on symptom reduction based on large 
scale meta-analysis of historical data from several currently approved antipsychotic 

 
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medications in common usage. It could be translated into a difference of 7 points versus 
placebo if the standard deviation of change from Baseline is 14.6 points or a difference of 
8 points versus placebo if the standard deviation of change from Baseline is 16.7 points. 
Both scenarios of the standard deviation are consistent with historical observations. To 
account for a discontinuation rate of approximately 25% for a 6-week treatment period 
(as observed in Trial CVL-231-SCH-001), it is planned to randomize approximately 
372 participants. 
Statistical Methods 
The primary estimand has the following attributes:  
1. Treatments as randomized 
2. Modified intent-to-treat (mITT) population as the primary population of interest  
3. Change from Baseline at Week 6 in total PANSS score as the primary endpoint of 
interest 
4. The population level summary of interest is the treatment differences estimated based 
on the least square mean and the corresponding 95% confidence interval from the 
mixed model for repeated measures (MMRM) model with treatment, visit, and 
treatment by visit interaction as fixed effect, participant as a random effect, and 
baseline PANSS score as a covariate. An unstructured covariance structure will be 
used for the repeated measures. The Kenward-Roger approximation will be used to 
estimate the denominator degrees of freedom. If the unstructured covariance matrix 
results in convergence issue, the heterogeneous Toeplitz covariance structure 
followed by the heterogeneous first-order autoregressive (AR(1)) structure will be 
used. If a reduced covariance matrix becomes necessary, the sandwich variance 
estimator will be used. 
5. To address intercurrent events (ICEs) with the primary outcome data available, a 
treatment policy strategy will be used to include all collected outcomes in the primary 
statistical analysis, consistent with the intent-to-treat principle. The only exception 
will be the cases of concomitant use of protocol prohibited other antipsychotic and, in 
such cases, the data collected under the influence of confounding ICEs will be treated 
as missing. 
6. To address ICE of trial or treatment discontinuation with no outcome data collected 
post discontinuation, the primary analysis of MMRM described above will be 
followed by pattern mixture model (PMM) approach with varying level of shift 
parameters for missing values due to discontinuations that are potentially missing not 
at random (MNAR), including discontinuation due to lack of efficacy or due to 
adverse events. This will be implemented using delta adjustment imputation method. 
Further details will be described in the statistical analysis plan (SAP). 

 
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The statistical hypothesis testing on the primary endpoint (emraclidine 30 mg QD vs 
placebo and emraclidine 15 mg QD vs placebo) will be based on the estimated treatment 
difference from the model at Week 6 and will be tested in a hierarchical order with each 
at 2-sided alpha level 0.05. The evaluation of other time points will also be derived from 
the same model.   
The number and proportion of responders (ie, participants with 30% reduction from 
Baseline in the PANSS total score at Week 6 or the last assessment before 
discontinuation) will be summarized. A logistic regression model, with baseline PANSS 
as a covariate, will be used to compare the proportion of responders in each active arm 
with placebo. If expected counts are <5, then a Fisher’s Exact test will be used. 
The secondary estimand has the following attributes:  
1. Treatments as randomized 
2. mITT population as the primary population of interest 
3. Change from Baseline to Week 6 in CGI-S score as the endpoint of interest 
4. The population level summary of interest is the treatment differences estimated based 
on the least square mean and the corresponding 95% confidence interval from the 
MMRM model with treatment, visit, and treatment by visit interaction as fixed effect, 
participant as a random effect, and baseline CGI-S score as a covariate. An 
unstructured covariance structure will be used for the repeated measures. If the 
unstructured covariance matrix results in convergence issue, the heterogeneous 
Toeplitz covariance structure followed by the heterogeneous first-order 
autoregressive (AR(1)) structure will be used. When a reduced covariance matrix is 
used, the sandwich variance estimator will be used. The Kenward-Roger 
approximation will be used to estimate the denominator degrees of freedom. 
5. ICEs will be addressed using the same strategies as described above for the primary 
endpoint. 
The number and proportion of participants with ≥1 and ≥2 point improvements from 
Baseline at the last CGI-S assessment (at Week 6 or the last assessment before 
discontinuation) will be summarized. A logistic regression model, with baseline CGI-S as 
a covariate, will be used to compare the proportion of responders in each active arm with 
placebo. If expected counts are <5, then a Fisher’s Exact test will be used. 
Treatment-emergent adverse events will be coded according to the Medical Dictionary 
for Regulatory Activities and summarized by treatment group, system organ class, and 
preferred term. Further summaries will be done by seriousness, severity, and relationship 
to IMP. 
Other safety endpoints will be summarized with descriptive statistics by treatment group, 
including, vital sign measurements, clinical laboratory assessments and metabolic 

 
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parameters, and physical and neurological examination results (including body weight), 
suicidality assessments using Columbia-Suicide Severity Rating Scale and 
extrapyramidal symptoms assessed by Abnormal Involuntary Movement Scale, Simpson 
Angus Scale, and Barnes Akathisia Rating Scale. 
1.2 
Schema 
Figure 1 
Trial Schematic 
 
Abbreviations: QD=once daily; R=randomization. 
Note: Assessment time points are planned for the last day of the indicated week (eg, Day 7, 14, 21, etc) 
with a ±2 day window (see Schedule of Assessments in Section 1.3). 
a. Participants will be admitted to the inpatient facility at the time they sign the ICF and remain in the 
inpatient facility for the duration of treatment. 
b. Extension of screening (up to a maximum of 21 days total) is allowed following discussion and 
documented approval by the medical monitor prior to the expiration of the Screening Period. 
1.3 
Schedule of Assessments 
 

 
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Table 1 
Schedule of Assessments 
Trial Periods/Phases 
Screening 
Perioda,b,c 
Treatment Period 
Follow-upd 
Week 
-2 to -1 
- 
- 
1 
2 
3e 
- 
4 
5 
6f 
ETg 
10 
Day 
-15 to -1 
1/ 
Baselineh 
4 
7±2 
14±2 
21±2 
24 
28±2 
35±2 
42±2 
45±2 
NA 
73±3 
Entrance and History 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
Xi 
 
 
 
 
 
 
 
 
 
 
 
Medical and psychiatric 
historyj 
------------------------→ 
 
 
 
 
 
 
 
 
 
 
 
MINI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demography  
X 
 
 
 
 
 
 
 
 
 
 
 
 
History of drug and 
alcohol use 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Review of birth control 
methods 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Breathalyzer test for 
alcoholk 
X 
 
 
 
 
 
 
 
 
 
 
 
 
SARS-CoV-2 testingc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Efficacy/Health Economics Assessmentsl 
PANSS 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
 
CGI-S 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
 
CGI-Im 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 

 
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Trial Periods/Phases 
Screening 
Perioda,b,c 
Treatment Period 
Follow-upd 
Week 
-2 to -1 
- 
- 
1 
2 
3e 
- 
4 
5 
6f 
ETg 
10 
Day 
-15 to -1 
1/ 
Baselineh 
4 
7±2 
14±2 
21±2 
24 
28±2 
35±2 
42±2 
45±2 
NA 
73±3 
BACS  
 
X 
 
 
 
 
 
 
 
 
X 
X 
 
SF-6D 
 
X 
 
 
 
 
 
 
 
 
X 
X 
 
Safety Assessments 
Physical/neurological 
examinationn 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
Limited physical 
examinationo 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Height (Screening only) 
and weight 
X 
X 
 
 
 
X 
 
 
 
 
X 
X 
 
ECGp 
X 
X 
 
X 
X 
X 
 
X 
X 
 
X 
X 
 
Heart rate and blood 
pressure (including 
orthostatic)q 
X 
X 
 
X 
X 
X 
 
X 
X 
 
X 
X 
 
Respiratory rate and 
temperature 
X 
X 
 
X 
X 
X 
 
X 
X 
 
X 
X 
 
C-SSRSr 
X 
X 
 
X 
X 
X 
 
X 
X 
 
X 
X 
 
EPS (SAS, AIMS, 
BARS)s 
X 
X 
 
 
 
X 
 
 
 
 
X 
X 
 
Prior/concomitant 
treatmentst 
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------→ 
Adverse event 
monitoringu 
 
---------------------------------------------------------------------------------------------------------------------------------------------------→ 

 
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Trial Periods/Phases 
Screening 
Perioda,b,c 
Treatment Period 
Follow-upd 
Week 
-2 to -1 
- 
- 
1 
2 
3e 
- 
4 
5 
6f 
ETg 
10 
Day 
-15 to -1 
1/ 
Baselineh 
4 
7±2 
14±2 
21±2 
24 
28±2 
35±2 
42±2 
45±2 
NA 
73±3 
Laboratory 
Blood for safety 
laboratory sample 
X 
X 
 
 
 
X 
 
 
 
 
X 
X 
 
Urine for safety 
laboratory 
X 
X 
 
 
 
X 
 
 
 
 
X 
X 
 
Prolactin levelv 
 
X 
 
 
 
 
 
 
 
 
X 
X 
 
Serum pregnancy testw 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy testw 
 
X 
 
 
 
 
 
 
 
 
X 
X 
 
Urine drug screenx 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B, C, HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
PK blood sample 
 
 
Xy 
 
 
 
Xz 
 
 
 
 
Xaa 
 
Blood sample for future 
biospecimen researchbb 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Other 
Daily morning dose of 
IMP 
 
---------------------------------------------------------------------------------------------------------------------------------→ 
 
Abbreviations: AIMS=Abnormal Involuntary Movement Scale; BACS= Brief Assessment of Cognition in Schizophrenia; BARS=Barnes Akathisia Rating Scale; 
CGI-I=Clinical Global Impression-Improvement of Symptoms; CGI-S=Clinical Global Impression-Severity of Symptoms; C-SSRS=Columbia-Suicide Severity 
Rating Scale; ECG=electrocardiogram; EPS=extrapyramidal symptoms; ET=early termination; HIV=human immunodeficiency virus; IMP=investigational 
medicinal product; MINI=Mini International Neuropsychiatric Interview; PANSS=Positive and Negative Syndrome Scale; PK=pharmacokinetic; SAS=Simpson-
Angus Scale; SF-6D=Short Form-6 Dimensions. 
a. 
Extension of screening (up to a maximum of 21 days total) is allowed following discussion and documented approval by the medical monitor prior to the 
expiration of the Screening Period.  
b. Participants will be admitted to the inpatient facility at the time they sign the ICF and remain in the inpatient facility for the duration of treatment.  

 
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c. 
Participants must have SARS-CoV-2 testing done with a negative test result prior to admission to the inpatient facility; refer to site procedures for additional 
details on testing. Additional SARS-CoV-2 testing may be performed after admission per the investigator’s discretion and according to site procedures.  
d. Contact with participant via phone call or other means of communication to check on their status. 
e. 
Beginning at the Week 3 time point, participants may receive supervised day passes for urgent issues at the investigator’s discretion as described in 
Section 4.1.2. A breathalyzer test and a urine drug screen must be performed upon return to the inpatient facility for any participant issued a supervised day 
pass. If the breathalyzer test is positive, the medical monitor should be contacted to determine the next steps. Participants returning from a day pass who 
have a positive urine drug screen should be discontinued from the trial. However, if the positive urine drug screen results from use of marijuana (any 
THC-containing product), prescription, or over-the-counter medications or products that, in the investigator’s documented opinion, does not signal a clinical 
condition that would impact the safety of the participant or interpretation of the trial results, the participant may continue in the trial following consultation 
and approval by the medical monitor. 
f. 
A minimum of 3 days is required between the Week 6 Day 42 assessments (ie, PANSS, CGI-S, and CGI-I) and the Day 45 assessments (ie, all other scales 
and safety measures); eg, if the Week 6 Day 42 assessments are done on trial day 43, the earliest the Week 6 Day 45 assessments can be done is trial day 46.  
g. All Week 6 (ie, both Day 42 and Day 45 time points) assessments should be completed on a single day (ie, no need for 3-day separation) for any participant 
who discontinues early from the trial. All assessments should be completed prior to reinitiation of antipsychotic therapy, whenever possible. If antipsychotic 
therapy has been initiated, the efficacy scales (PANSS, CGI-S, CGI-I) should not be conducted.  
h. Unless indicated otherwise, all assessments to be completed prior to dosing. 
i. 
Inclusion/exclusion criteria will be assessed at Baseline to ensure ongoing participant eligibility, with the exception of age or assessments that are only 
scheduled during Screening (eg, height for body mass index calculation). This includes the PANSS total score assessment to ensure no decrease of ≥20% 
between Screening and Baseline, as per Exclusion Criterion #4 (see Section 5.2).  
j. 
Medical occurrences that begin before the start of dosing with IMP but after obtaining informed consent should be collected as medical and/or psychiatric 
history. 
k. An alcohol test (breathalyzer) is required at Screening and upon return to the inpatient facility for any participant who leaves the inpatient facility. The 
medical monitor should be contacted to determine the next steps for participants returning from a day pass who have a positive breathalyzer test. An alcohol 
test (breathalyzer) can be conducted at any time during the trial at the discretion of the investigator. 
l. 
PANSS and CGI-S/CGI-I assessments should be completed before other assessments, following the preferred order described in Section 8. 
m. All responses will be relative to the participant’s condition at Day 1, prior to first dose of IMP. 
n. Full physical and neurological examinations should be completed at Screening and Week 6/ET. Symptom-driven physical and/or neurological examinations 
may be done at any time during the trial at the investigator’s discretion. 
o. Details for limited physical examination are provided in Section 8.2.2.  
p. 12-lead ECG assessments will be performed after the participant has been at rest for approximately 3 minutes. At Screening, the average of 3 consecutive 
ECGs collected 1 to 2 minutes apart will be used to determine participant eligibility; at Baseline, only 1 reading is required for determination of eligibility. 
At approximately 2 hours following dosing at weekly time points, single 12-lead ECGs will be obtained. Additional ECGs can be performed at the 
investigator’s discretion (eg, if abnormalities are noted).  

 
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q. At Screening and Baseline, blood pressure and heart rate assessments should be performed in order to confirm eligibility (see Exclusion Criterion in 
Section 5.2). Triplicate supine heart rate and blood pressure measurements should be taken at approximately 1-minute intervals predose (Day 1 only, 
Baseline), and at approximately 2 hours after dosing on Day 1 and Weeks 1 through 6. The triplicate supine heart rate and blood pressure measurements will 
be followed by a single measurement after approximately 2 minutes in a standing position to allow for orthostatic assessments. Additional time points can be 
added at the investigator’s discretion (eg, if abnormalities are noted). Further details are provided in Section 8.2.3 and in the Operations Manual. 
r. 
The “Baseline/Screening” C-SSRS form will be completed for all participants at Screening to determine eligibility and the “Since Last Visit” C-SSRS form 
will be completed at Baseline to ensure that the participant continues to qualify for the trial. The “Since Last Visit” C-SSRS form will also be completed at 
weekly time points after Baseline. 
s. 
EPS assessments can be completed at any time during the trial, per investigator discretion, if symptoms are present. 
t. 
Prior and concomitant medications should be recorded from Screening through the participant’s last visit/contact. 
u. Adverse events (serious and nonserious) should be recorded from the first dose of IMP through the participant’s last visit/contact. 
v. The Week 6 prolactin results will be partially blinded; the investigator will be notified if the prolactin levels exceed a predefined limit with instructions to 
send the participant for appropriate follow-up. 
w. For women of childbearing potential only. Pregnancy tests can be performed at any time during the trial at the discretion of the investigator if pregnancy is 
suspected. Any urine pregnancy tests that are positive must be confirmed using a serum test. 
x. A urine drug screen is required at Screening (full panel including opioids) and Baseline (dipstick); see the exclusion criteria for exclusions based on the urine 
drug screen. In addition, the urine drug screen will be conducted upon return to the inpatient facility for any participant who leaves the inpatient facility as 
described in Section 4.1.2. Participants returning from a day pass who have a positive urine drug screen will be discontinued from the trial. The urine drug 
screen can be conducted at any time during the trial at the discretion of the investigator.  
y. PK samples will be obtained predose (within 15 minutes prior to dosing) and at 1, 4, and 8 hours following dosing on Day 4 and processed for plasma 
(2 aliquots required [primary/backup]) as described in Section 8.4 and the Lab Manual.  
z. 
PK samples will be obtained predose (within 15 minutes prior to dosing) and at 1, 2, 4, 8, 12, and 24 hours following dosing on Day 24 and processed for 
plasma (2 aliquots required [primary/backup]) as described in Section 8.4 and the Lab Manual. 
aa. A single PK sample will be collected from participants at time of discontinuation; the actual date and time of sample collection will be documented. 
bb. Future biospecimen research sample is optional and is only to be collected if signed consent is obtained from the participant. Sample can be collected at any 
time following confirmation of participant eligibility and prior to initiation of first dose. 
 

 
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2 INTRODUCTION 
2.1 
Trial Rationale 
Emraclidine (previously referred to as CVL-231) is a brain penetrant mAChR activator 
that selectively binds to the M4 muscarinic receptor subtype while sparing other 
muscarinic receptor subtypes (M1, M2, M3, and M5). Emraclidine is being developed for 
treatment of psychosis in schizophrenia. 
The aim of this trial is to investigate the efficacy, safety, and tolerability of 2 fixed doses 
of emraclidine (15 mg QD and 30 mg QD) in participants with schizophrenia who are 
experiencing an acute exacerbation of psychosis.  
2.2 
Background 
2.2.1 
Disease Overview 
Schizophrenia is characterized by positive symptoms (eg, hallucinations and delusions), 
negative symptoms (eg, emotional blunting and lack of motivation), and deficits in 
cognitive function (eg, attention, information processing, and working memory) (Shekhar 
et al, 2008). Treatment of schizophrenia is currently limited to typical and atypical 
antipsychotic medications that act by blocking various dopamine (D1 and D2) receptors 
in the brain (Shekhar et al, 2008; Howes and Kapur, 2009). However, these 
antipsychotics typically also bind to a number of additional receptor subtypes, including 
other dopaminergic, serotonergic, muscarinic, adrenergic, and histaminergic receptor 
subtypes (Miron et al, 2014). 
The first-generation antipsychotics (eg, chlorpromazine, haloperidol, and fluphenazine) 
are effective at controlling some symptoms of schizophrenia, especially positive 
symptoms such as delusions and hallucinations, due to a combination of D2 blockade and 
anticholinergic and antihistaminergic effects (Buoli et al, 2016; Altamura et al, 2011). 
However, the use of these first-generation antipsychotics is limited by severe 
antidopaminergic side effect such as EPS, tardive dyskinesia, and hyperprolactinemia 
(Schneider et al, 2006; Huybrechts et al, 2012; Foster et al, 2016).  
The “atypical” antipsychotics, of which clozapine was the prototype, have reduced 
extrapyramidal side effects yet retain antipsychotic potency, likely due to a more rapid 
dissociation from D2 receptors combined with potent serotonergic (5HT2A) blockade 
(Kapur and Seeman, 2000; Kapur and Seeman, 2001; Solmi et al, 2017). However, these 
atypical antipsychotics are associated with off-target receptor mediated metabolic effects 
and weight gain (Nasrallah, 2008). 
Recent literature suggests that for xanomeline, an M1/M4 preferring mAChR agonist, its 
antipsychotic efficacy may be driven primarily by M4 mAChR stimulation 
(Woolley et al, 2009; Byun et al, 2014; Brannan et al, 2021), and that a selective M4 
mAChR activator could convey similar clinical benefits. Presynaptic expression of the 

 
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M4 mAChR on cholinergic interneurons regulates striatal acetylcholine and dopamine 
equilibrium, the imbalance of which is hypothesized to contribute to the symptoms of 
psychosis observed in schizophrenia. (Howes and Kapur, 2009).  
2.2.2 
Nonclinical Experience 
Emraclidine is a novel, brain penetrant, orally bioavailable, small molecule, reversible 
activator of M4 mAChR. Presynaptic expression of the M4 mAChR on cholinergic 
interneurons regulates striatal acetylcholine and dopamine equilibrium, the imbalance of 
which is hypothesized to contribute to psychosis in schizophrenia (Howes and Kapur, 
2009).  
Nonadverse treatment-related increases in blood pressure and heart rate, decreases in PR 
interval and/or RR interval, and shortening of the QT interval (without changes in QTc) 
were observed in single-dose nonpivotal and pivotal dog cardiovascular safety 
pharmacology studies with resolution of these findings by 9 hours postdose. In the pivotal 
1- and 3-month repeat-dose toxicity studies, similar effects were observed (ie, increased 
heart rate and decreased PR, RR, and/or QT interval [without changes in QTc]). In the 
3-month dog study, the greatest (magnitude) increase in heart rate was observed on Day 1 
in the mid- and high-dose groups (≥3.75 mg/kg/day) and was considered adverse based 
on the magnitude of increase. By Days 43 and 91, heart rate was still increased in these 
dose groups compared with control animals, but the differences were of small magnitude, 
and all mean heart rate values were within the normal range for dogs. The reduced 
magnitude of heart rate increase on Days 43 and 91 are indicative and consistent with the 
development of tolerance to the emraclidine effects on heart rate. With the exception of 
Day 1 in the 3-month study, these heart rate increases in the pivotal 1- and 3-month dog 
toxicity studies were considered nonadverse as there were no corresponding adverse 
in-life or postmortem findings, including histopathological effects on cardiovascular 
tissues. Similarly, in the 9-month repeat-dose dog toxicity study, adverse (based on 
magnitude of increase) heart rates were generally observed at the start of the study (Day 1 
for the high dose group and Days 8 and 15 during dose-escalation) and appeared to 
attenuate as the study progressed (reduced magnitude of heart rate increase generally by 
Day 22 in previously affected groups). There were no corresponding adverse in-life or 
postmortem findings, including histopathological effects on cardiovascular tissues. 
Overall, the cardiovascular effects that were noted in all studies were monitorable, 
reversible, and not associated with cardiac or vascular pathologies. 
The nonclinical safety profile of emraclidine and CV-0000364 metabolite have been 
adequately characterized to support clinical trials of up to 13 weeks in duration in women 
of childbearing potential and men with use of highly effective contraception for the 
duration of systemic exposure. 
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2.2.3 
Clinical Experience 
Safety, tolerability, and PK of emraclidine were evaluated following single doses in 
healthy participants (Trial C2561001) and following multiple ascending doses in 
participants with schizophrenia (Trial CVL-231-SCH-001).  
In Trial C2561001, emraclidine single oral doses in the range of 0.3 mg to 30 mg were 
administered under fasted conditions. There were transient changes in heart rate and 
blood pressure that appeared to be dose related and were most prominent at the 30 mg 
dose level. These changes returned toward baseline by 24 hours. Two AEs of moderate 
severity associated with cardiovascular assessments (orthostatic hypotension and sinus 
tachycardia) were observed at the 30 mg dose level.  
In the Phase 1b, 2-part, multiple ascending dose trial in participants with schizophrenia 
(Trial CVL-231-SCH-001), 39 participants with stable schizophrenia received multiple 
doses of emraclidine of 5, 10, 20, or 30 mg QD for up to 14 days or 20 mg BID for up to 
28 days (7-day titration; 21 days target dose) during Part A. An additional 54 participants 
with acute exacerbation of psychosis received treatment with emraclidine 30 mg QD 
(27 participants) or 20 mg BID (27 participants) for up to 42 days in Part B of the trial.  
In contrast with healthy participants, the effect of emraclidine on blood pressure in 
participants with schizophrenia was variable, nonsustained, and had no clear dose 
relationship. In Part A of Trial CVL-231-SCH-001, emraclidine at doses ≥20 mg QD 
appeared to be associated with modest, transient increases in both systolic and diastolic 
blood pressure; none of these increases were associated with TEAEs. emraclidine was 
also associated with an increase in heart rate that appeared to be dose dependent and 
persisted throughout the Treatment Period. There were no TEAEs of tachycardia. In Part 
B of the trial, modest elevations in systolic and diastolic blood pressure and heart rate 
were observed with emraclidine compared with placebo early in the Treatment Period; 
these elevations decreased over time. The average change from Baseline during Week 6 
in systolic and diastolic blood pressure and heart rate for both the emraclidine 30 mg QD 
and 20 mg BID groups showing no clinically meaningful difference versus placebo. The 
average change for the emraclidine 30 mg QD group versus placebo at the 2-hour post 
morning dose time point during Week 6 were +1.2 mmHg, -0.1 mmHg, and +4.4 bpm for 
systolic blood pressure, diastolic blood pressure, and heart rate, respectively.  
Emraclidine was safe and generally well tolerated in participants with schizophrenia. The 
most frequently reported TEAEs in emraclidine treated participants (>5% of emraclidine 
participants) in Part A were headache (4/39 participants; 10%), dizziness (2/39; 5%), 
insomnia (2/39; 5%), and increased weight (2/39; 5%) and in Part B were headache 
(15/54; 28%), nausea (4/54; 7%), and back pain, blood creatinine phosphokinase 
increased, dizziness, dry mouth, increased weight, and somnolence (3/54; 6% each). No 
clinically meaningful changes were observed in ECGs, except increase in heart rate 
consistent with vital sign findings. No clinically relevant changes were observed in 
clinical laboratory findings, or clinical scales for extrapyramidal symptoms or suicidality. 

 
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The PK of emraclidine were characterized by rapid absorption and biphasic elimination, 
with the median Tmax ranging from 1.0 to 1.8 hours under fasted conditions (3.0 hours in 
the fed state) and the mean t1/2 ranging between 9.4 hours and 12.2 hours across 
following single doses in healthy participants. Increase in emraclidine Cmax and AUC 
appeared to be dose proportional. The results of a pilot food effect trial at the 10 mg dose 
suggest that administration of the compound immediately following a high-fat diet result 
in a slight reduction in Cmax without significantly affecting the overall bioavailability of 
emraclidine. Pharmacokinetic data from Trial CVL-231-SCH-001 suggest that PK of 
emraclidine in participants with schizophrenia is similar to that observed in healthy 
participants. The increase in Cmax values for emraclidine was roughly dose proportional. 
However, the high interparticipant variability in emraclidine AUC values, similar to 
results from the single ascending dose trial, affected accurate dose proportionality 
assessment. 
Both the emraclidine 30 mg QD and the 20 mg BID doses demonstrated clinically 
meaningful antipsychotic activity compared with placebo in Part B of 
Trial CVL-231-SCH-001. The emraclidine 30 mg QD dose resulted in a statistically 
significant and clinically meaningful mean reduction from Baseline of 19.5 points in the 
PANSS total score (12.7-point difference from placebo group; nominal p=0.023) at 
Week 6. The emraclidine 20 mg BID dose resulted in a statistically significant and 
clinically meaningful mean reduction from Baseline of 17.9 points in PANSS total score 
(11.1-point difference from placebo group; nominal p=0.047) at Week 6. These results 
were further supported by clinically meaningful improvements versus placebo on the 
PANSS positive, negative, and general psychopathology subscale scores, as well as on 
the CGI-S scale score. 
Please refer to the emraclidine Investigator’s Brochure for more detailed information. 
2.3 
Benefit/Risk Assessment 
This trial is designed primarily to evaluate the efficacy and safety of 2 fixed doses 
(15 mg QD and 30 mg QD) of emraclidine in the target patient population.  
Based on results from Part B of Trial CVL-231-SCH-001, treatment with 30 mg QD 
emraclidine in patients with schizophrenia experiencing an acute exacerbation of 
psychosis may be beneficial based on clinically meaningful reductions from Baseline in 
PANSS and CGI-S scores (see Section 2.2.3).  
Doses were chosen for this trial based on nonclinical safety and toxicology data and 
clinical safety data available to date (see Section 4.3). 
There is a potential for an increase in blood pressure and heart rate based on nonclinical 
findings and findings from the single and multiple ascending dose trials (see 
Section 2.2.2 and Section 2.2.3). The cardiovascular effects of emraclidine will be 
carefully monitored on an inpatient basis throughout the trial. The inpatient design will 
also facilitate careful monitoring of participants during and subsequent to washout from 
their antipsychotic drug treatment.  

 
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More detailed information about the known and expected benefits and potential risks  of 
emraclidine are found in the Investigator’s Brochure. 
3 OBJECTIVES AND ENDPOINTS 
Table 2 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
• 
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 
Primary Endpoint: 
• 
Change from Baseline at Week 6 in the 
PANSS total score 
Key Secondary Endpoint: 
• 
Change from Baseline at Week 6 in the 
CGI-S score 
Secondary Endpoints: 
• 
Change from Baseline at all time points in 
PANSS total score  
• 
Change from Baseline at all time points in 
CGI-S score  
• 
Percentage of responders at Week 6 
(responders defined as ≥30% reduction from 
Baseline in PANSS total score)  
Exploratory Endpoints: 
• 
CGI-I at Weeks 3 and 6 
• 
Change from Baseline at all time points in 
PANSS positive, negative, and general 
psychopathology subscale scores 
• 
Change from Baseline at all time points in 
PANSS Marder Factor scores 
Secondary 
• 
To evaluate the safety and tolerability 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 
• 
Treatment-emergent adverse events  
• 
Clinically significant changes in 
electrocardiograms, clinical laboratory 
assessments and metabolic parameters, 
standard vital sign measurements, and 
physical and neurological examination 
results, including body weight 
• 
Clinically significant findings in suicidality 
assessed using the C-SSRS 
• 
Extrapyramidal symptoms evaluated using 
the change from Baseline in SAS, AIMS, and 
BARS assessments 

 
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Objectives 
Endpoints 
Exploratory 
• 
To evaluate the plasma pharmacokinetics of 
emraclidine and its metabolite, CV-0000364, 
following 2 fixed oral doses (15 mg QD and 
30 mg QD) of emraclidine in adult participants 
with schizophrenia experiencing an acute 
exacerbation of psychosis 
• 
Pharmacokinetic parameters for emraclidine 
and its metabolite, CV-0000364 (Cmax and 
AUCtau) 
• 
To evaluate quality of life and cognition 
following 2 fixed oral doses (15 mg QD and 
30 mg QD) of emraclidine in adult participants 
with schizophrenia experiencing an acute 
exacerbation of psychosis 
• 
Change from Baseline at Week 6 in BACS 
symbol coding test 
• 
Change from Baseline at Week 6 in SF-6D 
Abbreviations: AIMS=Abnormal Involuntary Movement Scale; AUC=area under the concentration-time 
curve; BACS=Brief Assessment of Cognition in Schizophrenia; BARS=Barnes Akathisia Rating Scale; 
CGI-I=Clinical Global Impression-Improvement of Symptoms; CGI-S=Clinical Global Impression-
Severity of Symptoms; Cmax=maximum (peak) plasma concentration; C-SSRS=Columbia-Suicide Severity 
Rating Scale; PANSS=Positive and Negative Syndrome Scale; QD=once daily; SAS=Simpson Angus 
Scale; SF-6D=Short Form-6 Dimensions. 
4 TRIAL DESIGN 
4.1 
Overall Design 
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 emraclidine (15 mg QD and 30 mg QD) in male and female participants aged 18 
to 65 years, inclusive, who have schizophrenia and are experiencing an acute 
exacerbation of psychosis. The trial will include up to a 15-day Screening Period (up to a 
maximum of 21 days allowed with approval of the medical monitor), a 45-day Inpatient 
Treatment Period, and a 28-day Follow-up Period. Each participant will participate in the 
trial for up to approximately 13 weeks.  
4.1.1 
Screening Period 
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. All participants 
will be admitted to the inpatient facility at the time they sign the ICF and remain in the 
inpatient facility for the duration of treatment.  
Approximately 600 participants will be screened to achieve approximately 
372 participants qualified to be randomized to treatment in the trial. 
4.1.2 
Treatment Period 
On Day 1 (Baseline), participants will be randomized in a 1:1:1 ratio to the following 
treatment groups with approximately 124 participants per treatment group: 

 
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• 
Emraclidine 15 mg QD 
• 
Emraclidine 30 mg QD 
• 
Placebo QD 
The randomization will be stratified by geographic region with 2 strata: United States or 
all other countries. 
The daily dosing schedule will start on Day 1 with all participants receiving a single daily 
dose of IMP in the morning.  
Participants are to remain in the inpatient facility for the entire duration of the trial (ie, 
from ICF signing through Week 6/ET); however, beginning at the Week 3 time point, 
participants who are sufficiently stable (per investigator assessment) may receive day 
passes for urgent issues. While away from the site, participants must be supervised by 
hospital/research staff (medical monitor approval for supervision by a family member or 
caregiver may be obtained). Participants are not permitted to stay away from the inpatient 
facility overnight; if, in unforeseen circumstances, the participant is unable to return to 
the facility the same day, the medical monitor should be contacted to discuss continuing 
participant eligibility. In addition, the participant must agree to submit to testing (ie, urine 
drug screen and alcohol breathalyzer test) upon return to the site. If the breathalyzer test 
is positive, the medical monitor should be contacted to determine the continued eligibility 
of the participant. Participants returning from a day pass who have a positive urine drug 
screen should be discontinued from the trial. However, if the positive urine drug screen 
results from use of marijuana (any THC-containing product), prescription, or 
over-the-counter medications or products that, in the investigator’s documented opinion, 
does not signal a clinical condition that would impact the safety of the participant or 
interpretation of the trial results, the participant may continue in the trial following 
consultation and approval by the medical monitor. 
All participants will continue dosing through Day 45 of Week 6. For the Week 6 time 
point, trial assessments will be completed on 2 separate days; on Day 42, the PANSS, 
CGI-S, and CGI-I will be completed, and on the last day of the treatment period, Day 45, 
the remaining scale and safety assessments will be completed. A minimum of 3 days is 
required between the completion of the Day 42 assessments and the Day 45 assessments, 
as noted in the Schedule of Assessments (Table 1). Participants will receive their last 
dose of IMP on Day 45. 
Participants who complete all trial visits, through Week 6 (Day 45), may be offered entry 
into an optional open-label rollover trial when the trial has been initiated for rollover 
participation. 
4.1.3 
Follow-up Period 
All participants (completers and early withdrawals), with the exception of those entering 
the optional open-label rollover trial, will have a follow-up safety contact at 
approximately 28 days after the last dose of IMP.  

 
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Participants may be allowed to stay in the inpatient facility up to 7 days after their last 
dose of IMP if necessary to achieve stabilization on alternate therapy with review and 
approval by the medical monitor. 
4.1.4 
Definition of Completed Participant 
A participant is considered to have completed the trial if he/she has completed the 
inpatient Treatment Period of the trial including the last inpatient visit (Day 45), as 
shown in the Schedule of Assessments in Section 1.3.  
4.2 
Scientific Rationale for Trial Design 
The randomized, double-blind, placebo-controlled, parallel-group trial design minimizes 
the risk of bias and is considered appropriate for evaluating the effects of a trial treatment 
for indications in which use of a placebo is ethical (US FDA, 2001). Randomization 
reduces bias in the assignment of participants to a treatment group, the double-blind 
design prevents differential treatment and assessments, and the placebo-controlled design 
controls for all potential influences on the actual or apparent course of the disease other 
than those arising from the pharmacologic action of the drug. 
The 6-week duration of the current trial is of sufficient length to show a treatment effect 
on acute exacerbation of schizophrenia symptoms and has been used for prior trials of 
antipsychotics evaluated to treat acute psychotic symptoms in patients with schizophrenia 
(Correll et al, 2020; Correll et al, 2016; Leucht et al, 2013; McEvoy et al, 2007; Kane et 
al, 2015). As described in Section 2.2.3, emraclidine 30 mg QD demonstrated 
antipsychotic activity compared with placebo in Part B of Trial CVL-231-SCH-001 based 
on assessment of PANSS total score and CGI-S score at 6 weeks.  
The PANSS is a widely used and validated measure of the severity of core positive and 
negative symptoms associated with schizophrenia, as defined by the DSM-5. The change 
from Baseline in the PANSS total score has been the basis of approval for many 
antipsychotic agents, including Latuda, Rexulti, and Caplyta (Latuda Package Insert, 
2013; Rexulti Package Insert, 2018; Caplyta Package Insert, 2019). The CGI-S, which is 
also widely used and accepted, is included as a supplementary scale to provide a global 
assessment of clinical status. The BACS is a highly sensitive measure of cognitive 
defects in patients with schizophrenia; the symbol coding test of the BACS is included in 
the trial to evaluate the potential effect of emraclidine on attention and processing speed 
(Keefe et al, 2004; Dickinson et al, 2007). 
The safety assessments, including those for assessing EPS, are considered standard for 
evaluation of an antipsychotic compound in a population with schizophrenia. The 
C-SSRS is commonly used for stringent monitoring of the risk for suicidality in clinical 
trials (Posner et al, 2011).  

 
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4.3 
Justification for Dose 
Emraclidine doses and dosing frequency in this trial are based on the safety/tolerability 
data and PK profile of emraclidine from Trials C2561001 and CVL-231-SCH-001. The 
targeted maximum dose level of 30 mg QD in this trial represents the top end of the 
therapeutic dose range for emraclidine. The emraclidine 30 mg QD dose demonstrated 
clinically meaningful and statistically significant antipsychotic activity compared with 
placebo as assessed by changes from Baseline at Week 6 in the PANSS total score in a 
Phase 1b trial in participants with an acute exacerbation of schizophrenia. emraclidine 
30 mg QD, dosed for up to 6 weeks without titration, has been deemed safe and well 
tolerated in participants with schizophrenia. As mentioned above, this dose was 
associated with a maximum increase of 4.4 bpm in supine heart rate and 1.2 mmHg in 
supine systolic blood pressure (Week 6 average at 2 hours post morning dose compared 
with placebo).  
The 15 mg QD dose is selected to understand the efficacy at a lower dose. Based on 
range of doses evaluated in the multiple ascending dose trial (CVL-231-SCH-001), the 
15 mg QD dose is expected to be safe and well tolerated. The 2 doses of 30 mg QD and 
15 mg QD will facilitate the evaluation of efficacy of emraclidine across a wide exposure 
range for a thorough understanding of exposure responsiveness of emraclidine effects. 
4.4 
End of Trial Definition 
The end of the trial is defined as the date of the last visit (including follow-up safety 
contact) of the last participant in the trial globally. 
The definition of a completed participant is provided in Section 4.1.4. 
5 TRIAL POPULATION 
Men and women, 18 to 65 years of age, inclusive, with a primary diagnosis of 
schizophrenia who are experiencing an acute exacerbation or relapse of psychotic 
symptoms will be enrolled into the trial. 
5.1 
Inclusion Criteria 
Individuals are eligible for participation in this trial only if all of the following criteria 
apply: 
General 
1.  
Male and female participants, ages 18 to 65 years, inclusive, at the time of signing the ICF. 
Target Disease Characteristics 
2.  
Primary diagnosis of schizophrenia per DSM-5, as confirmed by the MINI for Psychotic 
Disorders version 7.0.2. 
3.  
CGI-S ≥4 (moderately to severely ill) at the time of signing the ICF and Baseline. 

 
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4.  
PANSS Total Score between 85 and 120, inclusive, at the time of signing the ICF and at 
Baseline.  
Additionally, participants must meet a score of ≥4 (moderate or greater) for ≥2 of the following 
Positive Scale items at the time of signing the ICF and at Baseline: 
• 
Positive Scale Item 1 (delusions) 
• 
Positive Scale Item 2 (conceptual disorganization) 
• 
Positive Scale Item 3 (hallucinatory behavior) 
• 
Positive Scale Item 6 (suspiciousness/persecution) 
5.  
Experiencing an acute exacerbation or relapse of psychotic symptoms, with onset less than 
60 days prior to signing the ICF. 
• 
Participant requires hospitalization for this acute exacerbation or relapse of symptoms 
• 
If participant is already an inpatient at the time of signing the ICF, has been hospitalized 
for ≤14 days for the current episode of psychosis at the time of signing the ICF, 
excluding hospitalization for psychosocial reasons 
6.  
Scores as follows (normal to mild symptoms) at the time of signing the ICF and Baseline 
(Day 1): 
• 
All individual items of the SAS <2 
• 
All individual items (Items 1-7) of the AIMS <2 
• 
Clinical global assessment item of the BARS <3 
7.  
Willing to discontinue all prohibited medications to meet protocol-required washouts prior to and 
during the trial period. 
8.   Resides in a stable living environment as demonstrated by the ability to provide contact 
information for themselves and/or family/friend/caregiver. 
Other and Administrative Criteria 
9.  
Agree to comply with the following contraception requirements during the trial and for 7 days 
after the last dose of IMP: 
• 
Sexually active men must agree to use a condom and practice contraception during treatment 
and until the end of relevant systemic exposure (ie, 7 days after the last dose of IMP). 
• 
Sexually active women of childbearing potential must use highly effective contraception as 
defined in Section 10.4.1.1 
 
In addition, male participants should not donate sperm for a minimum of 7 days following the last 
dose of IMP. 
10.  
Body mass index of 18.0 to 40.0 kg/m2 and a total body weight ≥50 kg (110 lbs). 
11.  
Capable of giving signed informed consent, which includes compliance with the requirements 
and restrictions listed in the ICF and in Section 10.1.3. 
12.  
Ability, in the opinion of the investigator, to understand the nature of the trial, participate in trial 
visits, and comply with protocol requirements, including the prescribed dosage regimens, 
scheduled visits, laboratory tests, outcomes measures, and other trial procedures. 
Abbreviations: AIMS=Abnormal Involuntary Movement Scale; BARS=Barnes Akathisia Rating Scale; 
CGI-S=Clinical Global Impression–Severity of Symptoms; DSM-5=Diagnostic and Statistical Manual of 
Mental Disorders, Fifth Edition; ICF=informed consent form; IMP=investigational medicinal product; 
MINI=Mini International Neuropsychiatric Interview; PANSS=Positive and Negative Syndrome Scale; 
SAS=Simpson Angus Scale. 

 
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5.2 
Exclusion Criteria  
Individuals are not eligible for participation in this trial if any of the following criteria 
apply: 
Target Disease 
1.  
Current DSM-5 diagnosis other than schizophrenia including, but not limited to, intellectual 
disability; schizoaffective disorder; major depressive disorder; schizophreniform disorder; 
psychotic depression; bipolar disorder; post-traumatic stress disorder; generalized anxiety 
disorder, obsessive compulsive disorder, eating disorders (bulimia, anorexia), or other 
anxiety disorders as a primary diagnosis (note: anxiety symptoms secondary to 
schizophrenia are allowed); delirium, dementia, amnestic, or other cognitive disorders. 
Acute depressive symptoms within 30 days prior to signing the ICF that require treatment 
with an antidepressant are exclusory. 
Acute manic symptoms within 30 days prior to signing the ICF that require treatment with a 
mood stabilizer are exclusory. 
Additional excluded conditions include borderline, paranoid, histrionic, schizotypal, 
schizoid, or antisocial personality disorder. 
2.  
Any of the following: 
• 
Schizophrenia considered resistant/refractory to antipsychotic treatment by history 
(failure to respond to 2 or more courses of adequate pharmacological treatment 
defined as an adequate dose per label and a treatment duration of at least 4 weeks) 
• 
History of response to clozapine treatment only or failure to respond to clozapine 
treatment for schizophrenia 
3.  
Any of the following regarding history of schizophrenia: 
• 
Time from initial onset of schizophrenia <2 years based on prior records or 
participant self-report 
• 
Presenting with an initial diagnosis of schizophrenia  
• 
Presenting for the first time with an acute psychotic episode requiring treatment 
4.   
Reduction (improvement) in PANSS total score of ≥20% between Screening and Baseline. 
5.  
Either of the following: 
• 
History of tardive dyskinesia 
• 
Extrapyramidal symptoms that required medication within 6 months prior to 
signing the ICF 
Other Medical History and Concurrent Conditions 
6.  
Current or past history of significant pulmonary, gastrointestinal, renal, hepatic, metabolic, 
genitourinary, endocrine (including diabetes mellitus), malignancy (except for basal cell 
carcinoma of the skin and cervical carcinoma in situ, at the discretion of the investigator), 
hematological, immunological, neurological, or psychiatric disease that, in the opinion of 
the investigator or medical monitor, could compromise either participant safety or the 
results of the trial. 
Medical conditions that are minor or well-controlled may be considered acceptable if the 
condition does not expose the participant to an undue risk of significant AEs or interfere 
with the assessment of safety or efficacy during the course of the trial. The medical monitor 
should be contacted in any instance where the investigator is uncertain regarding the 
stability of a participant’s medical conditions(s) and the potential impact of the condition(s) 
on trial participation. 

 
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7.  
Current or past history of significant cardiovascular disease including any of the following: 
ischemic heart disease, myocardial infarction, cardiac valvulopathy, cardiac surgery 
revascularization (coronary artery bypass grafting) or stenting or percutaneous transluminal 
coronary angioplasty, receiving more than 2 medications to treat hypertension or have not 
been on stable doses of antihypertensive medications for >3 months, orthostatic 
hypotension, angina, unstable angina, cerebrovascular accident or stroke or transient 
ischemic attack, pacemaker, atrial fibrillation, atrial flutter, paroxysmal atrial tachycardia, or 
non-sustained or sustained ventricular tachycardia, pulmonary arterial hypertension, sick 
sinus syndrome, Type 2 second-degree or third-degree atrioventricular block, congestive 
heart failure, personal or family history of sudden death or long QT syndrome, unexplained 
syncope, syncope within the last 3 years regardless of etiology, or symptomatic orthostatic 
dizziness (by history or observed at the Screening Visit during the vital sign assessments). 
8.  
Active central nervous system infection, demyelinating disease, degenerative neurological 
disease, mental retardation, brain tumor, prior hospitalization for severe head trauma, 
seizures (excluding febrile seizures in childhood), or any central nervous system disease 
deemed to be progressive during the course of the trial that may confound the interpretation 
of the trial results. 
9.  
Diagnosis of moderate to severe substance or alcohol-use disorder (excluding nicotine or 
caffeine) as per DSM-5 criteria within 12 months prior to signing the ICF. 
Participants with mild substance or alcohol-use disorder may be included in the trial 
following consultation and approval by the medical monitor. 
10.  
“Yes” responses for any of the following items on the C-SSRS (within the past 6 months):  
• 
Suicidal Ideation Item 4 (Active Suicidal Ideation with Some Intent to Act, without 
Specific Plan) 
• 
Suicidal Ideation Item 5 (Active Suicidal Ideation with Specific Plan and Intent) 
“Yes” responses for any of the following items on the C-SSRS (within past 2 years): 
• 
Any of the Suicidal Behavior items (Actual Attempt, Interrupted Attempt, Aborted 
Attempt, Preparatory Acts or Behavior) 
Serious risk of suicide in the opinion of the investigator is also exclusionary. 
11.  
Any condition or surgery that could possibly affect drug absorption, including, but not 
limited to, complicated appendectomy or cholecystectomy, bowel resections, bariatric 
weight loss surgery, gastric banding, or gastrectomy. 
12.  
Have recently been diagnosed with and hospitalized for symptomatic COVID-19 or test 
positive for SARS-CoV-2 at Screening. 
Prior or Concomitant Therapies 
13.  
Use of prohibited medications prior to randomization within the required wash-out period 
(Table 4) or likely to require prohibited concomitant therapy (Table 5) during the trial. 
14.  
Transcranial magnetic stimulation or electroconvulsive therapy within 90 days of signing 
the ICF. 
Laboratory Test Results 
15.  
Positive result for HIV antibody, hepatitis B surface antigen, or hepatitis C antibody with 
detectable viral RNA levels at Screening.  
Note: Positive or indeterminate test result for hepatitis C antibody should follow with 
hepatitis C virus PCR RNA test. If result is positive, the participant is excluded. 

 
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16.  
Positive drug screen or a positive test for alcohol (note: individuals who test positive for 
alcohol may be rescreened). 
Participants with a positive urine drug screen resulting from use of marijuana (any 
THC-containing product), prescription, or over-the-counter medications or products that, in 
the investigator’s documented opinion, do not signal a clinical condition that would impact 
the safety of the participant or interpretation of the trial results may continue evaluation for 
the trial following consultation and approval by the medical monitor. 
17.  
Any of the following clinical laboratory test results at the Screening Visit, confirmed by a 
single repeat measurement, if deemed necessary: 
• 
AST or ALT ≥2 × ULN 
• 
Total bilirubin >1.5 × ULN. If Gilbert’s syndrome is suspected, total bilirubin >1.5 
× ULN is acceptable if the conjugated or direct bilirubin fraction is <20% of total 
bilirubin 
18.  
Positive pregnancy test result prior to receiving IMP. 
Note: female participants who are pregnant, breastfeeding, or planning to become pregnant 
during IMP treatment or within 7 days after the last dose of IMP are also excluded. 
Other Exclusionary Safety Assessments 
19.  
12-lead ECG demonstrating any of the following at the Screening Visit and at Baseline: 
• 
QTcF interval >450 ms 
• 
QRS interval >120 ms (unless right bundle branch block) 
• 
PR interval >200 ms 
• 
LVH with ST depressions and/or T wave inversions in leads with relatively tall R 
waves (ie, LVH with associated ST-T wave abnormalities) 
• 
Type 2 second-degree or third-degree atrioventricular block 
• 
Heart rate <45 bpm or >100 bpm 
• 
Abnormal ECG changes (such as clinically significant ST depression or elevation 
or T wave inversion) 
• 
Abnormal heart rhythm (atrial fibrillation and atrial flutter) 
Note: at Screening, eligibility will be based on the average of a centrally read triplicate set 
of ECGs. 
At Baseline Visit, if any of the above criteria are met on the machine read of the ECG, the 
medical monitor should be consulted to determine whether the participant is eligible for 
randomization. 
The medical monitor should be contacted in any instance where the investigator is uncertain 
regarding the interpretation of ECG results. 

 
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20.  
Blood pressure measurements demonstrating any of the following at the Screening Visit 
and/or at Baseline: 
• 
Systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg 
o 
Blood pressure will be measured in triplicate at approximately 1-minute 
intervals in a supine position after at least 3 minutes of rest. The triplicate 
measures will be individually recorded and the average of the last 2 
measurements will be used to determine eligibility. 
• 
Orthostatic hypotension, defined as a decrease of ≥20 mmHg in systolic blood 
pressure and/or ≥10 mmHg in diastolic blood pressure after at least 2 minutes of 
standing compared with the average of the resting supine blood pressure 
measurements as measured above 
21.  
Any other abnormal safety findings unless, based on the investigator’s judgment, the 
findings are not medically significant and would not impact the safety of the participant or 
the interpretation of the trial results. The medical monitor should be contacted to discuss 
individual cases, as needed.  
Tests with abnormal results that are potentially exclusionary should be repeated to ensure 
reproducibility of the result before excluding a potential participant based on criteria 
provided in the protocol. 
Lifestyle or Other Miscellaneous Exclusion 
22.  
Refusal to abstain from grapefruit-containing foods or beverages or Seville 
orange-containing foods or beverages from 7 days prior to dosing through Week 6/ET. 
23.  
Chronic consumption of >400 mg/day of caffeine-containing drinks or food (eg, >4 cups 
[8 ounces] of brewed coffee, 9 cans [12 ounces] of diet cola, 12 cans [12 ounces] of cola, 
8.5 cups of brewed black tea, 2 energy shot drinks) based on participant self-report. 
24.  
Considering or scheduled to undergo any surgical procedure during the trial. 
25.  
Prisoners or participants who are compulsorily detained (involuntarily incarcerated) for 
treatment of either a psychiatric or physical illness (eg, infectious disease). 
26.  
Any other condition that would preclude IMP administration or trial participation (eg, 
difficulty swallowing, poor venous access). 
27.  
Known allergy or hypersensitivity to emraclidine, closely related compounds, or any of its 
specified ingredients. 
28.  
Received IMP in a prior clinical trial of emraclidine. 
29.   
History of participation in any clinical trial involving an IMP as defined by the following:  
• 
Current enrollment or past participation within 90 days prior to signing the ICF, with 
the exception of a trial with a long-term follow-up period where dosing occurred more 
than 12 months prior to signing the ICF for this trial (discussion with and approval by 
the medical monitor required prior to enrollment)  
• 
Enrollment in more than 1 interventional trial within 12 months prior to signing the ICF 
Note: Prior participation in an interventional trial and a rollover extension trial with the 
same IMP within the last 12 months is permitted 
30.  
Anyone who should not participate in the trial in the opinion of the sponsor, investigator, or 
medical monitor, eg, participants who would be considered a risk for violent or destructive 
behavior. 

 
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31.  
Employee of the investigator, clinic, or sponsor with direct involvement in the proposed 
trial or other trials under the direction of the investigator or clinic, as well as family 
members of the employee or investigator. 
Abbreviations: AE=adverse event; ALT=alanine aminotransferase; AST=aspartate aminotransferase; 
C-SSRS=Columbia-Suicide Severity Rating Scale; DSM-5=Diagnostic and Statistical Manual of Mental 
Disorders, Fifth Edition; ECG=electrocardiogram; ET=early termination; HIV=human immunodeficiency 
virus; ICF=informed consent form; IMP=investigational medicinal product; LVH=left ventricular 
hypertrophy; PANSS=Positive and Negative Syndrome Scale; QTcF=QT interval corrected for heart rate 
using Fridericia’s formula; THC=tetrahydrocannabinol; ULN=upper limit of normal range. 
5.3 
Lifestyle Considerations 
5.3.1 
Meals and Dietary Restrictions 
Participants should fast for at least 8 hours prior to screening safety laboratory 
evaluations, if at all possible. If this is not possible, nonfasting screening laboratory 
evaluations may be obtained for eligibility determination. Participants must fast for a 
minimum of 8 hours prior to baseline and Week 6 safety laboratory assessments and 
should avoid consuming high-fat meals for 8 hours prior to any other safety laboratory 
assessments.  
Participants should refrain from eating or drinking food/food products which are 
strong/moderate inhibitors of cytochrome P450 3A4 (including but not limited to 
grapefruit, grapefruit juice, or grapefruit-related citrus fruits/juices [eg, Seville oranges, 
pomelos]) from 7 days prior to dosing through Week 6/ET. 
5.3.2 
Caffeine, Alcohol, and Tobacco 
Chronic consumption of >400 mg/day of caffeine-containing drinks or food (eg, >4 cups 
[8 ounces] of brewed coffee, 9 cans [12 oz] of diet cola, 12 cans [12 oz] of cola, 8.5 cups 
of brewed black tea, 2 energy shot drinks) will be prohibited while participants are in the 
inpatient facility.  
Participants should abstain from alcohol from time of signing ICF (check-in to inpatient 
facility) until Week 6/ET (check-out of inpatient facility). Participants will undergo an 
alcohol breath test at Screening (check-in), upon return to the inpatient facility if they 
leave, and at the discretion of the investigator. 
For participants who smoke, the number of cigarettes (or equivalent) smoked per day will 
be collected at both Screening and Baseline.  
5.3.3 
Activity 
Participants should abstain from strenuous exercise during the trial.  

 
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5.4 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical trial 
but are not subsequently randomly assigned to IMP. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to 
meet the Consolidated Standards of Reporting Trials publishing requirements and to 
respond to queries from health authorities. Minimal information includes demography, 
screen failure details, and eligibility criteria. 
Individuals who do not meet the criteria for participation in this trial (screen failure) at 
screening may be rescreened once at the discretion of the investigator and after 
consultation with the medical monitor unless screen failure is due to a positive urine drug 
screen for illicit substances. Rescreened participants will be assigned a new participant 
number. 
6 TRIAL INTERVENTION AND CONCOMITANT THERAPY 
Trial intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a trial participant according 
to the trial protocol.  
In this protocol, the trial interventions are referred to as IMPs. An IMP is a 
pharmaceutical form of an active substance or placebo being tested or used as a reference 
in a clinical trial, including products already with a marketing authorization but used or 
assembled (formulated or packaged) in a way different from the authorized form, or when 
used for an unauthorized indication, or when used to gain further information about the 
authorized form. 
6.1 
Trial Interventions Administered 
A summary of the IMP to be administered during this trial is presented in Table 3. 

 
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Table 3 
Investigational Medicinal Product 
Treatment 
Group 
Emraclidine 15 mg QD 
Emraclidine 30 mg QD 
Placebo 
Type  
Drug 
Drug 
Not applicable 
Dose 
Formulation 
Tablet 
Tablet 
Matching tablet 
Unit Dose 
Strength 
15 mg 
30 mg 
0 mg 
Dosage Level 
15 mg QD 
30 mg QD 
0 mg QD 
Route of 
Administration 
Oral 
Oral 
Oral 
Sourcing 
Provided centrally by the 
sponsor 
Provided centrally by the 
sponsor 
Provided centrally by the 
sponsor 
Packaging and 
Labeling 
IMP will be provided in 
bottles. Each bottle will be 
labeled as required per US 
requirement. 
IMP will be provided in 
bottles. Each bottle will be 
labeled as required per US 
requirement. 
Trial treatment will be 
provided in bottles. Each 
bottle will be labeled as 
per country requirement. 
Abbreviations: IMP=investigational medicinal product; QD=once daily; US=United States. 
Information regarding potential overdose with IMP is provided in Section 8.3.6. 
6.2 
Preparation, Handling, Storage, and Accountability 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit (original shipment and/or moving of IMP supply from 1 office 
or facility to another within the trial site’s network) for all IMP received and any 
discrepancies are reported and resolved before use of the IMP. 
Only participants enrolled in the trial may receive IMP and only authorized trial site staff 
may supply or administer IMP. All IMP must be stored in a secure, environmentally 
controlled, and monitored (manual or automated) area in accordance with the labeled 
storage conditions with access limited to the investigator and authorized trial site staff. 
The investigator is responsible for IMP accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records). 
Further guidance and information for the preparation, handling, storage, accountability, 
and disposition of unused IMP are provided in the pharmacy manual.  
6.3 
Measures to Minimize Bias: Randomization and Blinding 
6.3.1 
Participant Assignment to Treatment 
All participants will be centrally randomized in a 1:1:1 ratio to 1 of 3 treatment groups 
(placebo, emraclidine 15 mg QD, or emraclidine 30 mg QD) on Day 1 via an IRT 

 
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according to a computer-generated randomization scheme. Participants will be 
sequentially assigned to the next available randomization number and will receive the 
IMP that corresponds to that randomization number. Once a randomization number has 
been assigned, it will not be reassigned. 
The randomization will be stratified by geographic region with 2 strata: United States or 
all other countries. 
6.3.2 
Blinding 
During the entire trial, treatment will be blinded such that participants, the 
sponsor/designee, raters for clinician-administered scales, the investigator, and other site 
and trial personnel will not have knowledge of the treatment assignment at any visit. 
Access to the treatment codes will be restricted to personnel who are responsible for 
generating and maintaining the randomization code, packaging the IMPs, operating the 
IRT, analyzing the PK blood samples, or reporting SAEs or AESI to regulatory agencies. 
At the initiation of the trial, investigators and site personnel will be instructed on the 
method for breaking the blind. In case of an emergency, the investigator has the sole 
responsibility for determining if unblinding of the treatment assignment for an individual 
participant is warranted. Participant safety must always be the first consideration in 
making such a determination. If the investigator decides that unblinding is warranted, the 
investigator should make every effort to contact the medical monitor before unblinding a 
participant’s treatment assignment unless this could delay emergency treatment of the 
participant. The medical monitor must be notified within 24 hours after breaking the 
blind for a trial participant.  
Documentation of unblinding should be recorded in the participant’s medical record, 
including the reason for breaking the blind, the date and time the blind was broken, and 
the names of the personnel involved. Once the blind is broken for a participant, treatment 
with the IMP may not be reinitiated for that participant. 
6.4 
Trial Intervention Compliance 
The date and dose (and time on days with PK assessments) of each IMP administration, 
along with information on any missed or inappropriately administered dose, will be 
recorded in source documents and the eCRF. Compliance will be ensured by a hand and 
mouth check during the oral dosing administration.  
6.5 
Dose Modification 
No dose modifications are permitted during the trial.  
6.6 
Intervention After the End of the Trial 
Participants who complete through Day 45 of the trial may have the opportunity to 
receive open-label treatment with emraclidine in an open-label extension trial 

 
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(Protocol CVL-231-2003) if available. Participants who are ineligible or elect not to enter 
the open-label extension trial will resume treatment with available antipsychotic 
medications at the discretion of and as determined by their physician. 
6.7 
Prior and Concomitant Therapy 
6.7.1 
Time Period for Recording Prior and Concomitant Therapy 
The investigator will record all therapies (including vaccines, over-the-counter or 
prescription medicines, vitamins, and/or herbal supplements) taken by the participant 
from 30 days prior to signing the ICF through the end of the evaluation period (defined as 
the time period during which participants are evaluated for primary and/or secondary 
objectives).  
For concomitant medications, the following will be recorded in the eCRF: medication, 
indication, dose, frequency, route, start date and end date. For concomitant therapy, the 
following will be recorded in the eCRF: therapy, indication, start date, and end date. 
The medical monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. 
6.7.2 
Prohibited Therapy 
All participants must agree to discontinue all prohibited medications during the Screening 
Period in order to meet the protocol-specified washout periods. Table 4 provides the 
required duration of washout for selected prohibited medications. All other prohibited 
medications must be discontinued at least 24 hours before the first dose of IMP. 

 
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Table 4 
List of Medications Prohibited Before Randomization 
Prohibited Prior Medications 
Washout (if applicable) 
Antipsychotic agents 
 
Oral (or immediate-release intramuscular) aripiprazole or cariprazine 
 
Other oral (or immediate-release intramuscular) antipsychotic agents 
 
Depot or long-acting injectable antipsychotic agents 
 
14 days 
7 days 
1.5 cycles (per 
prescribing information) 
Antidepressants 
 
Fluoxetine or Symbyax 
 
Monoamine oxidase inhibitors 
 
Citalopram and escitalopram 
 
Venlafaxine and desvenlafaxine 
 
All other antidepressants 
 
28 days 
14 days 
7 days 
7 days 
14 days 
Mood stabilizers (ie, lithium and/or anticonvulsants) 
14 days 
All other psychoactive substances (except benzodiazepines) 
7 days 
Varenicline (eg, Chantix) 
7 days 
Beta receptor antagonists to treat hypertension 
Not applicable 
Other antihypertensive agents 
 
Receiving more than 2 medications to treat hypertension 
 
Have not been on stable doses of antihypertensive medications for 
>3 months 
Not applicable 
Table 5 lists all medications prohibited during the trial, including exceptions, where 
appropriate. 
Table 5 
List of Medications Prohibited During the Treatment Period 
Psychotropic agents including, but not limited to, the following: 
a) Antipsychotics, including depot or long-acting injectable formulations 
b) Antidepressants (including monoamine oxidase inhibitors) 
c) Mood stabilizers (ie, lithium and/or anticonvulsants) 
d) Benzodiazepines, except specific benzodiazepines when used to treat anxiety, agitation, or insomnia 
secondary to schizophreniaa 
e) Prescription stimulants (including appetite suppressants and treatments for attention-deficit 
hyperactivity disorder or narcolepsy) 
f) Opioid analgesics, unless approval is obtained from the medical monitor. Approval for opioid use 
may be considered for a documented and clinically appropriate indication (eg, episodic pain, tooth 
extraction) if prescribed at a medically appropriate dose and frequency 
Hypnotics, including ramelteon and other non-benzodiazepine sleep aids, except for specific medications 
when used to manage active insomniab 
Antihistamines (except for loratadine and cetirizine) 
Varenicline (eg, Chantix) 
Vitamins, other nutritional supplements, and non-prescription herbal preparations, unless approved in 
advance by the medical monitor 
Investigational agents 

 
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Any drug or product that is a moderate to strong inducer of CYP3A metabolism, which has the potential 
to lower emraclidine exposure levels. An example list of strong (>80% reduction in AUC) and moderate 
(50% to 80% reduction in AUC) inducers is provided in Section 10.7. Previous use of a CYP3A inducer 
must not have been taken at least 8 weeks prior to dosing.   
Any drug or product that is classified as a significant (ie, strong or moderate) inhibitor of the CYP3A 
metabolic pathway, which has the potential to increase emraclidine exposure levels. An example list of 
strong (eg, >5-fold increase in AUC) and moderate (eg, 2-to 5-fold increase in AUC) inhibitors is 
provided in Section 10.7. Previous use of a significant inhibitor of CYP3A must not have been taken for 
at least 2 weeks prior to dosing. 
Participants taking a drug that is a substrate for the renal transporters OCT2, MATE1, and MATE2K 
(eg, metformin). 
Anticholinergic agents, beta-receptor antagonists (eg, propranolol), and VMAT2 inhibitors (eg, 
valbenazine and deutetrabenazine). 
Initiation or change in antihypertensive therapy is prohibited during the trial unless discussed with and 
approved by the medical monitor. 
Abbreviations: AUC=area under the concentration-time curve; CYP=cytochrome P450; MATE=multidrug 
and toxin extrusion transporter; OCT=organic cation transporter; VMAT2=vesicular monoamine 
transporter 2. 
a. See Section 6.7.3 for details on benzodiazepine use during the trial. 
b. See Section 6.7.4 for details on non-benzodiazepine sleep aid use during the trial. 
6.7.3 
Benzodiazepine Use During the Trial 
The use of intramuscular benzodiazepines is prohibited during this trial. However, use of 
oral lorazepam as management for anxiety, agitation, and insomnia secondary to 
schizophrenia (either as an ongoing comorbidity noted at screening or as an AE) will be 
allowed both during the washout period between the screening and baseline assessments, 
and during the treatment phase.  
During the washout period, the prior use of other benzodiazepines must be discontinued 
in favor of oral lorazepam up to a maximum dose of 4 mg/day. In countries where oral 
lorazepam is not available, equivalent doses (as defined in the Operations Manual) of an 
alternate short-acting benzodiazepine may be used. As an exception, oral lorazepam (or 
equivalent) can be used up to a maximum dose of 6 mg/day if needed to treat symptoms 
of agitation during the Screening Period and on days with intensive PK sampling (ie, 
Day 24). 
The prescribed benzodiazepines should be discontinued as soon as the symptoms for 
which it was initiated subsides, as per the investigator’s discretion, to avoid any 
withdrawal effects. 
Benzodiazepines must not be administered within 12 hours prior to any scheduled 
efficacy or safety assessments. Investigators are encouraged to delay scale administration 
until a full 12 hours have elapsed since the last benzodiazepine dose, if at all possible, 
including at screening and baseline assessments. However, if delaying administration of 
efficacy and safety scales is not feasible, the scales should still be administered and the 

 
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use of benzodiazepine documented, including a notation of the drug name, dose, and time 
of administration on the eCRF. 
6.7.4 
Non-benzodiazepine Sleep Aids 
Non-benzodiazepine sleep aids (ie, zolpidem, zaleplon, zopiclone, and eszopiclone only) 
are permitted for the treatment of insomnia, but not within 10 hours of administration of a 
benzodiazepine, regardless of indication. For the non-benzodiazepine sleep aids, site 
personnel should utilize one of the listed medications that are approved for this indication 
and the specific prescribing information should be used to determine the maximum 
allowable daily dose for the treatment of insomnia. Non-benzodiazepine sleep aids must 
not be administered within 12 hours prior to scheduled efficacy and safety assessments, 
including EPS scales. Investigators are encouraged to delay scale administration until 
12 hours have elapsed, if at all possible. However, if delaying the administration of 
efficacy and safety scales is not feasible, the scales should still be administered and the 
use of the sleep aid documented, including a notation of the drug name, dose, and time of 
administration on the eCRF. 
6.7.5 
Psychotherapy 
With the exception of group therapy on the unit, newly initiated psychological therapy is 
prohibited during the trial.   
Except for inpatient group therapy, participants may only receive psychological therapy 
(individual, group, marriage, or family therapy) if they have been participating in therapy 
regularly for at least 8 weeks prior to screening and can commit to maintain their 
participation during the course of the trial at the current frequency. Permission for 
initiation of new therapy may be obtained only from the medical monitor. 
7 DISCONTINUATION OF TRIAL INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
Details on discontinuation of individual trial sites or of the trial as a whole are provided 
in Section 10.1.8.  
7.1 
Discontinuation of Trial Intervention 
If a participant permanently discontinues IMP, refer to the Schedule of Assessments 
(Section 1.3) for data to be collected following IMP discontinuation. 
If a participant discontinues IMP due to an AE, the investigator or other trial personnel 
will make every effort to follow the event until it has resolved or stabilized.  
7.2 
Participant Discontinuation/Withdrawal From the Trial 
All participants have the right to withdraw from the trial at any time without prejudice. 
Participants cannot withdraw consent for use of data already collected as part of the trial, 

 
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but can withdraw consent for future participation. The investigator can also discontinue a 
participant from the trial at any time for safety, behavioral, or compliance reasons. Unless 
a participant provides written withdrawal of consent or there is other written 
documentation by the investigator confirming the participant’s verbal intent to 
completely withdraw from the trial, participants should be followed for all 
protocol-specified evaluations and assessments, if possible. 
At the time of discontinuation from the trial, if possible, an early termination visit should 
be conducted. See the Schedule of Assessments (Section 1.3) for data to be collected at 
the time of discontinuation and follow-up and for any further evaluations that need to be 
completed. All assessments should be completed prior to reinitiating antipsychotic 
therapy, whenever possible. If antipsychotic therapy has been initiated, the efficacy scales 
(PANSS, CGI-S, CGI-I) should not be conducted. 
The reason for discontinuation from the trial will be recorded in the eCRF. 
7.3 
Lost to Follow-up 
Participants will be considered lost to follow-up if they repeatedly fail to return for 
scheduled visits and are unable to be contacted by the trial site personnel. The following 
actions must be taken if a participant fails to return to the site for a required trial visit: 
• Trial site personnel must attempt to contact the participant and reschedule the missed 
visit as soon as possible and counsel the participant on the importance of maintaining 
the assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the trial. 
• Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls, and a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the 
participant’s medical record. 
Participants who continue to be unreachable will be considered to have withdrawn from 
the trial. 
8 TRIAL ASSESSMENTS AND PROCEDURES 
The timing and frequency of trial procedures are provided in the Schedule of 
Assessments (Section 1.3). Protocol waivers or exemptions are not allowed. 
At each time point during the trial, efficacy and health economics assessments should be 
completed before safety assessments in the following preferred order: 
1. PANSS 
2. CGI-S/CGI-I 

 
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3. Vital sign measurements  
4. ECGs 
5. Laboratory blood draws (clinical safety laboratory assessments/PK) 
6. BACS/SF-6D 
7. Safety scale assessments (C-SSRS/SAS/AIMS/BARS) 
Immediate safety concerns should be discussed with the medical monitor immediately 
upon occurrence or awareness to determine if the participant should continue or 
discontinue IMP.  
Adherence to the trial design requirements, including those specified in the Schedule of 
Assessments, is essential and required for trial conduct. 
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants who are screened and to confirm eligibility or record 
reasons for screening failure, as applicable.  
The MINI for Psychotic Disorders version 7.0.2 (Sheehan et al, 1998; Sheehan et al, 
1997) will be conducted at the Screening Visit to confirm the participant’s diagnosis of 
schizophrenia and to rule out exclusionary comorbid psychiatric diagnoses. Detailed 
instructions for administration of this structured interview will be provided in the 
Operations Manual.  
8.1 
Efficacy Assessments 
Trained and qualified (details provided in the Operations Manual) clinicians should 
administer the efficacy assessments and the number of raters should be kept to a 
minimum. All efforts should be made to ensure the same clinician administers the scales 
for a given participant throughout the trial.  
All efficacy assessments will be completed using an approved electronic data capture 
system. 
Benzodiazepines and non-benzodiazepine sleep aids are not permitted within 12 hours of 
administration of clinician-administered scales (see Section 6.7).  
The timing and frequency of efficacy assessments are provided in the Schedule of 
Assessments (Section 1.3).  
8.1.1 
Positive and Negative Syndrome Scale 
The PANSS (Kay et al, 1999) is a clinical scale that has been extensively used as a 
reliable and valid measure of the negative and positive symptoms of schizophrenia 

 
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(Liechti et al, 2017). The scale is used for measuring symptom severity in participants 
with schizophrenia and is widely used in clinical trials of antipsychotic medications. The 
PANSS consists of 3 subscales containing a total of 30 symptom constructs. For each 
symptom construct, severity is rated on a 7-point scale, with a score of 1 indicating the 
absence of symptoms and a score of 7 indicating extremely severe symptoms. The 
symptom constructs for each subscale are as follows: 
1. Positive Subscale – delusions, conceptual disorganization, hallucinatory behavior, 
excitement, grandiosity, suspiciousness/persecution, and hostility 
2. Negative Subscale – blunted affect, emotional withdrawal, poor rapport, passive 
pathetic withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of 
conversation, stereotyped thinking 
3. General Psychopathology Subscale – somatic concern, anxiety, guilt feelings, tension, 
mannerism and posturing, depression, motor retardation, uncooperative, unusual 
thought content, disorientation, poor attention, lack of judgment and insight, 
disturbance of volition, poor impulse control, preoccupation, and active social 
avoidance 
Although the PANSS is structured as a scale to assess the above 3 dimensions of 
schizophrenia, retrospective factor analyses have been performed using scores from the 
30 individual PANSS items to categorize symptoms into 5 dimensions, which are 
collectively referred to as Marder Factor scores (Marder et al, 1997). These 5 dimensions 
include the following: negative symptoms, positive symptoms, disorganized thought, 
uncontrolled hostility/excitement, and anxiety/depression.  
All efforts to ensure the same rater administers the PANSS for a given participant at all 
time points should be made. The PANSS assessment should be completed prior to all 
other efficacy scales. Instructions for administering the PANSS will be provided to the 
site.  
8.1.2 
Clinical Global Impression-Severity of Symptoms Scale 
The severity of symptoms for each participant will be rated using the CGI-S (Guy, 1976). 
To perform this assessment, the investigator (or designee) will answer the following 
question: “Considering your total clinical experience with this particular population, how 
ill is the participant at this time?” Response choices are 0=not assessed; 1=normal, not at 
all ill; 2=borderline ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; and 
7=among the most extremely ill participants. 
8.1.3 
Clinical Global Impression-Improvement Scale 
The CGI-I is an observer-rated scale that will be used to measure the participant’s 
symptom severity compared with before initiation of treatment with IMP (Guy, 1976). It 
is important to note that the observer or rater will provide their assessment of the 

 
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participant’s current level of symptoms compared with their symptoms at Baseline 
(Day 1).   
The investigator (or designee) will rate the participant’s change from Baseline in 
symptom severity using the following response choices: 0=not assessed, 1=very much 
improved, 2=much improved, 3=minimally improved, 4=no change, 5=minimally worse, 
6=much worse, and 7=very much worse. 
8.1.4 
Brief Assessment of Cognition in Schizophrenia – Symbol Coding 
Test 
The symbol coding test of the BACS evaluates the cognitive domain related to processing 
speed, which is identified as important for clinical trials in schizophrenia. The test 
consists of participants matching the numerals 1 to 9 to symbols on an electronic platform 
over a 90-second period. The outcome measure is the number of correct numerals over 
the time period and ranges from 0 to 110 (Keefe et al, 2004).  
8.2 
Safety Assessments 
The timing and frequency of safety assessments are provided in the Schedule of 
Assessments (Section 1.3). 
8.2.1 
Height and Weight 
Height will be measured at Screening only with a stadiometer, measuring stick, or tape.  
The following guidelines will aid in the standardization of body weight measurements: 
• Scales should be calibrated and reliable; scales should be at zero just prior to each 
participant’s weigh-in session 
• A participant should void prior to being weighed, if possible, and be minimally 
clothed (ie, no shoes or heavy overgarments) 
• Weight should be recorded before a participant’s meal and at approximately the same 
time at each required visit 
8.2.2 
Physical and Neurological Examinations 
A full physical examination will include a review of the following body systems: head, 
ears, eyes, nose, mouth, skin, heart and lungs, lymph nodes, gastrointestinal, and 
musculoskeletal systems. 
A limited physical examination will include evaluation of cardiovascular, pulmonary, and 
gastrointestinal systems. 

 
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A full neurological examination will include an assessment of the participant’s mental 
status (level of consciousness, orientation, speech, memory, etc), cranial nerves, motor 
(muscle appearance, tone, strength and reflexes), sensation (including Romberg sign), 
coordination, and gait. 
The investigator (or designee) is responsible for performing the physical and neurological 
examinations. If the appointed designee is to perform these examinations, he or she must 
be permitted by local regulations and his or her name must be included on the delegation 
of authority log. Whenever possible, the same individual should perform all physical and 
neurological examinations.  
Any condition present at the post-treatment physical and neurological examinations that 
was not present at the baseline examination should be documented as an AE and followed 
to a satisfactory conclusion. 
8.2.3 
Vital Sign Measurements 
Vital signs include systolic and diastolic blood pressures, heart rate, respiratory rate, and 
body temperature. Triplicate blood pressure and heart rate measurements will be obtained 
after the participant has been supine and at rest for at least 3 minutes. Measurements will 
be obtained at approximately 1-minute intervals at the time points indicated in the 
Schedules of Assessments (Section 1.3). The triplicate values will be individually 
recorded, and the values will be averaged by the sponsor for all time point assessments 
following confirmation of eligibility. For determination of eligibility, the average of the 
last 2 values will be used (see Section 5.2). Additional details are provided in the 
Operations Manual. 
The supine measurements will be followed by a single measurement in the standing 
position (after standing for approximately 2 minutes) to allow for orthostatic assessments. 
Orthostatic hypotension is defined as a decrease of ≥20 mmHg in systolic blood pressure 
and/or ≥10 mmHg in diastolic blood pressure upon standing compared with the average 
of the resting supine blood pressure measurement (as measured above). 
Any abnormal measurements in vital signs need to be repeated for confirmation. After 
confirmation, clinically significant measurements occurring during the trial will be 
recorded in the AE section of the eCRF. 
If the increase in blood pressure is clinically significant and therefore reported as an AE, 
the NCI-CTCAE toxicity grades summarized in Section 10.3.3 (Table 12) should be 
followed. 
Further details on taking vital sign measurements are provided in the appropriate trial 
specific manuals.  
Abnormal vital sign measurements that are defined as AESIs are discussed in 
Section 8.3.7. 

 
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8.2.4 
Electrocardiograms 
Electrocardiogram recordings will be obtained after the participant has been supine and at 
rest for approximately 3 minutes. Additional 12-lead ECGs may be obtained at the 
investigator’s discretion and should always be obtained in the event of an early 
termination. The ECG results will be evaluated at the investigational site to determine the 
participant’s eligibility and to monitor safety during the trial. The principal investigator 
(or qualified designee) will review, sign, and date each ECG reading, noting whether or 
not any abnormal results are of clinical significance. The ECG will be repeated if any 
results are considered to be clinically significant. Any clinically significant changes 
occurring during the trial will be recorded in the AE section of the eCRF. A central ECG 
service will be used for reading all ECGs in order to standardize interpretations for the 
safety analysis. Additional guidance on collection of ECGs will be provided in the 
Operations Manual. 
At Screening, triplicate 12-lead ECGs are required to assess participant eligibility. A 
triplicate set of ECGs is 3 consecutive ECGs collected 1 to 2 minutes apart over a 
5-minute period. If, during screening, according to the investigator’s judgment, any 
abnormal ECG finding is deemed medically significant (impacting the safety of the 
participant or the interpretation of the trial results) or meets an exclusion criterion (see 
Section 5.2), the participant should be excluded from the trial. The central ECG service 
will provide the QTcF corrections and average of the 3 ECGs performed to determine 
eligibility. 
At all other specified time points in the Schedule of Assessments (Section 1.3) where an 
ECG recording must be performed, only a single ECG is required.  
Exclusion criteria for screening do not apply as mandatory discontinuation criteria for 
participants who are already randomized. A repeat ECG should be performed in case of 
any clinically significant abnormality that is identified in a randomized participant during 
the treatment period and, in these cases, the medical monitor should be consulted on the 
appropriateness of the participant continuing in the trial. 
8.2.5 
Clinical Safety Laboratory Assessments 
See Section 10.2 for the list of clinical laboratory tests to be performed and the Schedule 
of Assessments (Section 1.3) for the timing and frequency. 
The investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the trial as an AE. The laboratory reports 
must be filed with the source documents.  
All laboratory tests with values considered clinically significantly abnormal during 
participation in the trial should be repeated until the values return to normal or baseline or 
are no longer considered clinically significant by the investigator or medical monitor. If 
clinically significant values do not return to normal/baseline within a period of time 

 
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judged reasonable by the investigator, the etiology should be identified and the medical 
monitor notified. 
All protocol-required laboratory tests, as defined in Section 10.2, must be conducted in 
accordance with the laboratory manual and the Schedule of Assessments. 
8.2.6 
Suicidal Ideation and Behavior Risk Monitoring 
Suicidality will be monitored during the trial using the C-SSRS. This semi-structured 
interview was originally developed to evaluate the link between antidepressants and 
suicidal behavior and ideation in youth and adverse events from pediatric clinical trials 
(Posner et al, 2011). It was designed to quantify the severity of suicidal ideation and 
behavior. Trial personnel administering the C-SSRS must have completed the appropriate 
training and have valid certification. Access to training on the scale will be provided by 
the sponsor or designee. 
This trial will use the “Baseline/Screening” and “Since Last Visit” versions of the scale. 
The “Baseline/Screening” version will be completed for all participants at Screening to 
determine eligibility. The exclusion criteria based on the C-SSRS are provided in 
Section 5.2. 
The “Since Last Visit” C-SSRS form will be completed after the Screening visit. The 
investigator will review the results of the “Since Last Visit” C-SSRS during the trial to 
determine whether it is safe for the participant to continue in the trial. If a participant has 
any “YES” answers on the C-SSRS for the suicidal ideation or suicidal behavior items, 
the investigator will evaluate whether a risk assessment by a qualified mental health 
professional (or the investigator alone if the investigator is a qualified mental health 
professional) is needed and discuss with the medical monitor whether the participant 
should continue in or be discontinued from the trial. 
8.2.7 
Extrapyramidal Symptoms 
Trained and experienced clinicians should administer the EPS assessments and the 
number of raters should be kept to a minimum. All efforts should be made to ensure the 
same clinician administer the scales for a given participant throughout the trial.  
Benzodiazepines and non-benzodiazepine sleep aids are not permitted within 12 hours of 
administration of EPS scales (see Section 6.7).  
8.2.7.1 
Simpson-Angus Scale 
The SAS (Simpson and Angus, 1970) consists of a list of 10 symptoms of parkinsonism 
(gait, arm dropping, shoulder shaking, elbow rigidity, wrist rigidity, head rotation, 
glabella tap, tremor, salivation, and akathisia). 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. 

 
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8.2.7.2 
Abnormal Involuntary Movement Scale 
The AIMS assessment (Guy, 1976) consists of 10 items describing symptoms of 
dyskinesia. Facial and oral movements (items 1 through 4), extremity movements (items 
5 and 6), and trunk movements (item 7) are observed unobtrusively while the participant 
is at rest, and the investigator also makes global judgments on the participant’s 
dyskinesias (items 8 through 10). 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 participant’s dental status. 
The participant should be sitting on a hard, firm chair while the scale is administered.  
The AIMS Movement Rating Score is defined as the sum of items 1 through 7 
(ie, items 1 through 4, facial and oral movements; items 5 and 6, extremity movements; 
and item 7, trunk movements). 
8.2.7.3 
Barnes Akathisia Rating Scale 
The BARS (Barnes, 1989) consists of 4 items related to akathisia: objective observation 
of akathisia by the investigator, subjective feelings of restlessness by the participant, 
subjective distress due to akathisia, and global clinical assessment of 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. To complete this scale, participants are observed while 
they are seated and then standing for a minimum of 2 minutes in each position. 
Symptoms observed in other situations (eg, while engaged in neutral conversation or 
engaged in other activity) may also be rated. Subjective phenomena are to be elicited by 
direct questioning.  
8.3 
Adverse Events, Serious Adverse Events, and Other Safety 
Reporting 
The definitions of AEs and SAEs can be found in Section 10.3. Definitions of AESIs are 
provided in Section 8.3.7.  
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant’s legally authorized representative). The investigator and any 
qualified designees are responsible for detecting, documenting, and recording events that 
meet the definition of an AE, SAE, or AESI and remain responsible for following up 
AESIs and AEs that are serious, considered related to the IMP or trial procedures, or that 
caused the participant to discontinue IMP (see Section 7.1). 
Further details about AE recording and follow-up are provided in Section 10.3. 

 
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8.3.1 
Time Period and Frequency for Collecting AE and SAE/AESI 
Information 
All AEs and SAEs/AESIs will be recorded from the first dose of IMP until follow-up 
contact at the time points specified in the Schedule of Assessments (Section 1.3). 
Medical occurrences that begin before the start of IMP dosing but after obtaining 
informed consent will be recorded as medical and/or psychiatric history. 
All SAEs/AESIs will be recorded and reported to the sponsor or designee immediately 
and under no circumstance should this exceed 24 hours, as indicated in Section 10.3. The 
investigator will submit any updated SAE/AESI data to the sponsor or designee within 
24 hours of it being available. 
Investigators are not obligated to actively seek AEs, AESIs, or SAEs after conclusion of 
the trial participation. However, if the investigator learns of any SAE, including a death, 
at any time after a participant has been discharged from the trial, or AESI, and he/she 
considers the event to be related to the IMP or trial participation, the investigator must 
promptly notify the sponsor. 
8.3.2 
Method of Detecting AEs and SAEs/AESIs 
The method of recording, evaluating, and assessing causality of AEs and SAEs/AESIs 
and the procedures for completing and transmitting SAE/AESI reports are provided in 
Section 10.3. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs/AESIs. 
Open-ended and nonleading verbal questioning of the participant is the preferred method 
to inquire about AE occurrences. 
8.3.3 
Follow-up of AEs and SAEs/AESIs 
After the initial AE/SAE/AESI report, the investigator is required to proactively follow 
each participant at subsequent visits/contacts. All SAEs/AESIs will be followed until 
resolution, stabilization, the event is otherwise explained, or the participant is lost to 
follow-up (as defined in Section 7.3). Further information on follow-up procedures is 
given in Section 10.3. 
8.3.4 
Regulatory Reporting Requirements for SAEs/AESIs 
Prompt notification by the investigator to the sponsor regarding an SAE/AESI is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and 
the safety of an IMP under clinical investigation are met. 
The sponsor has a legal responsibility to notify both the local health authority and other 
health authorities about the safety of an IMP under clinical investigation. The sponsor 

 
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will comply with country-specific regulatory requirements relating to safety reporting to 
the health authority, IRBs/IECs, and investigators. 
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and sponsor policy and forwarded to 
investigators as necessary. 
An investigator who receives an investigator safety report describing an SAE/AESI or 
other specific safety information (eg, summary or listing of SAEs/AESIs) from the 
sponsor will review, acknowledge, and then file it along with the Investigator’s Brochure 
and will notify the IRB/IEC, if appropriate, according to local requirements. 
8.3.5 
Pregnancy 
Details of all pregnancies in female participants or in female partners of male participants 
will be collected after the start of IMP and until final contact.  
If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Section 10.4.2. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 
8.3.6 
Treatment of Overdose 
An overdose is defined as a known deliberate or accidental administration of 
investigational drug, to or by a trial participant, at a dose above that which is assigned to 
that individual participant according to the protocol. 
There is no specific antidote for overdose with emraclidine. In the event of an overdose, 
treatment should consist of general supportive measures.  
The investigator should complete the following for any emraclidine overdose: 
1. Contact the medical monitor immediately 
2. Closely monitor the participant for any AE/SAE and clinically significant vital signs, 
ECG, or laboratory abnormalities. Additional safety procedures may need to be 
performed at the investigator’s discretion.  
3. Document the quantity of the excess dose as well as the duration of the overdose (if 
multiple time points) in the eCRF 
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the medical monitor based on the clinical evaluation of the 
participant. 

 
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8.3.7 
Adverse Events of Special Interest 
All AESIs should be reported according to the procedures and timelines for SAEs (see 
Section 10.3.4). 
The following events will be reported as AESIs: 
• AEs that result in the discontinuation of IMP including those resulting from 
elevations in liver test results (see Section 10.6)  
• Heart rate >120 bpm  
○ Confirm heart rate by ECG 
○ Repeat heart rate measurement 30 and 60 minutes after participant is at rest 
○ Report as an AESI and notify the medical monitor if heart rate remains >120 bpm 
60 minutes after initial elevation OR if it is not sinus tachycardia 
○ Continue to follow the participant as clinically appropriate 
• QTcF is >500 ms or the QTc value represents a >60 ms increase from Baseline 
○ Repeat ECG 
○ Report as an AESI and notify the medical monitor 
○ Repeat ECGs every 30 minutes until QTcF <450 ms or improves to <30 ms from 
baseline value  
○ Continue to follow the participant as clinically appropriate if QTcF does not 
improve 
• Systolic blood pressure reading (average of triplicates) ≥160 mmHg but <200 mmHg 
and/or diastolic blood pressure reading ≥100 mmHg but <120 mmHg  
○ Repeat blood pressure measurements after 5 minutes of participant at rest in a 
quiet room. If blood pressure (average of triplicates) reading continues to be 
≥160 mmHg systolic and/or ≥100 mmHg diastolic, additional blood pressure 
measurements should be performed after 30 minutes and 60 minutes from the 
initial elevation 
○ If blood pressure elevation continues to be ≥160 mmHg systolic and/or 
≥100 mmHg diastolic 60 minutes after initial elevation, report as an AESI and 
notify the medical monitor  
○ Withhold IMP 

 
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○ Consider referring participant to a health care facility for further evaluation and 
treatment as appropriate 
○ Resume IMP only upon consultation with the medical monitor 
• Systolic blood pressure ≥200 mmHg and/or diastolic blood pressure ≥120 mmHg 
○ Repeat blood pressure measurements after 5 minutes of participant at rest in a 
quiet room. If blood pressure (average of triplicates) reading continues to be 
≥200 mmHg systolic and/or ≥120 mmHg diastolic, additional blood pressure 
measurement should be performed after 30 minutes from the initial elevation 
○ If blood pressure continues to be ≥200 mmHg systolic and/or ≥120 mmHg 
diastolic after 30 minutes from initial elevation, report as an AESI and notify the 
medical monitor 
○ If blood pressure does not improve, perform a physical examination and obtain 
the following tests: serum blood urea nitrogen, creatinine, serum cystatin-C, 
plasma renin activity, serum catecholamines (metanephrines, normetanephrines), 
serum aldosterone, endothelin level; urinalysis; and an ECG 
○ Refer participant to a health care facility for further evaluation, monitoring, and 
treatment. 
○ Withhold IMP 
○ IMP may be resumed only after discussing with the medical monitor 
8.4 
Pharmacokinetics 
Venous blood samples will be collected in appropriately labeled tubes, at the times 
specified in the Schedule of Assessments (Section 1.3), to evaluate the PK of emraclidine 
and its metabolite CV-0000354. Additional details about sample collection, processing, 
and shipment will be provided in the Lab Manual.  
All PK samples should be obtained at the exact nominal time relative to dosing. Samples 
obtained within 20% of the nominal time point (eg, within 12 minutes of a 60-minute 
sample) will not be considered a protocol deviation, as long as the exact time of sampling 
is captured in the source documents. 
A fully validated bioanalytical method will be used to quantitate the concentrations of 
emraclidine and CV-0000364 (metabolite) in plasma. Plasma samples collected in this 
trial may be used to further development of the bioanalytical method or identification of 
metabolites. The backup plasma samples may be stored for a duration of approximately 
up to 1 year after the date of the final clinical study report. 

 
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Plasma concentration data from this trial combined with other data may also be used to 
build and/or update a population PK model for emraclidine for the purpose of further 
characterizing the PK or PK/pharmacodynamic behavior of the compound. Any 
population PK assessment will be described in a separate report. 
Statistical analyses for PK parameters are summarized in Section 9.3.6. 
8.5 
Biomarkers 
Biomarkers are not evaluated in this trial.  
8.6 
Future Biospecimen Research 
Studying the variation in genetic markers and other biomarkers may help to explain some 
of the variability in response seen with some drugs among different individuals. This is 
referred to as pharmacogenomic/biomarker research. Comparing the DNA, RNA, protein, 
and metabolite variation patterns of participants who respond well and those who respond 
poorly to treatment may help to better define the most appropriate group of participants in 
which to target a given treatment. Collecting biospecimens for exploratory 
pharmacogenomic/biomarker analyses and retaining them at Cerevel makes it possible to 
better understand the drug’s mechanism of action and to seek explanations for differences 
in, for example, exposure, pharmacodynamics, tolerability, or safety not anticipated prior 
to the beginning of this trial. 
Future biospecimen research samples will be collected from participants who provide 
additional consent specifically for this sample collection. Research performed on these 
samples may include genetic analyses, gene expression profiling, proteomics, 
metabolomics and/or the measurement of other analytes. Such research is for biomarker 
testing to address emergent questions not described elsewhere in the protocol (as part of 
the main trial). The objective of collecting these specimens is to explore and identify 
biomarkers that inform the scientific understanding of diseases or their therapeutic 
treatments. 
Additional details about future biospecimen research samples are provided in 
Section 10.5. 
8.7 
Health Economics and Resource Utilization 
8.7.1 
Short Form – 6 Dimensions Version 2.0 
The SF-6D is a new, internationally adopted measure for assessing the cost-effectiveness 
of health care interventions. The SF-6D was developed by reducing the SF-36 to a 
6-dimension classification (physical functioning, role participation, social functioning, 
bodily pain, mental health, and vitality) and developing an algorithm to generate a 
continuous index for health (Brazier et al, 2002). The algorithm shows how much value 
people place on different health limitations, and how they will trade-off between them; 
for example, how much vitality a patient will sacrifice for a reduction in pain. Version 2.0 

 
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of the SF-6D (SF-6Dv2) is an improved version of the SF-6D, the SF-6Dv2 classification 
system describes more distinct levels of health than SF-6D, changes the descriptions used 
for a number of dimensions, and provides clearer wording for health state valuation 
(Brazier et al, 2020). 
9 STATISTICAL CONSIDERATIONS 
9.1 
Statistical Hypotheses 
The primary hypotheses are summarized below. The tests will be conducted in 
hierarchical order from H1 to H2 at a 2-sided  level of 0.05. If both primary hypotheses 
H1 and H2 are successful, the key secondary endpoint of change from baseline CGI-S at 
Week 6 will be similarly tested in hierarchical order with respect to the 2 doses. The 
overall type I error rate thus is maintained at the 0.05 level. 
Primary Endpoint 
Emraclidine 30 mg QD vs 
Placebo 
Emraclidine 15 mg QD vs 
Placebo 
Change from Baseline to 
Week 6 in PANSS total score 
H1 : µactive=µplacebo 
vs  µactive ≠  µplacebo 
H2 : µactive=µplacebo 
vs  µactive ≠  µplacebo 
Abbreviations: PANSS=Positive and Negative Syndrome Scale; QD=once daily. 
9.2 
Analysis Sets 
The analysis sets that are defined for this trial are described in Table 6. 
Table 6 
Analysis Set Descriptions 
 
Population 
Description 
Analysis 
ITT 
All randomized participants 
Demographic and Baseline 
Characteristics 
FAS 
All randomized participants who 
receive at least 1 dose of IMP. This will 
be the safety analysis set. 
Safety analysis 
mITT 
All randomized participants who 
receive at least 1 dose of IMP and have 
both a baseline and at least 1 
postbaseline PANSS assessment 
Primary analysis set for efficacy 
Endpoint 
completers 
All participants in the mITT population 
who complete the PANSS assessment 
at Week 6 
Sensitivity analysis for efficacy 
PK Analysis Set 
All randomized participants who 
receive at least 1 dose of IMP and have 
at least 1 measurable emraclidine 
concentration 
PK analysis 
Abbreviations: FAS=full analysis set; IMP=investigational medicinal product; ITT=intent-to-treat; 
mITT=modified intent-to-treat; PANSS=Positive and Negative Syndrome Scale; PK=pharmacokinetic. 

 
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9.3 
Statistical Analyses 
9.3.1 
General Considerations 
Descriptive statistical methods will be used to summarize the data from this trial, with 
statistical testing performed for the efficacy endpoints. All statistical analyses will be 
conducted with the SAS® System, version 9.4 or higher. The remainder of this section is 
a summary of the planned statistical analyses of the primary and secondary endpoints as 
well as a description of planned safety analyses. Full details of these analyses will be 
included in the statistical analysis plan. 
9.3.2 
Primary Endpoint/Estimand Analyses 
The primary estimand has the following attributes:  
1. Treatments as randomized 
2. mITT population as the primary population of interest 
3. Change from Baseline to Week 6 in total PANSS score as the primary endpoint of 
interest 
4. The population level summary of interest is the treatment differences estimated based 
on the least square mean and the corresponding 95% confidence interval from the 
MMRM model with treatment, visit, and treatment by visit interaction as fixed effect, 
participant as a random effect, and baseline PANSS score as a covariate. An 
unstructured covariance structure will be used for the repeated measures. The 
Kenward-Roger approximation will be used to estimate the denominator degrees of 
freedom. If the unstructured covariance matrix results in convergence issue, the 
heterogeneous Toeplitz covariance structure followed by the heterogeneous 
first-order autoregressive (AR(1)) structure will be used. If a reduced covariance 
matrix becomes necessary, the sandwich variance estimator will be used.  
5. To address ICEs with the primary outcome data available, a treatment policy strategy 
will be used to include all collected outcomes in the primary statistical analysis, 
consistent with the intent-to-treat principle. The only exception will be the cases of 
concomitant use of protocol prohibited other antipsychotic and, in such cases, the data 
collected under the influence of confounding ICEs will be treated as missing. 
6. To address ICE of trial or treatment discontinuation with no outcome data collected 
post discontinuation, the primary analysis of MMRM described above will be 
followed by PMM approach with varying level of shift parameters for missing values 
due to discontinuations that are potentially missing not at random (MNAR), including 
discontinuation due to lack of efficacy or due to adverse events. This will be 
implemented using delta adjustment imputation method. Further details will be 
described in the SAP. 

 
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The statistical hypothesis testing on the primary endpoint (H1 and H2 above) will be 
based on the estimated treatment difference from the model at Week 6. The evaluation of 
other time points will also be derived from the same model.  
The number and proportion of responders (ie, participants with 30% reduction from 
Baseline in the PANSS total score at Week 6 or the last assessment before 
discontinuation) will be summarized. A logistic regression model, with baseline PANSS 
as a covariate, will be used to compare the proportion of responders in each active arm 
with placebo. If expected counts are <5, then a Fisher’s Exact test will be used. 
9.3.3 
Secondary Endpoint/Estimand Analyses 
The secondary estimand has the following attributes:  
1. Treatments as randomized 
2. mITT population as the population of interest 
3. Change from Baseline to Week 6 in CGI-S score as the endpoint of interest 
4. The population level summary of interest is the treatment differences estimated based 
on the least square mean and the corresponding 95% confidence interval from the 
MMRM model with treatment, visit, and treatment by visit interaction as fixed effect, 
participant as a random effect, and baseline CGI-S score as a covariate. An 
unstructured covariance structure will be used for the repeated measures. If the 
unstructured covariance matrix results in convergence issue, the heterogeneous 
Toeplitz covariance structure followed by the heterogeneous first-order 
autoregressive (AR(1)) structure will be used. When a reduced covariance matrix is 
used, the sandwich variance estimator will be used. The Kenward-Roger 
approximation will be used to estimate the denominator degrees of freedom. 
5. ICEs will be addressed using the same strategies as described above for the primary 
endpoint 
The number and proportion of participants with ≥1 and ≥2 point improvements from 
Baseline at the last CGI-S assessment (at Week 6 or the last assessment before 
discontinuation) will be summarized. A logistic regression model, with baseline CGI-S as 
a covariate, will be used to compare the proportion of responders in each active arm with 
placebo. If expected counts are < 5, then a Fisher’s Exact test will be used. 
9.3.4 
Other Endpoints 
Other endpoints, including change from Baseline in BACS and SF-6D measurements, 
will be analyzed similarly using MMRM models.  

 
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9.3.5 
Safety Analyses 
Treatment-emergent adverse events will be coded according to MedDRA and 
summarized by treatment group, system organ class, and preferred term. Further 
summaries will be done by seriousness, severity, and relationship to IMP.  
Heart rate and blood pressure measurements will be taken weekly at approximately 
2 hours after IMP administration. The weekly measurements and corresponding changes 
from Baseline will be summarized by descriptive statistics. The change from Baseline 
will be analyzed using MMRM with treatment group, visit, and treatment by visit 
interaction as fixed effects and participant as a random effect, with the baseline value as a 
covariate. The difference between each emraclidine group versus placebo at each week 
will be estimated based on the least squares mean from the MMRM with the 95% CIs. 
Other safety endpoints will be summarized with descriptive statistics by treatment group, 
including clinical laboratory assessments and metabolic parameters, and physical and 
neurological examination results (including body weight), suicidality assessments using 
C-SSRS, and EPS assessed by AIMS, SAS, and BARS. 
9.3.6 
Other Analyses 
Plasma concentrations of emraclidine and its major metabolite (if required) will be 
summarized by dose, visit, and nominal time (if applicable). All PK exposure-response 
analyses will be described in a separate PK analysis plan that will be finalized before 
database lock. 
Plasma concentrations will also be pooled with data from other trials in a population PK 
analysis to describe the time course of plasma concentrations of emraclidine and the 
influence of covariates (eg, body weight, age, sex, race, concomitant medications). The 
results of population PK analysis and response-exposure analyses will be presented 
separately from the main clinical study report. 
9.4 
Interim Analyses  
No interim analysis is planned. 
9.5 
Sample Size Determination 
A sample size of approximately 93 participants in each treatment group completing the 
Week 6 assessments (approximately 279 in total) should provide at least 90% power to 
detect an effect size of 0.48 in change from Baseline in PANSS total score at Week 6 
between either active treatment group versus placebo at the =0.05 level. The effect size 
of 0.48 represents a clinically meaningful effect on symptom reduction based on large 
scale meta-analysis of historical data from several currently approved antipsychotic 
medications in common usage (Leucht et al, 2013). It could be translated into a difference 
of 7 points versus placebo if the standard deviation of change from baseline is 14.6 points 
or a difference of 8 points versus placebo if the standard deviation of change from 

 
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baseline is 16.7 points. Both scenarios of the standard deviation are consistent with 
historical observations. To account for a discontinuation rate of approximately 25% for a 
6-week treatment period (as observed in Trial CVL-231-SCH-001), it is planned to 
randomize approximately 372 participants. 
 
 

 
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10 SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1 Regulatory, Ethical, and Trial Oversight Considerations 
10.1.1 
Regulatory and Ethical Considerations 
This trial will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines 
• Applicable ICH GCP Guidelines 
• Applicable laws and regulations 
The protocol, ICF, Investigator’s Brochure, and other relevant documents (eg, 
advertisements) must be submitted to an IRB/IEC by the investigator and reviewed and 
approved by the IRB/IEC before the trial is initiated. Any amendments to the protocol 
will require IRB/IEC approval before implementation of changes made to the trial design, 
except for changes necessary to eliminate an immediate hazard to trial participants. 
The investigator will be responsible for the following: 
• Providing written summaries of the status of the trial to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established 
by the IRB/IEC 
• Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
• Providing oversight of the conduct of the trial at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, EU Regulation 536/2014 for 
clinical trials (if applicable), and all other applicable local regulations 
10.1.2 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the trial and for 1 year after completion of the trial. 

 
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10.1.3 
Informed Consent Process 
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.  
The medical record must include a statement that informed consent was obtained before 
the participant was enrolled in the trial and the date the consent was obtained. The 
authorized person obtaining the informed consent must also agree to (eg, provide 
electronic agreement or written signature) the ICF. 
Participants must be reconsented to the most current version of the ICF(s) during their 
participation in the trial. 
A copy of the ICF(s) must be provided to the participant. 
As described in Section 10.5, additional consent will be required for participants from 
whom future biospecimen research samples will be collected. 
10.1.4 
Data Protection 
Participants will be assigned a unique identifier by the sponsor or designee. Any 
participant records or datasets that are transferred to the sponsor will contain the 
identifier only; participant names or any information which would make the participant 
identifiable will not be transferred. 
The participant must be informed that his/her personal trial-related data will be used by 
the sponsor in accordance with local data protection law. The level of disclosure must 
also be explained to the participant who will be required to give consent for their data to 
be used as described in the informed consent. 
The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from health authorities. 
10.1.5 
Dissemination of Clinical Trial Data 
Cerevel fulfills its commitment to publicly disclose clinical trial results through posting 
trial results on ClinicalTrials.gov, the European Clinical Trials Database, and other public 
registries in accordance with applicable local laws/regulations. 

 
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In all cases, trial results are reported by Cerevel in an objective, accurate, balanced, and 
complete manner and are reported regardless of trial outcome or the country in which the 
trial was conducted. 
Clinical trial US Basic Results are posted on Clinicaltrials.gov for all Cerevel-sponsored 
interventional trials conducted in participants that evaluate the safety and/or efficacy of a 
Cerevel product, regardless of the geographical location in which the trial is conducted. 
US Basic Results are submitted for posting within 1 year of the primary completion date 
as defined in Section 4.4 for trials in adult populations or within 6 months of the primary 
completion date for trials in pediatric populations. 
Cerevel posts EU Basic Results on EudraCT for all Cerevel-sponsored interventional 
trials that are in scope of EU requirements. EU Basic Results are submitted for posting 
within 1 year of the primary completion date as defined in Section 4.4 for trials in adult 
populations or within 6 months of the primary completion date for trials in pediatric 
populations. 
10.1.6 
Data Quality Assurance 
All participant data relating to the trial will be recorded on the eCRF unless transmitted to 
the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the eCRF. 
Guidance on completion of the eCRF will be provided in the CRF Completion 
Guidelines. 
The investigator must permit trial-related monitoring, audits, IRB/IEC review, and health 
authority inspections and provide direct access to source data documents. 
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as risk management and mitigation strategies and analytical risk-based monitoring), 
methods, responsibilities, and requirements, including handling of noncompliance issues 
and monitoring techniques (central, remote, or onsite monitoring) are provided in the 
Clinical Monitoring Plan. 
The sponsor or designee is responsible for the data management of this trial including 
quality checking of the data. 
The sponsor assumes accountability for actions delegated to other individuals (eg, 
CROs). 
Records and documents, including signed ICFs, pertaining to the conduct of this trial 
must be retained by the investigator for the longest of the following periods: 

 
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• At least 2 years after the date on which approval to market the drug is obtained (or if 
IMP development is discontinued, the date health authorities were notified of 
discontinuation) 
• At least 3 years after the sponsor notified the investigator that the final report has 
been filed with health authorities  
• A longer period if required by local regulations or institutional policies 
No records may be destroyed during the retention period without the written approval of 
the sponsor. No records may be transferred to another location or party without written 
notification to the sponsor. 
10.1.7 
Source Documents 
Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site. 
Data reported entered in the eCRF that are transcribed from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending 
on the trial. Also, current medical records must be available. 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
Trial monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the trial is being conducted in accordance with the currently approved protocol and any 
other trial agreements, ICH GCP, and all applicable regulatory requirements. 
10.1.8 
Trial and Site Closure 
The sponsor or designee reserves the right to close a trial site or terminate the trial at any 
time for any reason at the sole discretion of the sponsor. Trial sites will be closed upon 
trial completion. A trial site is considered closed when all required documents and trial 
supplies have been collected and a trial site closure visit has been performed. 
The investigator may initiate trial site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for early closure of a trial site by the sponsor or investigator may include, but are 
not limited to, the following: 
• Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor’s procedures, or GCP guidelines 

 
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• Inadequate recruitment of participants by the investigator 
• Total number of participants included earlier than expected 
The investigator will notify the sponsor promptly if the trial is terminated by the 
investigator or the IRB/IEC. 
If the sponsor terminates or suspends the trial for any reason, prompt notification will be 
given to investigators, IRBs/IECs, health authorities in accordance with regulatory 
requirements. 
10.1.9 
Publication Policy 
The results of this trial may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor 
before submission. This allows the sponsor to protect proprietary information and to 
provide comments. 
The sponsor will comply with the requirements for publication of trial results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multicenter trials only in their entirety and not as individual site data. In 
this case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
10.2 Clinical Laboratory Tests 
Protocol-required tests detailed in Table 7 will be performed by a central laboratory, with 
the exception of those specified to be done locally in the Operations Manual. 
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5. 
Additional tests may be performed at any time during the trial as determined necessary by 
the investigator or required by local regulations. 
Serology (screening for human immunodeficiency virus, hepatitis B virus, hepatitis C 
virus) will be done at Screening. 
Serum/urine pregnancy tests are required for all women of childbearing potential at the 
time points indicated in the Schedule of Assessments; however, pregnancy tests can be 
done anytime during the trial at the investigator’s discretion. 
Participants must have SARS-CoV-2 testing done with a negative test result prior to 
admission to the inpatient facility, refer to site procedures for additional details on 

 
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10.4 Contraceptive Guidance and Collection of Pregnancy Information 
10.4.1 
Definitions 
10.4.1.1 
Highly Effective Form of Contraception (Failure Rate <1%) 
A highly effective form of contraception (failure rate of <1%) is defined as follows: 
• Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation: 
○ Oral 
○ Intravaginal 
○ Transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation: 
○ Oral 
○ Injectable 
○ Implantable 
• Intrauterine device 
• Intrauterine hormone-releasing system 
• Bilateral tubal occlusion 
• Vasectomized partner 
• Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the trial intervention. The reliability of sexual abstinence needs to be evaluated 
in relation to the duration of the clinical trial and the preferred and usual lifestyle of 
the participant.  
10.4.1.2 
Women of Childbearing Potential, Women of Nonchildbearing 
Potential, and Fertile Men 
A woman is considered to be a woman of childbearing potential following menarche and 
until becoming postmenopausal unless permanently sterile.  
A woman is considered to be of nonchildbearing potential if she fulfills either of the 
following criteria: 

 
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• Underwent permanent sterilization including hysterectomy, bilateral oophorectomy, 
or bilateral salpingectomy 
• Is in a postmenopausal state, which is defined as no menses for 12 consecutive 
months without an alternative medical cause, and confirmed with an FSH level 
>40 IU/mL. 
A man is considered fertile after puberty unless permanently sterile by bilateral 
orchidectomy. 
10.4.2 
Collection of Pregnancy Information 
10.4.2.1 
Male Participants With Partners Who Become Pregnant 
• The investigator will attempt to collect pregnancy information on any male 
participant’s female partner who becomes pregnant while the male participant is in 
this trial. This applies only to male participants who receive trial intervention. 
• After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the appropriate 
form and submit it to the sponsor within 24 hours of learning of the partner’s 
pregnancy. The female partner will also be followed to determine the outcome of the 
pregnancy. Information on the status of the mother and child will be forwarded to the 
sponsor. Generally, the follow-up will be no longer than 12 weeks following the 
estimated delivery date. Any termination of the pregnancy will be reported regardless 
of fetal status (presence or absence of anomalies) or indication for the procedure.  
10.4.2.2 
Female Participants Who Become Pregnant 
• 
The investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this trial. Information will be recorded on 
the appropriate form and submitted to the sponsor within 24 hours of learning of a 
participant’s pregnancy.  
• 
The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate and 
the information will be forwarded to the sponsor. Generally, follow-up will not be 
required for longer than 12 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure. 
• 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE. A spontaneous abortion is always considered to be an SAE and will be 
reported as such. Any post-trial pregnancy related SAE considered reasonably 
related to the trial intervention by the investigator will be reported to the sponsor as 
described in Section 8.3.4. While the investigator is not obligated to actively seek 

 
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this information in former trial participants, he or she may learn of an SAE through 
spontaneous reporting. 
• 
Any female participant who becomes pregnant while participating in the trial will 
discontinue trial intervention and be withdrawn from the trial. 

 
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10.5 Future Biospecimen Research 
Use/Analysis of DNA 
• Genetic variation may impact a participant’s response to IMP, susceptibility to, and 
severity and progression of disease. Variable response to IMP may be due to genetic 
determinants that impact drug absorption, distribution, metabolism, and excretion; 
mechanism of action of the intervention; disease etiology; and/or molecular subtype 
of the disease being treated. Therefore, where local regulations and IRB/IEC allow, a 
sample will be collected for DNA analysis from consenting participants. 
• DNA samples will be used for research related to emraclidine or schizophrenia and 
related diseases. They may also be used to develop tests/assays including diagnostic 
tests related to emraclidine and/or interventions of this drug class and schizophrenia. 
Genetic research may consist of the analysis of one or more candidate genes or the 
analysis of genetic markers throughout the genome or analysis of the entire genome 
(as appropriate). 
• The samples may be analyzed as part of a multitrial assessment of genetic factors 
involved in the response to emraclidine or interventions of this class to understand 
trial disease or related conditions. 
• The results of genetic analyses may be reported in the CSR or in a separate trial 
summary. 
• The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 
• The samples will be retained while research on emraclidine or trial treatments of this 
class or schizophrenia continues but no longer than 15 years or other period as per 
local requirements. 
 
 

 
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10.6 Liver Safety: Suggested Actions and Follow-up Assessments  
10.6.1 
Assessment of Elevations in Liver Test Results 
Elevations in liver test results occurring during a clinical trial may result from DILI. 
However, since DILI is a diagnosis of exclusion, it is essential to exclude other etiologies 
(see Section 10.6.4) that may lead to elevated results in liver tests.  
When amionotransferase (ALT or AST) levels increase to ≥3 × ULN during a clinical 
trial, current US guidance (US FDA, 2009) recommends close observation and diagnostic 
workup for causes of hepatic injury (see Section 10.6.4) other than the IMP. The 
International Consensus Criteria for idiosyncratic DILI only uses ALT to define DILI 
when referring to aminotransferase levels (Watkins, 2019). The CIOMS Working Group 
on DILI suggests using serum ALT as it is more specific than AST to detect and monitor 
the liver injury, irrespective of the cause (EASL, 2019; CIOMS, 2020; Kwo et al, 2017). 
The medical monitor must be consulted when ALT levels increase to ≥3 × ULN. 
Table 16 describes liver test monitoring during the close observation period of elevated 
liver tests during a clinical trial. Close observation is required until the elevations in liver 
test results return to baseline levels or normalize.  
Table 16 
Monitoring of Liver Tests 
Result 
Frequency for Repeating Liver (AST, ALT, 
Bilirubin [Total and Direct]) and INR Tests 
If either of the following: 
• 
ALT ≥3 × ULN and total  bilirubin ≥2 × ULN 
or INR >1.5 
• 
ALT ≥3 × ULN with symptoms and signs of 
hepatitis 
Every 24 hours until laboratory abnormalities 
improve 
If ALT ≥3 × ULN and total  bilirubin or INR are 
within the normal range 
Every 48 to 72 hours until laboratory 
abnormalities  improve 
If the liver test abnormalities improve AND 
participants’ symptoms improve or participants are 
asymptomatic 
Frequency may decrease to once weekly 
Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; INR=international 
normalized ratio; ULN=upper limit of normal. 
10.6.2 
Criteria for Permanent Discontinuation of IMP (Potential Hy’s Law 
Cases) 
The following criteria may suggest the presence of severe liver injury regardless of the 
etiology; “Hy’s law” points to advanced and potentially severe DILI when other possible 
causes of liver injury have been excluded. When all of the following criteria are met, the 
IMP should be permanently discontinued and not restarted under any condition and the 
event should be reported as an SAE. 

 
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1. ALT increases to ≥3 × ULN  
2. Total bilirubin increases to ≥2 × ULN or INR >1.5 
3. Alkaline phosphatase value <2 × ULN (ie, absence of significant cholestasis) 
4. No alternative cause explains the combination of the above laboratory abnormalities; 
important alternative causes are included in Table 18. 
10.6.3 
Criteria for Temporary Withholding or Permanent Discontinuation 
of IMP 
Participants who develop abnormal results in liver tests (AST, ALT, alkaline 
phosphatase, total bilirubin) during the trial treatment period may meet the criteria for 
discontinuation of IMP treatment specified in the FDA guidance (Table 17). 
Table 17 
Criteria for Temporarily Withholding IMP in Association With 
Abnormalities in Liver Test Results 
Baseline ALT Value 
ALT Elevation 
<3 × ULN 
• 
>8 × ULN 
• 
>5 × ULN for more than 2 weeks 
• 
≥3 × ULN and (total bilirubin ≥2 × ULN or INR >1.5) 
• 
≥3 × ULN with the presence of signs and symptoms consistent 
with acute hepatitis and/or eosinophilia (≥500 eosinophils/µL) 
Abbreviations: ALT=alanine aminotransferase; IMP=investigational medicinal product; INR=international 
normalized ratio; ULN=upper limit of normal. 
IMP should be withheld pending an investigation (Table 19) of alternative causes of 
abnormalities in liver test results (Table 18). Clinical and laboratory follow-up should 
continue during the withholding period until the abnormalities in liver test results return 
to baseline values. 
Resumption of IMP can only occur with the express consent of the sponsor and/or their 
medical designee and only if another cause for the liver test abnormalities is identified 
and liver tests return to within the normal range.  

 
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10.6.4 
Evaluation of Alternative Causes of Liver Test Result 
Abnormalities 
Table 18 
Alternative Causes of Abnormalities in Liver Test Results 
Biliary obstruction, focal liver lesions (benign or malignant), vascular liver disease (such as portal vein 
thrombosis or Budd-Chiari syndrome) 
Viral hepatitis (eg, hepatitis A/B/C/D/E, Epstein-Barr virus, cytomegalovirus, herpes simplex virus, 
varicella, toxoplasmosis, and parvovirus) 
Autoimmune hepatitis  
Exposure to hepatotoxic agents/drugs or hepatotoxins (other than IMP), including herbal and dietary 
supplements, plants, and mushrooms 
Alcoholic hepatitis 
Nonalcoholic steatohepatitis and hepatic steatosis  
Congestive heart failure, hypotension, ischemic hepatitis 
Others: sepsis, sinusoidal obstruction syndrome, primary biliary cholangitis, primary sclerosing 
cholangitis, Wilson disease, hemochromatosis, alpha-1-antitrypsin deficiency  
Abbreviations: IMP=investigational medicinal product. 
Table 19 
Investigation of Alternative Etiologies for Elevated Liver Test 
Results 
Initial set of testsa 
Complementary Tests and Parameters 
Etiologies 
Complete blood count with differential (eg, 
eosinophilia) 
Infection (sepsis), immune-related DILI 
(eosinophilia), high MCV (alcoholic hepatitis) 
ALT, AST, GGT, serum PEth 
Alcoholic hepatitis (AST:ALT ratio ≥2) 
ALP and GGT 
Biliary obstruction 
CPK, haptoglobin, LDH, and peripheral blood 
smear 
Rhabdomyolysis and hemolysis 
HAV IgM 
Hepatitis A 
HBsAg, anti-HBc IgM, total anti-HBc, anti-HBs, 
HBV-DNA (by PCR) 
Hepatitis B (acute, reactivation of chronic or 
occult hepatitis B) 
anti-HCV, HCV-RNA (by PCR) 
Acute hepatitis C 
HEV IgM and IgG 
Acute hepatitis E 
Liver imaging (ultrasound, CT, or MRI) 
Biliary obstruction, focal lesions, vascular liver 
disease, hepatic steatosis 
Serum total Ig G, ANA, anti-smooth muscle 
antibody 
Autoimmune hepatitis 
Serum acetaminophen (paracetamol) concentration 
Acetaminophen (paracetamol) overdose 

 
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Obtain a more detailed history as follows: 
• 
Prior and concurrent diseases or illness 
• 
Exposure to environmental and/or industrial chemical agents 
• 
Presence of symptoms (if applicable) including right upper quadrant pain, hypersensitivity-type 
reactions, fatigue, nausea, vomiting, and fever 
• 
Prior and concurrent alcohol use, recreational drug use, and special diets 
• 
Concomitant use of medications (including nonprescription medicines and herbal and dietary 
supplements), plants, and mushrooms 
Additional set of testsb 
Complementary Tests and Parameters 
Etiologies 
Echocardiogram 
Congestive heart failure 
CMV IgM (CMV-DNA) 
Acute CMV infection 
EBV IgM (EBV-DNA) 
Acute EBV infection 
HSV IgM (HSV-DNA) 
Acute HSV infection 
Anti-mitochondrial autoantibodies 
PBC 
24 hours urine copper and serum ceruloplasmin 
Wilson disease 
Iron studies (serum iron and ferritin) and 
transferrin saturation 
Hemochromatosis 
Serum alpha-1 antitrypsin 
Alpha-1-antitrypsin deficiency 
MRI, ERCP, ANA, perinuclear anti-neutrophil 
cytoplasmic 
PSC 
Hepatology consult may be requested (a liver biopsy may be considered in consultation with a 
hepatologist). The medical monitor should be contacted for questions regarding adequate 
follow-up tests. 
Abbreviations: ALP=alkaline phosphatase; ALT=alanine aminotransferase; ANA=anti-nuclear antibody; 
anti-HBc=hepatitis B core antibody; anti-HBs=hepatitis B surface antibody; anti-HCV=hepatitis C virus 
antibody; AST=aspartate aminotransferase; CMV=cytomegalovirus; CPK=creatinine phosphokinase; 
CT=computed tomography; DILI= drug-induced liver injury; DNA=deoxyribonucleic acid; 
EBV=Epstein-Barr virus; ERCP=endoscopic retrograde cholangiopancreatography; GGT=gamma 
glutamyltransferase; HAV=hepatitis A virus; HBsAg=hepatitis B surface antigen; HBV=hepatitis B virus; 
HCV=hepatitis C virus; HEV=hepatitis E virus; HSV=herpes simplex virus; Ig=immunoglobulin; 
LDH=lactate dehydrogenase; MCV=mean corpuscular volume; MRI=magnetic resonance imaging; 
PBC=primary biliary cholangitis; PCR=polymerase chain reaction; PEth=phosphatidylethanol; 
PSC=primary sclerosing cholangitis; RNA=ribonucleic acid. 
a. To be done for all participants. 
b. To be done when clinically indicated.  
 
 

 
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10.7 Moderate to Strong Inducers and Inhibitors of Cytochrome P450 3A 
(not exhaustive) 
Note that this is not a complete list and that the investigator is responsible for ensuring 
that participants are not receiving any strong or moderate inducers or inhibitors of 
cytochrome P450 3A during the trial.  
CYP 3A Inhibitors/ 
CYP 3A Inducers 
Antivirals 
Antivirals 
Nirmatrelvir/ritonavira 
Efavirenz 
Indinavir 
Nevirapine 
Nelfinavir 
Etravirine 
Ritonavir 
Tipranivir 
Saquinavir 
Miscellaneous 
Boceprevir 
Barbiturates 
Lopinavir/ritonavir 
Carbamazepine 
Amprenavir 
Cenobamate 
Atazanavir 
Eslicarbazepine 
Telaprevir 
Glucocorticoids (systemic) 
Darunavir/ritonavir 
Modafinil 
Fosamprenavir 
Oxcarbazepine 
Antibiotics 
Phenobarbital 
Clarithromycin 
Phenytoin 
Erythromycin 
Rifabutin 
Telithromycin 
Rifampin 
Ciprofloxacin 
St. John’s wort 
Anti-infectives 
Bosentan  
Itraconazole 
 
Ketoconazole 
 
Fluconazole 
 
Posaconazole 
 
Voriconazole 
 
Anti-anginal/hypertensive therapy 
 
Diltiazem 
 
Verapamil 
 
Anti-cancer therapy 
 
Crizotinib 
 
Imatinib 
 
Miscellaneous 
 
Nefazodone 
 
Aprepitant 
Grapefruit juiceb 
Conivaptan 
 

 
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a. 
Paxlovid (nirmatrelvir co-packed with ritonavir) is prohibited. 
b. A 7-day washout prior to dosing is required if grapefruit juice was being consumed continually. 
 
 

 
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10.8 Abbreviations 
Abbreviation Definition 
AE 
adverse event 
AESI 
adverse event of special interest 
AIMS 
Abnormal Involuntary Movement Scale 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
BACS 
Brief Assessment of Cognition in Schizophrenia 
BARS 
Barnes Akathisia Rating Scale 
BID 
twice daily 
bpm 
beats per minute 
CFR 
Code of Federal Regulations 
CGI-S 
Clinical Global Impression-Severity of Symptoms 
CIOMS 
Council for International Organizations of Medical Sciences 
Cmax 
maximum (peak) plasma concentration 
COVID-19 
coronavirus disease-2019 
CRF 
case report form 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CYP 
cytochrome P450 
DILI 
drug-induced liver injury 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EPS 
extrapyramidal symptoms 
ET 
early termination 
EU 
European Union 
GCP 
Good Clinical Practice 
ICE 
intercurrent event 
ICF 
informed consent form 
ICH 
International Council for Harmonisation  
IEC 
Independent Ethics Committee 
IMP 
investigational medicinal product 
INN 
International Nonproprietary Name 

 
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Abbreviation Definition 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
mAChR 
muscarinic acetylcholine receptor 
MedDRA 
Medical Dictionary for Regulatory Activities 
MINI 
Mini International Neuropsychiatric Interview 
MMRM 
mixed model for repeated measures 
MNAR 
missing not at random 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse Events 
PANSS 
Positive and Negative Syndrome Scale 
PK 
pharmacokinetic(s) 
PMM 
pattern mixture model 
QD 
once daily 
QTc 
corrected QT interval 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus-2 
SAS 
Simpson Angus Scale 
SF-6D 
Short Form-6 Dimensions 
t1/2 
terminal half-life 
TEAE 
treatment-emergent adverse event 
THC 
tetrahydrocannabinol 
Tmax 
time of maximum plasma concentration 
ULN 
upper limit of normal 
US 
United States 
 
 

 
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10.9 Protocol Amendment History 
The Document History table, which lists all versions of the protocol, and the Protocol 
Amendment Summary of Changes Table for the current amendment is located directly 
before the Table of Contents. 
Document History 
Protocol Version 
Date 
3.0 
15 Mar 2023 
2.0 
23 Feb 2022 
1.0 
07 Dec 2021 
Amendment: Protocol Version 2.0 (23 Feb 2022) 
This amendment is considered to be substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
Overall Rationale for the Amendment: 
The overall rationale for the amendment is to address feedback from US FDA.  
Section # and Namea 
Description of Change 
Brief Rationale 
Overall 
Replaced CVL-231 with 
emraclidine 
Updated drug name to newly 
approved official INN for 
CVL-231, emraclidine 
Title Page 
Added EudraCT number 
Required for trials conducted in 
European Union 
Signature Page 
Updated sponsor signatory 
Change in internal 
responsibilities 
1.1 Synopsis 
1.2 Schema 
4.1 Overall Design 
5 Trial Population 
5.1 Inclusion Criteria 
Increased upper limit of age range 
from 55 to 65 years 
Ensure representation of full 
age spectrum of adult patients 
with schizophrenia 
1.1 Synopsis 
4.1.2 Treatment Period 
6.3.1 Participant Assignment 
to Treatment 
Added information regarding 
stratification by geographic region 
Provide additional clarity 
1.1 Synopsis 
4.1.2 Treatment Period 
Added flexibility to contact medical 
monitor if participant unable to 
return to facility on the same day as 
a day pass was given 
Provide flexibility in trial 
procedures to allow for 
unforeseen circumstances 

 
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Section # and Namea 
Description of Change 
Brief Rationale 
1.1 Synopsis 
4.1.2 Treatment Period 
1.3 Schedule of Assessments 
Provided additional text to describe 
that some positive urine drug screen 
results may not require participant 
discontinuation after discussion and 
approval of medical monitor 
Provide clarification and ensure 
consistency with exclusion 
criteria 
1.1 Synopsis 
9.3.2 Primary 
Endpoint/Estimand Analyses 
9.3.3 Secondary 
Endpoint/Estimand Analyses 
Provided additional details 
regarding MMRM model analyses 
for primary and secondary 
estimands 
Provide additional clarity 
1.1 Synopsis 
9.3.2 Primary 
Endpoint/Estimand Analyses 
9.3.3 Secondary 
Endpoint/Estimand Analyses 
Provided additional details 
regarding sensitivity analyses for 
primary and secondary estimands 
Provide additional clarity 
1.3 Schedule of Assessments 
10.2 Clinical Laboratory Tests 
Revised testing procedures for 
SARS-CoV-2 to require negative 
test prior to admission and to adhere 
to site procedures 
Add flexibility for different 
testing procedures across 
multiple sites and countries 
1.3 Schedule of Assessments 
5.2 Exclusion Criteria 
8.2.3 Vital Sign 
Measurements 
Updated to have triplicate rather 
than duplicate vital sign 
measurements with average of last 2 
values used for assessment of 
eligibility 
Consistency with American 
Heart Association requirements 
1.3 Schedule of Assessments 
Removed footnote regarding timing 
of respiratory rate and temperature 
assessments 
Provide flexibility as timing of 
these assessments is not critical 
1.3 Schedule of Assessments 
Modified wording of footnote bb 
regarding future biospecimen 
research sample to indicate only 
collected from participants who are 
enrolled in trial 
Avoid sampling from 
participants who are screen 
failures 
2.2.2 Nonclinical Experience 
Removed paragraph on nonclinical 
mechanistic information related to 
neurobehavioral components 
associated with neurodegenerative 
diseases 
Not relevant to current trial 
2.2.3 Clinical Experience 
Minor wording modifications for 
clarity in describing changes in vital 
sign and ECG measurements 
Additional clarification 
2.3 Benefit/Risk Assessment 
Minor wording modifications for 
clarification and removal of 
inappropriate information 
Additional 
clarification/correction 

 
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Section # and Namea 
Description of Change 
Brief Rationale 
5.1 Inclusion Criteria 
Modified Inclusion Criterion #9 
regarding contraception 
requirements for men 
Clarification to indicate all 
male participants must use a 
condom, practice contraception, 
and not donate sperm during 
trial and for 7 days following 
last dose of IMP 
5.2 Exclusion Criteria 
Changed “mental retardation” to 
“intellectual disability” in Exclusion 
Criterion #1 
Consistency with DSM-5 
nomenclature 
5.2 Exclusion Criteria  
Added “for schizophrenia” to 
Exclusion Criterion #2 bullet 2 
Additional clarity 
5.2 Exclusion Criteria 
6.7.2 Prohibited Therapy 
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. 
To ensure a population with 
minimal cardiovascular risk is 
enrolled in the trial 
5.2 Exclusion Criteria 
Increased the exclusionary heart rate 
value from 90 to 100 bpm in 
Exclusion Criterion #19 
Increase generalizability of trial 
population to overall patient 
population 
5.3.1 Meals and Dietary 
Restrictions 
Added in restriction for grapefruit- 
or Seville orange-containing foods 
and beverages while in trial 
Inadvertent omission in prior 
version of protocol; as specified 
in prohibited medications 
section, grapefruit- or Seville 
orange-containing food or 
beverages are prohibited 
6.3.2 Blinding 
Removed text indicating 
information regarding 
documentation of unblinding is in 
eCRF 
Inaccurate as only limited 
information on unblinding in 
eCRF (time blind is broken and 
name of personnel involved 
only in medical record) 
6.7.2 Prohibited Therapy 
10.7 Medications Known to 
Prolong QT Interval and/or 
Cause Torsade de Pointes 
Removed medications known to 
prolong QT interval from list of 
prohibited concomitant medications 
Based on lack of evidence 
suggesting emraclidine 
increases the QT interval, there 
is no need to restrict 
medications that prolong the 
QT interval 
10.4.1.1 Highly Effective 
Form of Contraception 
(Failure Rate <1%) 
Removed extraneous information 
regarding abstinence 
Consistency with CTFG 
guidance 
10.4.1.2 Women of 
Childbearing Potential, 
Women of Nonchildbearing 
Potential, and Fertile Men 
Modified descriptions of women of 
childbearing potential, women of 
nonchildbearing potential, and 
fertile men 
Consistency with updated 
Cerevel standards and CTFG 
language 

 
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Section # and Namea 
Description of Change 
Brief Rationale 
10.6.1 Assessment of 
Elevations in Liver Test 
Results 
Added explanation and supporting 
references for the use of ALT 
(rather than ALT and AST) to detect 
and monitor liver injury  
Although the FDA guidance 
refers to both ALT and AST 
level elevations as markers for 
hepatic injury, more recent 
information suggests ALT is 
more specific than AST.  
10.7 Moderate to Strong 
Inducers and Inhibitors of 
Cytochrome P450 3A (not 
exhaustive) 
Updated time period for washout of 
grapefruit juice to 7 days 
Consistency with other sections 
of protocol 
Overall 
Minor grammatical and wording 
corrections/clarifications made 
throughout protocol 
Correct errors or provide 
further clarification  
Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; CTFG=Clinical Trials 
Facilitation Group; DSM-5=Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; 
ECG=electrocardiogram; eCRF=electronic case report form; IMP=investigational medicinal product; 
INN=International Nonproprietary Name; MMRM=mixed model for repeated measures. 
a. Numbering (eg, section numbers and numbered lists) refers to current version of the protocol.  
 

 
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