Clinical trial NCT03669250
Conditions: Schizophrenia
Keywords: MMN EEG P50 gamma power P300 auditory gating
Sponsor: Cerevance Alpha, Inc.
Start date: 2018-11-09; Completion date: 2020-03-06
Enrollment: 22 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This is a phase 1, double-blind, placebo-controlled, 3 period cross-over study to evaluate CVN058 target engagement by measuring auditory evoked potential mismatch negativity (MMN) downstream to 5-hydroxytryptamine receptor 3 (5-HT3) as a pharmacodynamic (PD) marker.

Detailed description:
Male and female subjects with schizophrenia, age 18 to 50 years old, inclusive, will be randomized to 1 of 6 treatment sequences (Table 2.a) to receive 1 of 3 dose regimens in each period: a single oral administration of CVN058 (15 mg or 150 mg) or matching placebo. The sequence will determine the order in which a subject will take each of the 3 regimens. Discontinued subjects may be replaced at the discretion of the sponsor so that approximately 20 completed subjects are available for analysis.

The study includes three 1-day treatment periods, with a minimum of 7-day washout, maximum 10 day washout (2 total washouts, after Periods 1 and 2) between periods, and a 7-10 day follow-up call post dosing of the last period. Subjects may be inpatients or outpatients at the discretion of the Investigator.

Arms: arm 1: CVN058 prepared in concentrations of 10mg/mL, and are compounded by the clinical site. Subjects will receive one dose of CVN058 at 15mg or 75mg substitution of 15mg. arm 2: CVN058 prepared in concentrations of 10mg/mL, and are compounded by the clinical site. Subjects will receive one dose of CVN058 at 150mg. arm 3: Matching placebo.
Interventions: intervention 1: CVN058 intervention 2: Placebo comparator
Intervention descriptions: intervention 1: CVN058 will be given at two doses, a low does and a high dose intervention 2: inactive placebo

Protocol documents:
Prot_000.pdf: 
Cerevance Alpha, Inc. 
CVN058 Oral Solution 
Clinical Study Report: CVN058-103 
IND 121,520 
CONFIDENTIAL 
16.1.1 PROTOCOL AND PROTOCOL AMENDMENTS 
The following original protocol and protocol amendment versions were reviewed and approved 
by a duly constituted IRB and were implemented for this study: 
Original Protocol Version 1.0, Issue Date: 21 May 2018 
Protocol Version 2.0, incorporating Amendment #1, Issue Date: 02 July 2018 
Protocol Version 3.0, incorporating Amendment #2, Issue Date: 28 Sep 2018 
Protocol Version 4.0, incorporating Amendment #3, Issue Date: 27 Mar 2019 
Protocol Version 5.0, incorporating Amendment #4, Issue Date: 24 Sep 2019 


PROTOCOL 
A Placebo-Controlled Study to Evaluate the Effect of a Single Dose of CVN058 on 
Mismatch Negativity in Subjects with Stable Schizophrenia 
Short title: CVN058 Effect on Mismatch Negativity in Schizophrenics 
Sponsor: 
Cerevance Alpha (hereafter, “Cerevance”) 
One Marina Park Drive, suite 1410 
Boston, MA 02210 
Study Number: 
CVN058-103 
IND Number: 
121,520 
EudraCT Number: 
N/A 
Compound: 
CVN058  
Date: 
21 MAY 2018 
Amendment Number: 
N/A 
CONFIDENTIAL PROPERTY OF CEREVANCE 
This document is a confidential communication of Cerevance. Acceptance of this document constitutes the 
agreement by the recipient that no information contained herein will be published or disclosed without written 
authorization from Cerevance except to the extent necessary to obtain informed consent from those persons to whom 
the drug may be administered. Furthermore, the information is only meant for review and compliance by the 
recipient, his or her staff, and applicable institutional review committee and regulatory agencies to enable conduct of 
the study. 
            NCT Number: NCT03669250 
 This NCT number has been applied to the document for purposes of posting on Clinicaltrials.gov






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INVESTIGATOR AGREEMENT  
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, and 
any other product information provided by the sponsor. I agree to conduct this study in 
accordance with the requirements of this protocol and also to protect the rights, safety, privacy, 
and well-being of study subjects in accordance with the following: 
• The ethical principles that have their origin in the Declaration of Helsinki. 
• International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline. 
• All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations. 
• Regulatory requirements for reporting serious adverse events defined in Section 10.2 of this 
protocol. 
• Terms outlined in the Clinical Study Site Agreement. 
• Appendix B – Responsibilities of the Investigator. 
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in the clinical trial agreement with Cerevance. 
Signature of Investigator 
Date 
Investigator Name (print or type) 
Investigator’s Title 
Location of Facility (City, State/Provence) 
Location of Facility (Country) 


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TABLE OF CONTENTS 
1.0 
ADMINISTRATIVE INFORMATION ..............................................................................2 
1.1 
Contacts..........................................................................................................................2 
1.2 
Approval ........................................................................................................................3 
2.0 
STUDY SUMMARY.........................................................................................................10 
3.0 
LIST OF ABBREVIATIONS ............................................................................................14 
4.0 
INTRODUCTION .............................................................................................................16 
4.1 
Background ..................................................................................................................16 
4.2 
Non-Clinical .................................................................................................................17 
4.3 
Clinical .........................................................................................................................17 
4.4 
Rationale for the Proposed Study ................................................................................18 
5.0 
STUDY OBJECTIVES AND ENDPOINTS .....................................................................20 
5.1 
Objectives ....................................................................................................................20 
5.1.1 Primary Objective ..................................................................................................20 
5.1.2 Secondary Objective ..............................................................................................20 
5.1.3 Exploratory Objectives ..........................................................................................20 
5.2 
Endpoints .....................................................................................................................20 
5.2.1 Primary Endpoints .................................................................................................20 
5.2.2 Secondary Endpoint ...............................................................................................20 
5.2.3 Exploratory Endpoints ...........................................................................................20 
6.0 
STUDY DESIGN AND DESCRIPTION ..........................................................................22 
6.1 
Study Design ................................................................................................................22 
6.2 
Justification for Study Design, Dose, and Endpoints ..................................................23 
6.3 
Premature Termination or Suspension of Study or Investigational Site ......................24 
6.3.1 Criteria for Premature Termination or Suspension of the Study ...........................24 
6.3.2 Criteria for Premature Termination or Suspension of Investigational Sites ..........24 
6.3.3 Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s)...................................................................24 
7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS ...............25 
7.1 
Inclusion Criteria .........................................................................................................25 
7.2 
Exclusion Criteria ........................................................................................................25 
7.3 
Excluded Medications, Dietary Products, Procedures, and Treatments ......................27 
7.4 
Diet, Fluid, Activity Control ........................................................................................28 
7.5 
Criteria for Discontinuation or Withdrawal of a Subject .............................................29 
7.6 
Procedures for Discontinuation or Withdrawal of a Subject .......................................30 


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8.0 
CLINICAL TRIAL MATERIAL MANAGEMENT.........................................................31 
8.1 
Study Medication and Materials ..................................................................................31 
8.1.1 Dosage Form, Manufacturing, Packaging, and Labeling ......................................31 
8.1.1.1 Investigational Drug .........................................................................................31 
8.1.1.2 Sponsor-Supplied Drug ....................................................................................31 
8.1.1.3 Ancillary Materials ..........................................................................................31 
8.1.2 Storage ...................................................................................................................32 
8.1.3 Dose and Regimen .................................................................................................32 
8.1.4 Overdose ................................................................................................................32 
8.2 
Investigational Drug Assignment and Dispensing Procedures ....................................33 
8.3 
Randomization Code Creation and Storage .................................................................33 
8.4 
Investigational Drug Blind Maintenance .....................................................................33 
8.5 
Unblinding Procedure ..................................................................................................33 
8.6 
Accountability and Destruction of Sponsor-Supplied Drugs .......................................34 
9.0 
STUDY PLAN ...................................................................................................................36 
9.1 
Study Procedures .........................................................................................................36 
9.1.1 Informed Consent Procedure .................................................................................36 
9.1.1.1 Pharmacogenomic Informed Consent Procedure .............................................36 
9.1.2 Demographics, Medical History, and Medication History Procedure ...................36 
9.1.3 Physical Examination Procedure ...........................................................................36 
9.1.4 Weight, Height, and BMI.......................................................................................37 
9.1.5 Vital Sign Procedure ..............................................................................................37 
9.1.6 Documentation of Concomitant Medications ........................................................37 
9.1.7 Documentation of Concurrent Medical Conditions ...............................................37 
9.1.8 Procedures for Clinical Laboratory Samples .........................................................38 
9.1.9 Contraception and Pregnancy Avoidance Procedure .............................................39 
9.1.10 Pregnancy ...............................................................................................................40 
9.1.11 ECG Procedure ......................................................................................................41 
9.1.12 Pharmacogenomic Sample Collection ...................................................................41 
9.1.13 Pharmacokinetic Sample Collection ......................................................................42 
9.1.13.1 
Collection of Blood for Pharmacokinetic Sampling ..................................42 
9.1.13.2 
Bioanalytical Methods ...............................................................................43 
9.1.14 Pharmacokinetic Parameters ..................................................................................43 
9.1.15 Pharmacodynamic Sample Collection ...................................................................43 
9.1.16 Pharmacodynamic Parameters ...............................................................................44 


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9.1.17 Positive and Negative Syndrome Scale .................................................................45 
9.1.18 Columbia Suicide Severity Rating Scale ...............................................................45 
9.1.19 Documentation of Screen Failure ..........................................................................46 
9.1.20 Documentation of Randomization .........................................................................46 
9.2 
Monitoring Subject Treatment Compliance .................................................................46 
9.3 
Schedule of Observations and Procedures ...................................................................47 
9.3.1 Screening................................................................................................................47 
9.3.2 Treatment Phase .....................................................................................................47 
9.3.3 Final Visit/End of Treatment .................................................................................47 
9.3.4 Early Termination ..................................................................................................47 
9.3.5 Follow-up Visit/Telephone Call ............................................................................47 
9.4 
Biological Sample Retention and Destruction .............................................................47 
9.5 
Blood Volume ..............................................................................................................48 
10.0 
PRETREATMENT EVENTS AND ADVERSE EVENTS ..............................................49 
10.1 
Definitions....................................................................................................................49 
10.1.1 PTEs .......................................................................................................................49 
10.1.2 AEs .........................................................................................................................49 
10.1.3 Additional Points to Consider for PTEs and AEs ..................................................49 
10.1.4 SAEs ......................................................................................................................52 
10.1.5 Severity of PTEs and AEs......................................................................................53 
10.1.6 Causality of AEs ....................................................................................................53 
10.1.7 Relationship to Study Procedures ..........................................................................53 
10.1.8 Start Date ...............................................................................................................53 
10.1.9 Stop Date ................................................................................................................53 
10.1.10 
Frequency .........................................................................................................53 
10.1.11 
Action Concerning Study Medication .............................................................53 
10.1.12 
Outcome ...........................................................................................................54 
10.2 
Procedures ....................................................................................................................54 
10.2.1 Collection and Reporting of AEs ...........................................................................54 
10.2.1.1 
PTE and AE Collection Period ..................................................................54 
10.2.1.2 
PTE and AE Reporting ..............................................................................55 
10.2.2 Collection and Reporting of SAEs .........................................................................55 
10.2.3 Reporting of Abnormal Liver Function Tests ........................................................56 
10.3 
Follow-up of SAEs ......................................................................................................56 
10.3.1 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities .....56 


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11.0 
STUDY-SPECIFIC COMMITTEES .................................................................................58 
12.0 
DATA HANDLING AND RECORDKEEPING ..............................................................59 
12.1 
CRFs (Electronic) ........................................................................................................59 
12.2 
Record Retention .........................................................................................................59 
13.0 
STATISTICAL METHODS ..............................................................................................61 
13.1 
Statistical and Analytical Plans ....................................................................................61 
13.1.1 Analysis Sets ..........................................................................................................61 
13.1.2 Analysis of Demographics and Other Baseline Characteristics ............................61 
13.1.3 Pharmacokinetic Analysis ......................................................................................61 
13.1.4 Pharmacodynamic Analysis ...................................................................................62 
13.1.5 Safety Analysis ......................................................................................................62 
13.2 
Determination of Sample Size .....................................................................................62 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................63 
14.1 
Study-Site Monitoring Visits .......................................................................................63 
14.2 
Protocol Deviations ......................................................................................................63 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections ..................................64 
15.0 
ETHICAL ASPECTS OF THE STUDY ...........................................................................65 
15.1 
IRB and/or IEC Approval ............................................................................................65 
15.2 
Subject Information, Informed Consent, and Subject Authorization ..........................65 
15.3 
Subject Confidentiality ................................................................................................67 
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy ..................................67 
15.4.1 Publication and Disclosure ....................................................................................67 
15.4.2 Clinical Trial Registration ......................................................................................68 
15.4.3 Clinical Trial Results Disclosure ...........................................................................68 
15.5 
Insurance and Compensation for Injury .......................................................................68 
16.0 
REFERENCES ..................................................................................................................69 
 
LIST OF IN-TEXT TABLES 
Table 6.a 
Treatment Sequences .............................................................................................22 
Table 7.a 
Prohibited Medications ..........................................................................................28 
Table 8.a 
Composition of CVN058 and Matching Placebo ..................................................31 
Table 8.b 
Treatment and Medication Type ............................................................................32 
Table 9.a 
Clinical Laboratory Tests .......................................................................................38 
Table 9.c 
Collection of Blood Samples for CVN058 Pharmacokinetic Analysis .................43 
Table 9.d 
Approximate Blood Volume ..................................................................................48 


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Table 10.a 
Medically Significant AE List ...............................................................................52 
Table 14.a 
Windows for Pharmacokinetic Blood Sample Collection .....................................64 
 
LIST OF IN-TEXT FIGURES 
Figure 6.a 
Schematic of Study Design ....................................................................................23 
 
LIST OF APPENDICES 
Appendix A 
Schedule of Study Procedures ...............................................................................71 
Appendix B 
Responsibilities of the Investigator ........................................................................73 
 


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2.0 
STUDY SUMMARY 
Name of Sponsor(s): 
Cerevance Alpha, Inc.  
(hereafter referred to as “Cerevance”) 
Compound: 
CVN058 
Title of Protocol: A Placebo-Controlled Study to 
Evaluate the Effect of a Single Dose of CVN058 on 
Mismatch Negativity in Subjects with Stable 
Schizophrenia 
IND No.: 121,520 
EudraCT No.: 
Not Applicable 
Study Number: CVN058-103 
Phase: 1 
Study Design: 
This is a phase 1, double-blind, placebo-controlled, 3 period cross-over study to evaluate CVN058 target 
engagement by measuring auditory evoked potential mismatch negativity (MMN) downstream to 5-
hydroxytryptamine receptor 3 (5-HT3) as a pharmacodynamic (PD) marker.   
Male and female subjects with schizophrenia, age 18 to 50 years old, inclusive, will be randomized to 1 of 6 
treatment sequences (Table 2.a) to receive 1 of 3 dose regimens in each period: a single oral administration of 
CVN058 (15 mg or 150 mg) or matching placebo. The sequence will determine the order in which a subject will 
take each of the 3 regimens. Discontinued subjects may be replaced at the discretion of the sponsor so that 
approximately 20 completed subjects are available for analysis. 
The study includes three 1-day treatment periods, with a minimum of 7-day washout, maximum 10 day washout 
(2 total washouts, after Periods 1 and 2) between periods, and a 7-10 day follow-up call post dosing of the last 
period. Subjects may be inpatients or outpatients at the discretion of the Investigator. 
Table 2.a Treatment Sequences 
Sequence 
Period 1 
Period 2 
Period 3 
1 
A 
B 
C 
2 
B 
A 
C 
3 
C 
A 
B 
4 
A 
C 
B 
5 
B 
C 
A 
6 
C 
B 
A 
A: Placebo 
B: CVN058 15 mg 
C: CVN058 150 mg  
At each testing session, subjects undergo post dose electroencephalography (EEG) testing including: MMN, P50, 
gamma power, and P300. Study drug will be administered with water. Testing sessions will begin approximately 
1.5 hours post-dose. Prior to dosing and at various time points post dose, blood samples will be collected for the 
assessment of plasma concentrations of CVN058 and biomarkers.  
Study procedures will be conducted at approximately the same times across Treatment Periods to minimize 
diurnal effects on outcomes. The effect of CVN058 on MMN as well as on exploratory measures (e.g., P50 
auditory gating, gamma power, and P300) will be compared to placebo.  
 
A schematic of the study design is presented below: 
  
 
 


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Primary Objective: 
To determine whether improvement in MMN is demonstrated after administration of CVN058 compared to 
placebo in subjects with schizophrenia. 
Secondary Objective: 
Assess the safety and tolerability of single doses of CVN058 in subjects with schizophrenia. 
Exploratory Objectives: 
• 
To determine whether improvement in P50 auditory gating, gamma power, and P300 is demonstrated 
after administration of CVN058 compared to placebo in subjects with schizophrenia. 
• 
To assess the pharmacokinetics (PK) of CVN058 following a single dose to subjects with 
schizophrenia. 
• 
To explore the exposure-response relationship for CVN058 in subjects with schizophrenia. 
Subject Population:  
Subjects with stable schizophrenia on antipsychotic medication(s).  
Number of Subjects: 
Estimated total: at least 20 evaluable subjects who 
complete the study  
Number of Sites: 
Approximately 2 (United States) 
Dose Level(s): 
Placebo: solution vehicle, oral administration  
CVN058: 15 mg solution, oral administration  
CVN058: 150 mg solution, oral administration 
Route of Administration: 
Oral 
Duration of Treatment: 
Single oral dose in each of the 3 periods.  
Period of Evaluation: 
Screening Days (Part 1): Up to 28 days. 
3 Treatment Periods, each <1 day duration;  
with a 7-10 day washout between periods 
Follow-up call 7-10 days following the last dose of 
study drug in Treatment Period 3. 


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Total Duration: Up to 58 days. 
Main Criteria for Inclusion: 
Subjects 18 to 50 years of age, inclusive, at the time of informed consent. 
The subject weighs at least 50 kg and has a body mass index (BMI) between 18 and 40 kg/m2 inclusive at 
Screening. 
Subject meets schizophrenia criteria as defined by the Diagnostic & Statistical Manual of Mental Disorders, 5th 
Edition (DSM–V).  
Subjects are on a stable dose of antipsychotic medication(s) for at least 2 months prior to Screening as 
documented by medical history and assessed by site staff. 
Subject has a Positive and Negative Syndrome Scale (PANSS) total score of <95. 
Main Criteria for Exclusion: 
Subject currently receiving treatment with any excluded medication or dietary supplement. 
Subjects who have a history of gastrointestinal disease that would influence the absorption of study drug or have 
a history of any surgical intervention known to impact absorption (e.g., bariatric surgery or bowel resection). 
Subjects having clinical laboratory evaluations (including clinical chemistry, hematology and complete 
urinalysis) outside the reference range for the testing laboratory, unless the results are deemed to be not clinically 
significant (NCS) by the investigator at Screening 
Subjects with moderate to severe substance use disorder, unstable mood or anxiety disorder. 
Subject has a current diagnosis of a significant psychiatric illness other than schizophrenia per DSM-V and is in 
an acute phase/episode. 
Subject has clinically meaningful hearing loss. 
Main Criteria for Evaluation and Analyses: 
Pharmacodynamics: 
MMN will be measured as a PD marker for CVN058. Exploratory measurements include P50 auditory gating, 
gamma power, and P300, which are EEG markers commonly impaired in subjects with schizophrenia.  
Pharmacokinetics:  
Blood samples will be collected for the determination of plasma concentrations of CVN058, and its metabolite if 
appropriate, at the following time points: Pre-dose (within 15 minutes prior to dosing), and at 1 (pre-EEG) and 4 
(post-EEG) hours post dose. The following PK parameters will be determined from concentrations of CVN058, 
and its metabolite if appropriate, in plasma: maximum observed plasma concentration (Cmax), time to reach Cmax 
(tmax), and area under the curve from time 0 to the time of the last quantifiable concentration (AUCt). Other 
parameters may be calculated if appropriate.  
Pharmacogenomics: 
Whole blood will be collected and stored for possible deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) 
isolation and analysis.  
DNA samples will be used to evaluate drug metabolic enzyme and transporter polymorphisms that may 
contribute to variability in the PK of CVN058. Also, since pharmacogenomics is an evolving science, many 
genes and their functions are not yet fully understood. Future data may suggest a role of some gene in drug 
response, which may lead to additional hypothesis-generating exploratory research and diagnostic development 
on stored samples. 
Statistical Considerations: 
Observed values for the PD parameters (MMN and exploratory PD parameters) at each time point and will be 
summarized by treatment and compared to time matched assessments during placebo dosing using summary 
statistics. Comparison of post dose PD parameters to time match placebo period timepoints will be analyzed 
using analysis of covariance (ANCOVA) with baseline value as a covariate and factors for time point, sequence, 


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subject nested within sequence, period, and treatment. Two-sided 95% confidence intervals will be constructed 
for the least squares mean differences between CVN058 and placebo in changes of PD parameters from time-
matched period Baseline to each postdose time point. 
Effect size will be calculated for comparisons of CVN058 to placebo using Cohen’s d which expresses the 
difference between the means of 2 groups as a function of their pooled standard deviation. 
Plasma PK concentrations and parameters of CVN058, and its metabolite if appropriate, will be listed and 
summarized by treatment using descriptive statistics. Exposure-response relationships for CVN058 will be 
explored graphically. 
Adverse events (AEs) will be presented in listings, and treatment-emergent AEs (TEAEs) will be summarized by 
treatment. Individual results of vital signs will be listed and observed values and changes from Baseline in vital 
signs will be summarized by treatment.  
Sample Size Justification:  
Enrollment of 20 subjects with schizophrenia is estimated to provide >80% power to detect a median effect size 
of Cohen’s d=0.5. Discontinued or withdrawn subjects and subjects for whom MMN is not available for all three 
study periods may be replaced. The sample size chosen of 20 completed subjects is expected to be sufficient to 
explore the changes in MMN between CVN058 and placebo as well as safety and tolerability of CVN058 in this 
population. 
 


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3.0 
LIST OF ABBREVIATIONS 
5-HT 
5-hydroxytryptamine (serotonin) 
5-HT3 
5-hydroxytryptamine (serotonin) receptor 3 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
AUCt 
area under the plasma concentration-time curve from 0 to time of last quantifiable 
concentration 
BA 
bioavailability 
BMI 
body mass index 
CIAS 
cognitive impairment associated with schizophrenia 
CL/F 
apparent clearance after extravascular administration 
Cmax 
maximum observed plasma concentration 
CNS 
central nervous system 
CRO 
contract research organization 
CS 
clinically significant 
CSF 
cerebrospinal fluid 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DSM -V 
Diagnostic & Statistical Manual of Mental Disorders, 5th Edition – Text Revision 
eCRF 
electronic case report form  
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
EEG 
electroencephalography 
EMA 
European Medicines Agency  
ERP 
evoked response potential 
FDA 
Food and Drug Administration 
FM 
Frequency-modulation 
FSH 
follicle-stimulating hormone 
FSI 
fast-spiking interneurons 
Fz 
frontal electrodes 
Fz,Cz 
frontocentral electrodes 
GABA 
γ-aminobutyric acid 
GCP 
Good Clinical Practice 
GGT 
γ-glutamyl transferase 
HBsAg 
hepatitis B surface antigen 
hCG 
human chorionic gonadotropin 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
ICH 
International Conference on Harmonisation 
IEC 
independent ethics committee 
INR 
international normalized ratio 
IRB 
institutional review board 


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IUD 
intrauterine device 
K2EDTA 
potassium ethylenediamine tetraacetic acid 
LFT 
liver function test 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMN 
mismatch negativity 
NCS 
not clinically significant 
NMDAR 
N-methyl-D-aspartate receptor 
NFSI 
non-fasting spiking interneurons 
OTC 
Over-the-counter 
PANSS 
Positive and Negative Syndrome Scale 
PD 
pharmacodynamic(s) 
PI 
principal investigator 
PK 
pharmacokinetic(s) 
PT 
prothrombin time 
PTE 
pretreatment event 
PV 
parvalbumin 
Pz 
parietal electrodes  
P50 Ratio 
ratio of S2 to S1  
RNA 
ribonucleic acid 
QTcB 
QT interval with Bazett correction method 
QTcF 
QT interval with Fridericia correction method 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SSR 
steady state response 
SUSAR 
suspected unexpected serious adverse reaction 
t1/2z 
terminal elimination half-life 
CVN058 
also known as ENV8058 and TAK-058 
TEAE 
treatment-emergent adverse event 
tmax 
time to reach Cmax 
ULN 
upper limit of normal 
Vz/F 
apparent volume of distribution during the terminal phase 
WHODRUG  
World Health Organization Drug Dictionary 


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4.0 
INTRODUCTION 
4.1 
Background 
Schizophrenia is a complex disorder comprising several clinical features that are highly variable 
among affected individuals. Probably the most well-known schizophrenia symptom domains are 
the so-called positive symptoms, e.g., hallucinations, delusions, disorganization of thought, 
bizarre behavior, and incongruity of affect. Negative symptoms include avolition (loss of 
motivation), blunt affect, alogia (reduced speech), and anhedonia (reduced ability to experience 
pleasure). Cognitive impairment associated with schizophrenia (CIAS) usually precedes 
psychosis and is observed in most cases involving deficits in a broad range of domains. Finally, 
patients with schizophrenia often experience depression and anxiety, express hostility, and 
become demoralized (Thaker, 2001).  
Cognitive impairment is considered a core feature of schizophrenia and represents an area of 
significant unmet medical need. Cognitive deficits in schizophrenia include problems in speed of 
processing, attention/vigilance, working memory, verbal learning, visual learning, reasoning and 
problem solving, and social cognition (Green, 2006). These cognitive deficits are believed to 
underlie much of the significant functional impairments observed in schizophrenia, such as 
impairment in independent living skills, social functions, vocational functioning, and self-care 
(Harvey, 2007). Thus, the core nature of CIAS and the associations that have been demonstrated 
with functional disability suggest that improving cognitive impairment may lead to improved 
functional outcomes (Heinrichs, 2005). 
The understanding of CIAS has evolved significantly in recent years and led to new therapeutic 
strategies. In postmortem samples from schizophrenic patients, studies consistently reveal 
reduced levels of enzymes that synthesize the inhibitory neurotransmitter γ-aminobutyric acid 
(GABA) in the prefrontal cortex (McNally, 2013) a key center for higher cognitive function. The 
GABAergic neurons deficient in the cortex are termed fast-spiking interneurons (FSIs), and they 
express the marker parvalbumin (PV) (McNally, 2013). These PV+ FSIs are chemically coupled 
and release GABA in a rhythmic pattern that synchronizes the activity of local cortical pyramidal 
neurons (Cardin, 2009). This synchronization, which is essential for cognition, is disrupted in 
patients [(McNally, 2013), (Cardin, 2009)] [(Whittington, 1997), (Rotaru, 2012), (Gonzalez-
Burgos, 2012)]. These and other human and animal model data implicate FSI hypofunction, and 
a resulting imbalance in the excitation/inhibition balance in cortical regions, in CIAS. 
Based on this emerging insight into disease pathophysiology, a therapeutic that restores the 
normal function of the cortical pyramidal neuron/FSI microcircuit would be expected to improve 
cognitive function in patients with schizophrenia. One strategy for boosting the function of this 
circuit is to inhibit a second population of inhibitory GABAergic interneurons, known as non-
fast spiking interneurons (NFSIs), which project locally onto the FSIs and the dendrites of the 
pyramidal neurons. These NFSIs are modulated by a wide variety of inputs, particularly 
excitatory glutamatergic efferents from the thalamus, and noradrenergic, cholinergic, and 
serotonergic efferents from subcortical regions [(Tian, 2010), (Kawaguchi, 1998), (Kawaguchi, 


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1997), (Lee, 2010)]. Thus, NFSIs appear to integrate state-dependent information and release 
GABA to regulate pyramidal neuron/FSI microcircuits. 
Mismatch negativity (MMN) is an established biomarker of cortical function (Javitt, 2015). This 
signal is obtained as an evoked potential during an auditory oddball task, in which a subject is 
repeatedly exposed to auditory tones and a small proportion of those tones (the “deviant” stimuli) 
differ from the others (the “standard” stimuli) in their frequency or duration. Typically, the tones 
are presented and the evoked potentials are recorded while subjects are engaged on a different 
task, such as reading. Normally, the occurrence of a deviant stimulus increases the amplitude of 
the negative component in the evoked potential occurring at around 200 msec. MMN is the 
difference in amplitude between deviant and standard stimuli responses, and is considered to 
represent an aspect of preattentive novelty detection. MMN is consistently reduced in 
schizophrenia patients relative to healthy individuals, a finding extensively replicated and with a 
large effect size (Cohen’s d = 1). MMN reduction in schizophrenia has been shown to reflect 
impaired N-methyl-D-aspartate receptor (NMDAR) function at the level of supratemporal 
auditory cortex, dependent on cortical interneuron modulation of pyramidal cell activity and 
NMDA receptor-dependent (Lee, 2017). 
4.2 
Non-Clinical 
CVN058 (also known as ENV8058 or TAK-058) is a small molecule that potently and 
selectively antagonizes the 5-hydroxytryptamine (5-HT) receptor type 3 (5-HT3). 5-HT3 is a cys-
loop family ligand-gated ion channel that allows cations to pass into the neurons when activated 
by serotonin, and is highly expressed in NFSIs [(Lee, 2010), (Lummis, 2012)]. The receptor is a 
pentamer consisting of at least two 5-HT3a subunits and 3 other subunits; in the central nervous 
system (CNS) the receptor is almost exclusively a homomeric pentamer comprised of 5-HT3a 
(Kawaguchi, 1997). The 5-HT3 channel opens when serotonin molecules interact with the 2 
ligand recognition sites in the extracellular side of the receptor. Influxed calcium and other 
positive ions depolarize the NFSIs, leading to GABA release. CVN058 is orally absorbed and 
readily passes the blood brain barrier, allowing it to occupy cortical 5-HT3 receptors (50% 
occupancy of rat cortical 5-HT3 receptors is achieved at plasma concentrations of approximately 
5.8 ng/mL). CNS 5-HT3 receptor occupancy is correlated with efficacy in a rat model of 
cognition where it reverses deficits in novel object recognition induced by subchronic 
phencyclidine treatment. Thus, CVN058 is a novel therapeutic candidate that may improve 
cognitive function by inhibiting specific subsets of cortical interneurons.  
Additional information from the nonclinical studies can be found in the current Investigator’s 
Brochure. 
4.3 
Clinical 
Two human clinical studies of CVN058 have been completed (ENV8058_101 and TAK-058-
1002). 
CVN058 was well tolerated up to a dose of 150 mg administered orally as a single dose in 
aqueous solution (Study ENV8058_101). There were no deaths or other serious adverse events 


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(SAEs) reported in this study and no subject discontinued study due to a treatment-emergent 
adverse event (TEAE). There were no clinically significant (CS) laboratory abnormalities, 
electrocardiogram (ECG) changes or changes in vital signs in the completed single dose study. 
The mean Cmax and area under the plasma concentration–time curve (AUC) values of CVN058 
increased less than proportionally with increasing CVN058 dose across the dose range of 5 to 
150 mg, but mean Cmax and AUC values increase in an approximately dose proportional manner 
across the 5 to 45 mg dose range. The rate of appearance of CVN058 in plasma was rapid with 
median time to Cmax (tmax) values of 1 to 1.25 hours across the dose range of 5 to 150 mg. The 
mean terminal elimination half-life (t1/2z) values of CVN058 ranged from approximately 2.8 to 
10.5 hours across the cohorts; the lower doses (5 to 30 mg) had lower mean t1/2z values compared 
to the higher doses (45 to 150 mg). There were no trends with mean apparent clearance (CL/F) 
values of CVN058 with increasing dose from 5 to 45 mg, but faster apparent clearance was 
observed at the 75 and 150 mg doses, possibly due to decreased bioavailability (BA) at higher 
doses. The mean apparent volume of distribution (Vz/F) increased as dose increased. Excretion 
of unchanged CVN058 in the urine was ≤2.3% of the administered CVN058 dose over the dose 
range evaluated. 
In the multiple-rising dose study (TAK-058-1002), CVN058 was well-tolerated at daily doses of 
25, 75, and 150 mg for 7 days, and at a single 300 mg dose, in aqueous solution. There were no 
deaths or other SAEs reported in this study and no subject discontinued study due to a TEAE. 
There were no clinically significant laboratory abnormalities, ECG changes or changes in vital 
signs in the completed single dose study. Following single or multiple doses, the mean Cmax and 
AUC values of CVN058 increased less than proportionally with increasing CVN058 dose across 
the dose range of 25 to 300 mg. No accumulation was observed following daily administration. 
CVN058 concentrations in cerebrospinal fluid (CSF) were assessed after daily doses of CVN058 
75 mg for 5 days. The CSF concentrations averaged 17.5 ng/mL, or approximately 1% of the 
concentration in plasma. 
4.4 
Rationale for the Proposed Study 
This study will explore central target engagement and proof of mechanism by measuring 
auditory evoked potential MMN as a pharmacodynamic (PD) marker of CNS response to the 
selective 5-HT3 receptor antagonist CVN058. It has been reported that subjects with 
schizophrenia commonly demonstrate a deficit in neural processing that is manifested as a 
reduction in MMN and impairment of auditory sensory gating (P50) (Javitt and Sweet, 2015). 
Other 5-HT3 receptor antagonists have been reported to improve impairments in auditory evoked 
potentials in schizophrenic subjects. In a study with ondansetron, a 5-HT3 receptor antagonist, 
using P50 auditory gating as the auditory evoked potential measure, subjects were given a single 
dose of ondansetron (16 mg) or placebo in a double-blind, placebo-controlled, randomized and 
balanced crossover design (Adler, 2005). Serial measurements of the P50 evoked potential were 
done at Baseline and 1, 2, and 3 hours after receipt of placebo or ondansetron. The results of the 
study indicated that ondansetron significantly enhanced P50 auditory gating in subjects with 
schizophrenia. Tropisetron, a 5-HT3 antagonist that also has α7 nicotinic cholinergic agonist 


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activity, has similarly been shown to improve P50 auditory gating in subjects with schizophrenia 
(Koike, 2005).  
While the P50 signal is likely a reflection of brainstem and thalamic network activity and is 
sensitive to antipsychotic treatment, MMN is thought to reflect excitation-inhibition balance in 
cortical circuits and is not sensitive to antipsychotic treatment (Javitt and Sweet, 2015). 
Therefore, to evaluate the potential for CVN058 to improve cognitive function in schizophrenics, 
MMN will be used as a PD marker. The study will be performed as a 3-way crossover to assess 
the effect on MMN of CVN058 at two dose levels relative to placebo, with each subject serving 
as his or her own control to reduce variability. P50 auditory gating will also be measured, as an 
exploratory endpoint, along with other potentially informative electrophysiological and 
psychometric parameters. 
Medications that might inhibit or mask the effects of CVN058 will not be permitted as 
concomitant medications. These include serotonin reuptake inhibitors which increase synaptic 
serotonin levels, as well as drugs that bind to 5-HT3 at clinically relevant concentrations or are 
reported to inhibit signaling through 5-HT3 non-competitively, including some anti-psychotic 
drugs [(Eisensamer, 2005), (Eisensamer, 2003), (Rammes, 2004)]. Permissible anti-psychotic 
medications are risperidone (Risperdal), haloperidol (Haldol), quetiapine (Seroquel), aripiprazole 
(Abilify) and paliperidone (Invega). 


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5.0 
STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Objectives 
5.1.1 Primary Objective 
• To determine whether improvement in MMN is demonstrated after administration of 
CVN058 compared to placebo in subjects with schizophrenia.  
5.1.2 Secondary Objective 
• To assess the safety and tolerability of single doses of CVN058 in subjects with 
schizophrenia. 
5.1.3 Exploratory Objectives  
• To determine whether improvement in P50 auditory gating, gamma power, and P300 is 
demonstrated after administration of CVN058 compared to placebo in subjects with 
schizophrenia. 
• To assess the pharmacokinetics (PK) of CVN058 following a single dose to subjects with 
schizophrenia. 
• To explore the exposure-response relationship for CVN058 in subjects with schizophrenia. 
5.2 
Endpoints 
5.2.1 Primary Endpoints  
• Mean amplitude of duration MMN at 5 electrodes surrounding frontal (Fz) electrodes 
following administration of CVN058 compared to placebo. 
5.2.2 Secondary Endpoint 
• Percentage of subjects who experience at least 1 TEAE  
• Percentage of subjects who experience at least 1 clinically significant abnormal laboratory 
test result 
5.2.3 Exploratory Endpoints 
• Mean P50 ratio (S2/S1) at 5 electrodes surrounding Cz following administration of CVN058 
compared to placebo 
• Mean P50 differences (S2-S1) at 5 electrodes surrounding Cz following administration of 
CVN058 compared to placebo. 
• Pre-stimulus gamma amplitude following administration of CVN058 compared to placebo  


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• P300 amplitude and latency at average of 5 centroparietal electrodes around parietal 
electrodes (Pz) following administration of CVN058 compared to placebo 
• MMN amplitude to additional deviants (frequency, intensity, location, frequency-modulation 
[FM]) and latency to all deviants following administration of CVN058 compared to placebo 
• CVN058, its metabolite if appropriate, Cmax, tmax, and area under the plasma concentration-
time curve from 0 to the last quantifiable concentration (AUCt). 


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6.0 
STUDY DESIGN AND DESCRIPTION 
6.1 
Study Design  
This is a phase 1, double-blind, placebo-controlled, 3 period cross-over study to evaluate 
CVN058 target engagement by measuring auditory evoked potential MMN downstream to 5-
hydroxytryptamine receptor 3 (5-HT3) as a PD marker.  
Male and female subjects with schizophrenia, age 18 to 50 years old, inclusive, will be 
randomized to 1 of 6 treatment sequences (Table 6.a) to receive 1 of 3 dose regimens in each 
period; a single oral administration of CVN058 (15 mg or 150 mg), or a matching placebo. The 
sequence will determine the order in which a subject will receive each of the 3 regimens. 
Discontinued subjects may be replaced so that 20 completed subjects are available for analysis. 
Each treatment period is less than 1 day in duration, with a minimum of 7-day washout, 
maximum 10 day washout between doses. A follow-up telephone call will occur approximately 
7-10 days following the last dose received. Subjects may be inpatients or outpatients at the 
discretion of the Investigator. 
Table 6.a 
Treatment Sequences 
Sequence 
Period 1 
Period 2 
Period 3 
1 
A 
B 
C 
2 
B 
A 
C 
3 
C 
A 
B 
4 
A 
C 
B 
5 
B 
C 
A 
6 
C 
B 
A 
A: Placebo 
B: CVN058 15 mg 
C: CVN058 150 mg 
 
At each testing session, subjects will undergo post dose EEG testing including: MMN, P50, 
gamma power, and P300. Study drug will be administered with water in the morning. Testing 
sessions will begin approximately 1.5 hours post-dose. Prior to dose and at various time points 
postdose, blood samples will be collected for the assessment of plasma concentrations of 
CVN058 and biomarkers.  
Study procedures will be conducted at approximately the same times across Treatment Periods to 
minimize diurnal effects on outcomes.  The effect of CVN058 on MMN as well as on 
exploratory measures (e.g., P50 auditory gating, gamma power, and P300) will be compared to 
placebo.  
A schematic of the study design is presented in Figure 6.a. 


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Figure 6.a 
Schematic of Study Design 
 
6.2 
Justification for Study Design, Dose, and Endpoints 
This study will explore CNS target engagement by measuring alterations in auditory evoked 
potentials, similar to the demonstration of an effect on P50 auditory gating using the 5-HT3 
antagonist, ondansetron (Adler, 2005). The study design was based on that published study, 
adapted for CVN058 as study drug and MMN as the primary endpoint. It has been reported that 
most subjects with schizophrenia demonstrate a deficit in neural processing that is manifested as 
a reduction in MMN and impairment of auditory sensory gating (P50). According to Adler et al, 
ondansetron improves the P50 deficit after a single dose administration (Adler, 2005).  
The study will be a randomized, 3 period crossover study (CVN058 at two dose levels, and 
placebo) in order to evaluate the effect of CVN058 on MMN as well as on exploratory measures 
(i.e., P50 auditory gating, gamma power, and P300) compared to placebo. The study will be 
double-blind and placebo-controlled in order to avoid subjective bias in the assessment of the PD 
markers. In addition, conduct of study procedures for each subject will occur at approximately 
the same time per day across each of the Treatment Periods to avoid diurnal changes that may 
otherwise confound the analysis.  
The 150 mg level of CVN058 is expected to saturate CNS 5-HT3 receptors throughout the EEG 
session, but is 50% lower than the highest dosage for which safety and tolerability has been 
demonstrated in previous phase 1 studies in healthy subjects, thus presumably maximizing the 
PD signal within the established limits of safe use. The lower dose level of 15 mg CVN058 is 
expected to attain a lower CNS 5-HT3 receptor occupancy, decreasing to possibly 70-80% by the 
end of the EEG session. The 10-fold difference in these dosages should help establish a dose-
response relationship for evoked response potential (ERP) effects of CVN058. From a safety 
perspective, single doses ranging from 5 mg to 300 mg CVN058 have been safe and well-


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tolerated. Daily doses of 25, 75, and 150 mg of CVN058 for 7 days have also been studied, and 
were similarly safe and well-tolerated. 
The timing of dosing was selected to allow the EEG assessments to occur at the corresponding 
estimated tmax values of CVN058. The length of the washout periods is considered adequate 
based on the PK profile of CVN058. 
In addition, based on the EEG deficits reported in subjects with schizophrenia, P50 auditory 
gating, gamma frequency, and P300 neurophysiological markers will be measured. 
6.3 
Premature Termination or Suspension of Study or Investigational Site 
6.3.1 Criteria for Premature Termination or Suspension of the Study 
The study will be completed as planned unless new information or other evaluation regarding the 
safety or efficacy of the study medication indicates a change in the known risk/benefit profile for 
the compound, such that the risk/benefit is no longer acceptable for subjects participating in the 
study. 
6.3.2 Criteria for Premature Termination or Suspension of Investigational Sites 
A study site may be terminated prematurely or suspended if the site (including the investigator) 
is found in significant violation of Good Clinical Practice (GCP), protocol, or contractual 
agreement, is unable to ensure adequate performance of the study, or as otherwise permitted by 
the contractual agreement. 
6.3.3 Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s) 
In the event that the sponsor, an institutional review board (IRB) / independent ethics committee 
(IEC), or regulatory authority elects to terminate or suspend the study or the participation of an 
investigational site, a study-specific procedure for early termination or suspension will be 
provided by the sponsor; the procedure will be followed by applicable investigational sites 
during the course of termination or study suspension. 


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7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS 
All entry criteria, including test results, need to be confirmed prior to randomization. Subjects 
who do not initially meet eligibility criteria may be re-screened at investigator’s discretion.  
7.1 
Inclusion Criteria 
Subject eligibility is determined according to the following criteria prior to entry into the study:  
1. In the opinion of the investigator, the subject is capable of understanding and complying with 
protocol requirements. 
2. The subject signs and dates a written, informed consent form and any required privacy 
authorization prior to the initiation of any study procedures. 
3. The subject is aged 18 to 50 years, inclusive, at the time of informed consent. 
4. The subject weighs at least 50 kg and has a body mass index (BMI) between 18 and 40 kg/m2 
inclusive at Screening. 
5. The subject meets schizophrenia criteria as defined by the Diagnostic and Statistical Manual 
of Mental Disorders 5th edition (DSM-V) (American Psychiatric Association, 2013). 
6. The subject is on a stable dose of allowed antipsychotic medication(s) for at least 2 months 
prior to Screening as documented by medical history and assessed by site staff. 
7. The subject has a Positive and Negative Syndrome Scale (PANSS) total score of <95 at 
Screening. 
7.2 
Exclusion Criteria 
Any subject who meets any of the following criteria will not qualify for entry into the study:  
1. A male subject who is nonsterilized* and sexually active with a female partner of 
childbearing potential* does not agree to use adequate contraception* from signing of 
informed consent throughout the duration of the study and for 12 weeks after last dose of 
study drug. 
2. A female subject of childbearing potential* who is sexually active with a nonsterilized* male 
partner does not agree to use acceptable methods of contraception* from signing of informed 
consent throughout the duration of the study and for 12 weeks after last dose of study drug. 
*Definitions and acceptable methods of contraception are defined in 
Section 9.1.9 Contraception and Pregnancy Avoidance Procedure and 
reporting responsibilities are defined in Section 9.1.10 Pregnancy. 
3. If female, the subject is pregnant or lactating or intending to become pregnant before, during, 
or within 12 weeks after the last dose of study medication; or intending to donate ova during 
such time period. 


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4. The subject has uncontrolled, clinically significant neurologic, cardiovascular, pulmonary, 
hepatic, renal, metabolic, gastrointestinal, or endocrine disease or other abnormality that may 
impact the ability of the subject to participate or potentially confound the study results.  
5. The subject has a history of gastrointestinal disease that would influence the absorption of 
study drug, or history of any surgical intervention known to impact absorption (e.g., bariatric 
surgery or bowel resection). 
6. The subject has clinical laboratory evaluations (including clinical chemistry, hematology and 
complete urinalysis) outside the reference range for the testing laboratory, unless the results 
are deemed to be NCS by the investigator at Screening. 
7. The subject has received any investigational compound within 30 days prior to signing of 
informed consent. 
8. The subject has taken any excluded medication or dietary supplement within time frames 
listed in the Excluded Medications table in Section 7.3. 
9. The subject does not have a stable indoor living situation (e.g., living independently, with 
family, or group home)  
10. The subject is an immediate family member, study site employee, or is in a dependent 
relationship with a study site employee who is involved in the conduct of this study 
(e.g., spouse, parent, child, sibling) or may consent under duress. 
11. Subjects with moderate to severe substance use disorder according to DSM-5 criteria. 
12. The subject has a positive urine drug result for drugs of abuse (defined as any illicit drug use, 
including marijuana) at Screening.  
13. The subject has a history of cancer requiring chemotherapy within the past 5 years prior to 
the first dose of study medication. This criterion does not include subjects successfully 
treated for basal cell or stage I squamous cell carcinoma of the skin. 
14. The subject has a positive test result for hepatitis B surface antigen (HBsAg), hepatitis C 
virus (HCV) antibody (unless having completed curative therapy), or known history of 
human immunodeficiency virus (HIV) antibody at Screening.  
15. The subject has a QT interval with Fridericia’s correction method (QTcF) >450 msec (males) 
or >470 msec (females) or PR outside the range of 120 to 220 msec, confirmed by triplicate 
testing at 5 minute intervals, at the Screening Visit. 
16. The subject has poor peripheral venous access.  
17. The subject has hair or scalp condition(s) that would prevent the application of the EEG 
electrodes. 
18. The subject has a current diagnosis of a significant psychiatric illness other than 
schizophrenia, per DSM-V and is in an acute phase/episode. 
19. Subject has clinically meaningful hearing loss per investigator’s judgment. 


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20. The subject has donated or lost 450 mL or more of his or her blood volume (including 
plasmapheresis), or had a transfusion of any blood product, within 3 months prior to Day 1. 
21. The subject has an abnormal (clinically significant) Screening ECG. Entry of any subject 
with an abnormal (not clinically significant) ECG must be approved and documented by 
signature of the principal investigator (PI).  
22. The subject has abnormal Screening laboratory values that suggest a clinically significant 
underlying disease, or subject with the following lab abnormalities: alanine aminotransferase 
(ALT) and/or aspartate aminotransferase (AST) >2x the upper limit of normal (ULN). 
23. The subject has abnormal Screening vital sign values that suggest a clinically significant 
underlying disease. 
24. The subject has a risk of suicide according to the Investigator’s clinical judgment, a 
Screening Visit Columbia-Suicide Severity Rating Scale [C-SSRS]) score of greater than 3, 
or has a history of suicide attempt. 
7.3 
Excluded Medications, Dietary Products, Procedures, and Treatments  
Use of the agents in Table 7.a (prescription or nonprescription) is prohibited from the time points 
specified until completion of all study activities.  


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Table 7.a 
Prohibited Medications  
28 Days Prior to Check-in  
1 Days Prior to Check-in  
1 Hour Prior to 
Each EEG 
Assessment  
Nutraceuticals and dietary supplements (e.g., St. John’s wort, 
ginseng, kava kava, ginkgo biloba, Chinese herbs, and melatonin) 
 
Alcohol-containing 
products 
Products containing 
nicotine, caffeine or 
xanthine (e.g., tea) 
Antipsychotic medications, except risperidone (Risperdal), 
haloperidol (Haldol), quetiapine (Seroquel), aripiprazole (Abilify) 
and paliperidone (Invega) 
 
Sedative hypnotic 
medications (barbiturates 
and benzodiazepines) 
 
5-HT3 receptor antagonists, including ondansetron (Zofran, 
Zuplenz), granisetron (Kytril, Sancuso, Granisol, Sustol), 
palonosetron (Aloxi), dolasetron (Anzemet)  
 
 
 
5-HT3 allosteric modulators buproprion (Wellbutrin, Zyban) and 
hydroxybupropion 
 
 
 
Serotonin Reuptake Inhibitors (SSRI, SNRI), including sertraline 
(Zoloft), fluoxetine (Prozac, Sarafem), citalopram (Celexa), 
escitalopram (Lexapro), paroxetine (Paxil, Pexeva, Brisdelle) , 
vortioxetine (Trintellix), and fluvoxamine (Luvox) 
 
 
 
Mirtazapine (Remeron), desipramine, imipramine, trimipramine, 
reboxetine 
 
 
  
Subjects must be instructed not to take any medications, including over-the-counter (OTC) 
products, without first consulting with the investigator. Subjects must be instructed to not make 
any changes to their concomitant medications during the course of the study without first 
consulting with the investigator. 
During study participation, subjects will maintain usual dosing schedule of antipsychotic 
medication(s) and approved concomitant medications. Sedative hypnotics will not be allowed 
after 10 pm the night prior to testing, and until completion of testing the following day. 
7.4 
Diet, Fluid, Activity Control  
Subjects should have their customary breakfast before each study visit. The contents of the meal 
should be summarized on the electronic case report form (eCRF). 
During EEG and ERP assessments, subjects will remain still in a seated or partially recumbent 
position, according to the EEG acquisition guidelines. Subjects will refrain from strenuous 
exercise from 72 hours before Check-in through check-out, relative to each Treatment Period. 
If subject is a smoker; they must refrain from smoking at least 1 hour prior to the EEG testing at 
all time points. 


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On each dosing day, CVN058 or placebo will be administered with approximately 240 mL of 
water.  
7.5 
Criteria for Discontinuation or Withdrawal of a Subject 
The primary reason for discontinuation or withdrawal of the subject from the study or study 
medication should be recorded in the eCRF using the following categories. For screen failure 
subjects, refer to Section 9.1.17. 
1. Pretreatment event (PTE) or AE. The subject has experienced a PTE or AE that requires 
early termination because continued participation imposes an unacceptable risk to the 
subject’s health or the subject is unwilling to continue because of the PTE or AE. 
2. Liver Function Test (LFT) Abnormalities 
Study medication should be discontinued immediately with appropriate clinical follow-up 
(including repeat laboratory tests, until a subject’s laboratory profile has returned to 
normal/baseline status, see Section 9.1.8), if the following circumstances occur at any 
time during study medication treatment: 
– ALT or AST >8 ×ULN, or 
– ALT or AST >5 ×ULN and persists for more than 2 weeks, or 
– ALT or AST >3 ×ULN in conjunction with elevated total bilirubin >2 × ULN or 
international normalized ratio (INR) >1.5, or 
– ALT or AST >3 ×ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%). 
3. Significant protocol deviation. The discovery post randomization or after the first dose of 
study medication that the subject failed to meet protocol entry criteria or did not adhere to 
protocol requirements, and continued participation poses an unacceptable risk to the subject’s 
health. 
4. Lost to follow-up. The subject did not return to the clinic and attempts to contact the subject 
were unsuccessful. Attempts to contact the subject must be documented. 
5. Voluntary withdrawal. The subject (or subject’s legally acceptable representative) wishes to 
withdraw from the study. The reason for withdrawal, if provided, should be recorded in the 
eCRF. 
Note: All attempts should be made to determine the underlying reason for the withdrawal 
and, where possible, the primary underlying reason should be recorded (i.e., withdrawal due 
to an AE). 
6. Study termination. The sponsor, IRB, IEC, or regulatory agency terminates the study. 
7. Pregnancy. The subject is found to be pregnant. 
Note: If the subject is found to be pregnant, the subject must be withdrawn immediately. The 
procedure is described in Section 9.1.10. 


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8. Other. 
Note: The specific reasons should be recorded in the “specify” field of the eCRF. 
7.6 
Procedures for Discontinuation or Withdrawal of a Subject 
The investigator may discontinue a subject’s study participation at any time during the study 
when the subject meets the study termination criteria described in Section 7.5. In addition, a 
subject may discontinue his or her participation without giving a reason at any time during the 
study. Should a subject’s participation be discontinued, the primary criterion for termination 
must be recorded by the investigator. In addition, efforts should be made to perform all 
procedures scheduled for the Early Termination Visit. Discontinued or withdrawn subjects be 
replaced. 


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8.0 
CLINICAL TRIAL MATERIAL MANAGEMENT 
This section contains information regarding all medication and materials provided directly by the 
sponsor, and/or sourced by other means, that are required by the study protocol, including 
important sections describing the management of clinical trial material. 
8.1 
Study Medication and Materials 
8.1.1 Dosage Form, Manufacturing, Packaging, and Labeling 
Study drug refers to CVN058 and matching placebo. Study drug will be provided in bulk supply. 
An unblinded pharmacist will manage and prepare doses as oral solutions, as needed. 
In this protocol, the term study medication refers to all or any of the drugs defined below. 
8.1.1.1 Investigational Drug 
CVN058 and Matching Placebo  
CVN058 drug substance is supplied as bulk powder to the clinical site to be compounded into an 
oral solution. A matching placebo containing all of the components of the active oral suspension 
with the exception of the drug substance will also be compounded by the site. Compounding 
instructions will be outlined in a separate pharmacy manual and provided by the sponsor. 
CVN058 oral solution will be prepared in concentrations of 10 mg/mL. The composition of the 
oral solutions (active and placebo) can be found in Table 8.a. 
The oral solution will be labeled with the appropriate study information and caution statements. 
Table 8.a 
Composition of CVN058 and Matching Placebo 
Component 
10 mg/mL solution 
Placebo 
CVN058 (free base) 
10 g 
Not Applicable 
Citric Acid Monohydrate, USP 
15.76 g 
15.76 g 
Sterile Water for Irrigation, USP 
q.s. to 1,000 mL 
q.s.to 1,000 mL 
q.s.=quantity sufficient, USP= United States Pharmacopeia. 
 
8.1.1.2 Sponsor-Supplied Drug 
CVN058 drug substance is supplied to the clinical site by Cerevance by way of a contract 
manufacturing organization, Johnson-Mathey Pharma Services, Devens, MA. 
8.1.1.3 Ancillary Materials 
Ancillary materials will be provided by either the clinical site and/or sponsor based on 
availability.  
Ancillary material details are provided in the pharmacy manual. 


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Unused ancillary materials, if provided by the sponsor, will be accounted for and disposed of as 
directed by the sponsor or their designee.  
8.1.2 Storage 
All clinical trial material must be kept in an appropriate, limited-access, secure place until it is 
used or returned to the sponsor or designee for destruction. 
All study medication must be stored under the conditions specified on the label, and remain in 
the original container until dispensed. A daily temperature log of the drug storage area must be 
maintained every working day. 
CVN058 powdered drug substance is stored at room temperature. CVN058 oral solution and 
matching placebo can be stored protected from light at 2°C-8°C (35.6°F-46.4°F) for up to 28 
days. CVN058 oral solution and matching placebo are stable at room temperature for up to 24 
hours. 
8.1.3 Dose and Regimen 
The investigator or investigator’s designee will instruct the subject on dosing procedures. 
All dosing will occur while subjects are in the clinic under the supervision of the PI or designee, 
who will be blinded to the dose. 
Subjects will receive CVN058 (15 mg or 150 mg) or matching placebo in each of the 3 periods.  
Table 8.b describes the treatment and medication type that would be provided for each period. 
Table 8.b 
Treatment and Medication Type 
Regimen 
Planned Treatment 
Medication Type 
A 
Placebo 
Placebo  
B 
CVN058 15 mg 
CVN058  
C 
CVN058 150 mg 
CVN058 
 
8.1.4 Overdose 
An overdose is defined as a known deliberate or accidental administration of investigational 
drug, to or by a study subject, at a dose above that which is assigned to that individual subject 
according to the study protocol. 
All cases of overdose (with or without associated AEs) will be documented on an Overdose page 
of the eCRF, in order to capture this important safety information consistently in the database. 
Cases of overdose without manifested signs or symptoms are not considered AEs. AEs 
associated with an overdose will be documented on AE CRF(s) according to Section 10.0, 
Pretreatment Events and Adverse Events. 
The SAEs associated with overdose should be reported according to the procedure outlined in 
Section 10.2.2, Collection and Reporting of SAEs. 


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In the event of drug overdose, the subject should be treated, e.g., administration of supportive 
therapy as directed by the subject’s clinical status, removal of unabsorbed material from the 
gastrointestinal tract and initiation of additional clinical monitoring.  
8.2 
Investigational Drug Assignment and Dispensing Procedures 
Subjects will be assigned a 6-digit, site specific, subject number in the sequential order in which 
they are randomized beginning with NNN-001, where NNN represents a site specific identifier 
which will be provided by the Sponsor. Replacement subjects will be assigned a new number 
(e.g. site number followed by subject number). The 6-digit subject number assigned will be 
entered in the subject’s eCRF and any noted on any subject specific source record and lab sample 
tubes. 
This 6-digit subject number will also be used by the clinical site to facilitate the prelabeling of 
PK samples, and will be the only subject identifier used on all PK sample collections. It should 
also be contained on the PK transport vials shipped to the bioanalytical laboratory, and will be 
used by the laboratory to report the subject data results. 
8.3 
Randomization Code Creation and Storage  
The randomization schedule will be generated under the direction of Cerevance statistician or 
designee and a copy will be provided to the site pharmacist prior to the start of study. All 
randomization information will be stored in a secured area, accessible only by authorized 
personnel. 
8.4 
Investigational Drug Blind Maintenance  
The investigational drug blind is maintained through a randomization schedule held by the 
dispensing pharmacist.  
8.5 
Unblinding Procedure  
The investigational drug blind shall not be broken by the investigator unless information 
concerning the investigational drug is necessary for the medical treatment of the subject. All 
study assessments and causality should be performed, if possible, prior to unblinding. In the 
event of a medical emergency, if possible, the medical monitor should be contacted before the 
investigational drug blind is broken to discuss the need for unblinding. 
For unblinding a subject, the investigational drug blind can be obtained by contacting the 
dispensing pharmacist. 
The sponsor must be notified as soon as possible if the investigational drug blind is broken. The 
date, time, and reason the blind is broken must be recorded in the source documents and the 
same information (except the time) must be recorded on the eCRF. 
If any site personnel are unblinded, investigational drug must be stopped immediately and the 
subject must be withdrawn from the study. 
No change should be made to any assessment of the subject after unblinding. 


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8.6 
Accountability and Destruction of Sponsor-Supplied Drugs 
Drug supplies will be counted and reconciled at the site before being returned to the sponsor or 
designee or destroyed per site’s procedures. 
The investigator or designee must ensure that the sponsor-supplied drug is used in accordance 
with the protocol and is dispensed only to subjects enrolled in the study. To document 
appropriate use of sponsor-supplied drug, the investigator or designee must maintain records of 
all sponsor-supplied drug delivery to the site, site inventory, dispensation and use by each 
subject, and return to the sponsor or designee. 
Upon receipt of sponsor-supplied drug, the investigator or designee must verify the contents of 
the shipments against the packing list. The verifier should ensure that the quantity is correct, and 
the medication is in good condition. If quantity and conditions are acceptable, investigator or 
designee should acknowledge the receipt of the shipment by signing bottom half of the packing 
list and faxing per instructions provided on the form. If there are any discrepancies between the 
packing list versus the actual product received, Cerevance must be contacted to resolve the issue. 
The packing list should be filed in the investigator’s essential document file. 
The investigator or designee must maintain 100% accountability for all sponsor-supplied drugs 
received and dispensed during his or her entire participation in the study. Proper drug 
accountability includes, but is not limited to: 
• Continuously monitoring expiration dates. 
• Frequently verifying that actual inventory matches documented inventory. 
• Verifying that the log is completed for the drug lot used to prepare each dose. 
• Verifying that all containers used are documented accurately on the log. 
• Verifying that required fields are completed accurately and legibly. 
If any dispensing errors or discrepancies are discovered, the sponsor must be notified 
immediately. 
The investigator or designee must record the current inventory of all sponsor-supplied drugs 
CVN058 or placebo on a sponsor-approved drug accountability log. The following information 
will be recorded at a minimum: protocol number and title, name of investigator, site identifier 
and number, description of sponsor-supplied drugs, expiration date and amount dispensed, 
including initials of the person dispensing the drug, and the date and amount returned to the site 
by the subject, including the initials of the person receiving the sponsor-supplied drug. The log 
should include all required information as a separate entry for each subject to whom sponsor-
supplied drug is dispensed. 
All study drug that was not returned to the site by a subject must be investigated by the site and 
appropriately documented on the drug accountability log. 
Prior to site closure or at appropriate intervals, a representative from the sponsor or its designee 
will perform sponsor-supplied drug accountability and reconciliation before sponsor-supplied 


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drugs are returned to the sponsor or its designee for destruction. The investigator or designee will 
retain a copy of the documentation regarding sponsor-supplied drug accountability, return, 
and/or destruction, and originals will be sent to the sponsor or designee. 
The investigator will be notified of any expiry date or retest date extension of sponsor-supplied 
drug during the study conduct. On expiry date notification from the sponsor or designee, the site 
must complete all instructions outlined in the notification, including segregation of expired 
sponsor-supplied drug for return to the sponsor or its designee for destruction. 


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9.0 
STUDY PLAN 
9.1 
Study Procedures 
The following sections describe the study procedures and data to be collected. For each 
procedure, subjects are to be assessed by the same investigator or site personnel whenever 
possible. The Schedule of Study Procedures is located in Appendix A. 
9.1.1 Informed Consent Procedure 
The requirements of the informed consent are described in Section 15.2. 
Informed consent must be obtained prior to the subject entering into the study, and before any 
protocol-directed procedures are performed. 
A unique subject Screening number will be assigned to each subject at the time that the informed 
consent is obtained; this Screening number will be used until the subject has been randomized 
into the study, at which time the Subject number will be primary method of identification on 
study records. 
9.1.1.1 Pharmacogenomic Informed Consent Procedure 
Pharmacogenomics informed consent is a component of the overall study informed consent. The 
requirements are described in Section 15.2. 
The pharmacogenomic sample collection is optional.. 
9.1.2 Demographics, Medical History, and Medication History Procedure 
Demographic information to be obtained will include date of birth, sex, Hispanic ethnicity, race 
as described by the subject, height, weight, caffeine consumption, reproductive status (including 
last menstrual period) and smoking status of the subject at Screening.  
Medical history to be obtained will include determining whether the subject has any significant 
conditions or diseases relevant to the disease under study that stopped at or prior to signing of 
informed consent. Ongoing conditions are considered concurrent medical conditions 
(see Section 9.1.7). 
Medication history information to be obtained includes any medication relevant to eligibility 
criteria stopped at or within 45 days (for subjects with schizophrenia) prior to signing of 
informed consent. 
9.1.3 Physical Examination Procedure 
A physical examination will consist of the following body systems: (1) eyes; (2) ears, nose, 
throat; (3) cardiovascular system; (4) respiratory system; (5) gastrointestinal system; 
(6) dermatologic system; (7) extremities; (8) musculoskeletal system; (9) nervous system; 
(10) lymph nodes; and (11) other. 


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Any abnormal change from the initial Screening physical examination must be assessed by the 
investigator as not clinically significant (NCS) or clinically significant (CS) and recorded in the 
source document and eCRF. 
Any CS change, as determined by the investigator, from the baseline physical examination will 
be recorded as an AE or pretreatment event in source documentation and on the Pretreatment 
Event/AE eCRF. 
9.1.4 Weight, Height, and BMI 
A subject should have weight and height measured while wearing indoor clothing and with shoes 
off. The BMI is calculated using metric units with the formula provided below:  
The standard for collecting height is centimeters without decimal places and for weight it is 
kilograms (kg) with 1 decimal place. BMI should be derived as: 
Metric:  
BMI = weight (kg)/height (m)2 
Note that although height is measured in centimeters, the BMI formula uses meters for height; 
meters can be determined by dividing centimeters by 100. Thus, for example, if height=176 cm 
(1.76 m) and weight=79.2 kg, then BMI=79.2/1.762=25.56818 kg/m2. 
Results for BMI will be expressed with 1 decimal place and rounding is allowed. The above 
value should be captured as 25.6 kg/m2 in the database. 
9.1.5 Vital Sign Procedure  
When vital signs are scheduled at the same time as blood draws, the blood draw will take priority 
and vital signs will be obtained within 0.5 hour before or after the scheduled blood draw. 
Vital signs consisting of body temperature (oral), respiration rate, supine blood pressure and 
pulse will be measured in a seated resting state (>10 minutes). 
9.1.6 Documentation of Concomitant Medications 
Concomitant medication is any drug given in addition to the study medication. These may be 
prescribed by a physician or obtained by the subject over the counter. Concomitant medication is 
not provided by Cerevance. At each study visit, subjects will be asked whether they have taken 
any medication other than the study medication (used from signing of informed consent through 
the end of the study), and all medication including vitamin supplements, OTC medications, and 
oral herbal preparations, must be recorded in the eCRF. Documentation will include generic 
medication name, dose, unit, frequency, route of administration, start and end dates, and reason 
for use.  
9.1.7 Documentation of Concurrent Medical Conditions 
Concurrent medical conditions are those significant ongoing conditions or diseases that are 
present at signing of informed consent. This includes clinically significant laboratory, ECG, or 


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physical examination abnormalities noted at the Screening examination. The condition (i.e., 
diagnosis) should be described. 
9.1.8 Procedures for Clinical Laboratory Samples 
All samples will be collected in accordance with acceptable laboratory procedures and as 
stipulated in the Schedule of Study Procedures (Appendix A). Abnormal Screening labs may be 
repeated once at the discretion of the investigator for assessment of eligibility. Subjects who still 
do not meet eligibility criteria may be re-screened at investigator’s discretion. 
Table 9.a lists the tests that will be obtained for each laboratory specimen  
Table 9.a 
Clinical Laboratory Tests 
Hematology 
Serum Chemistry 
Urinalysis 
 
RBC 
WBC with differential (% 
and absolute) 
Hemoglobin 
Hematocrit 
Platelets 
Prothrombin time /INR 
ALT 
Albumin 
Alkaline phosphatase 
AST 
Total bilirubin 
Direct bilirubin 
Total protein 
Creatinine 
Blood urea nitrogen 
Creatine kinase 
GGT 
Potassium 
Sodium 
Glucose 
Chloride 
Bicarbonate 
Calcium 
pH 
Specific gravity 
Protein 
Glucose 
Blood  
Nitrite 
Microscopic Analysis 
(only if positive dipstick 
results):  
RBC/high power field 
WBC/high power field 
Epithelial cells, casts etc 
 
Diagnostic Screening: 
Serum 
Urine 
Saliva (d) 
Serum hCG (a) 
At Screening Only:  
Hepatitis panel, including HBsAg 
and anti-HCV 
FSH (b) 
Drug screen including 
amphetamines, barbiturates, 
benzodiazepines, cannabinoids, 
cocaine, opiates, alcohol, and 
cotinine (c) 
Alcohol 
cotinine 
FSH=follicle-stimulating hormone, GGT=γ-glutamyl transferase, RBC=red blood cells, WBC=white blood cells. 
(a) Serum hCG pregnancy test will be done at Screening. 
(b) FSH level will be obtained for female subjects at Screening if they are postmenopausal (i.e., last regular 
menstrual cycle >2 years) and not surgically sterile. The result must be >40 IU/L to obviate the need for 
contraception.  
(c) To be performed at Screening.  
(d) Alcohol and cotinine saliva samples may be collected, if needed. 


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The local laboratory will perform laboratory tests for hematology, serum chemistries, and 
urinalysis. The results of laboratory tests will be returned to the investigator, who is responsible 
for reviewing and filing these results. 
If subjects experience ALT or AST >3 ×ULN, follow-up laboratory tests (at a minimum, serum 
alkaline phosphatase, ALT, AST, total bilirubin, GGT, and INR) should be performed within a 
maximum of 7 days and preferably within 48 to 72 hours after the abnormality was noted. 
(Please refer to Section 7.5 for discontinuation criteria, and Section 10.2.3 for the appropriate 
guidance on Reporting of Abnormal Liver Function Tests in relation to ALT or AST >3 ×ULN 
in conjunction with total bilirubin >2 ×ULN.) 
If the ALT or AST remains elevated >3 ×ULN on these 2 consecutive occasions, the investigator 
must contact the Medical Monitor for consideration of additional testing, close monitoring, 
possible discontinuation of study medication, discussion of the relevant subject details and 
possible alternative etiologies. The abnormality should be recorded as an AE (please refer to 
Section 10.2.3 Reporting of Abnormal Liver Function Tests for reporting requirements). 
All laboratory safety data will be transferred electronically to Cerevance or designee in the 
format requested by Cerevance. If the laboratory is unable to electronically transfer data, the 
study site coordinator or designee is responsible for transcribing laboratory results into the eCRF. 
The investigator will maintain a copy of the laboratory accreditation and the reference ranges for 
the laboratory used. 
Laboratory reports must be signed and dated by the PI or sub-investigator indicating that the 
report has been reviewed and any abnormalities have been assessed for clinical significance.  
All CS laboratory abnormalities must be recorded as a PTE/AE in the subject’s source 
documents and on the appropriate eCRF. A CS laboratory abnormality that has been verified by 
retesting will be followed until the abnormality returns to an acceptable level or a satisfactory 
explanation has been obtained. 
9.1.9 Contraception and Pregnancy Avoidance Procedure 
From signing of informed consent, throughout the duration of the study, and for 12 weeks after 
last dose of study medication, nonsterilized** male subjects who are sexually active with a 
female partner of childbearing potential* must use barrier contraception (e.g., condom with 
spermicidal cream or jelly). In addition, they must be advised not to donate sperm during this 
period.  
From signing of informed consent, throughout the duration of the study, and for 12 weeks after 
last dose of study medication, female subjects of childbearing potential* who are sexually active 
with a nonsterilized male partner** must use adequate contraception. In addition they must be 
advised not to donate ova during this period. 


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*Females NOT of childbearing potential are defined as those who have been surgically sterilized 
(hysterectomy, bilateral oophorectomy or tubal ligation) or who are postmenopausal (e.g., 
defined as at least 2 years since last regular menses with an FSH>40 IU/L or at least 5 years 
since last regular menses, confirmed before any study medication is implemented). 
**Sterilized males should be at least 1 year postvasectomy and have confirmed that they have 
obtained documentation of the absence of sperm in the ejaculate. 
An acceptable method of contraception is defined as one that has no higher than a 1% failure 
rate. In this study, where medications and devices containing hormones are excluded, the 
only acceptable methods of contraception are: 
Barrier methods (each time the subject has 
intercourse): 
Intrauterine devices (IUDs): 
Male condom PLUS spermicide. 
Cap (plus spermicidal cream or jelly) PLUS 
male condom and spermicide. 
Diaphragm (plus spermicidal cream or jelly) 
PLUS male condom and spermicide. 
Copper T PLUS condom or spermicide. 
 
Subjects will be provided with information on acceptable methods of contraception as part of the 
subject informed consent process and will be asked to sign a consent form stating that they 
understand the requirements for avoidance of pregnancy, donation of ova, and sperm donation 
during the course of the study. 
During the course of the study, regular serum human chorionic gonadotropin (hCG) pregnancy 
tests will be performed only for women of childbearing potential, and subjects will receive 
guidance with respect to the avoidance of pregnancy. In addition to a negative serum hCG 
pregnancy test at Screening, subjects also must have a negative urine hCG pregnancy test prior to 
receiving any dose of study medication. Male subjects must be advised not to donate sperm from 
signing of informed consent to 12 weeks after the last dose of study medication. 
9.1.10 Pregnancy 
If any subject is found to be pregnant during the study she should be withdrawn and any sponsor-
supplied drug should be immediately discontinued. In addition, any pregnancies in the partner of 
a male subject during the study or for 12 weeks after the last dose should also be recorded 
following authorization from the subject’s partner.  
If the pregnancy occurs during administration of active study medication, e.g., after Visit 1 or 
within 12 weeks of the last dose of active study medication, the pregnancy should be reported 
immediately, using a pregnancy notification form, to the contact listed in Section 1.0. 
Should the pregnancy occur during or after administration of blinded drug, the investigator must 
inform the subject of their right to receive treatment information. If the subject chooses to 


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receive unblinded treatment information, the individual blind should be broken by the 
investigator. Subjects who have only received placebo need not be followed. 
If the female subject and/or female partner of a male subject agrees to the primary care physician 
being informed, the investigator should notify the primary care physician that the subject/female 
partner of the subject was participating in a clinical study at the time she became pregnant and 
provide details of treatment the subject received (blinded or unblinded, as applicable). 
All reported pregnancies will be followed up to final outcome, using the pregnancy form. The 
outcome, including any premature termination, must be reported to the sponsor. An evaluation 
after the birth of the child will also be conducted. 
9.1.11 ECG Procedure  
A standard 12-lead ECG will be recorded in a supine position resting for at least 10 minutes at 
Screening to assess eligibility. The ECGs will be recorded in triplicate at approximately 5 minute 
intervals. The investigator (or a qualified physician at the investigational site) will interpret the 
ECG using 1 of the following categories: within normal limits, abnormal but NCS, or abnormal 
and CS. A copy of the ECG trace should be kept with the subject’s notes. 
ECGs will be read automatically and also, the investigator or sub-investigator or a suitably 
qualified delegate will manually interpret the ECG using 1 of the following categories: within 
normal limits, abnormal NCS, or abnormal and CS. All 12-lead ECGs will be stored for manual 
measurement of intervals, if necessary.  
Twelve-lead ECGs will be recorded using an ECG machine that automatically calculates the 
heart rate and measures PR interval, RR interval, QRS interval, QT interval, and QTcF and 
QTcB (Fridericia’s and Bazett’s correction) intervals.  
One copy of the 12-lead ECG with the physician’s signature and date of assessment will be filed 
with the source documents and captured in the appropriate eCRF. All ECGs will be recorded at 
the time points detailed in the Schedule of Study Procedures (Appendix A). 
9.1.12 Pharmacogenomic Sample Collection 
Every subject must sign informed consent/be consented in order to participate in the study. 
Deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) form the basis for the genes that 
make the body produce proteins such as enzymes, drug transporters or drug targets, and may be 
evaluated for the genetic contribution how the drug is broken down, or how the drug affects the 
body. This is called a “pharmacogenomics research study.” Specific purposes of this study 
include: 
• Identifying genetic reasons why certain people respond differently to CVN058. 
• Finding out more information about how CVN058 works. 
• Generating information needed for research, development, and regulatory approval of tests to 
predict response to CVN058. 


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• Identifying variations in genes related to the biological target of CVN058. 
This information may be used, for example, to develop a better understanding of the safety and 
efficacy of CVN058 and other study medications, and for improving the efficiency, design and 
study methods of future research studies. 
The DNA samples will be used to evaluate common variations in genes which encode drug 
metabolizing enzymes and transporters. This could be helpful in understanding why there are 
differences in CVN058 kinetics between subjects. Also, since pharmacogenomics is an evolving 
science, many genes and their functions are not yet fully understood. Future data may suggest a 
role of some of these genes in drug response, which may lead to additional hypothesis-generating 
exploratory research and diagnostic development on stored samples. 
Whole blood will be collected and stored for possible DNA or RNA isolation and analysis.  
DNA sample collection: 
One 6 mL whole blood sample will be collected before study drug dosing on Day 1 of 
Period 1 only from each subject in the study, into plastic potassium ethylenediamine 
tetraacetic acid (K2EDTA) spray-coated tubes, and stored under frozen conditions.  
RNA sample collection: 
Two whole blood samples (2.5 mL per sample) will be collected from each subject into a 
PAXgene tube on Day 1 of each period at pre dose and post EEG for RNA 
pharmacogenomic analysis.  
If isolation of DNA from the first sample was not successful or possible, a second aliquot of 
blood may be taken, if feasible. 
Each pharmacogenomic sample for a study subject should be identifiable on the requisition form 
with the 6-digit subject ID. Detailed instructions for the handling, shipping, and storage of 
pharmacogenomic samples will be provided in the lab manual.  
The samples will be stored for no longer than 15 years after completion of the CVN058 study 
and/or until the drug development of CVN058 is no longer actively pursued by Cerevance or its 
collaborators. No samples will be stored for longer than permitted by the applicable law and 
samples will be destroyed upon notification from Cerevance. 
9.1.13 Pharmacokinetic Sample Collection 
9.1.13.1 Collection of Blood for Pharmacokinetic Sampling 
Blood samples (one 6-mL sample per scheduled time) will be collected for analysis of CVN058, 
and its metabolite if appropriate; plasma will be collected into chilled vacutainers containing 
K2EDTA according to the schedule in Appendix A. Instructions for sample processing and 
shipment will be provided in the lab manual. 
Serial blood samples for determination of CVN058, and its metabolite if appropriate, in plasma 
will be collected according to Table 9.b. 


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Table 9.b 
Collection of Blood Samples for CVN058 Pharmacokinetic Analysis 
Sample 
Type 
Dosing Day 
Time Postdose (hours) 
Plasma 
1 
Predose (within 15 minutes prior to dosing), 1 hour post dose (pre-EEG), and 4 hours 
post dose (post-EEG)   
 
The PK samples will be collected before any other assessments are performed, if scheduled at the 
same time point. The actual time of sample collection will be recorded on the source document 
and eCRF. 
Placebo samples will not be analyzed by the bioanalytical laboratory except 1 sample per subject 
receiving placebo around the expected time at which CVN058 Cmax is expected to occur to 
ensure from a safety perspective that no subjects have inadvertently received active treatment. 
9.1.13.2 Bioanalytical Methods 
Plasma concentrations of CVN058 will be measured by high-performance liquid 
chromatography with tandem mass spectrometry. If appropriate, plasma samples analyzed for 
CVN058 also may be analyzed for the CVN058 metabolite. 
9.1.14 Pharmacokinetic Parameters  
The PK parameters of CVN058, and its metabolite (if appropriate), will be derived using non-
compartmental analysis methods. The PK parameters will be determined from the concentration-
time data for all evaluable subjects. Actual sampling times, rather than scheduled sampling 
times, will be used in all computations involving sampling times. The following PK parameters 
will be determined from concentrations of CVN058, and its metabolite if appropriate, in plasma. 
Other parameters may be calculated as appropriate.  
Symbol/Term 
Definition 
Plasma 
AUCt 
Area under the plasma concentration-time curve from time 0 to time of the last 
quantifiable concentration. 
Cmax 
Maximum observed plasma concentration. 
tmax 
Time to reach Cmax. 
 
9.1.15 Pharmacodynamic Sample Collection  
MMN will be used as a PD assessment. At each testing session, the following PD assessments 
will be performed during the EEG: MMN, P50, gamma power, and P300. Collection of P50 may 
be omitted if the essential equipment is not available. The testing session during each Treatment 
Period will begin approximately 1.5 hours after administration of study drug.  


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9.1.16 Pharmacodynamic Parameters  
All EEG parameters will be obtained in accordance with the EEG acquisition guideline provided 
by Cerevance or their designee. It is anticipated that each EEG procedure will take 
approximately 3 hours to complete, including approximately 30 minutes to set up, 2 hours 
acquisition time, and 30 minutes to clean up. 
MMN 
MMN is a pre-attentive auditory component elicited by deviant stimuli in an auditory oddball 
task. MMN predominantly reflects activation of neuronal ensembles within primary auditory 
cortex, and thus indexes sensory level disturbance in schizophrenia. MMN will be obtained 
independently to pitch and duration deviant stimuli. MMN is maximal at frontocentral electrodes 
(Fz, Cz). Mean peak amplitude at 5 electrodes surrounding Fz within a predefined latency range 
will be the primary outcome measure. 
P50 
P50 auditory evoked potentials will be recorded. Participants will be seated and instructed to 
relax and to focus their eyes on a fixation point. Stimulus signal of 90-dB pulses of 0.1 msec in 
duration will be generated and recorded the event-related potential waveforms.  
32 pairs of auditory clicks will be presented every 10 seconds, with a 500 msec interclick 
interval. 
 
The conditioning P50 wave (S1) and test P50 wave (S2) will be identified as the power in the 
alpha/beta frequency bands as suggested by Smucny et al. (Smucny, 2013). The data from the 
vertex (Cz) and surrounding electrodes will be collected and the P50 gating ratios will be 
calculated as the ratio of the test P50 to the conditioning P50 power. In case the Cz gating ratio is 
>0.2 units above the surrounding electrodes, the value will be discarded and replaced with the 
value from surrounding electrodes. P50 ratio will be defined as the ratio of S2/S1 power. The S2-
S1 difference score as suggested by Smucny et al. (Smucny, 2013) will be used as an exploratory 
outcome measure.  
Quantitative Electroencephalogram, Gamma Power 
Five minute eyes open/close recordings will be obtained during each recording session. Ten 1-
second, artifact-free epochs will be chosen for quantitative analysis. Primary outcome measures 
will consist of power within delta (0.5 – 4 Hz), theta (4-7 Hz), alpha (8-13 Hz), delta (13-20 Hz), 
low gamma (20-40 Hz) and high gamma (40 – 60 Hz) over predesignated frontal, central, 
temporal and occipital sites. In addition, specific measures of 40 Hz activity will be assessed in 
response to repetitive 40 Hz auditory stimulation. 
P300 
As opposed to MMN, which are obtained under passive (i.e., no-task) conditions, auditory P300 
will be obtained only when subjects must attend to and detect novel task-relevant deviant stimuli. 
Generators for P300 are located in distributed frontoparietal networks and so represent an index 
of higher order, “cognitive” processing in schizophrenia. P300 will be obtained to deviant 
auditory stimuli in an auditory “oddball” paradigm. P300 is maximal in amplitude at Fz and Pz 


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electrodes. Primary outcome measures will consist of peak amplitude within prespecified latency 
range at the frontal/parietal sites. 
9.1.17 Positive and Negative Syndrome Scale 
The PANSS was developed and standardized for typological and dimensional assessment of 
schizophrenic phenomena. In this study, empirically derived factors are tested excluding those 
items that could not be assessed during the test sessions: positive symptom factor (delusions, 
unusual thoughts, somatic concern, grandiosity, suspiciousness, and hallucinations), negative 
symptom factor (emotional withdrawal, blunted affect, poor rapport, disturbance of volition, 
preoccupation, and motor retardation), cognitive factor (difficulty in abstract thinking, 
stereotyped thinking, cognitive disorganization, lack of judgment and insight, poor attention, 
tension, mannerisms, and posturing), hostility (excitement, hostility, impulse control, and 
uncooperativeness), emotional discomfort (depression, anxiety, and guilt). PANSS will be 
collected at Screening, Early Termination, and at the Follow-up Visit if clinically significant 
findings were observed upon discharge. In these cases, subjects must then be brought back to the 
clinic for re-evaluation per investigator’s discretion.  
The duration of the PANSS is approximately 30 minutes (Kay, 1990). 
9.1.18 Columbia Suicide Severity Rating Scale 
The determination and management of patients’ suicidality risk is the Investigators’ 
responsibility. For study purposes, suicidality will be assessed by the use of the C-SSRS. The C-
SSRS is a 3-part scale that measures suicidal ideation (e.g., subject endorses thoughts about a 
wish to be dead or has other thoughts of suicide), intensity of ideation (frequency, duration, 
controllability, deterrents, and reasons for ideation), and suicidal behavior (actually, interrupted, 
and aborted attempts at suicide) (Mundt, 2013). 
The C-SSRS is a 2-page questionnaire that prospectively assesses suicidal thoughts and behavior 
using a structured interview for patient responses. Suicidal ideation is classified on a 5-item 
scale: 1 (wish to be dead), 2 (nonspecific active suicidal thoughts), 3 (active suicidal ideation 
with any methods [not plan] without intent to act), 4 (active suicidal ideation with some intent to 
act, without specific plan), and 5 (active suicidal ideation with specific plan and intent). The C-
SSRS also captures information about the intensity of ideation, specifically the frequency, 
duration, controllability, deterrents, and reasons for the most severe types of ideation. Suicidal 
behavior is classified on a 5-item scale: 0 (no suicidal behavior), 1 (preparatory acts or behavior), 
2 (aborted attempt), 3 (interrupted attempt), and 4 (actual attempt). 
Different versions of the scale are available. In this study, “Baseline/Screening” version will be 
used at Screening Visit and “Since last visit” version at all subsequent visits. “Since the last 
visit” should collect information from the last visit where C-SSRS was administered. If the 
patient’s response generates a change in the findings report from negative to positive, the patient 
should be referred for immediate psychiatric evaluation on the same date as the site visit. 
Positive suicidality findings, if confirmed by the PI, is considered to be a serious event. If arising 
after signing informed consent but prior to administration of any study medication, it is 


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considered a Pretreatment Event (PTE). If arising after administration of any study medication, it 
is considered an SAE.  
The C-SSRS will be administered by the PI or a trained designee on paper and captured in the 
eCRF. The same interviewer should be used throughout the study for the same subject where 
possible. 
9.1.19 Documentation of Screen Failure 
Investigators must account for all subjects who sign informed consent. If the subject is found to 
be not eligible at this visit, the investigator should complete the eCRF screen failure form. 
The primary reason for screen failure is recorded in the eCRF using the following categories: 
• PTE/AE. 
• Did not meet inclusion criteria or did meet exclusion criteria. 
• Significant protocol deviation. 
• Lost to follow-up. 
• Voluntary withdrawal. 
• Study termination. 
• Other <specify reason>. 
Subject numbers assigned to subjects who fail Screening should not be reused. 
9.1.20 Documentation of Randomization 
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible 
for randomization into the treatment phase. Randomization will take place on Day 1 of 
Treatment Period 1. 
If the subject is found to be not eligible for randomization, the investigator should record the 
primary reason for failure on the applicable eCRF. 
9.2 
Monitoring Subject Treatment Compliance 
Study medication will be administered while subjects are under observation in the clinical 
research unit. Following administration of the study medication, appropriate mouth and/or hand 
checks will be performed to ensure that the dose is swallowed and noted in the source document. 
The date and time of each dose will be recorded in the source documents and on the eCRFs. An 
inventory of the study medication supplies dispensed will be performed by the site pharmacist or 
authorized study designee and recorded onto the Drug Accountability Log in the subject’s source 
document records or equivalent. The exact dose time of consecutive subjects may be staggered to 
facilitate logistics at the site. 


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9.3 
Schedule of Observations and Procedures 
The schedule for all study-related procedures for all evaluations is shown in Appendix A. 
Assessments should be completed at the designated visit/time point(s). 
9.3.1 Screening 
Subjects with schizophrenia will be screened within 28 days prior to enrollment. All subjects will 
be screened in accordance with predefined inclusion and exclusion criteria as described in 
Section 7.0. See Section 9.1.17 for procedures for documenting screen failures.  Following 
written informed consent, Screening procedures may be conducted on different days. 
Assessments to be conducted during the Screening period are outlined in Appendix A. 
9.3.2 Treatment Phase 
The treatment will be administered over 3 Periods, separated by 7-10 days for washout.  
Assessments to be conducted during the screening period are outlined in Appendix A. 
9.3.3 Final Visit/End of Treatment  
The Final Visit additional assessments will occur prior to Discharge from the clinic at the end of 
Treatment Period 3, Day 1, as outlined in Appendix A. 
For all subjects who received any study medication, the investigator must complete the End of 
Study eCRF page. 
9.3.4 Early Termination 
The reason for discontinuation must be documented in the source document and eCRF. The 
procedures outlined in Appendix A will be performed and documented. 
For all subjects receiving study medication, the investigator must complete the End of Study 
eCRF page. 
9.3.5 Follow-up Visit/Telephone Call  
The Follow-up Visit will occur by telephone approximately 7-10 days after receiving the last 
dose of study medication (Treatment Period 3) unless abnormal, clinically significant findings 
were observed upon discharge. In these cases, subjects must then be brought back to the clinic 
for re-evaluation per investigator’s discretion. 
9.4 
Biological Sample Retention and Destruction  
In this study, specimens for genome/gene analysis will be collected as described in Section 
9.1.12, Pharmacogenomic Sample Collection. The genetic material will be preserved and 
retained by a biorepository contracted by Cerevance for up to but not longer than 15 years or as 
required by applicable law.  


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The samples will be sent to a central laboratory that processes the blood sample and serves as a 
secure storage facility. The sponsor and researchers working with the sponsor will have access to 
the samples collected and any test results. All samples collected during the study will be stored 
securely with limited access and the sponsor will require anyone who works with the samples to 
agree to hold the research information and any results in confidence. 
The sample will be labeled with a unique sample identifier similar to labeling in the main study. 
During the “storage” stage, the sample will be used in the analysis of the study drug and related 
disease states. At this stage, sample and data are linked to personal health information with code 
numbers. This link means that patients may be identifiable but only indirectly. The code numbers 
will be kept secure by the sponsor.  
Subjects who consented and provided a pharmacogenomic sample for DNA and RNA analysis 
can withdraw their consent and request disposal of a stored sample at any time prior to analysis. 
Notify sponsor of consent withdrawal. 
9.5 
Blood Volume 
Total blood sampling volume for an individual subject is shown in Table 9.c. 
Table 9.c 
Approximate Blood Volume 
Sample Type 
Sample 
Volume 
(mL) 
Screening  
(x1) 
 
Number of Samples per 
Period  
(x 3 Periods) 
End of 
Treatment 
Total 
Volume 
(mL) 
Safety 
Laboratory 
Samples (a) 
12.5 
1 
-- 
1 
25 
Hepatitis Panel 
5 
1 
-- 
 
5 
FSH (b) 
3 
1 
-- 
 
3 
PK Samples 
6 
-- 
9 
-- 
54 
DNA Sample 
6 
-- 
1 (c) 
-- 
6 
RNA Samples 
5 
-- 
6 
-- 
30 
 
Total Blood Sampling Volume (per Study) 
 
123 
(a) Includes Hematology, serum chemistry, and coagulation panel. 
(b) FSH level will be obtained for female subjects at Screening if they are postmenopausal (i.e. last regular 
menstrual cycle >2 years) and not surgically sterile. 
(c) Only collected in Day 1, Period 1. 
 
The maximum volume of blood at any single day is approximately 40 mL, and the approximate 
total volume of blood for the study is approximately 123 mL.  
Direct venipuncture is the preferred method of blood collection. Any other method will need to 
be approved by the Sponsor. 


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10.0 
PRETREATMENT EVENTS AND ADVERSE EVENTS 
10.1 
Definitions 
10.1.1 PTEs 
A PTE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study but prior to administration of any study 
medication; it does not necessarily have to have a causal relationship with study participation. 
10.1.2 AEs 
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a drug; it does not necessarily have to have a causal relationship with this 
treatment. 
An AE can therefore be any unfavorable and unintended sign (e.g., a clinically significant 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug 
whether or not it is considered related to the drug. 
10.1.3 Additional Points to Consider for PTEs and AEs 
An untoward finding generally may: 
• Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent 
events for pre existing conditions or underlying disease should not be considered PTEs or 
AEs.) 
• Necessitate therapeutic intervention. 
• Require an invasive diagnostic procedure. 
• Require discontinuation or a change in dose of study medication or a concomitant 
medication. 
• Be considered unfavorable by the investigator for any reason.  
• PTEs/AEs caused by a study procedure (e.g., a bruise after blood draw) should be recorded 
as a PTE/AE. 
Diagnoses vs signs and symptoms: 
• Each event should be recorded to represent a single diagnosis. Accompanying signs 
(including abnormal laboratory values or ECG findings) or symptoms should NOT be 
recorded as additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be 
recorded appropriately as a PTE(s) or as an AE(s). 
Laboratory values and ECG findings: 
• Changes in laboratory values or ECG parameters are only considered to be PTEs or AEs if 
they are judged to be clinically significant (i.e., if some action or intervention is required or if 


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the investigator judges the change to be beyond the range of normal physiologic fluctuation). 
A laboratory re-test and/or continued monitoring of an abnormal value are not considered an 
intervention. In addition, repeated or additional noninvasive testing for verification, 
evaluation or monitoring of an abnormality is not considered an intervention. 
• If abnormal laboratory values or ECG findings are the result of pathology for which there is 
an overall diagnosis (e.g., increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as a PTE or as an AE. 
Pre-existing conditions: 
• Pre-existing conditions (present at the time of signing of informed consent) are considered 
concurrent medical conditions and should NOT be recorded as PTEs or AEs. Baseline 
evaluations (e.g., laboratory tests, ECG, X-rays etc.) should NOT be recorded as PTEs unless 
related to study procedures. However, if the subject experiences a worsening or complication 
of such a concurrent condition, the worsening or complication should be recorded 
appropriately as a PTE (worsening or complication occurs before start of study medication) 
or an AE (worsening or complication occurs after start of study medication). Investigators 
should ensure that the event term recorded captures the change in the condition (e.g., 
“worsening of…”). 
• If a subject has a pre-existing episodic condition (e.g., asthma, epilepsy) any occurrence of an 
episode should only be captured as a PTE/AE if the episodes become more frequent, serious 
or severe in nature, that is, investigators should ensure that the AE term recorded captures the 
change in the condition from Baseline (e.g. “worsening of…”). 
• If a subject has a degenerative concurrent condition (e.g., cataracts, rheumatoid arthritis), 
worsening of the condition should only be captured as a PTE/AE if occurring to a greater 
extent to that which would be expected. Again, investigators should ensure that the AE term 
recorded captures the change in the condition (e.g., “worsening of…”). 
Worsening of PTEs or AEs: 
• If the subject experiences a worsening or complication of a PTE after starting administration 
of the study medication, the worsening or complication should be recorded appropriately as 
an AE. Investigators should ensure that the AE term recorded captures the change in the 
condition (e.g., “worsening of…”). 
• If the subject experiences a worsening or complication of an AE after any change in study 
medication, the worsening or complication should be recorded as a new AE. Investigators 
should ensure that the AE term recorded captures the change in the condition (e.g., 
“worsening of…”). 
Changes in severity of AEs /Serious PTEs: 
• If the subject experiences changes in severity of an AE/serious PTE, the event should be 
captured once with the maximum severity recorded. 


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Preplanned surgeries or procedures: 
• Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered PTEs or AEs. However, if a preplanned procedure is 
performed early (e.g., as an emergency) due to a worsening of the pre-existing condition, the 
worsening of the condition should be captured appropriately as a PTE or an AE. 
Complications resulting from any planned surgery should be reported as AEs. 
Elective surgeries or procedures: 
• Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as PTEs or AEs, but should be documented in the subject’s source 
documents. Complications resulting from an elective surgery should be reported as AEs. 
Overdose: 
• Cases of overdose with any medication without manifested side effects are NOT considered 
PTEs or AEs, but instead will be documented on an Overdose page of the eCRF. Any 
manifested side effects will be considered PTEs or AEs and will be recorded on the AE page 
of the eCRF. 
• Suicidal Ideation and Behavior:  
• A completed suicide is always a SAE based on its fatal outcome. C-SSRS score of 4 (active 
suicidal ideation with some intent to act) or 5 (active suicidal ideation with specific plan and 
intent) would likely indicate serious suicidal ideation and can be used to trigger intervention 
procedures to provide urgent care. Such procedures may include further evaluation and 
appropriate management; and/or immediate contact with (or need for a referral to) the 
subject’s mental health practitioner; and/or possible referral to the emergency room; and/or 
admission to an in-subject unit. For the purpose of this protocol active suicidal ideation level 
4 and 5 should be considered important medical events and reported as serious irrespective of 
whether the subject was hospitalized or not.  
• Unless the event meets other serious criteria, suicidal thoughts or suicidal ideations that do 
not include a definite plan or intention to act will be collected as non-serious adverse events 
in accordance with the standard AE reporting requirements (e.g., if a pre-existing suicidal 
ideation recorded on the screening C-SSRS got worse during the study, it should be reported 
as an AE).  
• A subject presenting with self-mutilation or other types of self-injury should be questioned 
by the investigator to clarify if the action was suicidal in intent. If the event was suicidal in 
intent, the investigator should include suicidal behavior as part of the verbatim term on the 
eCRF, that is, “slit wrists/suicidal behavior”. Such an event will be collected as a serious 
adverse event.  
• Acts of self-mutilation or self-injury without suicidal intention (i.e., self-imposed cigarette 
burns), will be collected as non-serious adverse events, unless they meet other seriousness 
criteria.  


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10.1.4 SAEs 
An SAE is defined as any untoward medical occurrence that at any dose: 
1. Results in DEATH. 
2. Is LIFE THREATENING. 
• The term “life threatening” refers to an event in which the subject was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have caused 
death if it were more severe. 
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization. 
4. Results in persistent or significant DISABILITY/INCAPACITY. 
5. Is a CONGENITAL ANOMALY/BIRTH DEFECT. 
• Report if you suspect that exposure to a medical product prior to conception or during 
pregnancy may have resulted in an adverse outcome in the child. 
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following: 
• May require intervention to prevent items 1 through 5 above. 
• May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization. 
• Includes any event or synonym described in the Medically Significant AE List 
(Table 10.a). 
Table 10.a 
Medically Significant AE List 
Term 
Acute respiratory failure/acute respiratory distress 
syndrome 
Hepatic necrosis 
Torsade de pointes / ventricular fibrillation / ventricular 
tachycardia 
Acute liver failure 
Anaphylactic shock 
Malignant hypertension 
Acute renal failure 
Convulsive seizure 
Pulmonary hypertension 
Agranulocytosis 
Pulmonary fibrosis 
Aplastic anemia 
Confirmed or suspected endotoxin shock 
Toxic epidermal necrolysis/Stevens-Johnson syndrome Confirmed or suspected transmission of infectious agent by 
a medicinal product 
 
Serotonin syndrome 
Neuroleptic malignant syndrome / malignant hyperthermia 
 
Spontaneous abortion / stillbirth and fetal death 
 
PTEs that fulfill 1 or more of the serious criteria above are also to be considered SAEs and 
should be reported and followed up in the same manner (see Sections 10.2.2 and 10.3). 


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10.1.5 Severity of PTEs and AEs 
The different categories of intensity (severity) are characterized as follows: 
Mild: 
The event is transient and easily tolerated by the subject. 
Moderate: 
The event causes the subject discomfort and interrupts the subject’s usual activities. 
Severe: 
The event causes considerable interference with the subject’s usual activities. 
10.1.6 Causality of AEs 
The relationship of each AE to study medication(s) will be assessed using the following 
categories: 
Related: 
An AE that follows a reasonable temporal sequence from administration of a drug (including 
the course after withdrawal of the drug), or for which possible involvement of the drug cannot 
be ruled out, although factors other than the drug, such as underlying diseases, complications, 
concomitant drugs and concurrent treatments, may also be responsible. 
Not Related: 
An AE that does not follow a reasonable temporal sequence from administration of a drug 
and/or that can reasonably be explained by other factors, such as underlying diseases, 
complications, concomitant drugs and concurrent treatments. 
10.1.7 Relationship to Study Procedures 
Relationship (causality) to study procedures should be determined for all PTEs and AEs. 
The relationship should be assessed as Related if the investigator considers that there is 
reasonable possibility that an event is due to a study procedure. Otherwise, the relationship 
should be assessed as Not Related. 
10.1.8 Start Date 
The start date of the AE/PTE is the date that the first signs/symptoms were noted by the subject 
and/or physician. 
10.1.9 
Stop Date  
The stop date of the AE/PTE is the date at which the subject recovered, the event resolved but 
with sequelae or the subject died. 
10.1.10 Frequency  
Episodic AEs/PTE (e.g., vomiting) or those which occur repeatedly over a period of consecutive 
days are intermittent. All other events are continuous. 
10.1.11 Action Concerning Study Medication  
• Drug withdrawn – a study medication is stopped due to the particular AE. 
• Dose not changed – the particular AE did not require stopping a study medication. 


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• Unknown – only to be used if it has not been possible to determine what action has been 
taken. 
• Not Applicable – a study medication was stopped for a reason other than the particular AE 
(e.g., the study has been terminated, the subject died, dosing with study medication was 
already stopped before the onset of the AE). 
10.1.12 Outcome 
• Recovered/Resolved – Subject returned to first assessment status with respect to the AE/PTE. 
• Recovering/Resolving – the intensity is lowered by one or more stages: the diagnosis or 
signs/symptoms has almost disappeared; the abnormal laboratory value improved, but has not 
returned to the normal range or to Baseline; the subject died from a cause other than the 
particular AE/PTE with the condition remaining “recovering/resolving”. 
• Not recovered/not resolved – there is no change in the diagnosis, signs or symptoms; the 
intensity of the diagnosis, signs/ symptoms or laboratory value on the last day of the 
observed study period has got worse than when it started; is an irreversible congenital 
anomaly; the subject died from another cause with the particular AE/PTE state remaining 
“Not recovered/not resolved”. 
• Resolved with sequelae – the subject recovered from an acute AE/PTE but was left with 
permanent/significant impairment (e.g., recovered from a cardiovascular accident but with 
some persisting paresis). 
• Fatal – the AEs/PTEs which are considered as the cause of death. 
• Unknown – the course of the AE/PTE cannot be followed up due to hospital change or 
residence change at the end of the subject’s participation in the study. 
10.2 
Procedures 
10.2.1 Collection and Reporting of AEs 
10.2.1.1 PTE and AE Collection Period 
Collection of PTEs will commence from the time the subject signs the informed consent to 
participate in the study and continue until the subject is first administered study medication on 
Day 1 Period 1 of Part 2 or until screen failure. For subjects who discontinue prior to study 
medication administration, PTEs are collected until the subject discontinues study participation. 
Collection of AEs will commence from the time that the subject is first administered study 
medication Day 1 Treatment Period 1. Routine collection of AEs will continue until 21 days 
following last dose. 


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10.2.1.2 PTE and AE Reporting 
At each study visit, the investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Subjects may report AEs occurring at any other time during the study. Subjects experiencing a 
serious PTE must be monitored until the symptoms subside and any clinically relevant changes 
in laboratory values have returned to Baseline or there is a satisfactory explanation for the 
change. Non-serious PTEs, related or unrelated to the study procedure, need not to be followed-
up for the purposes of the protocol. 
All subjects experiencing AEs, whether considered associated with the use of the study 
medication or not, must be monitored until the symptoms subside and any clinically relevant 
changes in laboratory values have returned to Baseline or until there is a satisfactory explanation 
for the changes observed. All PTEs and AEs will be documented in the PTE/AE page of the 
eCRF, whether or not the investigator concludes that the event is related to the drug treatment. 
The following information will be documented for each event: 
1. Event term. 
2. Start and stop date. 
3. Frequency. 
4. Severity. 
5. Investigator’s opinion of the causal relationship between the event and administration of 
study medication(s) (related or not related) (not completed for PTEs). 
6. Investigator’s opinion of the causal relationship to study procedure(s), including the details 
of the suspected procedure. 
7. Action concerning study medication (not applicable for PTEs). 
8. Outcome of event. 
9. Seriousness. 
10.2.2 Collection and Reporting of SAEs 
When an SAE occurs through the AE collection period it should be reported according to the 
following procedure: 
A Cerevance SAE form must be completed, in English, and signed by the investigator 
immediately or within 24 hours of first onset or notification of the event. The information should 
be completed as fully as possible but contain, at a minimum: 
• A short description of the event and the reason why the event is categorized as serious. 
• Subject identification number. 
• Investigator’s name. 
• Name of the study medication(s). 


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• Causality assessment. 
The SAE form should be transmitted within 24 hours to the attention of the contact listed in 
Section 1.0.  
Any SAE spontaneously reported to the investigator following the AE collection period should 
be reported to the sponsor if considered related to study participation. 
Reporting of Serious PTEs will follow the procedure described for SAEs. 
10.2.3 Reporting of Abnormal Liver Function Tests 
If a subject is noted to have ALT or AST elevated >3 ×ULN on 2 consecutive occasions, the 
abnormality should be recorded as an AE. In addition, an LFT Increases eCRF must be 
completed providing additional information on relevant recent history, risk factors, clinical signs 
and symptoms and results of any additional diagnostic tests performed. 
If a subject is noted to have ALT or AST >3 ×ULN and total bilirubin >2 ×ULN for which an 
alternative etiology has not been identified, the event should be recorded as an SAE and reported 
as per Section 10.2.2. The investigator must contact the Medical Monitor for discussion of the 
relevant subject details and possible alternative etiologies, such as acute viral hepatitis A or B or 
other acute liver disease or medical history/concurrent medical conditions. Follow-up laboratory 
tests as described in Section 9.1.8 must also be performed. In addition, an LFT Increases eCRF 
must be completed and transmitted with the Cerevance SAE form (as per Section 10.2.2). 
10.3 
Follow-up of SAEs 
If information is not available at the time of the first report, but becomes available at a later date, 
the investigator should complete a follow-up SAE form or provide other written documentation 
and fax it immediately within 24 hours of receipt. Copies of any relevant data from the hospital 
notes (e.g., ECGs, laboratory tests, discharge summary, postmortem results) should be sent to the 
addressee, if requested. 
All SAEs should be followed up until resolution or permanent outcome of the event. The 
timelines and procedure for follow-up reports are the same as those for the initial report. 
10.3.1 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities  
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, including the European 
Medicines Agency (EMA), investigators and IRBs or IECs, as applicable, in accordance with 
national regulations in the countries where the study is conducted. Relative to the first awareness 
of the event by/or further provision to the sponsor or sponsor’s designee, SUSARs will be 
submitted to the regulatory authorities as expedited report within 7 days for fatal and life-
threatening events and 15 days for other serious events, unless otherwise required by national 
regulations. The sponsor will also prepare an expedited report for other safety issues where these 
might materially alter the current benefit-risk assessment of an investigational medicinal product 
or that would be sufficient to consider changes in the investigational medicinal products 


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administration or in the overall conduct of the trial. The investigational site also will forward a 
copy of all expedited reports to his or her IRB or IEC in accordance with national regulations. 


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11.0 
STUDY-SPECIFIC COMMITTEES 
No steering committee, data safety monitoring committee, or clinical endpoint committee will be 
used in this study. 


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12.0 
DATA HANDLING AND RECORDKEEPING 
The full details of procedures for data handling will be documented in the Data Management 
Plan. AEs, PTEs, medical history, and concurrent conditions will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the World Health 
Organization Drug Dictionary (WHODRUG). 
12.1 
CRFs (Electronic) 
Completed eCRFs are required for each subject who signs an informed consent. 
The sponsor or its designee will supply investigative sites with access to eCRFs. The sponsor 
will make arrangements to train appropriate site staff in the use of the eCRFs. These forms are 
used to transmit the information collected in the performance of this study to the sponsor and 
regulatory authorities. eCRFs must be completed in English. 
After completion of the entry process, computer logic checks will be run to identify items, such 
as inconsistent dates, missing data, and questionable values. Queries may be issued by Cerevance 
personnel (or designees) and will be answered by the site.  
Corrections to eCRFs are recorded in an audit trail that captures the old information, the new 
information, identification of the person making the correction, the date the correction was made, 
and the reason for change. Reasons for significant corrections should additionally be included. 
The PI must review the eCRFs for completeness and accuracy and must sign and date the 
appropriate eCRFs as indicated. Furthermore, the investigator must retain full responsibility for 
the accuracy and authenticity of all data entered on the eCRFs. 
After the lock of the clinical study database, any change of, modification of or addition to the 
data on the eCRFs should be made by the investigator with use of change and modification 
records of the eCRFs. The principle investigator must review the data change for completeness 
and accuracy, and must sign, and date. 
The eCRFs will be reviewed for completeness and acceptability at the study site during periodic 
visits by study monitors. The sponsor or its designee will be permitted to review the subject’s 
medical and hospital records pertinent to the study to ensure accuracy of the eCRFs. The 
completed eCRFs are the sole property of the sponsor and should not be made available in any 
form to third parties, except for authorized representatives of appropriate governmental health or 
regulatory authorities, without written permission of the sponsor. 
12.2 
Record Retention 
The investigator agrees to keep the records stipulated in Section 12.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated informed consent forms, subject authorization forms 
regarding the use of personal health information (if separate from the informed consent forms), 
electronic copy of eCRFs, including the audit trail, and detailed records of drug disposition to 


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enable evaluations or audits from regulatory authorities, the sponsor or its designees. Any source 
documentation printed on degradable thermal sensitive paper should be photocopied by the site 
and filed with the original in the subject’s chart to ensure long-term legibility. Furthermore, 
International Conference on Harmonisation (ICH) E6 Section 4.9.5 requires the investigator to 
retain essential documents specified in ICH E6 (Section 8) until at least 2 years after the last 
approval of a marketing application for a specified drug indication being investigated or, if an 
application is not approved, until at least 2 years after the investigation is discontinued and 
regulatory authorities are notified. In addition, ICH E6 Section 4.9.5 states that the study records 
should be retained until an amount of time specified by applicable regulatory requirements or for 
a time specified in the Clinical Study Site Agreement between the investigator and sponsor. 
Refer to the Phase 1 Site Specifications document for the sponsor’s requirements on record 
retention. The investigator should contact and receive written approval from the sponsor before 
disposing of any such documents. 


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13.0 
STATISTICAL METHODS 
13.1 
Statistical and Analytical Plans 
A statistical analysis plan (SAP) will be prepared and finalized prior to the beginning of Part 2. 
This document will provide further details regarding the definition of analysis variables and 
analysis methodology to address all study objectives. 
A targeted data review will be conducted prior to database lock. This review will assess the 
accuracy and completeness of the study database, subject evaluability, and appropriateness of the 
planned statistical methods. 
13.1.1 Analysis Sets 
Safety Set 
The Safety Set will consist of all subjects who are randomized and receive study drug. Subjects 
in this analysis set will be used for demographic, baseline characteristics and safety summaries. 
Pharmacokinetic Set 
The PK Set will consist of all subjects who receive study drug and have at least 1 measurable 
plasma concentration of CVN058. 
Pharmacodynamic Set 
The PD Set will consist of all subjects who receive study drug and have at least 1 postdose PD 
measurement. 
If any subjects are found to be noncompliant in dosing schedule or with incomplete data, a 
decision will be made on a case-by-case basis as to their inclusion in the PK and PD endpoint 
analyses, but data for all subjects will be presented in the subject listings. 
13.1.2 Analysis of Demographics and Other Baseline Characteristics 
Demographic and baseline characteristics will be summarized by sequence and overall. 
Summary statistics (number of subjects, mean, median, standard deviation, minimum and 
maximum) will be generated for continuous variables (e.g., age and weight) and the number and 
percentage of subjects within each category will be presented for categorical variables (e.g., 
gender, ethnicity, race, smoking status, and caffeine consumption). 
13.1.3 Pharmacokinetic Analysis 
The concentration of CVN058, and its metabolite if appropriate, in plasma will be summarized 
over each scheduled sampling interval using descriptive statistics (arithmetic mean, SD, median, 
minimum and maximum). Individual plasma concentration data versus time will be presented in 
a data listing. 


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Descriptive statistics will be used to summarize the plasma PK parameters for CVN058, and its 
metabolite if appropriate. In addition, geometric mean and percent coefficient of variation will be 
computed for Cmax and AUCt. 
A more detailed analysis will be presented in the SAP. 
13.1.4 Pharmacodynamic Analysis  
Observed values for the PD parameters (MMN and exploratory PD parameters) at each time 
point will summarized by treatment and compared to placebo using summary statistics. 
Comparison of post dose PD parameters from time-matched placebo period timepoints will be 
analyzed using analysis of covariance (ANCOVA) with baseline value as a covariate and factors 
for time point, sequence, subject nested within sequence, period, and treatment. Two-sided 95% 
confidence intervals will be constructed for the LS mean differences between CVN058 and 
placebo in changes of PD parameters from time-matched period baseline to each postdose time 
point. 
Effect size will be calculated for comparisons of CVN058 to placebo using Cohen’s d which 
expresses the difference between the means of 2 groups as a function of their pooled standard 
deviation. 
Exposure-response relationships for CVN058 will be explored graphically. 
13.1.5 Safety Analysis 
The Safety Set will be used for all summaries of TEAEs, laboratory tests, and vital signs. All 
safety data will be summarized by treatment. 
AEs will be presented in listings. TEAEs will be classified according to system organ class and 
preferred term and will be tabulated with a breakdown by treatment and by event severity. 
Similar TEAE tabulations will be performed on those events assessed by the investigator as 
related to study drug. 
Individual results of vital signs will be listed and observed values and changes from Baseline in 
vital signs will be summarized by treatment. 
Physical exam findings, suicidality assessments (C-SSRS), and PANSS scores will be presented 
in data listings. 
13.2 
Determination of Sample Size 
Enrollment of 20 subjects with schizophrenia is estimated to provide >80% power to detect a 
median effect size of Cohen’s d=0.5. Discontinued or withdrawn subjects and subjects for whom 
MMN is not available for all three study periods may be replaced. The sample size chosen of 20 
completed subjects is considered to be sufficient to explore the changes in MMN between 
CVN058 and placebo as well as safety and tolerability of CVN058 in this population. 


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14.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
14.1 
Study-Site Monitoring Visits 
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and institution guarantee access to source documents by the sponsor or its 
designee contract research organization (CRO) and by the IRB or IEC. 
All aspects of the study and its documentation will be subject to review by the sponsor or 
designee (as long as blinding is not jeopardized), including but not limited to the Investigator’s 
Binder, study medication, subject medical records, informed consent documentation, 
documentation of subject authorization to use personal health information (if separate from the 
informed consent forms), and review of eCRFs and associated source documents. It is important 
that the investigator and other study personnel are available during the monitoring visits and that 
sufficient time is devoted to the process. 
14.2 
Protocol Deviations 
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will 
require deviation from protocol-specified procedures, the investigator should consult with the 
sponsor or designee (and IRB or IEC, as required) to determine the appropriate course of action. 
There will be no exemptions (a prospectively approved deviation) from the inclusion or 
exclusion criteria. 
The site should document all protocol deviations in the subject’s source documents. In the event 
of a significant deviation, the site should notify the sponsor or its designee (and IRB or EC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the subject, or confound interpretation of primary study 
assessment. PK samples collected outside of the intervals (listed in Table 14.a), ECGs, vital 
signs, and RNA pharmacogenomic samples collected outside of the listed intervals are minor 
deviations and do not require the Protocol Deviation Form to be completed but must be 
documented in the subject’s source documents. A Protocol Deviation eCRF should be completed 
by the site and signed by the sponsor or designee for any significant deviation from the protocol.  
Every attempt will be made to collect each PK blood sample at the designated time point, and the 
actual time of each blood sample will be recorded on the source document and eCRF. Table 14.a 
defines the windows allowed for sample collections.  
Protocol Deviations should be captured in the site source document for PK samples collected 
outside of the following intervals: 


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Table 14.a 
Windows for Pharmacokinetic Blood Sample Collection 
Minutes 
Nominal Sampling Time 
no more than 15 minutes predose 
0 hour 
±5 
immediately postdose to ≤2 hours 
±15 
>2 hours  
 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections 
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, 
including those of foreign governments (e.g., the Food and Drug Administration (FDA), the 
United Kingdom Medicines and Healthcare products Regulatory Agency, the Pharmaceuticals 
and Medical Devices Agency of Japan). If the study site is contacted for an inspection by a 
regulatory body, the sponsor should be notified immediately. The investigator and institution 
guarantee access for quality assurance auditors to all study documents as described in Section 
14.1. 


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15.0 
ETHICAL ASPECTS OF THE STUDY 
This study will be conducted with the highest respect for the individual participants (i.e., 
subjects) according to the protocol, the ethical principles that have their origin in the Declaration 
of Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will 
conduct the study according to applicable local or regional regulatory requirements and align his 
or her conduct in accordance with the “Responsibilities of the Investigator” that are listed in 
Appendix B. The principles of Helsinki are addressed through the protocol and through 
appendices containing requirements for informed consent and investigator responsibilities. 
15.1 
IRB and/or IEC Approval 
IRBs and IECs must be constituted according to the applicable state and federal/local 
requirements of each participating region.  
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of 
the informed consent form, and, if applicable, subject recruitment materials and/or 
advertisements and other documents required by all applicable laws and regulations, must be 
submitted to a central or local IRB or IEC for approval. The IRB’s or IEC’s written approval of 
the protocol and subject informed consent must be obtained and submitted to the sponsor or 
designee before commencement of the study (i.e., before shipment of the sponsor-supplied drug 
or study specific Screening activity). The IRB or IEC approval must refer to the study by exact 
protocol title, number, and version date; identify versions of other documents (e.g., ICF) 
reviewed; and state the approval date. The sponsor will ship drug/notify site once the sponsor has 
confirmed the adequacy of site regulatory documentation and, when applicable, the sponsor has 
received permission from competent authority to begin the trial. Until the site receives 
drug/notification no protocol activities, including screening may occur. 
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the informed consent 
form, recruitment materials intended for viewing by subjects, local safety reporting requirements, 
reports and updates regarding the ongoing review of the study at intervals specified by the 
respective IRB or IEC, and submission of the investigator’s final status report to IRB or IEC. All 
IRB and IEC approvals and relevant documentation for these items must be provided to the 
sponsor or its designee. 
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor. 
15.2 
Subject Information, Informed Consent, and Subject Authorization 
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The informed consent form, subject authorization form (if 
applicable), and subject information sheet (if applicable) describe the planned and permitted 
uses, transfers, and disclosures of the subject’s personal and personal health information for 


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purposes of conducting the study. The informed consent form and the subject information sheet 
(if applicable) further explain the nature of the study, its objectives, and potential risks and 
benefits, as well as the date informed consent is given. The informed consent form will detail the 
requirements of the participant and the fact that he or she is free to withdraw at any time without 
giving a reason and without prejudice to his or her further medical care. 
The investigator is responsible for the preparation, content, and IRB or IEC approval of the 
informed consent form and if applicable, the subject authorization form. The informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) 
must be approved by both the IRB or IEC and the sponsor prior to use. 
The informed consent form, subject authorization form (if applicable), and subject information 
sheet (if applicable) must be written in a language fully comprehensible to the prospective 
subject. It is the responsibility of the investigator to explain the detailed elements of the informed 
consent form, subject authorization form (if applicable), and subject information sheet (if 
applicable) to the subject. Information should be given in both oral and written form whenever 
possible and in the manner deemed appropriate by the IRB or IEC. In the event the subject is not 
capable of rendering adequate written informed consent, then the subject’s legally acceptable 
representative may provide such consent for the subject in accordance with applicable laws and 
regulations. 
The subject, or the subject’s legally acceptable representative, must be given ample opportunity 
to: (1) inquire about details of the study and (2) decide whether or not to participate in the study. 
If the subject, or the subject’s legally acceptable representative, determines he or she will 
participate in the study, then the informed consent form and subject authorization form (if 
applicable) must be signed and dated by the subject, or the subject’s legally acceptable 
representative, at the time of consent and prior to the subject entering into the study. The subject 
or the subject’s legally acceptable representative should be instructed to sign using their legal 
names, not nicknames, using blue or black ballpoint ink. The investigator must also sign and date 
the informed consent form and subject authorization (if applicable) at the time of consent and 
prior to subject entering into the study; however, the sponsor may allow a designee of the 
investigator to sign to the extent permitted by applicable law. 
Once signed, the original informed consent form, subject authorization form (if applicable), and 
subject information sheet (if applicable) will be stored in the investigator’s site file. The 
investigator must document the date the subject signs the informed consent in the subject’s 
medical record. Copies of the signed informed consent form, the signed subject authorization 
form (if applicable), and subject information sheet (if applicable) shall be given to the subject. 
All revised informed consent forms must be reviewed and signed by relevant subjects or the 
relevant subject’s legally acceptable representative in the same manner as the original informed 
consent. The date the revised consent was obtained should be recorded in the subject’s medical 
record, and the subject should receive a copy of the revised informed consent form. 


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Subjects who consented and provided a pharmacogenomic sample for DNA and RNA analysis 
can withdraw their consent and request disposal of a stored sample at any time prior to analysis. 
Notify sponsor of consent withdrawal. 
15.3 
Subject Confidentiality 
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or 
date of birth, and subject initials may be used to verify the subject and accuracy of the subject’s 
unique identification number. 
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the 
sponsor requires the investigator to permit its monitor or designee’s monitor, representatives 
from any regulatory authority (e.g., FDA, Medicines and Healthcare products Regulatory 
Agency, Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and 
the appropriate IRBs and IECs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a subject’s study 
participation, and autopsy reports. Access to a subject’s original medical records requires the 
specific authorization of the subject as part of the informed consent process (see Section 15.2). 
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (i.e., subject name, address, and other identifier 
fields not collected on the subject’s eCRF). 
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy 
15.4.1 Publication and Disclosure 
The investigator is obliged to provide the sponsor with complete test results and all data derived 
by the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor. 
The sponsor may publish any data and information from the study (including data and 
information generated by the investigator) without the consent of the investigator. Manuscript 
authorship for any peer-reviewed publication will appropriately reflect contributions to the 
production and review of the document. All publications and presentations must be prepared in 
accordance with this section and the Clinical Study Site Agreement. In the event of any 
discrepancy between the protocol and the Clinical Study Site Agreement, the Clinical Study Site 
Agreement will prevail. 


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15.4.2 Clinical Trial Registration  
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations, and guidance, Cerevance will, at a minimum register 
interventional clinical trials it sponsors on ClinicalTrials.gov or other publicly accessible 
websites before start of study. Cerevance contact information, along with investigator’s city, 
state (for American investigators), country, and recruiting status will be registered and available 
for public viewing. For some registries, Cerevance will assist callers in locating trial sites closest 
to their homes by providing the investigator name, address, and phone number to the callers 
requesting trial information. Once subjects receive investigator contact information, they may 
call the site requesting enrollment into the trial. The investigative sites are encouraged to handle 
the trial inquiries according to their established subject Screening process. If the caller asks 
additional questions beyond the topic of trial enrollment, they should be referred to the sponsor. 
Any investigator who objects to Cerevance providing this information to callers must provide 
Cerevance with a written notice requesting that their information not be listed on the registry site. 
15.4.3 Clinical Trial Results Disclosure  
Cerevance may post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites, as required by applicable laws and/or regulations. 
15.5 
Insurance and Compensation for Injury 
Each subject in the study must be insured in accordance with the regulations applicable to the 
site where the subject is participating. If a local underwriter is required, then the sponsor or 
sponsor’s designee will obtain clinical study insurance against the risk of injury to clinical study 
subjects. Refer to the Clinical Study Site Agreement regarding the sponsor’s policy on subject 
compensation and treatment for injury. If the investigator has questions regarding this policy, he 
or she should contact the sponsor or sponsor’s designee. 


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16.0 
REFERENCES 
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2. Green MF. Cognitive impairment and functional outcome in schizophrenia and bipolar 
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3. Harvey PD, Velligan DI, Bellack AS. Performance-based measures of functional skills: 
usefulness in clinical treatment studies. Schizophr Bull 2007;33(5):1138-48. 
4. Heinrichs RW. The primacy of cognition in schizophrenia. Am Psychol 2005;60(3):229-42. 
5. McNally JM, McCarley RW, Brown RE. Impaired GABAergic neurotransmission in 
schizophrenia underlies impairments in cortical gamma band oscillations. Curr Psychiatry 
Rep 2013;15(3):346. 
6. Cardin JA, Carlen M, Meletis K, Knoblich U, Zhang F, Deisseroth K, et al. Driving fast-
spiking cells induces gamma rhythm and controls sensory responses. Nature 
2009;459(7247):663-7. 
7. Whittington MA, Traub RD, Faulkner HJ, Stanford IM, Jefferys JG. Recurrent excitatory 
postsynaptic potentials induced by synchronized fast cortical oscillations. Proc Natl Acad Sci 
U S A 1997;94(22):12198-203. 
8. Rotaru DC, Lewis DA, Gonzalez-Burgos G. The role of glutamatergic inputs onto 
parvalbumin-positive interneurons: relevance for schizophrenia. Rev Neurosci 
2012;23(1):97-109. 
9. Gonzalez-Burgos G, Lewis DA. NMDA receptor hypofunction, parvalbumin-positive 
neurons, and cortical gamma oscillations in schizophrenia. Schizophr Bull 2012;38(5):950-7. 
10. Curley AA, Lewis DA. Cortical basket cell dysfunction in schizophrenia. J Physiol 
2012;590(Pt 4):715-24. 
11. Tian G, Kong Q, Lai L, Ray-Chaudhury A, Lin CG. Increased expression of cholesterol 24S-
hydroxylase results in disruption of glial glutamate transporter EAAT2 association with lipid 
rafts: a potential role in Alzheimer's disease. J Neurochem 2010;113(4):978-89. 
12. Kawaguchi Y, Shindou T. Noradrenergic excitation and inhibition of GABAergic cell types 
in rat frontal cortex. J Neurosci 1998;18(17):6963-76. 
13. Kawaguchi Y. Selective cholinergic modulation of cortical GABAergic cell subtypes. J 
Neurophysiol 1997;78(3):1743-7. 
14. Lee S, Hjerling-Leffler J, Zagha E, Fishell G, Rudy B. The largest group of superficial 
neocortical GABAergic interneurons expresses ionotropic serotonin receptors. J Neurosci 
2010;30(50):16796-808. 
15. Koike K, Hashimoto K, Takai N, Shimizu E, Komatsu N, Watanabe H, et al. Tropisetron 
improves deficits in auditory P50 suppression in schizophrenia. Schizophr Res 
2005;76(1):67-72. 


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16. Lummis SC. 5-HT3 receptors. J Biol Chem 2012;287(48):40239-45. 
17. Adler LE, Cawthra EM, Donovan KA, Harris JG, Nagamoto HT, Olincy A, et al. Improved 
p50 auditory gating with ondansetron in medicated schizophrenia patients. Am J Psychiatry 
2005;162(2):386-8. 
18. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders 
(DSM-5). 5th ed. Arlington, VA: American Psychiatric Association; 2013. 
19. Smucny J, Wylie K, Rojas D, Stevens K, Olincy A, Kronberg E, et al. Evidence for gamma 
and beta sensory gating deficits as translational endophenotypes for schizophrenia. 
Psychiatry Res 2013;214(2):169-74. 
20. Kay SR. Positive-negative symptom assessment in schizophrenia: psychometric issues and 
scale comparison. Psychiatr Q 1990;61(3):163-78. 
21. Mundt JC, Greist JH, Jefferson JW, Federico M, Mann JJ, Posner K. Prediction of suicidal 
behavior in clinical research by lifetime suicidal ideation and behavior ascertained by the 
electronic Columbia-Suicide Severity Rating Scale. J Clin Psychiatry 2013;74(9):887-93. 
22. Javitt D. Neurophysiological models for new treatment development in schizophrenia: early 
sensory approaches. The New York Academy of Sciences. 2015;1344: 92-104.  
23. Lee M, Sehatpour P, Hoptman MJ, Lakatos P, Dias EC, Kantrowitz JT, Martinez AM, Javitt 
DC. Neural mechanisms of mismatch negativity dysfunction in schizophrenia. Mol 
Psychiatry. 2017;22(11):1585-1593. doi: 10.1038/mp.2017.3. 
24. Javitt D and Sweet R. Auditory dysfunction in schizophrenia: integrating clinical and basic 
features. Nat Rev Neurosci. 2015; 16(9): 535–550. doi:10.1038/nrn4002. 
25. Eisensamer B, Uhr M, Meyr S, Gimpl G, Deiml T, Rammes G, Lambert JJ, Zieglgänsberger 
W, Holsboer F, Rupprecht R. Antidepressants and antipsychotic drugs colocalize with 5-HT3 
receptors in raft-like domains. J Neurosci. 2005 Nov  2;25(44):10198-206. PubMed PMID: 
16267227. 
26. Eisensamer B, Rammes G, Gimpl G, Shapa M, Ferrari U, Hapfelmeier G, Bondy B, Parsons 
C, Gilling K, Zieglgänsberger W, Holsboer F, Rupprecht R. Antidepressants are functional 
antagonists at the serotonin type 3 (5-HT3) receptor. Mol Psychiatry. 2003 Nov;8(12):994-
1007. PubMed PMID: 14647397. 
27. Rammes G, Eisensamer B, Ferrari U, Shapa M, Gimpl G, Gilling K, Parsons C, Riering K, 
Hapfelmeier G, Bondy B, Zieglgänsberger W, Holsboer F, Rupprecht R. Antipsychotic drugs 
antagonize human serotonin type 3 receptor currents in a noncompetitive manner. Mol 
Psychiatry. 2004 Sep;9(9):846-58, 818. PubMed PMID: 15024394. 
 
 


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Appendix A Schedule of Study Procedures 
 
 
 
CVN058 and Placebo 
Treatment Periods 1, 2, and 3 
(a) 
End of 
Treatment 
 
Follow-up  
Study Day: 
Visit 1: 
Screening 
 
Day 1 
pre-dose 
Day 1 
post-dose 
Period 3, 
End Day 1  
Early 
Termination 
(c)  
Day 7-10 
After End of 
Treatment 
(b) 
Informed consent 
X 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
X 
 
 
 
 
Demographics and 
medical history 
X 
 
 
 
 
 
Medication history 
X 
 
 
 
 
 
Physical examination  
X 
X 
 
X 
X 
 
Vital signs (d) 
X 
X 
X 
 
X 
 
Weight, height, and BMI 
(e) 
X 
 
 
X 
X 
 
Concomitant medications 
(f) 
X 
X 
X 
 
X 
X 
Concurrent medical 
conditions (g) 
X 
 
 
 
 
 
Clinical laboratory tests 
(h) 
X 
 
 
X 
X 
 
Hepatitis panel 
X 
 
 
 
 
 
Audiometric Screening 
(i) 
X 
 
 
 
 
 
FSH (j) 
X 
 
 
 
 
 
Pregnancy test (hCG), 
serum except as noted 
X 
X (urine) 
 
 
X 
 
Urine drug and saliva 
alcohol screen 
X 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
EEG battery (k) 
 
 
X 
 
 
 
MMN (l) 
 
 
X 
 
 
 
DNA sample collection 
(m) 
 
X 
 
 
 
 
RNA sample collection 
(n) 
 
X 
X 
 
 
 
PK blood collection (o) 
 
X 
X 
 
X 
 
Study drug dosing (p) 
 
 
X 
 
 
 
PTE assessment (q) 
X 
X 
 
 
 
 
AE assessment (r) 
 
 
X 
 
X 
X 
C-SSRS (s) 
X 
 
X 
 
X 
 
PANSS (t) 
X 
 
X 
 
X 
 
Footnotes are on last table page. 


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(a) Minimum 7-day and maximum 10-day washout period is required in between Treatment Periods 1, 2 and 3.  
(b) The Follow-up Visit will occur by telephone 7-10 days after End of Treatment unless abnormal, clinically significant findings 
were observed upon discharge. In these cases, subjects must then be brought back to the clinic for re-evaluation per investigator’s 
discretion. 
(c) Conduct procedures for subjects discontinued early per Protocol Section 7.6. The PK sample should be collected at the Early 
Termination Visit, if within 1 hour of a scheduled PK time point. 
(d) Vital signs (oral temperature, respiration, pulse, and supine blood pressure) will be obtained at Screening, and in Periods 1, 2, 
and 3 (pre dose [within 30 minutes prior to dosing], and at 1 and 4 hours post dose), and at Early Termination (if applicable), and 
if clinically indicated according to Investigator discretion at the Follow-up visit.  
(e) Height and BMI will be collected at Screening only. 
(f) Record all patient medications from Screening and throughout the study. 
(g) All new concurrent medical conditions arising post-oi should be recorded as PTE or AE.  
(h) Clinical laboratory tests (hematology, serum chemistry, and urinalysis) will be collected at Screening and prior to check-out at 
End of Treatment or Early Termination, and at the Investigator discretion if a Follow-up Visit is indicated.  
(i) Audiometric Screening assessment conducted according to local practice.  
(j) A FSH level will be obtained on post menopausal women (defined as continuous amenorrhea of at least 2 years and not 
surgically sterile). 
(k) For the EEG battery, testing will be done at Day 1 starting approximately 1.5 hours post dose for each period and will last 
approximately 2 hours. NOTE: Subjects should refrain from drinking coffee and smoking approximately 1 hour prior to the EEG 
assessment until discharge from clinic at the end of the afternoon. 
(l) MMN will be the first EEG assessment conducted in the battery.  
(m) One blood sample (6 mL) will be collected for pharmacogenomic analysis prior to study drug administration on Day 1 of 
Period 1 only. If isolation of DNA from the first sample was not successful or possible, a second aliquot of blood may 
be taken, if feasible. 
(n) Two 2.5 mL whole blood samples will be collected for each Period (Periods 1, 2, and 3) on Day 1 at pre-dose, and 4 hours 
post- dose  
(o) Blood samples (6 mL) for PK analyses will be collected at pre -dose (within 15 minutes prior to dosing), and 1 and 4 hours 
post dose. 
(p) Dosing will only occur on Day 1 of each period, and signals the start of the post-dose Day 1 visit assessments. 
(q) PTEs will be collected from signing of informed consent up until dosing on Day 1. 
(r) Any adverse event with onset or exacerbation after dosing on Day 1 of Period 1 will be captured as an AE or SAE. 
(s) The Screening/Baseline C-SSRS will be administered at Screening and the Since Last Visit C-SSRS will be administered after 
EEG/ERP collection on each dosing day, and End of Treatment or Early Termination (if applicable). 
(t) The Screening/Baseline PANSS will be collected at Screening, approximately 4 hours after each dose (post EEG) and at Early 
Termination (if applicable). 
 


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Appendix B Responsibilities of the Investigator 
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on investigators by the FDA are 
summarized in the “Statement of Investigator” (Form 1572) which must be completed and 
signed before the investigator may participate in this study. 
The investigator agrees to assume the following responsibilities by signing a Form 1572.  
1. Conduct the study in accordance with the protocol. 
2. Personally conduct or supervise the staff who will assist in the protocol. 
3. Ensure that study related procedures; including study specific (non-routine/non- standard 
panel) Screening assessments are NOT performed on potential subjects prior to the receipt of 
written approval from relevant governing bodies/authorities. 
4. Ensure that all colleagues and employees assisting in the conduct of the study are informed 
of these obligations. 
5. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform 
to 21 CFR Part 56 ICH, and local regulatory requirements. 
6. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and 
approval of the protocol. Promptly report to the IRB/IEC all changes in research activity and 
all anticipated risks to subjects. Make at least yearly reports on the progress of the study to 
the IRB/IEC, and issue a final report within 3 months of study completion. 
7. Ensure that requirements for informed consent, as outlined in 21 CRF Part 50 ICH and local 
regulations, are met. 
8. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each informed consent form should contain a subject 
authorization section that describes the uses and disclosures of a subject’s personal 
information (including personal health information) that will take place in connection with 
the study. If an informed consent form does not include such a subject authorization, then the 
investigator must obtain a separate subject authorization form from each subject or the 
subject’s legally acceptable representative. 
9. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc., and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents. 
10. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents. 


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11. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor. 
12. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours. 
 


 
 
 
PROTOCOL  
A Placebo-Controlled Study to Evaluate the Effect of a Single Dose of CVN058 on 
Mismatch Negativity in Subjects with Stable Schizophrenia 
 
Short title: CVN058 Effect on Mismatch Negativity in Schizophrenics 
 
Sponsor: 
Cerevance Alpha (hereafter, “Cerevance”) 
One Marina Park Drive, suite 1410 
Boston, MA 02210 
Study Number: 
CVN058-103 
IND Number: 
121,520 
EudraCT Number: 
N/A 
Compound: 
 
CVN058  
Date: 
02 JUL 2018 
Amendment Number:  
1 
 
 
 
 
 
 
CONFIDENTIAL PROPERTY OF CEREVANCE 
This document is a confidential communication of Cerevance. Acceptance of this document constitutes the 
agreement by the recipient that no information contained herein will be published or disclosed without written 
authorization from Cerevance except to the extent necessary to obtain informed consent from those persons to whom 
the drug may be administered. Furthermore, the information is only meant for review and compliance by the 
recipient, his or her staff, and applicable institutional review committee and regulatory agencies to enable conduct of 
the study. 






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INVESTIGATOR AGREEMENT  
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, and 
any other product information provided by the sponsor. I agree to conduct this study in 
accordance with the requirements of this protocol and also to protect the rights, safety, privacy, 
and well-being of study subjects in accordance with the following: 
• The ethical principles that have their origin in the Declaration of Helsinki. 
• International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline. 
• All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations. 
• Regulatory requirements for reporting serious adverse events defined in Section 10.2 of this 
protocol. 
• Terms outlined in the Clinical Study Site Agreement. 
• Appendix B – Responsibilities of the Investigator. 
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in the clinical trial agreement with Cerevance. 
Signature of Investigator 
Date 
Investigator Name (print or type) 
Investigator’s Title 
Location of Facility (City, State/Provence) 
Location of Facility (Country) 


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TABLE OF CONTENTS 
1.0 
ADMINISTRATIVE INFORMATION ..............................................................................2 
1.1 
Contacts..........................................................................................................................2 
1.2 
Approval ........................................................................................................................3 
2.0 
LIST OF ABBREVIATIONS ............................................................................................13 
3.0 
INTRODUCTION .............................................................................................................15 
3.1 
Background ..................................................................................................................15 
3.2 
Non-Clinical .................................................................................................................16 
3.3 
Clinical .........................................................................................................................16 
3.4 
Rationale for the Proposed Study ................................................................................17 
4.0 
STUDY OBJECTIVES AND ENDPOINTS .....................................................................19 
4.1 
Objectives ....................................................................................................................19 
4.1.1 Primary Objective ..................................................................................................19 
4.1.2 Secondary Objective ..............................................................................................19 
4.1.3 Exploratory Objectives ..........................................................................................19 
4.2 
Endpoints .....................................................................................................................19 
4.2.1 Primary Endpoints .................................................................................................19 
4.2.2 Secondary Endpoint ...............................................................................................19 
4.2.3 Exploratory Endpoints ...........................................................................................19 
5.0 
STUDY DESIGN AND DESCRIPTION ..........................................................................21 
5.1 
Study Design ................................................................................................................21 
5.2 
Justification for Study Design, Dose, and Endpoints ..................................................22 
5.3 
Premature Termination or Suspension of Study or Investigational Site ......................23 
5.3.1 Criteria for Premature Termination or Suspension of the Study ...........................23 
5.3.2 Criteria for Premature Termination or Suspension of Investigational Sites ..........23 
5.3.3 Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s)...................................................................23 
6.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS ...............24 
6.1 
Inclusion Criteria .........................................................................................................24 
6.2 
Exclusion Criteria ........................................................................................................24 
6.3 
Excluded Medications, Dietary Products, Procedures, and Treatments ......................26 
6.4 
Diet, Fluid, Activity Control ........................................................................................27 
6.5 
Criteria for Discontinuation or Withdrawal of a Subject .............................................27 
6.6 
Procedures for Discontinuation or Withdrawal of a Subject .......................................28 
7.0 
CLINICAL TRIAL MATERIAL MANAGEMENT.........................................................29 
7.1 
Study Medication and Materials ..................................................................................29 
7.1.1 Dosage Form, Manufacturing, Packaging, and Labeling ......................................29 
7.1.1.1 Investigational Drug .........................................................................................29 


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7.1.1.2 Sponsor-Supplied Drug ....................................................................................29 
7.1.1.3 Ancillary Materials ..........................................................................................29 
7.1.2 Storage ...................................................................................................................30 
7.1.3 Dose and Regimen .................................................................................................30 
7.1.4 Overdose ................................................................................................................30 
7.2 
Investigational Drug Assignment and Dispensing Procedures ....................................31 
7.3 
Randomization Code Creation and Storage .................................................................31 
7.4 
Investigational Drug Blind Maintenance .....................................................................31 
7.5 
Unblinding Procedure ..................................................................................................31 
7.6 
Accountability and Destruction of Sponsor-Supplied Drugs .......................................31 
8.0 
STUDY PLAN ...................................................................................................................34 
8.1 
Study Procedures .........................................................................................................34 
8.1.1 Informed Consent Procedure .................................................................................34 
8.1.1.1 Pharmacogenomic Informed Consent Procedure .............................................34 
8.1.2 Demographics, Medical History, and Medication History Procedure ...................34 
8.1.3 Physical Examination Procedure ...........................................................................34 
8.1.4 Weight, Height, and BMI.......................................................................................35 
8.1.5 Vital Sign Procedure ..............................................................................................35 
8.1.6 Documentation of Concomitant Medications ........................................................35 
8.1.7 Documentation of Concurrent Medical Conditions ...............................................35 
8.1.8 Procedures for Clinical Laboratory Samples .........................................................35 
8.1.9 Contraception and Pregnancy Avoidance Procedure .............................................37 
8.1.10 Pregnancy ...............................................................................................................38 
8.1.11 ECG Procedure ......................................................................................................39 
8.1.12 Pharmacogenomic Sample Collection ...................................................................39 
8.1.13 Pharmacokinetic Sample Collection ......................................................................40 
8.1.13.1 
Collection of Blood for Pharmacokinetic Sampling ..................................40 
8.1.13.2 
Bioanalytical Methods ...............................................................................41 
8.1.14 Pharmacokinetic Parameters ..................................................................................41 
8.1.15 Pharmacodynamic Sample Collection ...................................................................41 
8.1.16 Pharmacodynamic Parameters ...............................................................................41 
8.1.17 Positive and Negative Syndrome Scale .................................................................42 
8.1.18 Columbia Suicide Severity Rating Scale ...............................................................43 
8.1.19 Documentation of Screen Failure ..........................................................................43 
8.1.20 Documentation of Randomization .........................................................................44 
8.2 
Monitoring Subject Treatment Compliance .................................................................44 
8.3 
Schedule of Observations and Procedures ...................................................................44 
8.3.1 Screening................................................................................................................44 


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8.3.2 Treatment Phase .....................................................................................................44 
8.3.3 Final Visit/End of Treatment .................................................................................44 
8.3.4 Early Termination ..................................................................................................45 
8.3.5 Follow-up Visit/Telephone Call ............................................................................45 
8.4 
Biological Sample Retention and Destruction .............................................................45 
8.5 
Blood Volume ..............................................................................................................45 
9.0 
PRETREATMENT EVENTS AND ADVERSE EVENTS ..............................................47 
9.1 
Definitions....................................................................................................................47 
9.1.1 PTEs .......................................................................................................................47 
9.1.2 AEs .........................................................................................................................47 
9.1.3 Additional Points to Consider for PTEs and AEs ..................................................47 
9.1.4 SAEs ......................................................................................................................49 
9.1.5 Severity of PTEs and AEs......................................................................................50 
9.1.6 Causality of AEs ....................................................................................................51 
9.1.7 Relationship to Study Procedures ..........................................................................51 
9.1.8 Start Date ...............................................................................................................51 
9.1.9 Stop Date ................................................................................................................51 
9.1.10 Frequency ...............................................................................................................51 
9.1.11 Action Concerning Study Medication ...................................................................51 
9.1.12 Outcome .................................................................................................................51 
9.2 
Procedures ....................................................................................................................52 
9.2.1 Collection and Reporting of AEs ...........................................................................52 
9.2.1.1 PTE and AE Collection Period ........................................................................52 
9.2.1.2 PTE and AE Reporting ....................................................................................52 
9.2.2 Collection and Reporting of SAEs .........................................................................53 
9.2.3 Reporting of Abnormal Liver Function Tests ........................................................53 
9.3 
Follow-up of SAEs ......................................................................................................54 
9.3.1 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities .....54 
10.0 
STUDY-SPECIFIC COMMITTEES .................................................................................55 
11.0 
DATA HANDLING AND RECORDKEEPING ..............................................................56 
11.1 
CRFs (Electronic) ........................................................................................................56 
11.2 
Record Retention .........................................................................................................56 
12.0 
STATISTICAL METHODS ..............................................................................................58 
12.1 
Statistical and Analytical Plans ....................................................................................58 
12.1.1 Analysis Sets ..........................................................................................................58 
12.1.2 Analysis of Demographics and Other Baseline Characteristics ............................58 
12.1.3 Pharmacokinetic Analysis ......................................................................................58 
12.1.4 Pharmacodynamic Analysis ...................................................................................59 


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12.1.5 Safety Analysis ......................................................................................................59 
12.2 
Determination of Sample Size .....................................................................................59 
13.0 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................60 
13.1 
Study-Site Monitoring Visits .......................................................................................60 
13.2 
Protocol Deviations ......................................................................................................60 
13.3 
Quality Assurance Audits and Regulatory Agency Inspections ..................................61 
14.0 
ETHICAL ASPECTS OF THE STUDY ...........................................................................62 
14.1 
IRB and/or IEC Approval ............................................................................................62 
14.2 
Subject Information, Informed Consent, and Subject Authorization ..........................62 
14.3 
Subject Confidentiality ................................................................................................63 
14.4 
Publication, Disclosure, and Clinical Trial Registration Policy ..................................64 
14.4.1 Publication and Disclosure ....................................................................................64 
14.4.2 Clinical Trial Registration ......................................................................................64 
14.4.3 Clinical Trial Results Disclosure ...........................................................................65 
14.5 
Insurance and Compensation for Injury .......................................................................65 
15.0 
REFERENCES ..................................................................................................................66 
 
LIST OF IN-TEXT TABLES 
Table 6.a 
Treatment Sequences .............................................................................................21 
Table 7.a 
Prohibited Medications ..........................................................................................26 
Table 8.a 
Composition of CVN058 and Matching Placebo ..................................................29 
Table 8.b 
Treatment and Medication Type ............................................................................30 
Table 9.a 
Clinical Laboratory Tests .......................................................................................36 
Table 9.b 
Collection of Blood Samples for CVN058 Pharmacokinetic Analysis .................40 
Table 9.c 
Approximate Blood Volume ..................................................................................46 
Table 10.a 
Medically Significant AE List ...............................................................................50 
Table 14.a 
Windows for Pharmacokinetic Blood Sample Collection .....................................61 
 
LIST OF IN-TEXT FIGURES 
Figure 6.a 
Schematic of Study Design ....................................................................................22 
 
LIST OF APPENDICES 
Appendix A 
Schedule of Study Procedures ...............................................................................68 
Appendix B 
Responsibilities of the Investigator ........................................................................70 
 


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STUDY SUMMARY 
Name of Sponsor(s): 
Cerevance Alpha, Inc.  
(hereafter referred to as “Cerevance”) 
Compound: 
CVN058 
Title of Protocol: A Placebo-Controlled Study to 
Evaluate the Effect of a Single Dose of CVN058 on 
Mismatch Negativity in Subjects with Stable 
Schizophrenia 
IND No.: 121,520 
EudraCT No.: 
Not Applicable 
Study Number: CVN058-103 
Phase: 1 
Study Design: 
This is a phase 1, double-blind, placebo-controlled, 3 period cross-over study to evaluate CVN058 target 
engagement by measuring auditory evoked potential mismatch negativity (MMN) downstream to 5-
hydroxytryptamine receptor 3 (5-HT3) as a pharmacodynamic (PD) marker.   
Male and female subjects with schizophrenia, age 18 to 50 years old, inclusive, will be randomized to 1 of 6 
treatment sequences (Table 2.a) to receive 1 of 3 dose regimens in each period: a single oral administration of 
CVN058 (15 mg or 150 mg) or matching placebo. The sequence will determine the order in which a subject will 
take each of the 3 regimens. Discontinued subjects may be replaced at the discretion of the sponsor so that 
approximately 20 completed subjects are available for analysis. 
The study includes three 1-day treatment periods, with a minimum of 7-day washout, maximum 10 day washout 
(2 total washouts, after Periods 1 and 2) between periods, and a 7-10 day follow-up call post dosing of the last 
period. Subjects may be inpatients or outpatients at the discretion of the Investigator. 
Table 2.a Treatment Sequences 
Sequence 
Period 1 
Period 2 
Period 3 
1 
A 
B 
C 
2 
B 
A 
C 
3 
C 
A 
B 
4 
A 
C 
B 
5 
B 
C 
A 
6 
C 
B 
A 
A: Placebo 
B: CVN058 15 mg 
C: CVN058 150 mg  
At each testing session, subjects undergo post dose electroencephalography (EEG) testing including: MMN, P50, 
gamma power, and P300. Study drug will be administered with water. Testing sessions will begin approximately 
1.5 hours post-dose. Prior to dosing and at various time points post dose, blood samples will be collected for the 
assessment of plasma concentrations of CVN058 and biomarkers.  
Study procedures will be conducted at approximately the same times across Treatment Periods to minimize 
diurnal effects on outcomes. The effect of CVN058 on MMN as well as on exploratory measures (e.g., P50 
auditory gating, gamma power, and P300) will be compared to placebo.  
 
A schematic of the study design is presented below: 
  
 
 
 


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Primary Objective: 
To determine whether improvement in MMN is demonstrated after administration of CVN058 compared to 
placebo in subjects with schizophrenia. 
Secondary Objective: 
Assess the safety and tolerability of single doses of CVN058 in subjects with schizophrenia. 
Exploratory Objectives: 
• 
To determine whether improvement in P50 auditory gating, gamma power, and P300 is demonstrated 
after administration of CVN058 compared to placebo in subjects with schizophrenia. 
• 
To assess the pharmacokinetics (PK) of CVN058 following a single dose to subjects with 
schizophrenia. 
• 
To explore the exposure-response relationship for CVN058 in subjects with schizophrenia. 
Subject Population:  
Subjects with stable schizophrenia on antipsychotic medication(s).  
Number of Subjects: 
Estimated total: at least 20 evaluable subjects who 
complete the study  
Number of Sites: 
Approximately 2 (United States) 
Dose Level(s): 
Placebo: solution vehicle, oral administration  
CVN058: 15 mg solution, oral administration  
CVN058: 150 mg solution, oral administration 
Route of Administration: 
Oral 
Duration of Treatment: 
Single oral dose in each of the 3 periods.  
Period of Evaluation: 
Screening Days (Part 1): Up to 28 days. 
3 Treatment Periods, each <1 day duration;  
with a 7-10 day washout between periods 
Follow-up call 7-10 days following the last dose of 
study drug in Treatment Period 3. 
Total Duration: Up to 58 days. 
Main Criteria for Inclusion: 
Subjects 18 to 50 years of age, inclusive, at the time of informed consent. 


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The subject weighs at least 50 kg and has a body mass index (BMI) between 18 and 40 kg/m2 inclusive at 
Screening. 
Subject meets schizophrenia criteria as defined by the Diagnostic & Statistical Manual of Mental Disorders, 5th 
Edition (DSM–V).  
Subjects are on a stable dose of antipsychotic medication(s) for at least 2 months prior to Screening as 
documented by medical history and assessed by site staff. 
Subject has a Positive and Negative Syndrome Scale (PANSS) total score of <95. 
Main Criteria for Exclusion: 
Subject currently receiving treatment with any excluded medication or dietary supplement. 
Subjects who have a history of gastrointestinal disease that would influence the absorption of study drug or have 
a history of any surgical intervention known to impact absorption (e.g., bariatric surgery or bowel resection). 
Subjects having clinical laboratory evaluations (including clinical chemistry, hematology and complete 
urinalysis) outside the reference range for the testing laboratory, unless the results are deemed to be not clinically 
significant (NCS) by the investigator at Screening. 
Subjects with moderate to severe substance use disorder, unstable mood or anxiety disorder. 
Subject has a current diagnosis of a significant psychiatric illness other than schizophrenia per DSM-V and is in 
an acute phase/episode. 
Subject has clinically meaningful hearing loss. 
Main Criteria for Evaluation and Analyses: 
Pharmacodynamics: 
MMN will be measured as a PD marker for CVN058. Exploratory measurements include P50 auditory gating, 
gamma power, and P300, which are EEG markers commonly impaired in subjects with schizophrenia.  
Pharmacokinetics:  
Blood samples will be collected for the determination of plasma concentrations of CVN058, and its metabolite if 
appropriate, at the following time points: Pre-dose (within 15 minutes prior to dosing), and at 1 (pre-EEG) and 5 
(post-EEG) hours post dose. The following PK parameters will be determined from concentrations of CVN058, 
and its metabolite if appropriate, in plasma: maximum observed plasma concentration (Cmax), time to reach Cmax 
(tmax), and area under the curve from time 0 to the time of the last quantifiable concentration (AUCt). Other 
parameters may be calculated if appropriate.  
Pharmacogenomics: 
Whole blood will be collected and stored for possible deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) 
isolation and analysis.  
DNA samples will be used to evaluate drug metabolic enzyme and transporter polymorphisms that may 
contribute to variability in the PK of CVN058. Also, since pharmacogenomics is an evolving science, many 
genes and their functions are not yet fully understood. Future data may suggest a role of some gene in drug 
response, which may lead to additional hypothesis-generating exploratory research and diagnostic development 
on stored samples. 
Statistical Considerations: 
Observed values for the PD parameters (MMN and exploratory PD parameters) at each time point and will be 
summarized by treatment and compared to time matched assessments during placebo dosing using summary 
statistics. Comparison of post dose PD parameters to time match placebo period timepoints will be analyzed 
using analysis of covariance (ANCOVA) with baseline value as a covariate and factors for time point, sequence, 
subject nested within sequence, period, and treatment. Two-sided 95% confidence intervals will be constructed 
for the least squares mean differences between CVN058 and placebo in changes of PD parameters from time-
matched period Baseline to each postdose time point. 
Effect size will be calculated for comparisons of CVN058 to placebo using Cohen’s d which expresses the 
difference between the means of 2 groups as a function of their pooled standard deviation. 
Plasma PK concentrations and parameters of CVN058, and its metabolite if appropriate, will be listed and 
summarized by treatment using descriptive statistics. Exposure-response relationships for CVN058 will be 


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explored graphically. 
Adverse events (AEs) will be presented in listings, and treatment-emergent AEs (TEAEs) will be summarized by 
treatment. Individual results of vital signs will be listed and observed values and changes from Baseline in vital 
signs will be summarized by treatment.  
Sample Size Justification:  
Enrollment of 20 subjects with schizophrenia is estimated to provide >80% power to detect a median effect size 
of Cohen’s d=0.5. Discontinued or withdrawn subjects and subjects for whom MMN is not available for all three 
study periods may be replaced. The sample size chosen of 20 completed subjects is expected to be sufficient to 
explore the changes in MMN between CVN058 and placebo as well as safety and tolerability of CVN058 in this 
population. 
 


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2.0 
LIST OF ABBREVIATIONS 
5-HT 
5-hydroxytryptamine (serotonin) 
5-HT3 
5-hydroxytryptamine (serotonin) receptor 3 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
AUCt 
area under the plasma concentration-time curve from 0 to time of last quantifiable 
concentration 
BA 
bioavailability 
BMI 
body mass index 
CIAS 
cognitive impairment associated with schizophrenia 
CL/F 
apparent clearance after extravascular administration 
Cmax 
maximum observed plasma concentration 
CNS 
central nervous system 
CRO 
contract research organization 
CS 
clinically significant 
CSF 
cerebrospinal fluid 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DSM -V 
Diagnostic & Statistical Manual of Mental Disorders, 5th Edition – Text Revision 
eCRF 
electronic case report form  
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
EEG 
electroencephalography 
EMA 
European Medicines Agency  
ERP 
evoked response potential 
FDA 
Food and Drug Administration 
FM 
frequency-modulation 
FSH 
follicle-stimulating hormone 
FSI 
fast-spiking interneurons 
Fz 
frontal electrodes 
Fz,Cz 
frontocentral electrodes 
GABA 
γ-aminobutyric acid 
GCP 
Good Clinical Practice 
GGT 
γ-glutamyl transferase 
HBsAg 
hepatitis B surface antigen 
hCG 
human chorionic gonadotropin 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
ICH 
International Conference on Harmonisation 
IEC 
independent ethics committee 
INR 
international normalized ratio 
IRB 
institutional review board 
IUD 
intrauterine device 
K2EDTA 
potassium ethylenediamine tetraacetic acid 


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LFT 
liver function test 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMN 
mismatch negativity 
NCS 
not clinically significant 
NMDAR 
N-methyl-D-aspartate receptor 
NFSI 
non-fasting spiking interneurons 
OTC 
Over-the-counter 
PANSS 
Positive and Negative Syndrome Scale 
PD 
pharmacodynamic(s) 
PI 
principal investigator 
PK 
pharmacokinetic(s) 
PT 
prothrombin time 
PTE 
pretreatment event 
PV 
parvalbumin 
Pz 
parietal electrodes  
P50 Ratio 
ratio of S2 to S1  
RNA 
ribonucleic acid 
QTcB 
QT interval with Bazett correction method 
QTcF 
QT interval with Fridericia correction method 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SSR 
steady state response 
SUSAR 
suspected unexpected serious adverse reaction 
t1/2z 
terminal elimination half-life 
CVN058 
also known as ENV8058 and TAK-058 
TEAE 
treatment-emergent adverse event 
tmax 
time to reach Cmax 
ULN 
upper limit of normal 
Vz/F 
apparent volume of distribution during the terminal phase 
WHODRUG  
World Health Organization Drug Dictionary 


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3.0 
INTRODUCTION 
3.1 
Background 
Schizophrenia is a complex disorder comprising several clinical features that are highly variable 
among affected individuals. Probably the most well-known schizophrenia symptom domains are 
the so-called positive symptoms, e.g., hallucinations, delusions, disorganization of thought, 
bizarre behavior, and incongruity of affect. Negative symptoms include avolition (loss of 
motivation), blunt affect, alogia (reduced speech), and anhedonia (reduced ability to experience 
pleasure). Cognitive impairment associated with schizophrenia (CIAS) usually precedes 
psychosis and is observed in most cases involving deficits in a broad range of domains. Finally, 
patients with schizophrenia often experience depression and anxiety, express hostility, and 
become demoralized (Thaker, 2001).  
Cognitive impairment is considered a core feature of schizophrenia and represents an area of 
significant unmet medical need. Cognitive deficits in schizophrenia include problems in speed of 
processing, attention/vigilance, working memory, verbal learning, visual learning, reasoning and 
problem solving, and social cognition (Green, 2006). These cognitive deficits are believed to 
underlie much of the significant functional impairments observed in schizophrenia, such as 
impairment in independent living skills, social functions, vocational functioning, and self-care 
(Harvey, 2007). Thus, the core nature of CIAS and the associations that have been demonstrated 
with functional disability suggest that improving cognitive impairment may lead to improved 
functional outcomes (Heinrichs, 2005). 
The understanding of CIAS has evolved significantly in recent years and led to new therapeutic 
strategies. In postmortem samples from schizophrenic patients, studies consistently reveal 
reduced levels of enzymes that synthesize the inhibitory neurotransmitter γ-aminobutyric acid 
(GABA) in the prefrontal cortex (McNally, 2013) a key center for higher cognitive function. The 
GABAergic neurons deficient in the cortex are termed fast-spiking interneurons (FSIs), and they 
express the marker parvalbumin (PV) (McNally, 2013). These PV+ FSIs are chemically coupled 
and release GABA in a rhythmic pattern that synchronizes the activity of local cortical pyramidal 
neurons (Cardin, 2009). This synchronization, which is essential for cognition, is disrupted in 
patients [(McNally, 2013), (Cardin, 2009)] [(Whittington, 1997), (Rotaru, 2012), (Gonzalez-
Burgos, 2012)]. These and other human and animal model data implicate FSI hypofunction, and 
a resulting imbalance in the excitation/inhibition balance in cortical regions, in CIAS. 
Based on this emerging insight into disease pathophysiology, a therapeutic that restores the 
normal function of the cortical pyramidal neuron/FSI microcircuit would be expected to improve 
cognitive function in patients with schizophrenia. One strategy for boosting the function of this 
circuit is to inhibit a second population of inhibitory GABAergic interneurons, known as non-
fast spiking interneurons (NFSIs), which project locally onto the FSIs and the dendrites of the 
pyramidal neurons. These NFSIs are modulated by a wide variety of inputs, particularly 
excitatory glutamatergic efferents from the thalamus, and noradrenergic, cholinergic, and 
serotonergic efferents from subcortical regions [(Tian, 2010), (Kawaguchi, 1998), (Kawaguchi, 
1997), (Lee, 2010)]. Thus, NFSIs appear to integrate state-dependent information and release 
GABA to regulate pyramidal neuron/FSI microcircuits. 
Mismatch negativity (MMN) is an established biomarker of cortical function (Javitt, 2015). This 
signal is obtained as an evoked potential during an auditory oddball task, in which a subject is 


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repeatedly exposed to auditory tones and a small proportion of those tones (the “deviant” stimuli) 
differ from the others (the “standard” stimuli) in their frequency or duration. Typically, the tones 
are presented and the evoked potentials are recorded while subjects are engaged on a different 
task, such as reading. Normally, the occurrence of a deviant stimulus increases the amplitude of 
the negative component in the evoked potential occurring at around 200 msec. MMN is the 
difference in amplitude between deviant and standard stimuli responses, and is considered to 
represent an aspect of preattentive novelty detection. MMN is consistently reduced in 
schizophrenia patients relative to healthy individuals, a finding extensively replicated and with a 
large effect size (Cohen’s d = 1). MMN reduction in schizophrenia has been shown to reflect 
impaired N-methyl-D-aspartate receptor (NMDAR) function at the level of supratemporal 
auditory cortex, dependent on cortical interneuron modulation of pyramidal cell activity and 
NMDA receptor-dependent (Lee, 2017). 
3.2 
Non-Clinical 
CVN058 (also known as ENV8058 or TAK-058) is a small molecule that potently and 
selectively antagonizes the 5-hydroxytryptamine (5-HT) receptor type 3 (5-HT3). 5-HT3 is a cys-
loop family ligand-gated ion channel that allows cations to pass into the neurons when activated 
by serotonin, and is highly expressed in NFSIs [(Lee, 2010), (Lummis, 2012)]. The receptor is a 
pentamer consisting of at least two 5-HT3a subunits and 3 other subunits; in the central nervous 
system (CNS) the receptor is almost exclusively a homomeric pentamer comprised of 5-HT3a 
(Kawaguchi, 1997). The 5-HT3 channel opens when serotonin molecules interact with the 2 
ligand recognition sites in the extracellular side of the receptor. Influxed calcium and other 
positive ions depolarize the NFSIs, leading to GABA release. CVN058 is orally absorbed and 
readily passes the blood brain barrier, allowing it to occupy cortical 5-HT3 receptors (50% 
occupancy of rat cortical 5-HT3 receptors is achieved at plasma concentrations of approximately 
5.8 ng/mL). CNS 5-HT3 receptor occupancy is correlated with efficacy in a rat model of 
cognition where it reverses deficits in novel object recognition induced by subchronic 
phencyclidine treatment. Thus, CVN058 is a novel therapeutic candidate that may improve 
cognitive function by inhibiting specific subsets of cortical interneurons.  
Additional information from the nonclinical studies can be found in the current Investigator’s 
Brochure. 
3.3 
Clinical 
Two human clinical studies of CVN058 have been completed (ENV8058_101 and TAK-058-
1002). 
CVN058 was well tolerated up to a dose of 150 mg administered orally as a single dose in 
aqueous solution (Study ENV8058_101). There were no deaths or other serious adverse events 
(SAEs) reported in this study and no subject discontinued study due to a treatment-emergent 
adverse event (TEAE). There were no clinically significant (CS) laboratory abnormalities, 
electrocardiogram (ECG) changes or changes in vital signs in the completed single dose study. 
The mean Cmax and area under the plasma concentration–time curve (AUC) values of CVN058 
increased less than proportionally with increasing CVN058 dose across the dose range of 5 to 
150 mg, but mean Cmax and AUC values increase in an approximately dose proportional manner 
across the 5 to 45 mg dose range. The rate of appearance of CVN058 in plasma was rapid with 


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median time to Cmax (tmax) values of 1 to 1.25 hours across the dose range of 5 to 150 mg. The 
mean terminal elimination half-life (t1/2z) values of CVN058 ranged from approximately 2.8 to 
10.5 hours across the cohorts; the lower doses (5 to 30 mg) had lower mean t1/2z values compared 
to the higher doses (45 to 150 mg). There were no trends with mean apparent clearance (CL/F) 
values of CVN058 with increasing dose from 5 to 45 mg, but faster apparent clearance was 
observed at the 75 and 150 mg doses, possibly due to decreased bioavailability (BA) at higher 
doses. The mean apparent volume of distribution (Vz/F) increased as dose increased. Excretion 
of unchanged CVN058 in the urine was ≤2.3% of the administered CVN058 dose over the dose 
range evaluated. 
In the multiple-rising dose study (TAK-058-1002), CVN058 was well-tolerated at daily doses of 
25, 75, and 150 mg for 7 days, and at a single 300 mg dose, in aqueous solution. There were no 
deaths or other SAEs reported in this study and no subject discontinued study due to a TEAE. 
There were no clinically significant laboratory abnormalities, ECG changes or changes in vital 
signs in the completed single dose study. Following single or multiple doses, the mean Cmax and 
AUC values of CVN058 increased less than proportionally with increasing CVN058 dose across 
the dose range of 25 to 300 mg. No accumulation was observed following daily administration. 
CVN058 concentrations in cerebrospinal fluid (CSF) were assessed after daily doses of CVN058 
75 mg for 5 days. The CSF concentrations averaged 17.5 ng/mL, or approximately 1% of the 
concentration in plasma. 
3.4 
Rationale for the Proposed Study 
This study will explore central target engagement and proof of mechanism by measuring 
auditory evoked potential MMN as a pharmacodynamic (PD) marker of CNS response to the 
selective 5-HT3 receptor antagonist CVN058. It has been reported that subjects with 
schizophrenia commonly demonstrate a deficit in neural processing that is manifested as a 
reduction in MMN and impairment of auditory sensory gating (P50) (Javitt and Sweet, 2015). 
Other 5-HT3 receptor antagonists have been reported to improve impairments in auditory evoked 
potentials in schizophrenic subjects. In a study with ondansetron, a 5-HT3 receptor antagonist, 
using P50 auditory gating as the auditory evoked potential measure, subjects were given a single 
dose of ondansetron (16 mg) or placebo in a double-blind, placebo-controlled, randomized and 
balanced crossover design (Adler, 2005). Serial measurements of the P50 evoked potential were 
done at Baseline and 1, 2, and 3 hours after receipt of placebo or ondansetron. The results of the 
study indicated that ondansetron significantly enhanced P50 auditory gating in subjects with 
schizophrenia. Tropisetron, a 5-HT3 antagonist that also has α7 nicotinic cholinergic agonist 
activity, has similarly been shown to improve P50 auditory gating in subjects with schizophrenia 
(Koike, 2005).  
While the P50 signal is likely a reflection of brainstem and thalamic network activity and is 
sensitive to antipsychotic treatment, MMN is thought to reflect excitation-inhibition balance in 
cortical circuits and is not sensitive to antipsychotic treatment (Javitt and Sweet, 2015). 
Therefore, to evaluate the potential for CVN058 to improve cognitive function in schizophrenics, 
MMN will be used as a PD marker. The study will be performed as a 3-way crossover to assess 
the effect on MMN of CVN058 at two dose levels relative to placebo, with each subject serving 
as his or her own control to reduce variability. P50 auditory gating will also be measured, as an 


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exploratory endpoint, along with other potentially informative electrophysiological and 
psychometric parameters. 
Medications that might inhibit or mask the effects of CVN058 will not be permitted as 
concomitant medications. These include serotonin reuptake inhibitors which increase synaptic 
serotonin levels, as well as drugs that bind to 5-HT3 at clinically relevant concentrations or are 
reported to inhibit signaling through 5-HT3 non-competitively, including some antipsychotic 
drugs [(Eisensamer, 2005), (Eisensamer, 2003), (Rammes, 2004)]. Permissible antipsychotic 
medications are risperidone (Risperdal), haloperidol (Haldol), quetiapine (Seroquel), aripiprazole 
(Abilify) and paliperidone (Invega). 


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4.0 
STUDY OBJECTIVES AND ENDPOINTS 
4.1 
Objectives 
4.1.1 Primary Objective 
• To determine whether improvement in MMN is demonstrated after administration of 
CVN058 compared to placebo in subjects with schizophrenia.  
4.1.2 Secondary Objective 
• To assess the safety and tolerability of single doses of CVN058 in subjects with 
schizophrenia. 
4.1.3 Exploratory Objectives  
• To determine whether improvement in P50 auditory gating, gamma power, and P300 is 
demonstrated after administration of CVN058 compared to placebo in subjects with 
schizophrenia. 
• To assess the pharmacokinetics (PK) of CVN058 following a single dose to subjects with 
schizophrenia. 
• To explore the exposure-response relationship for CVN058 in subjects with schizophrenia. 
4.2 
Endpoints 
4.2.1 Primary Endpoints  
• Mean amplitude of duration MMN at 5 electrodes surrounding frontal (Fz) electrodes 
following administration of CVN058 compared to placebo. 
4.2.2 Secondary Endpoint 
• Percentage of subjects who experience at least 1 TEAE  
• Percentage of subjects who experience at least 1 clinically significant abnormal laboratory 
test result 
4.2.3 Exploratory Endpoints 
• Mean P50 ratio (S2/S1) at 5 electrodes surrounding Cz following administration of CVN058 
compared to placebo 
• Mean P50 differences (S2-S1) at 5 electrodes surrounding Cz following administration of 
CVN058 compared to placebo. 
• Pre-stimulus gamma amplitude following administration of CVN058 compared to placebo  
• P300 amplitude and latency at average of 5 centroparietal electrodes around parietal 
electrodes (Pz) following administration of CVN058 compared to placebo 


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• MMN amplitude to additional deviants (frequency, intensity, location, frequency-modulation 
[FM]) and latency to all deviants following administration of CVN058 compared to placebo 
• CVN058, its metabolite if appropriate, Cmax, tmax, and area under the plasma concentration-
time curve from 0 to the last quantifiable concentration (AUCt). 


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5.0 
STUDY DESIGN AND DESCRIPTION 
5.1 
Study Design  
This is a phase 1, double-blind, placebo-controlled, 3 period cross-over study to evaluate 
CVN058 target engagement by measuring auditory evoked potential MMN downstream to 5-
hydroxytryptamine receptor 3 (5-HT3) as a PD marker.  
Male and female subjects with schizophrenia, age 18 to 50 years old, inclusive, will be 
randomized to 1 of 6 treatment sequences (Table 6.a) to receive 1 of 3 dose regimens in each 
period; a single oral administration of CVN058 (15 mg or 150 mg), or a matching placebo. The 
sequence will determine the order in which a subject will receive each of the 3 regimens. 
Discontinued subjects may be replaced so that 20 completed subjects are available for analysis. 
Each treatment period is less than 1 day in duration, with a minimum of 7-day washout, 
maximum 10 day washout between doses. A follow-up telephone call will occur approximately 
7-10 days following the last dose received. Subjects may be inpatients or outpatients at the 
discretion of the Investigator. 
Table 6.a 
Treatment Sequences 
Sequence 
Period 1 
Period 2 
Period 3 
1 
A 
B 
C 
2 
B 
A 
C 
3 
C 
A 
B 
4 
A 
C 
B 
5 
B 
C 
A 
6 
C 
B 
A 
A: Placebo 
B: CVN058 15 mg 
C: CVN058 150 mg 
 
At each testing session, subjects will undergo post dose EEG testing including: MMN, P50, 
gamma power, and P300. Study drug will be administered with water in the morning. Testing 
sessions will begin approximately 1.5 hours post-dose. Prior to dose and at various time points 
postdose, blood samples will be collected for the assessment of plasma concentrations of 
CVN058 and biomarkers.  
Study procedures will be conducted at approximately the same times across Treatment Periods to 
minimize diurnal effects on outcomes.  The effect of CVN058 on MMN as well as on 
exploratory measures (e.g., P50 auditory gating, gamma power, and P300) will be compared to 
placebo.  
A schematic of the study design is presented in Figure 6.a. 


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Figure 6.a 
Schematic of Study Design 
 
5.2 
Justification for Study Design, Dose, and Endpoints 
This study will explore CNS target engagement by measuring alterations in auditory evoked 
potentials, similar to the demonstration of an effect on P50 auditory gating using the 5-HT3 
antagonist, ondansetron (Adler, 2005). The study design was based on that published study, 
adapted for CVN058 as study drug and MMN as the primary endpoint. It has been reported that 
most subjects with schizophrenia demonstrate a deficit in neural processing that is manifested as 
a reduction in MMN and impairment of auditory sensory gating (P50). According to Adler et al., 
ondansetron improves the P50 deficit after a single dose administration (Adler, 2005).  
The study will be a randomized, 3 period crossover study (CVN058 at two dose levels, and 
placebo) in order to evaluate the effect of CVN058 on MMN as well as on exploratory measures 
(i.e., P50 auditory gating, gamma power, and P300) compared to placebo. The study will be 
double-blind and placebo-controlled in order to avoid subjective bias in the assessment of the PD 
markers. In addition, conduct of study procedures for each subject will occur at approximately 
the same time per day across each of the Treatment Periods to avoid diurnal changes that may 
otherwise confound the analysis.  
The 150 mg level of CVN058 is expected to saturate CNS 5-HT3 receptors throughout the EEG 
session, but is 50% lower than the highest dosage for which safety and tolerability has been 
demonstrated in previous phase 1 studies in healthy subjects, thus presumably maximizing the 
PD signal within the established limits of safe use. The lower dose level of 15 mg CVN058 is 
expected to attain a lower CNS 5-HT3 receptor occupancy, decreasing to possibly 70-80% by the 
end of the EEG session. The 10-fold difference in these dosages should help establish a dose-
response relationship for evoked response potential (ERP) effects of CVN058. From a safety 
perspective, single doses ranging from 5 mg to 300 mg CVN058 have been safe and well-


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tolerated. Daily doses of 25, 75, and 150 mg of CVN058 for 7 days have also been studied, and 
were similarly safe and well-tolerated. 
The timing of dosing was selected to allow the EEG assessments to occur at the corresponding 
estimated tmax values of CVN058. The length of the washout periods is considered adequate 
based on the PK profile of CVN058. 
In addition, based on the EEG deficits reported in subjects with schizophrenia, P50 auditory 
gating, gamma frequency, and P300 neurophysiological markers will be measured. 
5.3 
Premature Termination or Suspension of Study or Investigational Site 
5.3.1 Criteria for Premature Termination or Suspension of the Study 
The study will be completed as planned unless new information or other evaluation regarding the 
safety or efficacy of the study medication indicates a change in the known risk/benefit profile for 
the compound, such that the risk/benefit is no longer acceptable for subjects participating in the 
study. 
5.3.2 Criteria for Premature Termination or Suspension of Investigational Sites 
A study site may be terminated prematurely or suspended if the site (including the investigator) 
is found in significant violation of Good Clinical Practice (GCP), protocol, or contractual 
agreement, is unable to ensure adequate performance of the study, or as otherwise permitted by 
the contractual agreement. 
5.3.3 Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s) 
In the event that the sponsor, an institutional review board (IRB) / independent ethics committee 
(IEC), or regulatory authority elects to terminate or suspend the study or the participation of an 
investigational site, a study-specific procedure for early termination or suspension will be 
provided by the sponsor; the procedure will be followed by applicable investigational sites 
during the course of termination or study suspension. 


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6.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS 
All entry criteria, including test results, need to be confirmed prior to randomization. Subjects 
who do not initially meet eligibility criteria may be re-screened at investigator’s discretion.  
6.1 
Inclusion Criteria 
Subject eligibility is determined according to the following criteria prior to entry into the study:  
1. In the opinion of the investigator, the subject is capable of understanding and complying with 
protocol requirements. 
2. The subject signs and dates a written, informed consent form and any required privacy 
authorization prior to the initiation of any study procedures. 
3. The subject is aged 18 to 50 years, inclusive, at the time of informed consent. 
4. The subject weighs at least 50 kg and has a body mass index (BMI) between 18 and 40 kg/m2 
inclusive at Screening. 
5. The subject meets schizophrenia criteria as defined by the Diagnostic and Statistical Manual 
of Mental Disorders 5th edition (DSM-V) (American Psychiatric Association, 2013). 
6. The subject is on a stable dose of allowed antipsychotic medication(s) for at least 2 months 
prior to Screening as documented by medical history and assessed by site staff. 
7. The subject has a Positive and Negative Syndrome Scale (PANSS) total score of <95 at 
Screening. 
6.2 
Exclusion Criteria 
Any subject who meets any of the following criteria will not qualify for entry into the study:  
1. A male subject who is nonsterilized* and sexually active with a female partner of 
childbearing potential* does not agree to use adequate contraception* from signing of 
informed consent throughout the duration of the study and for 12 weeks after last dose of 
study drug. 
2. A female subject of childbearing potential* who is sexually active with a nonsterilized* male 
partner does not agree to use acceptable methods of contraception* from signing of informed 
consent throughout the duration of the study and for 12 weeks after last dose of study drug. 
*Definitions and acceptable methods of contraception are defined in 
Section 9.1.9 Contraception and Pregnancy Avoidance Procedure and 
reporting responsibilities are defined in Section 9.1.10 Pregnancy. 
3. If female, the subject is pregnant or lactating or intending to become pregnant before, during, 
or within 12 weeks after the last dose of study medication; or intending to donate ova during 
such time period. 
4. The subject has uncontrolled, clinically significant neurologic, cardiovascular, pulmonary, 
hepatic, renal, metabolic, gastrointestinal, or endocrine disease or other abnormality that may 
impact the ability of the subject to participate or potentially confound the study results.  


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5. The subject has a history of gastrointestinal disease that would influence the absorption of 
study drug, or history of any surgical intervention known to impact absorption (e.g., bariatric 
surgery or bowel resection). 
6. The subject has clinical laboratory evaluations (including clinical chemistry, hematology and 
complete urinalysis) outside the reference range for the testing laboratory, unless the results 
are deemed to be NCS by the investigator at Screening. 
7. The subject has received any investigational compound within 30 days prior to signing of 
informed consent. 
8. The subject has taken any excluded medication or dietary supplement within time frames 
listed in the Excluded Medications table in Section 7.3. 
9. The subject does not have a stable indoor living situation (e.g., living independently, with 
family, or group home)  
10. The subject is an immediate family member, study site employee, or is in a dependent 
relationship with a study site employee who is involved in the conduct of this study 
(e.g., spouse, parent, child, sibling) or may consent under duress. 
11. Subjects with moderate to severe substance use disorder according to DSM-5 criteria. 
12. The subject has a positive urine drug result for drugs of abuse (defined as any illicit drug use, 
including marijuana) at Screening.  
13. The subject has a history of cancer requiring chemotherapy within the past 5 years prior to 
the first dose of study medication. This criterion does not include subjects successfully 
treated for basal cell or stage I squamous cell carcinoma of the skin. 
14. The subject has a positive test result for hepatitis B surface antigen (HBsAg), hepatitis C 
virus (HCV) antibody (unless having completed curative therapy), or known history of 
human immunodeficiency virus (HIV) antibody at Screening.  
15. The subject has a QT interval with Fridericia’s correction method (QTcF) >450 msec (males) 
or >470 msec (females) or PR outside the range of 120 to 220 msec, confirmed by triplicate 
testing at 5 minute intervals, at the Screening Visit. 
16. The subject has poor peripheral venous access.  
17. The subject has hair or scalp condition(s) that would prevent the application of the EEG 
electrodes. 
18. The subject has a current diagnosis of a significant psychiatric illness other than 
schizophrenia, per DSM-V and is in an acute phase/episode. 
19. Subject has clinically meaningful hearing loss per investigator’s judgment. 
20. The subject has donated or lost 450 mL or more of his or her blood volume (including 
plasmapheresis), or had a transfusion of any blood product, within 3 months prior to Day 1. 
21. The subject has an abnormal (clinically significant) Screening ECG. Entry of any subject 
with an abnormal (not clinically significant) ECG must be approved and documented by 
signature of the principal investigator (PI).  


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22. The subject has abnormal Screening laboratory values that suggest a clinically significant 
underlying disease, or subject with the following lab abnormalities: alanine aminotransferase 
(ALT) and/or aspartate aminotransferase (AST) >2x the upper limit of normal (ULN). 
23. The subject has abnormal Screening vital sign values that suggest a clinically significant 
underlying disease. 
24. The subject has a risk of suicide according to the Investigator’s clinical judgment, a 
Screening Visit Columbia-Suicide Severity Rating Scale [C-SSRS]) score of greater than 3, 
or has a history of suicide attempt. 
6.3 
Excluded Medications, Dietary Products, Procedures, and Treatments  
Use of the agents in Table 7.a (prescription or nonprescription) is prohibited from the time points 
specified until completion of all study activities.  
Table 7.a 
Prohibited Medications  
28 Days Prior to Check-in  
1 Days Prior to Check-in  
1 Hour Prior to 
Each EEG 
Assessment  
Nutraceuticals and dietary supplements (e.g., St. John’s wort, 
ginseng, kava kava, ginkgo biloba, Chinese herbs, and melatonin) 
 
Alcohol-containing 
products 
Products containing 
nicotine, caffeine or 
xanthine (e.g., tea) 
Antipsychotic medications, except risperidone (Risperdal), 
haloperidol (Haldol), quetiapine (Seroquel), aripiprazole (Abilify) 
and paliperidone (Invega) 
 
Sedative hypnotic 
medications (barbiturates 
and benzodiazepines) 
 
5-HT3 receptor antagonists, including ondansetron (Zofran, 
Zuplenz), granisetron (Kytril, Sancuso, Granisol, Sustol), 
palonosetron (Aloxi), dolasetron (Anzemet)  
 
 
 
5-HT3 allosteric modulators buproprion (Wellbutrin, Zyban) and 
hydroxybupropion 
 
 
 
Serotonin Reuptake Inhibitors (SSRI, SNRI), including sertraline 
(Zoloft), fluoxetine (Prozac, Sarafem), citalopram (Celexa), 
escitalopram (Lexapro), paroxetine (Paxil, Pexeva, Brisdelle), 
vortioxetine (Trintellix), and fluvoxamine (Luvox) 
 
 
 
Mirtazapine (Remeron), desipramine, imipramine, trimipramine, 
reboxetine 
 
 
  
Subjects must be instructed not to take any medications, including over-the-counter (OTC) 
products, without first consulting with the investigator. Subjects must be instructed to not make 
any changes to their concomitant medications during the course of the study without first 
consulting with the investigator. 


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During study participation, subjects will maintain usual dosing schedule of antipsychotic 
medication(s) and approved concomitant medications. Sedative hypnotics will not be allowed 
after 10 pm the night prior to testing, and until completion of testing the following day. 
6.4 
Diet, Fluid, Activity Control  
Subjects should have their customary breakfast before each study visit. The contents of the meal 
should be summarized on the electronic case report form (eCRF). 
During EEG and ERP assessments, subjects will remain still in a seated or partially recumbent 
position, according to the EEG acquisition guidelines. Subjects will refrain from strenuous 
exercise from 72 hours before Check-in through check-out, relative to each Treatment Period. 
If subject is a smoker; they must refrain from smoking at least 1 hour prior to the EEG testing at 
all time points. 
On each dosing day, CVN058 or placebo will be administered with approximately 240 mL of 
water.  
6.5 
Criteria for Discontinuation or Withdrawal of a Subject 
The primary reason for discontinuation or withdrawal of the subject from the study or study 
medication should be recorded in the eCRF using the following categories. For screen failure 
subjects, refer to Section 9.1.17. 
1. Pretreatment event (PTE) or AE. The subject has experienced a PTE or AE that requires 
early termination because continued participation imposes an unacceptable risk to the 
subject’s health or the subject is unwilling to continue because of the PTE or AE. 
2. Liver Function Test (LFT) Abnormalities 
Study medication should be discontinued immediately with appropriate clinical follow-up 
(including repeat laboratory tests, until a subject’s laboratory profile has returned to 
normal/baseline status, see Section 9.1.8), if the following circumstances occur at any 
time during study medication treatment: 
– ALT or AST >8 ×ULN, or 
– ALT or AST >5 ×ULN and persists for more than 2 weeks, or 
– ALT or AST >3 ×ULN in conjunction with elevated total bilirubin >2 × ULN or 
international normalized ratio (INR) >1.5, or 
– ALT or AST >3 ×ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%). 
3. Significant protocol deviation. The discovery post randomization or after the first dose of 
study medication that the subject failed to meet protocol entry criteria or did not adhere to 
protocol requirements, and continued participation poses an unacceptable risk to the subject’s 
health. 
4. Lost to follow-up. The subject did not return to the clinic and attempts to contact the subject 
were unsuccessful. Attempts to contact the subject must be documented. 


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5. Voluntary withdrawal. The subject (or subject’s legally acceptable representative) wishes to 
withdraw from the study. The reason for withdrawal, if provided, should be recorded in the 
eCRF. 
Note: All attempts should be made to determine the underlying reason for the withdrawal 
and, where possible, the primary underlying reason should be recorded (i.e., withdrawal due 
to an AE). 
6. Study termination. The sponsor, IRB, IEC, or regulatory agency terminates the study. 
7. Pregnancy. The subject is found to be pregnant. 
Note: If the subject is found to be pregnant, the subject must be withdrawn immediately. The 
procedure is described in Section 9.1.10. 
8. Other. 
Note: The specific reasons should be recorded in the “specify” field of the eCRF. 
6.6 
Procedures for Discontinuation or Withdrawal of a Subject 
The investigator may discontinue a subject’s study participation at any time during the study 
when the subject meets the study termination criteria described in Section 7.5. In addition, a 
subject may discontinue his or her participation without giving a reason at any time during the 
study. Should a subject’s participation be discontinued, the primary criterion for termination 
must be recorded by the investigator. In addition, efforts should be made to perform all 
procedures scheduled for the Early Termination Visit. Discontinued or withdrawn subjects be 
replaced. 


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7.0 
CLINICAL TRIAL MATERIAL MANAGEMENT 
This section contains information regarding all medication and materials provided directly by the 
sponsor, and/or sourced by other means, that are required by the study protocol, including 
important sections describing the management of clinical trial material. 
7.1 
Study Medication and Materials 
7.1.1 Dosage Form, Manufacturing, Packaging, and Labeling 
Study drug refers to CVN058 and matching placebo. Study drug will be provided in bulk supply. 
An unblinded pharmacist will manage and prepare doses as oral solutions, as needed. 
In this protocol, the term study medication refers to all or any of the drugs defined below. 
7.1.1.1 Investigational Drug 
CVN058 and Matching Placebo  
CVN058 drug substance is supplied as bulk powder to the clinical site to be compounded into an 
oral solution. A matching placebo containing all of the components of the active oral suspension 
with the exception of the drug substance will also be compounded by the site. Compounding 
instructions will be outlined in a separate pharmacy manual and provided by the sponsor. 
CVN058 oral solution will be prepared in concentrations of 10 mg/mL. The composition of the 
oral solutions (active and placebo) can be found in Table 8.a. 
The oral solution will be labeled with the appropriate study information and caution statements. 
Table 8.a 
Composition of CVN058 and Matching Placebo 
Component 
10 mg/mL solution 
Placebo 
CVN058 (free base) 
10 g 
Not Applicable 
Citric Acid Monohydrate, USP 
15.76 g 
15.76 g 
Sterile Water for Irrigation, USP 
q.s. to 1,000 mL 
q.s.to 1,000 mL 
q.s.=quantity sufficient, USP= United States Pharmacopeia. 
 
7.1.1.2 Sponsor-Supplied Drug 
CVN058 drug substance is supplied to the clinical site by Cerevance by way of a contract 
manufacturing organization, Johnson-Mathey Pharma Services, Devens, MA. 
7.1.1.3 Ancillary Materials 
Ancillary materials will be provided by either the clinical site and/or sponsor based on 
availability.  
Ancillary material details are provided in the pharmacy manual. 
Unused ancillary materials, if provided by the sponsor, will be accounted for and disposed of as 
directed by the sponsor or their designee.  


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7.1.2 Storage 
All clinical trial material must be kept in an appropriate, limited-access, secure place until it is 
used or returned to the sponsor or designee for destruction. 
All study medication must be stored under the conditions specified on the label, and remain in 
the original container until dispensed. A daily temperature log of the drug storage area must be 
maintained every working day. 
CVN058 powdered drug substance is stored at room temperature. CVN058 oral solution and 
matching placebo can be stored protected from light at 2°C-8°C (35.6°F-46.4°F) for up to 28 
days. CVN058 oral solution and matching placebo are stable at room temperature for up to 24 
hours. 
7.1.3 Dose and Regimen 
The investigator or investigator’s designee will instruct the subject on dosing procedures. 
All dosing will occur while subjects are in the clinic under the supervision of the PI or designee, 
who will be blinded to the dose. 
Subjects will receive CVN058 (15 mg or 150 mg) or matching placebo in each of the 3 periods.  
Table 8.b describes the treatment and medication type that would be provided for each period. 
Table 8.b 
Treatment and Medication Type 
Regimen 
Planned Treatment 
Medication Type 
A 
Placebo 
Placebo  
B 
CVN058 15 mg 
CVN058  
C 
CVN058 150 mg 
CVN058 
 
7.1.4 Overdose 
An overdose is defined as a known deliberate or accidental administration of investigational 
drug, to or by a study subject, at a dose above that which is assigned to that individual subject 
according to the study protocol. 
All cases of overdose (with or without associated AEs) will be documented on an Overdose page 
of the eCRF, in order to capture this important safety information consistently in the database. 
Cases of overdose without manifested signs or symptoms are not considered AEs. AEs 
associated with an overdose will be documented on AE CRF(s) according to Section 10.0, 
Pretreatment Events and Adverse Events. 
The SAEs associated with overdose should be reported according to the procedure outlined in 
Section 10.2.2, Collection and Reporting of SAEs. 
In the event of drug overdose, the subject should be treated, e.g., administration of supportive 
therapy as directed by the subject’s clinical status, removal of unabsorbed material from the 
gastrointestinal tract and initiation of additional clinical monitoring.  


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7.2 
Investigational Drug Assignment and Dispensing Procedures 
Subjects will be assigned a 7-digit subject number in the sequential order in which they are 
randomized beginning with a 3-digit code “NNN-” where NNN represents a site specific 
identifier which will be provided by the Sponsor. Replacement subjects will be assigned a new 
number (e.g. site number followed by subject number). The 7-digit subject number assigned will 
be entered in the subject’s eCRF and noted on any subject specific source record and lab sample 
tubes. 
This 7-digit subject number will also be used by the clinical site to facilitate the prelabeling of 
PK samples, and will be the only subject identifier used on all PK sample collections. It should 
also be contained on the PK transport vials shipped to the bioanalytical laboratory, and will be 
used by the laboratory to report the subject data results. 
7.3 
Randomization Code Creation and Storage  
The randomization schedule will be generated under the direction of Cerevance statistician or 
designee and a copy will be provided to the site pharmacist prior to the start of study. All 
randomization information will be stored in a secured area, accessible only by authorized 
personnel. 
7.4 
Investigational Drug Blind Maintenance  
The investigational drug blind is maintained through a randomization schedule held by the 
dispensing pharmacist.  
7.5 
Unblinding Procedure  
The investigational drug blind shall not be broken by the investigator unless information 
concerning the investigational drug is necessary for the medical treatment of the subject. All 
study assessments and assignment of causality for AEs should be performed, if possible, prior to 
unblinding. In the event of a medical emergency, if possible, the medical monitor should be 
contacted before the investigational drug blind is broken to discuss the need for unblinding. 
For unblinding a subject, the investigational drug blind can be obtained by contacting the 
dispensing pharmacist. 
The sponsor must be notified as soon as possible if the investigational drug blind is broken. The 
date, time, and reason the blind is broken must be recorded in the source documents and the 
same information (except the time) must be recorded on the eCRF. 
If any site personnel are unblinded, investigational drug must be stopped immediately and the 
subject must be withdrawn from the study. 
No change should be made to any assessment of the subject after unblinding. 
7.6 
Accountability and Destruction of Sponsor-Supplied Drugs 
Drug supplies will be counted and reconciled at the site before being returned to the sponsor or 
designee or destroyed per site’s procedures. 


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The investigator or designee must ensure that the sponsor-supplied drug is used in accordance 
with the protocol and is dispensed only to subjects enrolled in the study. To document 
appropriate use of sponsor-supplied drug, the investigator or designee must maintain records of 
all sponsor-supplied drug delivery to the site, site inventory, dispensation and use by each 
subject, and return to the sponsor or designee. 
Upon receipt of sponsor-supplied drug, the investigator or designee must verify the contents of 
the shipments against the packing list. The verifier should ensure that the quantity is correct, and 
the medication is in good condition. If quantity and conditions are acceptable, investigator or 
designee should acknowledge the receipt of the shipment by signing bottom half of the packing 
list and faxing per instructions provided on the form. If there are any discrepancies between the 
packing list versus the actual product received, Cerevance must be contacted to resolve the issue. 
The packing list should be filed in the investigator’s essential document file. 
The investigator or designee must maintain 100% accountability for all sponsor-supplied drugs 
received and dispensed during his or her entire participation in the study. Proper drug 
accountability includes, but is not limited to: 
• Continuously monitoring expiration dates. 
• Frequently verifying that actual inventory matches documented inventory. 
• Verifying that the log is completed for the drug lot used to prepare each dose. 
• Verifying that all containers used are documented accurately on the log. 
• Verifying that required fields are completed accurately and legibly. 
If any dispensing errors or discrepancies are discovered, the sponsor must be notified 
immediately. 
The investigator or designee must record the current inventory of all sponsor-supplied drugs 
CVN058 or placebo on a sponsor-approved drug accountability log. The following information 
will be recorded at a minimum: protocol number and title, name of investigator, site identifier 
and number, description of sponsor-supplied drugs, expiration date and amount dispensed, 
including initials of the person dispensing the drug, and the date and amount returned to the site 
by the subject, including the initials of the person receiving the sponsor-supplied drug. The log 
should include all required information as a separate entry for each subject to whom sponsor-
supplied drug is dispensed. 
All study drug that was not returned to the site by a subject must be investigated by the site and 
appropriately documented on the drug accountability log. 
Prior to site closure or at appropriate intervals, a representative from the sponsor or its designee 
will perform sponsor-supplied drug accountability and reconciliation before sponsor-supplied 
drugs are returned to the sponsor or its designee for destruction. The investigator or designee will 
retain a copy of the documentation regarding sponsor-supplied drug accountability, return, 
and/or destruction, and originals will be sent to the sponsor or designee. 
The investigator will be notified of any expiry date or retest date extension of sponsor-supplied 
drug during the study conduct. On expiry date notification from the sponsor or designee, the site 


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must complete all instructions outlined in the notification, including segregation of expired 
sponsor-supplied drug for return to the sponsor or its designee for destruction. 


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8.0 
STUDY PLAN 
8.1 
Study Procedures 
The following sections describe the study procedures and data to be collected. For each 
procedure, subjects are to be assessed by the same investigator or site personnel whenever 
possible. The Schedule of Study Procedures is located in Appendix A. 
8.1.1 Informed Consent Procedure 
The requirements of the informed consent are described in Section 15.2. 
Informed consent must be obtained prior to the subject entering into the study, and before any 
protocol-directed procedures are performed. 
A unique subject Screening number will be assigned to each subject at the time that the informed 
consent is obtained; this Screening number will be used until the subject has been randomized 
into the study, at which time the Subject number will be primary method of identification on 
study records. 
8.1.1.1 Pharmacogenomic Informed Consent Procedure 
Pharmacogenomics informed consent is a component of the overall study informed consent. The 
requirements are described in Section 15.2. 
The pharmacogenomic sample collection is optional. 
8.1.2 Demographics, Medical History, and Medication History Procedure 
Demographic information to be obtained will include date of birth, sex, Hispanic ethnicity, race 
as described by the subject, height, weight, caffeine consumption, reproductive status (including 
last menstrual period) and smoking status of the subject at Screening.  
Medical history to be obtained will include determining whether the subject has any significant 
conditions or diseases relevant to the disease under study that stopped at or prior to signing of 
informed consent. Ongoing conditions are considered concurrent medical conditions 
(see Section 9.1.7). 
Medication history information to be obtained includes any medication relevant to eligibility 
criteria stopped at or within 45 days (for subjects with schizophrenia) prior to signing of 
informed consent. 
8.1.3 Physical Examination Procedure 
A physical examination will consist of the following body systems: (1) eyes; (2) ears, nose, 
throat; (3) cardiovascular system; (4) respiratory system; (5) gastrointestinal system; 
(6) dermatologic system; (7) extremities; (8) musculoskeletal system; (9) nervous system; 
(10) lymph nodes; and (11) other. 
Any abnormal change from the initial Screening physical examination must be assessed by the 
investigator as not clinically significant (NCS) or clinically significant (CS) and recorded in the 
source document and eCRF. 


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Any CS change, as determined by the investigator, from the baseline physical examination will 
be recorded as an AE or pretreatment event in source documentation and on the Pretreatment 
Event/AE eCRF. 
8.1.4 Weight, Height, and BMI 
A subject should have weight and height measured while wearing indoor clothing and with shoes 
off. The BMI is calculated using metric units with the formula provided below:  
The standard for collecting height is centimeters without decimal places and for weight it is 
kilograms (kg) with 1 decimal place. BMI should be derived as: 
Metric:  
BMI = weight (kg)/height (m)2 
Note that although height is measured in centimeters, the BMI formula uses meters for height; 
meters can be determined by dividing centimeters by 100. Thus, for example, if height=176 cm 
(1.76 m) and weight=79.2 kg, then BMI=79.2/1.762=25.56818 kg/m2. 
Results for BMI will be expressed with 1 decimal place and rounding is allowed. The above 
value should be captured as 25.6 kg/m2 in the database. 
8.1.5 Vital Sign Procedure  
When vital signs are scheduled at the same time as blood draws, the blood draw will take priority 
and vital signs will be obtained within 0.5 hour before or after the scheduled blood draw. 
Vital signs consisting of body temperature (oral), respiration rate, blood pressure and pulse will 
be measured in a seated resting state (>10 minutes). 
8.1.6 Documentation of Concomitant Medications 
Concomitant medication is any drug given in addition to the study medication. These may be 
prescribed by a physician or obtained by the subject over the counter. Concomitant medication is 
not provided by Cerevance. At each study visit, subjects will be asked whether they have taken 
any medication other than the study medication (used from signing of informed consent through 
the end of the study), and all medication including vitamin supplements, OTC medications, and 
oral herbal preparations, must be recorded in the eCRF. Documentation will include generic 
medication name, dose, unit, frequency, route of administration, start and end dates, and reason 
for use.  
8.1.7 Documentation of Concurrent Medical Conditions 
Concurrent medical conditions are those significant ongoing conditions or diseases that are 
present at signing of informed consent. This includes clinically significant laboratory, ECG, or 
physical examination abnormalities noted at the Screening examination. The condition (i.e., 
diagnosis) should be described. 
8.1.8 Procedures for Clinical Laboratory Samples 
All samples will be collected in accordance with acceptable laboratory procedures and as 
stipulated in the Schedule of Study Procedures (Appendix A). Abnormal Screening labs may be 


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repeated once at the discretion of the investigator for assessment of eligibility. Subjects who still 
do not meet eligibility criteria may be re-screened at investigator’s discretion. 
Table 9.a lists the tests that will be obtained for each laboratory specimen  
Table 9.a 
Clinical Laboratory Tests 
Hematology 
Serum Chemistry 
Urinalysis 
 
RBC 
WBC with differential (% 
and absolute) 
Hemoglobin 
Hematocrit 
Platelets 
Prothrombin time /INR 
ALT 
Albumin 
Alkaline phosphatase 
AST 
Total bilirubin 
Direct bilirubin 
Total protein 
Creatinine 
Blood urea nitrogen 
Creatine kinase 
GGT 
Potassium 
Sodium 
Glucose 
Chloride 
Bicarbonate 
Calcium 
pH 
Specific gravity 
Protein 
Glucose 
Blood  
Nitrite 
Microscopic Analysis 
(only if positive dipstick 
results):  
RBC/high power field 
WBC/high power field 
Epithelial cells, casts etc 
 
Diagnostic Screening: 
Serum 
Urine 
Saliva (d) 
Serum hCG (a) 
At Screening Only:  
Hepatitis panel, including HBsAg 
and anti-HCV 
FSH (b) 
Drug screen including 
amphetamines, barbiturates, 
benzodiazepines, cannabinoids, 
cocaine, opiates, alcohol, and 
cotinine (c) 
Alcohol 
cotinine 
FSH=follicle-stimulating hormone, GGT=γ-glutamyl transferase, RBC=red blood cells, WBC=white blood cells. 
(a) Serum hCG pregnancy test will be done at Screening. 
(b) FSH level will be obtained for female subjects at Screening if they are postmenopausal (i.e., last regular 
menstrual cycle >2 years) and not surgically sterile. The result must be >40 IU/L to obviate the need for 
contraception.  
(c) To be performed at Screening.  
(d) Alcohol and cotinine saliva samples may be collected, if needed. 
The local laboratory will perform laboratory tests for hematology, serum chemistries, and 
urinalysis. The results of laboratory tests will be returned to the investigator, who is responsible 
for reviewing and filing these results. 
If subjects experience ALT or AST >3 ×ULN, follow-up laboratory tests (at a minimum, serum 
alkaline phosphatase, ALT, AST, total bilirubin, GGT, and INR) should be performed within a 
maximum of 7 days and preferably within 48 to 72 hours after the abnormality was noted. 
(Please refer to Section 7.5 for discontinuation criteria, and Section 10.2.3 for the appropriate 
guidance on Reporting of Abnormal Liver Function Tests in relation to ALT or AST >3 ×ULN 
in conjunction with total bilirubin >2 ×ULN.) 


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If the ALT or AST remains elevated >3 ×ULN on these 2 consecutive occasions, the investigator 
must contact the Medical Monitor for consideration of additional testing, close monitoring, 
possible discontinuation of study medication, discussion of the relevant subject details and 
possible alternative etiologies. The abnormality should be recorded as an AE (please refer to 
Section 10.2.3 Reporting of Abnormal Liver Function Tests for reporting requirements). 
All laboratory safety data will be transferred electronically to Cerevance or designee in the 
format requested by Cerevance. If the laboratory is unable to electronically transfer data, the 
study site coordinator or designee is responsible for transcribing laboratory results into the eCRF. 
The investigator will maintain a copy of the laboratory accreditation and the reference ranges for 
the laboratory used. 
Laboratory reports must be signed and dated by the PI or sub-investigator indicating that the 
report has been reviewed and any abnormalities have been assessed for clinical significance.  
All CS laboratory abnormalities must be recorded as a PTE/AE in the subject’s source 
documents and on the appropriate eCRF. A CS laboratory abnormality that has been verified by 
retesting will be followed until the abnormality returns to an acceptable level or a satisfactory 
explanation has been obtained. 
8.1.9 Contraception and Pregnancy Avoidance Procedure 
During the study and for 12 weeks after last dose of study medication, nonsterilized males and 
female subjects of childbearing potential who are sexually active must agree to use two effective 
methods of contraception.  
From signing of informed consent, throughout the duration of the study, and for 12 weeks after 
last dose of study medication, nonsterilized** male subjects who are sexually active with a 
female partner of childbearing potential* must use barrier contraception (e.g., condom with 
spermicidal cream or jelly). In addition, they must be advised not to donate sperm during this 
period.  
From signing of informed consent, throughout the duration of the study, and for 12 weeks after 
last dose of study medication, female subjects of childbearing potential* who are sexually active 
with a nonsterilized male partner** must use adequate contraception. In addition they must be 
advised not to donate ova during this period. 
*Females NOT of childbearing potential are defined as those who have been surgically sterilized 
(hysterectomy, bilateral oophorectomy or tubal ligation) or who are postmenopausal (e.g., 
defined as at least 2 years since last regular menses with an FSH>40 IU/L or at least 5 years 
since last regular menses, confirmed before any study medication is implemented). 
**Sterilized males should be at least 1 year postvasectomy and have confirmed that they have 
obtained documentation of the absence of sperm in the ejaculate. 
The following are acceptable forms of contraception: 


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Barrier methods (each time the subject has 
intercourse): 
Intrauterine devices (IUDs): 
• Male condom PLUS spermicide. 
• Cap (plus spermicidal cream or jelly). 
• Diaphragm (plus spermicidal cream or 
jelly). 
Hormonal Contraception (stable regimen) 
• Birth control pills or patch. 
• Injected hormonal contraceptive  
(such as Depo-Provera). 
• Vaginal hormonal ring  
(such as NuvaRing). 
• Copper T PLUS condom or spermicide. 
Subjects will be provided with information on acceptable methods of contraception as part of the 
subject informed consent process and will be asked to sign a consent form stating that they 
understand the requirements for avoidance of pregnancy, donation of ova, and sperm donation 
during the course of the study. 
During the course of the study, regular serum human chorionic gonadotropin (hCG) pregnancy 
tests will be performed only for women of childbearing potential, and subjects will receive 
guidance with respect to the avoidance of pregnancy. In addition to a negative serum hCG 
pregnancy test at Screening, subjects also must have a negative urine hCG pregnancy test prior to 
receiving any dose of study medication. Male subjects must be advised not to donate sperm from 
signing of informed consent to 12 weeks after the last dose of study medication. 
8.1.10 Pregnancy 
If any subject is found to be pregnant during the study she should be withdrawn and any sponsor-
supplied drug should be immediately discontinued. In addition, any pregnancies in the partner of 
a male subject during the study or for 12 weeks after the last dose should also be recorded 
following authorization from the subject’s partner.  
If the pregnancy occurs during administration of active study medication, e.g., after Visit 1 or 
within 12 weeks of the last dose of active study medication, the pregnancy should be reported 
immediately, using a pregnancy notification form, to the contact listed in Section 1.0. 
Should the pregnancy occur during or after administration of blinded drug, the investigator must 
inform the subject of their right to receive treatment information. If the subject chooses to 
receive unblinded treatment information, the individual blind should be broken by the 
investigator. Subjects who have only received placebo need not be followed. 
If the female subject and/or female partner of a male subject agrees to the primary care physician 
being informed, the investigator should notify the primary care physician that the subject/female 
partner of the subject was participating in a clinical study at the time she became pregnant and 
provide details of treatment the subject received (blinded or unblinded, as applicable). 


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All reported pregnancies will be followed up to final outcome, using the pregnancy form. The 
outcome, including any premature termination, must be reported to the sponsor. An evaluation 
after the birth of the child will also be conducted. 
8.1.11 ECG Procedure  
A standard 12-lead ECG will be recorded in a supine position resting for at least 10 minutes at 
Screening to assess eligibility. The ECGs will be recorded in triplicate at approximately 5 minute 
intervals. The investigator (or a qualified physician at the investigational site) will interpret the 
ECG using 1 of the following categories: within normal limits, abnormal but NCS, or abnormal 
and CS. A copy of the ECG trace should be kept with the subject’s notes. 
ECGs will be read automatically and also, the investigator or sub-investigator or a suitably 
qualified delegate will manually interpret the ECG using 1 of the following categories: within 
normal limits, abnormal NCS, or abnormal and CS. All 12-lead ECGs will be stored for manual 
measurement of intervals, if necessary.  
Twelve-lead ECGs will be recorded using an ECG machine that automatically calculates the 
heart rate and measures PR interval, RR interval, QRS interval, QT interval, and QTcF and 
QTcB (Fridericia’s and Bazett’s correction) intervals.  
One copy of the 12-lead ECG with the physician’s signature and date of assessment will be filed 
with the source documents and captured in the appropriate eCRF. All ECGs will be recorded at 
the time points detailed in the Schedule of Study Procedures (Appendix A). 
8.1.12 Pharmacogenomic Sample Collection 
Every subject must sign informed consent/be consented in order to participate in the study, but 
consent to participate in the pharmacogenomic sample collection (genetic substudy) is optional. 
Deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) form the basis for the genes that 
make the body produce proteins such as enzymes, drug transporters or drug targets, and may be 
evaluated for the genetic contribution how the drug is broken down, or how the drug affects the 
body. This is called a “pharmacogenomics research study.” Specific purposes of this study 
include: 
• Identifying genetic reasons why certain people respond differently to CVN058. 
• Finding out more information about how CVN058 works. 
• Generating information needed for research, development, and regulatory approval of tests to 
predict response to CVN058. 
• Identifying variations in genes related to the biological target of CVN058. 
This information may be used, for example, to develop a better understanding of the safety and 
efficacy of CVN058 and other study medications, and for improving the efficiency, design and 
study methods of future research studies. 
The DNA samples will be used to evaluate common variations in genes which encode drug 
metabolizing enzymes and transporters. This could be helpful in understanding why there are 
differences in CVN058 kinetics between subjects. Also, since pharmacogenomics is an evolving 


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science, many genes and their functions are not yet fully understood. Future data may suggest a 
role of some of these genes in drug response, which may lead to additional hypothesis-generating 
exploratory research and diagnostic development on stored samples. 
Whole blood will be collected and stored for possible DNA or RNA isolation and analysis.  
DNA sample collection: 
One 6 mL whole blood sample will be collected before study drug dosing on Day 1 of 
Period 1 only from each subject in the study, into plastic potassium ethylenediamine 
tetraacetic acid (K2EDTA) spray-coated tubes, and stored under frozen conditions.  
RNA sample collection: 
Two whole blood samples (2.5 mL per sample) will be collected from each subject into a 
PAXgene tube on Day 1 of each period at pre dose and post EEG for RNA 
pharmacogenomic analysis.  
If isolation of DNA from the first sample was not successful or possible, a second aliquot of 
blood may be taken, if feasible. 
Each pharmacogenomic sample for a study subject should be identifiable on the requisition form 
with the 7-digit subject ID. Detailed instructions for the handling, shipping, and storage of 
pharmacogenomic samples will be provided in the lab manual.  
The samples will be stored for no longer than 15 years after completion of the CVN058 study 
and/or until the drug development of CVN058 is no longer actively pursued by Cerevance or its 
collaborators. No samples will be stored for longer than permitted by the applicable law and 
samples will be destroyed upon notification from Cerevance. 
8.1.13 Pharmacokinetic Sample Collection 
8.1.13.1 Collection of Blood for Pharmacokinetic Sampling 
Blood samples (one 6-mL sample per scheduled time) will be collected for analysis of CVN058, 
and its metabolite if appropriate; plasma will be collected into chilled vacutainers containing 
K2EDTA according to the schedule in Appendix A. Instructions for sample processing and 
shipment will be provided in the lab manual. 
Serial blood samples for determination of CVN058, and its metabolite if appropriate, in plasma 
will be collected according to Table 9.b. 
Table 9.b 
Collection of Blood Samples for CVN058 Pharmacokinetic Analysis 
Sample 
Type 
Dosing Day 
Time Postdose (hours) 
Plasma 
1 
Predose (within 15 minutes prior to dosing), 1 hour post dose (pre-EEG), and 5 hours 
post dose (post-EEG)   
 
The PK samples will be collected before any other assessments are performed, if scheduled at the 
same time point. The actual time of sample collection will be recorded on the source document 
and eCRF. 


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Placebo samples will not be analyzed by the bioanalytical laboratory except 1 sample per subject 
receiving placebo around the expected time at which CVN058 Cmax is expected to occur to 
ensure from a safety perspective that no subjects have inadvertently received active treatment. 
8.1.13.2 Bioanalytical Methods 
Plasma concentrations of CVN058 will be measured by high-performance liquid 
chromatography with tandem mass spectrometry. If appropriate, plasma samples analyzed for 
CVN058 also may be analyzed for the CVN058 metabolite. 
8.1.14 Pharmacokinetic Parameters  
The PK parameters of CVN058, and its metabolite (if appropriate), will be derived using non-
compartmental analysis methods. The PK parameters will be determined from the concentration-
time data for all evaluable subjects. Actual sampling times, rather than scheduled sampling 
times, will be used in all computations involving sampling times. The following PK parameters 
will be determined from concentrations of CVN058, and its metabolite if appropriate, in plasma. 
Other parameters may be calculated as appropriate.  
Symbol/Term 
Definition 
Plasma 
AUCt 
Area under the plasma concentration-time curve from time 0 to time of the last 
quantifiable concentration. 
Cmax 
Maximum observed plasma concentration. 
tmax 
Time to reach Cmax. 
 
8.1.15 Pharmacodynamic Sample Collection  
MMN will be used as a PD assessment. At each testing session, the following PD assessments 
will be performed during the EEG: MMN, P50, gamma power, and P300. Collection of P50 may 
be omitted if the essential equipment is not available. The testing session during each Treatment 
Period will begin approximately 1.5 hours after administration of study drug.  
8.1.16 Pharmacodynamic Parameters  
All EEG parameters will be obtained in accordance with the EEG acquisition guideline provided 
by Cerevance or their designee. It is anticipated that each EEG procedure will take 
approximately 4 hours to complete, including approximately 30 minutes to set up, 3 hours 
acquisition time, and 30 minutes to clean up. 
MMN 
MMN is a pre-attentive auditory component elicited by deviant stimuli in an auditory oddball 
task. MMN predominantly reflects activation of neuronal ensembles within primary auditory 
cortex, and thus indexes sensory level disturbance in schizophrenia. MMN will be obtained 
independently to pitch and duration deviant stimuli. MMN is maximal at frontocentral electrodes 
(Fz, Cz). Mean peak amplitude at 5 electrodes surrounding Fz within a predefined latency range 
will be the primary outcome measure. 


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P50 
P50 auditory evoked potentials will be recorded. Participants will be seated and instructed to 
relax and to focus their eyes on a fixation point. Stimulus signal of 90-dB pulses of 0.1 msec in 
duration will be generated and recorded the event-related potential waveforms.  
32 pairs of auditory clicks will be presented every 10 seconds, with a 500 msec interclick 
interval. 
 
The conditioning P50 wave (S1) and test P50 wave (S2) will be identified as the power in the 
alpha/beta frequency bands as suggested by Smucny et al. (Smucny, 2013). The data from the 
vertex (Cz) and surrounding electrodes will be collected and the P50 gating ratios will be 
calculated as the ratio of the test P50 to the conditioning P50 power. In case the Cz gating ratio is 
>0.2 units above the surrounding electrodes, the value will be discarded and replaced with the 
value from surrounding electrodes. P50 ratio will be defined as the ratio of S2/S1 power. The S2-
S1 difference score as suggested by Smucny et al. (Smucny, 2013) will be used as an exploratory 
outcome measure.  
Quantitative Electroencephalogram, Gamma Power 
Five minute eyes open/close recordings will be obtained during each recording session. Ten 1-
second, artifact-free epochs will be chosen for quantitative analysis. Primary outcome measures 
will consist of power within delta (0.5 – 4 Hz), theta (4-7 Hz), alpha (8-13 Hz), delta (13-20 Hz), 
low gamma (20-40 Hz) and high gamma (40 – 60 Hz) over predesignated frontal, central, 
temporal and occipital sites. In addition, specific measures of 40 Hz activity will be assessed in 
response to repetitive 40 Hz auditory stimulation. 
P300 
As opposed to MMN, which are obtained under passive (i.e., no-task) conditions, auditory P300 
will be obtained only when subjects must attend to and detect novel task-relevant deviant stimuli. 
Generators for P300 are located in distributed frontoparietal networks and so represent an index 
of higher order, “cognitive” processing in schizophrenia. P300 will be obtained to deviant 
auditory stimuli in an auditory “oddball” paradigm. P300 is maximal in amplitude at Fz and Pz 
electrodes. Primary outcome measures will consist of peak amplitude within prespecified latency 
range at the frontal/parietal sites. 
8.1.17 Positive and Negative Syndrome Scale 
The PANSS was developed and standardized for typological and dimensional assessment of 
schizophrenic phenomena. In this study, empirically derived factors are tested excluding those 
items that could not be assessed during the test sessions: positive symptom factor (delusions, 
unusual thoughts, somatic concern, grandiosity, suspiciousness, and hallucinations), negative 
symptom factor (emotional withdrawal, blunted affect, poor rapport, disturbance of volition, 
preoccupation, and motor retardation), cognitive factor (difficulty in abstract thinking, 
stereotyped thinking, cognitive disorganization, lack of judgment and insight, poor attention, 
tension, mannerisms, and posturing), hostility (excitement, hostility, impulse control, and 
uncooperativeness), emotional discomfort (depression, anxiety, and guilt). PANSS will be 
collected at Screening, Early Termination, and at the Follow-up Visit if clinically significant 
findings were observed upon discharge. In these cases, subjects must then be brought back to the 
clinic for re-evaluation per investigator’s discretion.  


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The duration of the PANSS is approximately 30 minutes (Kay, 1990). 
8.1.18 Columbia Suicide Severity Rating Scale 
The determination and management of patients’ suicidality risk is the Investigators’ 
responsibility. For study purposes, suicidality will be assessed by the use of the C-SSRS. The C-
SSRS is a 3-part scale that measures suicidal ideation (e.g., subject endorses thoughts about a 
wish to be dead or has other thoughts of suicide), intensity of ideation (frequency, duration, 
controllability, deterrents, and reasons for ideation), and suicidal behavior (actually, interrupted, 
and aborted attempts at suicide) (Mundt, 2013). 
The C-SSRS is a 2-page questionnaire that prospectively assesses suicidal thoughts and behavior 
using a structured interview for patient responses. Suicidal ideation is classified on a 5-item 
scale: 1 (wish to be dead), 2 (nonspecific active suicidal thoughts), 3 (active suicidal ideation 
with any methods [not plan] without intent to act), 4 (active suicidal ideation with some intent to 
act, without specific plan), and 5 (active suicidal ideation with specific plan and intent). The C-
SSRS also captures information about the intensity of ideation, specifically the frequency, 
duration, controllability, deterrents, and reasons for the most severe types of ideation. Suicidal 
behavior is classified on a 5-item scale: 0 (no suicidal behavior), 1 (preparatory acts or behavior), 
2 (aborted attempt), 3 (interrupted attempt), and 4 (actual attempt). 
Different versions of the scale are available. In this study, “Baseline/Screening” version will be 
used at Screening Visit and “Since last visit” version at all subsequent visits. “Since the last 
visit” should collect information from the last visit where C-SSRS was administered. If the 
patient’s response generates a change in the findings report from negative to positive, the patient 
should be referred for immediate psychiatric evaluation on the same date as the site visit. 
Positive suicidality findings, if confirmed by the PI, is considered to be a serious event. If arising 
after signing informed consent but prior to administration of any study medication, it is 
considered a Pretreatment Event (PTE). If arising after administration of any study medication, it 
is considered an SAE.  
The C-SSRS will be administered by the PI or a trained designee on paper and captured in the 
eCRF. The same interviewer should be used throughout the study for the same subject where 
possible. 
8.1.19 Documentation of Screen Failure 
Investigators must account for all subjects who sign informed consent. If the subject is found to 
be not eligible at this visit, the investigator should complete the eCRF screen failure form. 
The primary reason for screen failure is recorded in the eCRF using the following categories: 
• PTE/AE. 
• Did not meet inclusion criteria or did meet exclusion criteria. 
• Significant protocol deviation. 
• Lost to follow-up. 
• Voluntary withdrawal. 


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• Study termination. 
• Other <specify reason>. 
Subject numbers assigned to subjects who fail Screening should not be reused. 
8.1.20 Documentation of Randomization 
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible 
for randomization into the treatment phase. Randomization will take place on Day 1 of 
Treatment Period 1. 
If the subject is found to be not eligible for randomization, the investigator should record the 
primary reason for failure on the applicable eCRF. 
8.2 
Monitoring Subject Treatment Compliance 
Study medication will be administered while subjects are under observation in the clinical 
research unit. Following administration of the study medication, appropriate mouth and/or hand 
checks will be performed to ensure that the dose is swallowed and noted in the source document. 
The date and time of each dose will be recorded in the source documents and on the eCRFs. An 
inventory of the study medication supplies dispensed will be performed by the site pharmacist or 
authorized study designee and recorded onto the Drug Accountability Log in the subject’s source 
document records or equivalent. The exact dose time of consecutive subjects may be staggered to 
facilitate logistics at the site. 
8.3 
Schedule of Observations and Procedures 
The schedule for all study-related procedures for all evaluations is shown in Appendix A. 
Assessments should be completed at the designated visit/time point(s). 
8.3.1 Screening 
Subjects with schizophrenia will be screened within 28 days prior to enrollment. All subjects will 
be screened in accordance with predefined inclusion and exclusion criteria as described in 
Section 7.0. See Section 9.1.17 for procedures for documenting screen failures.  Following 
written informed consent, Screening procedures may be conducted on different days. 
Assessments to be conducted during the Screening period are outlined in Appendix A. 
8.3.2 Treatment Phase 
The treatment will be administered over 3 Periods, separated by 7-10 days for washout.  
Assessments to be conducted during the screening period are outlined in Appendix A. 
8.3.3 Final Visit/End of Treatment  
The Final Visit additional assessments will occur prior to Discharge from the clinic at the end of 
Treatment Period 3, Day 1, as outlined in Appendix A. 
For all subjects who received any study medication, the investigator must complete the End of 
Study eCRF page. 


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8.3.4 Early Termination 
The reason for discontinuation must be documented in the source document and eCRF. The 
procedures outlined in Appendix A will be performed and documented. 
For all subjects receiving study medication, the investigator must complete the End of Study 
eCRF page. 
8.3.5 Follow-up Visit/Telephone Call  
The Follow-up Visit will occur by telephone approximately 7-10 days after receiving the last 
dose of study medication (Treatment Period 3) unless abnormal, clinically significant findings 
were observed upon discharge. In these cases, subjects must then be brought back to the clinic 
for re-evaluation per investigator’s discretion. 
8.4 
Biological Sample Retention and Destruction  
In this study, specimens for genome/gene analysis will be collected as described in Section 
9.1.12, Pharmacogenomic Sample Collection. The genetic material will be preserved and 
retained by a biorepository contracted by Cerevance for up to but not longer than 15 years or as 
required by applicable law.  
The samples will be sent to a central laboratory that processes the blood sample and serves as a 
secure storage facility. The sponsor and researchers working with the sponsor will have access to 
the samples collected and any test results. All samples collected during the study will be stored 
securely with limited access and the sponsor will require anyone who works with the samples to 
agree to hold the research information and any results in confidence. 
The sample will be labeled with a unique sample identifier similar to labeling in the main study. 
During the “storage” stage, the sample will be used in the analysis of the study drug and related 
disease states. At this stage, sample and data are linked to personal health information with code 
numbers. This link means that patients may be identifiable but only indirectly. The code numbers 
will be kept secure by the sponsor.  
Subjects who consented and provided a pharmacogenomic sample for DNA and RNA analysis 
can withdraw their consent and request disposal of a stored sample at any time prior to analysis. 
Notify sponsor of consent withdrawal. 
8.5 
Blood Volume 
Total blood sampling volume for an individual subject is shown in Table 9.c. 


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Table 9.c 
Approximate Blood Volume 
Sample Type 
Sample 
Volume 
(mL) 
Screening  
(x1) 
 
Number of Samples per 
Period  
(x 3 Periods) 
End of 
Treatment 
Total 
Volume 
(mL) 
Safety 
Laboratory 
Samples (a) 
12.5 
1 
-- 
1 
25 
Hepatitis Panel 
5 
1 
-- 
 
5 
FSH (b) 
3 
1 
-- 
 
3 
PK Samples 
6 
-- 
9 
-- 
54 
DNA Sample 
6 
-- 
1 (c) 
-- 
6 
RNA Samples 
5 
-- 
6 
-- 
30 
 
Total Blood Sampling Volume (per Study) 
 
123 
(a) Includes Hematology, serum chemistry, and coagulation panel. 
(b) FSH level will be obtained for female subjects at Screening if they are postmenopausal (i.e. last regular 
menstrual cycle >2 years) and not surgically sterile. 
(c) Only collected in Day 1, Period 1. 
 
The maximum volume of blood at any single day is approximately 40 mL, and the approximate 
total volume of blood for the study is approximately 123 mL.  
Direct venipuncture is the preferred method of blood collection. Any other method will need to 
be approved by the Sponsor. 


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9.0 
PRETREATMENT EVENTS AND ADVERSE EVENTS 
9.1 
Definitions 
9.1.1 PTEs 
A PTE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study but prior to administration of any study 
medication; it does not necessarily have to have a causal relationship with study participation. 
9.1.2 AEs 
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a drug; it does not necessarily have to have a causal relationship with this 
treatment. 
An AE can therefore be any unfavorable and unintended sign (e.g., a clinically significant 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug 
whether or not it is considered related to the drug. 
9.1.3 Additional Points to Consider for PTEs and AEs 
An untoward finding generally may: 
• Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent 
events for pre existing conditions or underlying disease should not be considered PTEs or 
AEs.) 
• Necessitate therapeutic intervention. 
• Require an invasive diagnostic procedure. 
• Require discontinuation or a change in dose of study medication or a concomitant 
medication. 
• Be considered unfavorable by the investigator for any reason.  
• PTEs/AEs caused by a study procedure (e.g., a bruise after blood draw) should be recorded 
as a PTE/AE. 
Diagnoses vs signs and symptoms: 
• Each event should be recorded to represent a single diagnosis. Accompanying signs 
(including abnormal laboratory values or ECG findings) or symptoms should NOT be 
recorded as additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be 
recorded appropriately as a PTE(s) or as an AE(s). 
Laboratory values and ECG findings: 
• Changes in laboratory values or ECG parameters are only considered to be PTEs or AEs if 
they are judged to be clinically significant (i.e., if some action or intervention is required or if 
the investigator judges the change to be beyond the range of normal physiologic fluctuation). 
A laboratory re-test and/or continued monitoring of an abnormal value are not considered an 


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intervention. In addition, repeated or additional noninvasive testing for verification, 
evaluation or monitoring of an abnormality is not considered an intervention. 
• If abnormal laboratory values or ECG findings are the result of pathology for which there is 
an overall diagnosis (e.g., increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as a PTE or as an AE. 
Pre-existing conditions: 
• Pre-existing conditions (present at the time of signing of informed consent) are considered 
concurrent medical conditions and should NOT be recorded as PTEs or AEs. Baseline 
evaluations (e.g., laboratory tests, ECG, X-rays etc.) should NOT be recorded as PTEs unless 
related to study procedures. However, if the subject experiences a worsening or complication 
of such a concurrent condition, the worsening or complication should be recorded 
appropriately as a PTE (worsening or complication occurs before start of study medication) 
or an AE (worsening or complication occurs after start of study medication). Investigators 
should ensure that the event term recorded captures the change in the condition (e.g., 
“worsening of…”). 
• If a subject has a pre-existing episodic condition (e.g., asthma, epilepsy) any occurrence of an 
episode should only be captured as a PTE/AE if the episodes become more frequent, serious 
or severe in nature, that is, investigators should ensure that the AE term recorded captures the 
change in the condition from Baseline (e.g. “worsening of…”). 
• If a subject has a degenerative concurrent condition (e.g., cataracts, rheumatoid arthritis), 
worsening of the condition should only be captured as a PTE/AE if occurring to a greater 
extent to that which would be expected. Again, investigators should ensure that the AE term 
recorded captures the change in the condition (e.g., “worsening of…”). 
Worsening of PTEs or AEs: 
• If the subject experiences a worsening or complication of a PTE after starting administration 
of the study medication, the worsening or complication should be recorded appropriately as 
an AE. Investigators should ensure that the AE term recorded captures the change in the 
condition (e.g., “worsening of…”). 
• If the subject experiences a worsening or complication of an AE after any change in study 
medication, the worsening or complication should be recorded as a new AE. Investigators 
should ensure that the AE term recorded captures the change in the condition (e.g., 
“worsening of…”). 
Changes in severity of AEs /Serious PTEs: 
• If the subject experiences changes in severity of an AE/serious PTE, the event should be 
captured once with the maximum severity recorded. 
Preplanned surgeries or procedures: 
• Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered PTEs or AEs. However, if a preplanned procedure is 
performed early (e.g., as an emergency) due to a worsening of the pre-existing condition, the 


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worsening of the condition should be captured appropriately as a PTE or an AE. 
Complications resulting from any planned surgery should be reported as AEs. 
Elective surgeries or procedures: 
• Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as PTEs or AEs, but should be documented in the subject’s source 
documents. Complications resulting from an elective surgery should be reported as AEs. 
Overdose: 
• Cases of overdose with any medication without manifested side effects are NOT considered 
PTEs or AEs, but instead will be documented on an Overdose page of the eCRF. Any 
manifested side effects will be considered PTEs or AEs and will be recorded on the AE page 
of the eCRF. 
• Suicidal Ideation and Behavior:  
• A completed suicide is always a SAE based on its fatal outcome. C-SSRS score of 4 (active 
suicidal ideation with some intent to act) or 5 (active suicidal ideation with specific plan and 
intent) would likely indicate serious suicidal ideation and can be used to trigger intervention 
procedures to provide urgent care. Such procedures may include further evaluation and 
appropriate management; and/or immediate contact with (or need for a referral to) the 
subject’s mental health practitioner; and/or possible referral to the emergency room; and/or 
admission to an in-subject unit. For the purpose of this protocol active suicidal ideation level 
4 and 5 should be considered important medical events and reported as serious irrespective of 
whether the subject was hospitalized or not.  
• Unless the event meets other serious criteria, suicidal thoughts or suicidal ideations that do 
not include a definite plan or intention to act will be collected as non-serious adverse events 
in accordance with the standard AE reporting requirements (e.g., if a pre-existing suicidal 
ideation recorded on the screening C-SSRS got worse during the study, it should be reported 
as an AE).  
• A subject presenting with self-mutilation or other types of self-injury should be questioned 
by the investigator to clarify if the action was suicidal in intent. If the event was suicidal in 
intent, the investigator should include suicidal behavior as part of the verbatim term on the 
eCRF, that is, “slit wrists/suicidal behavior”. Such an event will be collected as a serious 
adverse event.  
• Acts of self-mutilation or self-injury without suicidal intention (i.e., self-imposed cigarette 
burns), will be collected as non-serious adverse events, unless they meet other seriousness 
criteria.  
9.1.4 SAEs 
An SAE is defined as any untoward medical occurrence that at any dose: 
1. Results in DEATH. 
2. Is LIFE THREATENING. 


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• The term “life threatening” refers to an event in which the subject was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have caused 
death if it were more severe. 
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization. 
4. Results in persistent or significant DISABILITY/INCAPACITY. 
5. Is a CONGENITAL ANOMALY/BIRTH DEFECT. 
• Report if you suspect that exposure to a medical product prior to conception or during 
pregnancy may have resulted in an adverse outcome in the child. 
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following: 
• May require intervention to prevent items 1 through 5 above. 
• May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization. 
• Includes any event or synonym described in the Medically Significant AE List 
(Table 10.a). 
Table 10.a 
Medically Significant AE List 
Term 
Acute respiratory failure/acute respiratory distress 
syndrome 
Hepatic necrosis 
Torsade de pointes / ventricular fibrillation / ventricular 
tachycardia 
Acute liver failure 
Anaphylactic shock 
Malignant hypertension 
Acute renal failure 
Convulsive seizure 
Pulmonary hypertension 
Agranulocytosis 
Pulmonary fibrosis 
Aplastic anemia 
Confirmed or suspected endotoxin shock 
Toxic epidermal necrolysis/Stevens-Johnson syndrome Confirmed or suspected transmission of infectious agent by 
a medicinal product 
 
Serotonin syndrome 
Neuroleptic malignant syndrome / malignant hyperthermia 
 
Spontaneous abortion / stillbirth and fetal death 
 
PTEs that fulfill 1 or more of the serious criteria above are also to be considered SAEs and 
should be reported and followed up in the same manner (see Sections 10.2.2 and 10.3). 
9.1.5 Severity of PTEs and AEs 
The different categories of intensity (severity) are characterized as follows: 
Mild: 
The event is transient and easily tolerated by the subject. 
Moderate: 
The event causes the subject discomfort and interrupts the subject’s usual activities. 
Severe: 
The event causes considerable interference with the subject’s usual activities. 


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9.1.6 Causality of AEs 
The relationship of each AE to study medication(s) will be assessed using the following 
categories: 
Related: 
An AE that follows a reasonable temporal sequence from administration of a drug (including 
the course after withdrawal of the drug), or for which possible involvement of the drug cannot 
be ruled out, although factors other than the drug, such as underlying diseases, complications, 
concomitant drugs and concurrent treatments, may also be responsible. 
Not Related: 
An AE that does not follow a reasonable temporal sequence from administration of a drug 
and/or that can reasonably be explained by other factors, such as underlying diseases, 
complications, concomitant drugs and concurrent treatments. 
9.1.7 Relationship to Study Procedures 
Relationship (causality) to study procedures should be determined for all PTEs and AEs. 
The relationship should be assessed as Related if the investigator considers that there is 
reasonable possibility that an event is due to a study procedure. Otherwise, the relationship 
should be assessed as Not Related. 
9.1.8 Start Date 
The start date of the AE/PTE is the date that the first signs/symptoms were noted by the subject 
and/or physician. 
9.1.9 
Stop Date  
The stop date of the AE/PTE is the date at which the subject recovered, the event resolved but 
with sequelae or the subject died. 
9.1.10 
Frequency  
Episodic AEs/PTE (e.g., vomiting) or those which occur repeatedly over a period of consecutive 
days are intermittent. All other events are continuous. 
9.1.11 
Action Concerning Study Medication  
• Drug withdrawn – a study medication is stopped due to the particular AE. 
• Dose not changed – the particular AE did not require stopping a study medication. 
• Unknown – only to be used if it has not been possible to determine what action has been 
taken. 
• Not Applicable – a study medication was stopped for a reason other than the particular AE 
(e.g., the study has been terminated, the subject died, dosing with study medication was 
already stopped before the onset of the AE). 
9.1.12 
Outcome 
• Recovered/Resolved – Subject returned to first assessment status with respect to the AE/PTE. 


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• Recovering/Resolving – the intensity is lowered by one or more stages: the diagnosis or 
signs/symptoms has almost disappeared; the abnormal laboratory value improved, but has not 
returned to the normal range or to Baseline; the subject died from a cause other than the 
particular AE/PTE with the condition remaining “recovering/resolving”. 
• Not recovered/not resolved – there is no change in the diagnosis, signs or symptoms; the 
intensity of the diagnosis, signs/ symptoms or laboratory value on the last day of the 
observed study period has got worse than when it started; is an irreversible congenital 
anomaly; the subject died from another cause with the particular AE/PTE state remaining 
“Not recovered/not resolved”. 
• Resolved with sequelae – the subject recovered from an acute AE/PTE but was left with 
permanent/significant impairment (e.g., recovered from a cardiovascular accident but with 
some persisting paresis). 
• Fatal – the AEs/PTEs which are considered as the cause of death. 
• Unknown – the course of the AE/PTE cannot be followed up due to hospital change or 
residence change at the end of the subject’s participation in the study. 
9.2 
Procedures 
9.2.1 Collection and Reporting of AEs 
9.2.1.1 PTE and AE Collection Period 
Collection of PTEs will commence from the time the subject signs the informed consent to 
participate in the study and continue until the subject is first administered study medication on 
Day 1 Period 1 of Part 2 or until screen failure. For subjects who discontinue prior to study 
medication administration, PTEs are collected until the subject discontinues study participation. 
Collection of AEs will commence from the time that the subject is first administered study 
medication Day 1 Treatment Period 1. Routine collection of AEs will continue until 21 days 
following last dose. 
9.2.1.2 PTE and AE Reporting 
At each study visit, the investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Subjects may report AEs occurring at any other time during the study. Subjects experiencing a 
serious PTE must be monitored until the symptoms subside and any clinically relevant changes 
in laboratory values have returned to Baseline or there is a satisfactory explanation for the 
change. Non-serious PTEs, related or unrelated to the study procedure, need not to be followed-
up for the purposes of the protocol. 
All subjects experiencing AEs, whether considered associated with the use of the study 
medication or not, must be monitored until the symptoms subside and any clinically relevant 
changes in laboratory values have returned to Baseline or until there is a satisfactory explanation 
for the changes observed. All PTEs and AEs will be documented in the PTE/AE page of the 


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eCRF, whether or not the investigator concludes that the event is related to the drug treatment. 
The following information will be documented for each event: 
1. Event term. 
2. Start and stop date. 
3. Frequency. 
4. Severity. 
5. Investigator’s opinion of the causal relationship between the event and administration of 
study medication(s) (related or not related) (not completed for PTEs). 
6. Investigator’s opinion of the causal relationship to study procedure(s), including the details 
of the suspected procedure. 
7. Action concerning study medication (not applicable for PTEs). 
8. Outcome of event. 
9. Seriousness. 
9.2.2 Collection and Reporting of SAEs 
When an SAE occurs through the AE collection period it should be reported according to the 
following procedure: 
A Cerevance SAE form must be completed, in English, and signed by the investigator 
immediately or within 24 hours of first onset or notification of the event. The information should 
be completed as fully as possible but contain, at a minimum: 
• A short description of the event and the reason why the event is categorized as serious. 
• Subject identification number. 
• Investigator’s name. 
• Name of the study medication(s). 
• Causality assessment. 
The SAE form should be transmitted within 24 hours to the attention of the contact listed in 
Section 1.0.  
Any SAE spontaneously reported to the investigator following the AE collection period should 
be reported to the sponsor if considered related to study participation. 
Reporting of Serious PTEs will follow the procedure described for SAEs. 
9.2.3 Reporting of Abnormal Liver Function Tests 
If a subject is noted to have ALT or AST elevated >3 ×ULN on 2 consecutive occasions, the 
abnormality should be recorded as an AE. In addition, an LFT Increases eCRF must be 
completed providing additional information on relevant recent history, risk factors, clinical signs 
and symptoms and results of any additional diagnostic tests performed. 


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If a subject is noted to have ALT or AST >3 ×ULN and total bilirubin >2 ×ULN for which an 
alternative etiology has not been identified, the event should be recorded as an SAE and reported 
as per Section 10.2.2. The investigator must contact the Medical Monitor for discussion of the 
relevant subject details and possible alternative etiologies, such as acute viral hepatitis A or B or 
other acute liver disease or medical history/concurrent medical conditions. Follow-up laboratory 
tests as described in Section 9.1.8 must also be performed. In addition, an LFT Increases eCRF 
must be completed and transmitted with the Cerevance SAE form (as per Section 10.2.2). 
9.3 
Follow-up of SAEs 
If information is not available at the time of the first report, but becomes available at a later date, 
the investigator should complete a follow-up SAE form or provide other written documentation 
and fax it immediately within 24 hours of receipt. Copies of any relevant data from the hospital 
notes (e.g., ECGs, laboratory tests, discharge summary, postmortem results) should be sent to the 
addressee, if requested. 
All SAEs should be followed up until resolution or permanent outcome of the event. The 
timelines and procedure for follow-up reports are the same as those for the initial report. 
9.3.1 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities  
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, including the European 
Medicines Agency (EMA), investigators and IRBs or IECs, as applicable, in accordance with 
national regulations in the countries where the study is conducted. Relative to the first awareness 
of the event by/or further provision to the sponsor or sponsor’s designee, SUSARs will be 
submitted to the regulatory authorities as expedited report within 7 days for fatal and life-
threatening events and 15 days for other serious events, unless otherwise required by national 
regulations. The sponsor will also prepare an expedited report for other safety issues where these 
might materially alter the current benefit-risk assessment of an investigational medicinal product 
or that would be sufficient to consider changes in the investigational medicinal products 
administration or in the overall conduct of the trial. The investigational site also will forward a 
copy of all expedited reports to his or her IRB or IEC in accordance with national regulations. 


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10.0 
STUDY-SPECIFIC COMMITTEES 
No steering committee, data safety monitoring committee, or clinical endpoint committee will be 
used in this study. 


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11.0 
DATA HANDLING AND RECORDKEEPING 
The full details of procedures for data handling will be documented in the Data Management 
Plan. AEs, PTEs, medical history, and concurrent conditions will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the World Health 
Organization Drug Dictionary (WHODRUG). 
11.1 
CRFs (Electronic) 
Completed eCRFs are required for each subject who signs an informed consent. 
The sponsor or its designee will supply investigative sites with access to eCRFs. The sponsor 
will make arrangements to train appropriate site staff in the use of the eCRFs. These forms are 
used to transmit the information collected in the performance of this study to the sponsor and 
regulatory authorities. eCRFs must be completed in English. 
After completion of the entry process, computer logic checks will be run to identify items, such 
as inconsistent dates, missing data, and questionable values. Queries may be issued by Cerevance 
personnel (or designees) and will be answered by the site.  
Corrections to eCRFs are recorded in an audit trail that captures the old information, the new 
information, identification of the person making the correction, the date the correction was made, 
and the reason for change. Reasons for significant corrections should additionally be included. 
The PI must review the eCRFs for completeness and accuracy and must sign and date the 
appropriate eCRFs as indicated. Furthermore, the investigator must retain full responsibility for 
the accuracy and authenticity of all data entered on the eCRFs. 
After the lock of the clinical study database, any change of, modification of or addition to the 
data on the eCRFs should be made by the investigator with use of change and modification 
records of the eCRFs. The principle investigator must review the data change for completeness 
and accuracy, and must sign, and date. 
The eCRFs will be reviewed for completeness and acceptability at the study site during periodic 
visits by study monitors. The sponsor or its designee will be permitted to review the subject’s 
medical and hospital records pertinent to the study to ensure accuracy of the eCRFs. The 
completed eCRFs are the sole property of the sponsor and should not be made available in any 
form to third parties, except for authorized representatives of appropriate governmental health or 
regulatory authorities, without written permission of the sponsor. 
11.2 
Record Retention 
The investigator agrees to keep the records stipulated in Section 12.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated informed consent forms, subject authorization forms 
regarding the use of personal health information (if separate from the informed consent forms), 
electronic copy of eCRFs, including the audit trail, and detailed records of drug disposition to 
enable evaluations or audits from regulatory authorities, the sponsor or its designees. Any source 
documentation printed on degradable thermal sensitive paper should be photocopied by the site 
and filed with the original in the subject’s chart to ensure long-term legibility. Furthermore, 


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International Conference on Harmonisation (ICH) E6 Section 4.9.5 requires the investigator to 
retain essential documents specified in ICH E6 (Section 8) until at least 2 years after the last 
approval of a marketing application for a specified drug indication being investigated or, if an 
application is not approved, until at least 2 years after the investigation is discontinued and 
regulatory authorities are notified. In addition, ICH E6 Section 4.9.5 states that the study records 
should be retained until an amount of time specified by applicable regulatory requirements or for 
a time specified in the Clinical Study Site Agreement between the investigator and sponsor. 
Refer to the Phase 1 Site Specifications document for the sponsor’s requirements on record 
retention. The investigator should contact and receive written approval from the sponsor before 
disposing of any such documents. 


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12.0 
STATISTICAL METHODS 
12.1 
Statistical and Analytical Plans 
A statistical analysis plan (SAP) will be prepared and finalized prior to the beginning of Part 2. 
This document will provide further details regarding the definition of analysis variables and 
analysis methodology to address all study objectives. 
A targeted data review will be conducted prior to database lock. This review will assess the 
accuracy and completeness of the study database, subject evaluability, and appropriateness of the 
planned statistical methods. 
12.1.1 Analysis Sets 
Safety Set 
The Safety Set will consist of all subjects who are randomized and receive study drug. Subjects 
in this analysis set will be used for demographic, baseline characteristics and safety summaries. 
Pharmacokinetic Set 
The PK Set will consist of all subjects who receive study drug and have at least 1 measurable 
plasma concentration of CVN058. 
Pharmacodynamic Set 
The PD Set will consist of all subjects who receive study drug and have at least 1 postdose PD 
measurement. 
If any subjects are found to be noncompliant in dosing schedule or with incomplete data, a 
decision will be made on a case-by-case basis as to their inclusion in the PK and PD endpoint 
analyses, but data for all subjects will be presented in the subject listings. 
12.1.2 Analysis of Demographics and Other Baseline Characteristics 
Demographic and baseline characteristics will be summarized by sequence and overall. 
Summary statistics (number of subjects, mean, median, standard deviation, minimum and 
maximum) will be generated for continuous variables (e.g., age and weight) and the number and 
percentage of subjects within each category will be presented for categorical variables (e.g., 
gender, ethnicity, race, smoking status, and caffeine consumption). 
12.1.3 Pharmacokinetic Analysis 
The concentration of CVN058, and its metabolite if appropriate, in plasma will be summarized 
over each scheduled sampling interval using descriptive statistics (arithmetic mean, SD, median, 
minimum and maximum). Individual plasma concentration data versus time will be presented in 
a data listing. 
Descriptive statistics will be used to summarize the plasma PK parameters for CVN058, and its 
metabolite if appropriate. In addition, geometric mean and percent coefficient of variation will be 
computed for Cmax and AUCt. 
A more detailed analysis will be presented in the SAP. 


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12.1.4 Pharmacodynamic Analysis  
Observed values for the PD parameters (MMN and exploratory PD parameters) at each time 
point will summarized by treatment and compared to placebo using summary statistics. 
Comparison of post dose PD parameters from time-matched placebo period timepoints will be 
analyzed using analysis of covariance (ANCOVA) with baseline value as a covariate and factors 
for time point, sequence, subject nested within sequence, period, and treatment. Two-sided 95% 
confidence intervals will be constructed for the LS mean differences between CVN058 and 
placebo in changes of PD parameters from time-matched period baseline to each postdose time 
point. 
Effect size will be calculated for comparisons of CVN058 to placebo using Cohen’s d which 
expresses the difference between the means of 2 groups as a function of their pooled standard 
deviation. 
Exposure-response relationships for CVN058 will be explored graphically. 
12.1.5 Safety Analysis 
The Safety Set will be used for all summaries of TEAEs, laboratory tests, and vital signs. All 
safety data will be summarized by treatment. 
AEs will be presented in listings. TEAEs will be classified according to system organ class and 
preferred term and will be tabulated with a breakdown by treatment and by event severity. 
Similar TEAE tabulations will be performed on those events assessed by the investigator as 
related to study drug. 
Individual results of vital signs will be listed and observed values and changes from Baseline in 
vital signs will be summarized by treatment. 
Physical exam findings, suicidality assessments (C-SSRS), and PANSS scores will be presented 
in data listings. 
12.2 
Determination of Sample Size 
Enrollment of 20 subjects with schizophrenia is estimated to provide >80% power to detect a 
median effect size of Cohen’s d=0.5. Discontinued or withdrawn subjects and subjects for whom 
MMN is not available for all three study periods may be replaced. The sample size chosen of 20 
completed subjects is considered to be sufficient to explore the changes in MMN between 
CVN058 and placebo as well as safety and tolerability of CVN058 in this population. 


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13.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
13.1 
Study-Site Monitoring Visits 
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and institution guarantee access to source documents by the sponsor or its 
designee contract research organization (CRO) and by the IRB or IEC. 
All aspects of the study and its documentation will be subject to review by the sponsor or 
designee (as long as blinding is not jeopardized), including but not limited to the Investigator’s 
Binder, study medication, subject medical records, informed consent documentation, 
documentation of subject authorization to use personal health information (if separate from the 
informed consent forms), and review of eCRFs and associated source documents. It is important 
that the investigator and other study personnel are available during the monitoring visits and that 
sufficient time is devoted to the process. 
13.2 
Protocol Deviations 
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will 
require deviation from protocol-specified procedures, the investigator should consult with the 
sponsor or designee (and IRB or IEC, as required) to determine the appropriate course of action. 
There will be no exemptions (a prospectively approved deviation) from the inclusion or 
exclusion criteria. 
The site should document all protocol deviations in the subject’s source documents. In the event 
of a significant deviation, the site should notify the sponsor or its designee (and IRB or EC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the subject, or confound interpretation of primary study 
assessment. PK samples collected outside of the intervals (listed in Table 14.a), ECGs, vital 
signs, and RNA pharmacogenomic samples collected outside of the listed intervals are minor 
deviations and do not require the Protocol Deviation Form to be completed but must be 
documented in the subject’s source documents. A Protocol Deviation eCRF should be completed 
by the site and signed by the sponsor or designee for any significant deviation from the protocol.  
Every attempt will be made to collect each PK blood sample at the designated time point, and the 
actual time of each blood sample will be recorded on the source document and eCRF. Table 14.a 
defines the windows allowed for sample collections.  
Protocol Deviations should be captured in the site source document for PK samples collected 
outside of the following intervals: 


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Table 14.a 
Windows for Pharmacokinetic Blood Sample Collection 
Minutes 
Nominal Sampling Time 
no more than 15 minutes predose 
Pre-dose (-0.25 hour) 
±5 
Postdose 1 hour 
±15 
Postdose 5 hours  
 
13.3 
Quality Assurance Audits and Regulatory Agency Inspections 
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, 
including those of foreign governments (e.g., the Food and Drug Administration (FDA), the 
United Kingdom Medicines and Healthcare products Regulatory Agency, the Pharmaceuticals 
and Medical Devices Agency of Japan). If the study site is contacted for an inspection by a 
regulatory body, the sponsor should be notified immediately. The investigator and institution 
guarantee access for quality assurance auditors to all study documents as described in Section 
14.1. 


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14.0 
ETHICAL ASPECTS OF THE STUDY 
This study will be conducted with the highest respect for the individual participants (i.e., 
subjects) according to the protocol, the ethical principles that have their origin in the Declaration 
of Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will 
conduct the study according to applicable local or regional regulatory requirements and align his 
or her conduct in accordance with the “Responsibilities of the Investigator” that are listed in 
Appendix B. The principles of Helsinki are addressed through the protocol and through 
appendices containing requirements for informed consent and investigator responsibilities. 
14.1 
IRB and/or IEC Approval 
IRBs and IECs must be constituted according to the applicable state and federal/local 
requirements of each participating region.  
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of 
the informed consent form, and, if applicable, subject recruitment materials and/or 
advertisements and other documents required by all applicable laws and regulations, must be 
submitted to a central or local IRB or IEC for approval. The IRB’s or IEC’s written approval of 
the protocol and subject informed consent must be obtained and submitted to the sponsor or 
designee before commencement of the study (i.e., before shipment of the sponsor-supplied drug 
or study specific Screening activity). The IRB or IEC approval must refer to the study by exact 
protocol title, number, and version date; identify versions of other documents (e.g., ICF) 
reviewed; and state the approval date. The sponsor will ship drug/notify site once the sponsor has 
confirmed the adequacy of site regulatory documentation and, when applicable, the sponsor has 
received permission from competent authority to begin the trial. Until the site receives 
drug/notification no protocol activities, including screening may occur. 
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the informed consent 
form, recruitment materials intended for viewing by subjects, local safety reporting requirements, 
reports and updates regarding the ongoing review of the study at intervals specified by the 
respective IRB or IEC, and submission of the investigator’s final status report to IRB or IEC. All 
IRB and IEC approvals and relevant documentation for these items must be provided to the 
sponsor or its designee. 
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor. 
14.2 
Subject Information, Informed Consent, and Subject Authorization 
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The informed consent form, subject authorization form (if 
applicable), and subject information sheet (if applicable) describe the planned and permitted 
uses, transfers, and disclosures of the subject’s personal and personal health information for 
purposes of conducting the study. The informed consent form and the subject information sheet 
(if applicable) further explain the nature of the study, its objectives, and potential risks and 


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benefits, as well as the date informed consent is given. The informed consent form will detail the 
requirements of the participant and the fact that he or she is free to withdraw at any time without 
giving a reason and without prejudice to his or her further medical care. 
The investigator is responsible for the preparation, content, and IRB or IEC approval of the 
informed consent form and if applicable, the subject authorization form. The informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) 
must be approved by both the IRB or IEC and the sponsor prior to use. 
The informed consent form, subject authorization form (if applicable), and subject information 
sheet (if applicable) must be written in a language fully comprehensible to the prospective 
subject. It is the responsibility of the investigator to explain the detailed elements of the informed 
consent form, subject authorization form (if applicable), and subject information sheet (if 
applicable) to the subject. Information should be given in both oral and written form whenever 
possible and in the manner deemed appropriate by the IRB or IEC. In the event the subject is not 
capable of rendering adequate written informed consent, then the subject’s legally acceptable 
representative may provide such consent for the subject in accordance with applicable laws and 
regulations. 
The subject, or the subject’s legally acceptable representative, must be given ample opportunity 
to: (1) inquire about details of the study and (2) decide whether or not to participate in the study. 
If the subject, or the subject’s legally acceptable representative, determines he or she will 
participate in the study, then the informed consent form and subject authorization form (if 
applicable) must be signed and dated by the subject, or the subject’s legally acceptable 
representative, at the time of consent and prior to the subject entering into the study. The subject 
or the subject’s legally acceptable representative should be instructed to sign using their legal 
names, not nicknames, using blue or black ballpoint ink. The investigator must also sign and date 
the informed consent form and subject authorization (if applicable) at the time of consent and 
prior to subject entering into the study; however, the sponsor may allow a designee of the 
investigator to sign to the extent permitted by applicable law. 
Once signed, the original informed consent form, subject authorization form (if applicable), and 
subject information sheet (if applicable) will be stored in the investigator’s site file. The 
investigator must document the date the subject signs the informed consent in the subject’s 
medical record. Copies of the signed informed consent form, the signed subject authorization 
form (if applicable), and subject information sheet (if applicable) shall be given to the subject. 
All revised informed consent forms must be reviewed and signed by relevant subjects or the 
relevant subject’s legally acceptable representative in the same manner as the original informed 
consent. The date the revised consent was obtained should be recorded in the subject’s medical 
record, and the subject should receive a copy of the revised informed consent form. 
Subjects who consented and provided a pharmacogenomic sample for DNA and RNA analysis 
can withdraw their consent and request disposal of a stored sample at any time prior to analysis. 
Notify sponsor of consent withdrawal. 
14.3 
Subject Confidentiality 
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 


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the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or 
date of birth, and subject initials may be used to verify the subject and accuracy of the subject’s 
unique identification number. 
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the 
sponsor requires the investigator to permit its monitor or designee’s monitor, representatives 
from any regulatory authority (e.g., FDA, Medicines and Healthcare products Regulatory 
Agency, Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and 
the appropriate IRBs and IECs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a subject’s study 
participation, and autopsy reports. Access to a subject’s original medical records requires the 
specific authorization of the subject as part of the informed consent process (see Section 15.2). 
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (i.e., subject name, address, and other identifier 
fields not collected on the subject’s eCRF). 
14.4 
Publication, Disclosure, and Clinical Trial Registration Policy 
14.4.1 Publication and Disclosure 
The investigator is obliged to provide the sponsor with complete test results and all data derived 
by the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor. 
The sponsor may publish any data and information from the study (including data and 
information generated by the investigator) without the consent of the investigator. Manuscript 
authorship for any peer-reviewed publication will appropriately reflect contributions to the 
production and review of the document. All publications and presentations must be prepared in 
accordance with this section and the Clinical Study Site Agreement. In the event of any 
discrepancy between the protocol and the Clinical Study Site Agreement, the Clinical Study Site 
Agreement will prevail. 
14.4.2 Clinical Trial Registration  
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations, and guidance, Cerevance will, at a minimum register 
interventional clinical trials it sponsors on ClinicalTrials.gov or other publicly accessible 
websites before start of study. Cerevance contact information, along with investigator’s city, 
state (for American investigators), country, and recruiting status will be registered and available 
for public viewing. For some registries, Cerevance will assist callers in locating trial sites closest 
to their homes by providing the investigator name, address, and phone number to the callers 
requesting trial information. Once subjects receive investigator contact information, they may 
call the site requesting enrollment into the trial. The investigative sites are encouraged to handle 


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the trial inquiries according to their established subject Screening process. If the caller asks 
additional questions beyond the topic of trial enrollment, they should be referred to the sponsor. 
Any investigator who objects to Cerevance providing this information to callers must provide 
Cerevance with a written notice requesting that their information not be listed on the registry site. 
14.4.3 Clinical Trial Results Disclosure  
Cerevance may post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites, as required by applicable laws and/or regulations. 
14.5 
Insurance and Compensation for Injury 
Each subject in the study must be insured in accordance with the regulations applicable to the 
site where the subject is participating. If a local underwriter is required, then the sponsor or 
sponsor’s designee will obtain clinical study insurance against the risk of injury to clinical study 
subjects. Refer to the Clinical Study Site Agreement regarding the sponsor’s policy on subject 
compensation and treatment for injury. If the investigator has questions regarding this policy, he 
or she should contact the sponsor or sponsor’s designee. 


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15.0 
REFERENCES 
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4. Heinrichs RW. The primacy of cognition in schizophrenia. Am Psychol 2005;60(3):229-42. 
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spiking cells induces gamma rhythm and controls sensory responses. Nature 
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9. Gonzalez-Burgos G, Lewis DA. NMDA receptor hypofunction, parvalbumin-positive 
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11. Tian G, Kong Q, Lai L, Ray-Chaudhury A, Lin CG. Increased expression of cholesterol 24S-
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12. Kawaguchi Y, Shindou T. Noradrenergic excitation and inhibition of GABAergic cell types 
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14. Lee S, Hjerling-Leffler J, Zagha E, Fishell G, Rudy B. The largest group of superficial 
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15. Koike K, Hashimoto K, Takai N, Shimizu E, Komatsu N, Watanabe H, et al. Tropisetron 
improves deficits in auditory P50 suppression in schizophrenia. Schizophr Res 
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16. Lummis SC. 5-HT3 receptors. J Biol Chem 2012;287(48):40239-45. 


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17. Adler LE, Cawthra EM, Donovan KA, Harris JG, Nagamoto HT, Olincy A, et al. Improved 
p50 auditory gating with ondansetron in medicated schizophrenia patients. Am J Psychiatry 
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18. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders 
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and beta sensory gating deficits as translational endophenotypes for schizophrenia. 
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22. Javitt D. Neurophysiological models for new treatment development in schizophrenia: early 
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W, Holsboer F, Rupprecht R. Antidepressants and antipsychotic drugs colocalize with 5-HT3 
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26. Eisensamer B, Rammes G, Gimpl G, Shapa M, Ferrari U, Hapfelmeier G, Bondy B, Parsons 
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27. Rammes G, Eisensamer B, Ferrari U, Shapa M, Gimpl G, Gilling K, Parsons C, Riering K, 
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antagonize human serotonin type 3 receptor currents in a noncompetitive manner. Mol 
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Appendix A Schedule of Study Procedures 
 
 
 
CVN058 and Placebo 
Treatment Periods 1, 2, and 3 
(a) 
End of 
Treatment 
 
Follow-up  
Study Day: 
Visit 1: 
Screening 
 
Day 1 
pre-dose 
Day 1 
post-dose 
Period 3, 
End Day 1  
Early 
Termination 
(c)  
Day 7-10 
After End of 
Treatment 
(b) 
Informed consent 
X 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
X 
 
 
 
 
Demographics and 
medical history 
X 
 
 
 
 
 
Medication history 
X 
 
 
 
 
 
Physical examination  
X 
X 
 
X 
X 
 
Vital signs (d) 
X 
X 
X 
 
X 
 
Weight, height, and BMI 
(e) 
X 
 
 
X 
X 
 
Concomitant medications 
(f) 
X 
X 
X 
 
X 
X 
Concurrent medical 
conditions (g) 
X 
 
 
 
 
 
Clinical laboratory tests 
(h) 
X 
 
 
X 
X 
 
Hepatitis panel 
X 
 
 
 
 
 
Audiometric Screening 
and Tone Matching test 
(i) 
X 
 
 
 
 
 
FSH (j) 
X 
 
 
 
 
 
Pregnancy test (hCG), 
serum except as noted 
X 
X (urine) 
 
 
X 
 
Urine drug and saliva 
alcohol screen 
X 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
EEG battery (k) 
 
 
X 
 
 
 
MMN (l) 
 
 
X 
 
 
 
DNA sample collection 
(m) 
 
X 
 
 
 
 
RNA sample collection 
(n) 
 
X 
X 
 
 
 
PK blood collection (o) 
 
X 
X 
 
X 
 
Study drug dosing (p) 
 
 
X 
 
 
 
PTE assessment (q) 
X 
X 
 
 
 
 
AE assessment (r) 
 
 
X 
 
X 
X 
C-SSRS (s) 
X 
 
X 
 
X 
 
PANSS (t) 
X 
 
X 
 
X 
 
Footnotes are on last table page. 


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       02 JULY 2018
 
CONFIDENTIAL 
(a) Minimum 7-day and maximum 10-day washout period is required in between Treatment Periods 1, 2 and 3.  
(b) The Follow-up Visit will occur by telephone 7-10 days after End of Treatment unless abnormal, clinically significant findings 
were observed upon discharge. In these cases, subjects must then be brought back to the clinic for re-evaluation per investigator’s 
discretion. 
(c) Conduct procedures for subjects discontinued early per Protocol Section 7.6. The PK sample should be collected at the Early 
Termination Visit, if within 1 hour of a scheduled PK time point. 
(d) Vital signs (oral temperature, respiration, pulse, and blood pressure) will be obtained at Screening, and in Periods 1, 2, and 3 
(pre dose [within 30 minutes prior to dosing], and at 1 and 5 hours post dose), and at Early Termination (if applicable), and if 
clinically indicated according to Investigator discretion at the Follow-up visit.  
(e) Height and BMI will be collected at Screening only. 
(f) Record all patient medications from Screening and throughout the study. 
(g) All new concurrent medical conditions arising post-oi should be recorded as PTE or AE.  
(h) Clinical laboratory tests (hematology, serum chemistry, and urinalysis) will be collected at Screening and prior to check-out at 
End of Treatment or Early Termination, and at the Investigator discretion if a Follow-up Visit is indicated.  
(i) Audiometric Screening assessment conducted according to local practice.  
(j) A FSH level will be obtained on post menopausal women (defined as continuous amenorrhea of at least 2 years and not 
surgically sterile). 
(k) For the EEG battery, testing will be done at Day 1 starting approximately 1.5 hours post dose for each period and will last 
approximately 3 hours. NOTE: Subjects should refrain from drinking coffee and smoking approximately 1 hour prior to the EEG 
assessment until discharge from clinic at the end of the afternoon. 
(l) MMN will be the first EEG assessment conducted in the battery.  
(m) One blood sample (6 mL) will be collected for pharmacogenomic analysis prior to study drug administration on Day 1 of 
Period 1 only. If isolation of DNA from the first sample was not successful or possible, a second aliquot of blood may 
be taken, if feasible. 
(n) Two 2.5 mL whole blood samples will be collected for each Period (Periods 1, 2, and 3) on Day 1 at pre-dose, and 5 hours 
post-dose. 
(o) Blood samples (6 mL) for PK analyses will be collected at pre -dose (within 15 minutes prior to dosing), and 1 and 5 hours 
post dose. 
(p) Dosing will only occur on Day 1 of each period, and signals the start of the post-dose Day 1 visit assessments. 
(q) PTEs will be collected from signing of informed consent up until dosing on Day 1. 
(r) Any adverse event with onset or exacerbation after dosing on Day 1 of Period 1 will be captured as an AE or SAE. 
(s) The Screening/Baseline C-SSRS will be administered at Screening and the Since Last Visit C-SSRS will be administered after 
EEG/ERP collection on each dosing day, and End of Treatment or Early Termination (if applicable). 
(t) The Screening/Baseline PANSS will be collected at Screening, approximately 5 hours after each dose (post EEG) and at Early 
Termination (if applicable). 
 


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CONFIDENTIAL 
Appendix B Responsibilities of the Investigator 
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on investigators by the FDA are 
summarized in the “Statement of Investigator” (Form 1572) which must be completed and 
signed before the investigator may participate in this study. 
The investigator agrees to assume the following responsibilities by signing a Form 1572.  
1. Conduct the study in accordance with the protocol. 
2. Personally conduct or supervise the staff who will assist in the protocol. 
3. Ensure that study related procedures; including study specific (non-routine/non- standard 
panel) Screening assessments are NOT performed on potential subjects prior to the receipt of 
written approval from relevant governing bodies/authorities. 
4. Ensure that all colleagues and employees assisting in the conduct of the study are informed 
of these obligations. 
5. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform 
to 21 CFR Part 56 ICH, and local regulatory requirements. 
6. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and 
approval of the protocol. Promptly report to the IRB/IEC all changes in research activity and 
all anticipated risks to subjects. Make at least yearly reports on the progress of the study to 
the IRB/IEC, and issue a final report within 3 months of study completion. 
7. Ensure that requirements for informed consent, as outlined in 21 CRF Part 50 ICH and local 
regulations, are met. 
8. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each informed consent form should contain a subject 
authorization section that describes the uses and disclosures of a subject’s personal 
information (including personal health information) that will take place in connection with 
the study. If an informed consent form does not include such a subject authorization, then the 
investigator must obtain a separate subject authorization form from each subject or the 
subject’s legally acceptable representative. 
9. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc., and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents. 
10. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents. 
11. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor. 


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Study No. CVN058-103 
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CONFIDENTIAL 
12. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours. 
 


 
 
 
PROTOCOL  
A Placebo-Controlled Study to Evaluate the Effect of a Single Dose of CVN058 on 
Mismatch Negativity in Subjects with Stable Schizophrenia 
 
Short title: CVN058 Effect on Mismatch Negativity in Schizophrenics 
 
Sponsor: 
Cerevance Alpha (hereafter, “Cerevance”) 
One Marina Park Drive, suite 1410 
Boston, MA 02210 
Study Number: 
CVN058-103 
IND Number: 
121,520 
EudraCT 
Number: 
N/A 
Compound: 
 
CVN058  
Date: 
28 Sep 2018 
Amendment Number:  
2 
 
 
 
 
Previous Versions: 
 
02 Jul 2018 
Amendment Number:         1 
 
21 May 2018 
Original 
 
 
CONFIDENTIAL PROPERTY OF CEREVANCE 
This document is a confidential communication of Cerevance. Acceptance of this document constitutes the 
agreement by the recipient that no information contained herein will be published or disclosed without written 
authorization from Cerevance except to the extent necessary to obtain informed consent from those persons to whom 
the drug may be administered. Furthermore, the information is only meant for review and compliance by the 
recipient, his or her staff, and applicable institutional review committee and regulatory agencies to enable conduct of 
the study. 






CVN058 
 
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                    Page 4 of 72 
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        28 SEP 2018
 
CONFIDENTIAL 
INVESTIGATOR AGREEMENT  
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, and 
any other product information provided by the sponsor. I agree to conduct this study in 
accordance with the requirements of this protocol and also to protect the rights, safety, privacy, 
and well-being of study subjects in accordance with the following: 
• The ethical principles that have their origin in the Declaration of Helsinki. 
• International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline. 
• All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations. 
• Regulatory requirements for reporting serious adverse events defined in Section 10.2 of this 
protocol. 
• Terms outlined in the Clinical Study Site Agreement. 
• Appendix B – Responsibilities of the Investigator. 
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in the clinical trial agreement with Cerevance. 
Signature of Investigator 
Date 
Investigator Name (print or type) 
Investigator’s Title 
Location of Facility (City, State/Provence) 
Location of Facility (Country) 


CVN058 
 
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TABLE OF CONTENTS 
1.0 
ADMINISTRATIVE INFORMATION ..............................................................................2 
1.1 
Contacts..........................................................................................................................2 
1.2 
Approval ........................................................................................................................3 
2.0 
STUDY SUMMARY.........................................................................................................10 
3.0 
LIST OF ABBREVIATIONS ............................................................................................14 
4.0 
INTRODUCTION .............................................................................................................16 
4.1 
Background ..................................................................................................................16 
4.2 
Non-Clinical .................................................................................................................17 
4.3 
Clinical .........................................................................................................................17 
4.4 
Rationale for the Proposed Study ................................................................................18 
5.0 
STUDY OBJECTIVES AND ENDPOINTS .....................................................................20 
5.1 
Objectives ....................................................................................................................20 
5.1.1 Primary Objective ..................................................................................................20 
5.1.2 Secondary Objective ..............................................................................................20 
5.1.3 Exploratory Objectives ..........................................................................................20 
5.2 
Endpoints .....................................................................................................................20 
5.2.1 Primary Endpoints .................................................................................................20 
5.2.2 Secondary Endpoint ...............................................................................................20 
5.2.3 Exploratory Endpoints ...........................................................................................20 
6.0 
STUDY DESIGN AND DESCRIPTION ..........................................................................22 
6.1 
Study Design ................................................................................................................22 
6.2 
Justification for Study Design, Dose, and Endpoints ..................................................23 
6.3 
Premature Termination or Suspension of Study or Investigational Site ......................24 
6.3.1 Criteria for Premature Termination or Suspension of the Study ...........................24 
6.3.2 Criteria for Premature Termination or Suspension of Investigational Sites ..........24 
6.3.3 Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s)...................................................................24 
7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS ...............25 
7.1 
Inclusion Criteria .........................................................................................................25 
7.2 
Exclusion Criteria ........................................................................................................25 
7.3 
Excluded Medications, Dietary Products, Procedures, and Treatments ......................27 
7.4 
Diet, Fluid, Activity Control ........................................................................................28 
7.5 
Criteria for Discontinuation or Withdrawal of a Subject .............................................28 
7.6 
Procedures for Discontinuation or Withdrawal of a Subject .......................................29 
8.0 
CLINICAL TRIAL MATERIAL MANAGEMENT.........................................................30 
8.1 
Study Medication and Materials ..................................................................................30 


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8.1.1 Dosage Form, Manufacturing, Packaging, and Labeling ......................................30 
8.1.1.1 Investigational Drug .........................................................................................30 
8.1.1.2 Sponsor-Supplied Drug ....................................................................................30 
8.1.1.3 Ancillary Materials ..........................................................................................30 
8.1.2 Storage ...................................................................................................................31 
8.1.3 Dose and Regimen .................................................................................................31 
8.1.4 Overdose ................................................................................................................31 
8.2 
Investigational Drug Assignment and Dispensing Procedures ....................................32 
8.3 
Randomization Code Creation and Storage .................................................................32 
8.4 
Investigational Drug Blind Maintenance .....................................................................32 
8.5 
Unblinding Procedure ..................................................................................................32 
8.6 
Accountability and Destruction of Sponsor-Supplied Drugs .......................................32 
9.0 
STUDY PLAN ...................................................................................................................35 
9.1 
Study Procedures .........................................................................................................35 
9.1.1 Informed Consent Procedure .................................................................................35 
9.1.1.1 Pharmacogenomic Informed Consent Procedure .............................................35 
9.1.2 Demographics, Medical History, and Medication History Procedure ...................35 
9.1.3 Physical Examination Procedure ...........................................................................35 
9.1.4 Weight, Height, and BMI.......................................................................................36 
9.1.5 Vital Sign Procedure ..............................................................................................36 
9.1.6 Documentation of Concomitant Medications ........................................................36 
9.1.7 Documentation of Concurrent Medical Conditions ...............................................36 
9.1.8 Procedures for Clinical Laboratory Samples .........................................................36 
9.1.9 Contraception and Pregnancy Avoidance Procedure .............................................38 
9.1.10 Pregnancy ...............................................................................................................39 
9.1.11 ECG Procedure ......................................................................................................40 
9.1.12 Pharmacogenomic Sample Collection ...................................................................40 
9.1.13 Pharmacokinetic Sample Collection ......................................................................41 
9.1.13.1 
Collection of Blood for Pharmacokinetic Sampling ..................................41 
9.1.13.2 
Bioanalytical Methods ...............................................................................42 
9.1.14 Pharmacokinetic Parameters ..................................................................................42 
9.1.15 Pharmacodynamic Sample Collection ...................................................................42 
9.1.16 Pharmacodynamic Parameters ...............................................................................42 
9.1.17 Positive and Negative Syndrome Scale .................................................................43 
9.1.18 Columbia Suicide Severity Rating Scale ...............................................................44 
9.1.19 Documentation of Screen Failure ..........................................................................44 
9.1.20 Documentation of Randomization .........................................................................45 


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9.2 
Monitoring Subject Treatment Compliance .................................................................45 
9.3 
Schedule of Observations and Procedures ...................................................................45 
9.3.1 Screening................................................................................................................45 
9.3.2 Treatment Phase .....................................................................................................45 
9.3.3 Final Visit/End of Treatment .................................................................................46 
9.3.4 Early Termination ..................................................................................................46 
9.3.5 Follow-up Visit/Telephone Call ............................................................................46 
9.4 
Biological Sample Retention and Destruction .............................................................46 
9.5 
Blood Volume ..............................................................................................................46 
10.0 
PRETREATMENT EVENTS AND ADVERSE EVENTS ..............................................48 
10.1 
Definitions....................................................................................................................48 
10.1.1 PTEs .......................................................................................................................48 
10.1.2 AEs .........................................................................................................................48 
10.1.3 Additional Points to Consider for PTEs and AEs ..................................................48 
10.1.4 SAEs ......................................................................................................................50 
10.1.5 Severity of PTEs and AEs......................................................................................51 
10.1.6 Causality of AEs ....................................................................................................52 
10.1.7 Relationship to Study Procedures ..........................................................................52 
10.1.8 Start Date ...............................................................................................................52 
10.1.9 Stop Date ................................................................................................................52 
10.1.10 
Frequency .........................................................................................................52 
10.1.11 
Action Concerning Study Medication .............................................................52 
10.1.12 
Outcome ...........................................................................................................52 
10.2 
Procedures ....................................................................................................................53 
10.2.1 Collection and Reporting of AEs ...........................................................................53 
10.2.1.1 
PTE and AE Collection Period ..................................................................53 
10.2.1.2 
PTE and AE Reporting ..............................................................................53 
10.2.2 Collection and Reporting of SAEs .........................................................................54 
10.2.3 Reporting of Abnormal Liver Function Tests ........................................................54 
10.3 
Follow-up of SAEs ......................................................................................................55 
10.3.1 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities .....55 
11.0 
STUDY-SPECIFIC COMMITTEES .................................................................................56 
12.0 
DATA HANDLING AND RECORDKEEPING ..............................................................57 
12.1 
CRFs (Electronic) ........................................................................................................57 
12.2 
Record Retention .........................................................................................................57 
13.0 
STATISTICAL METHODS ..............................................................................................59 
13.1 
Statistical and Analytical Plans ....................................................................................59 


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13.1.1 Analysis Sets ..........................................................................................................59 
13.1.2 Analysis of Demographics and Other Baseline Characteristics ............................59 
13.1.3 Pharmacokinetic Analysis ......................................................................................59 
13.1.4 Pharmacodynamic Analysis ...................................................................................60 
13.1.5 Safety Analysis ......................................................................................................60 
13.2 
Determination of Sample Size .....................................................................................60 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................61 
14.1 
Study-Site Monitoring Visits .......................................................................................61 
14.2 
Protocol Deviations ......................................................................................................61 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections ..................................62 
15.0 
ETHICAL ASPECTS OF THE STUDY ...........................................................................63 
15.1 
IRB and/or IEC Approval ............................................................................................63 
15.2 
Subject Information, Informed Consent, and Subject Authorization ..........................63 
15.3 
Subject Confidentiality ................................................................................................65 
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy ..................................65 
15.4.1 Publication and Disclosure ....................................................................................65 
15.4.2 Clinical Trial Registration ......................................................................................65 
15.4.3 Clinical Trial Results Disclosure ...........................................................................66 
15.5 
Insurance and Compensation for Injury .......................................................................66 
16.0 
REFERENCES ..................................................................................................................67 
 
LIST OF IN-TEXT TABLES 
Table 6.a 
Treatment Sequences .............................................................................................22 
Table 7.a 
Prohibited Medications ..........................................................................................27 
Table 8.a 
Composition of CVN058 and Matching Placebo ..................................................30 
Table 8.b 
Treatment and Medication Type ............................................................................31 
Table 9.a 
Clinical Laboratory Tests .......................................................................................37 
Table 9.b 
Collection of Blood Samples for CVN058 Pharmacokinetic Analysis .................41 
Table 9.c 
Approximate Blood Volume ..................................................................................47 
Table 10.a 
Medically Significant AE List ...............................................................................51 
Table 14.a 
Windows for Pharmacokinetic Blood Sample Collection .....................................62 
 
LIST OF IN-TEXT FIGURES 
Figure 6.a 
Schematic of Study Design ....................................................................................23 
 


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CONFIDENTIAL 
LIST OF APPENDICES 
Appendix A 
Schedule of Study Procedures ...............................................................................69 
Appendix B 
Responsibilities of the Investigator ........................................................................71 
 


CVN058 
 
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CONFIDENTIAL 
2.0 
STUDY SUMMARY 
Name of Sponsor(s): 
Cerevance Alpha, Inc.  
(hereafter referred to as “Cerevance”) 
Compound: 
CVN058 
Title of Protocol: A Placebo-Controlled Study to 
Evaluate the Effect of a Single Dose of CVN058 on 
Mismatch Negativity in Subjects with Stable 
Schizophrenia 
IND No.: 121,520 
EudraCT No.: 
Not Applicable 
Study Number: CVN058-103 
Phase: 1 
Study Design: 
This is a phase 1, double-blind, placebo-controlled, 3 period cross-over study to evaluate CVN058 target 
engagement by measuring auditory evoked potential mismatch negativity (MMN) downstream to 5-
hydroxytryptamine receptor 3 (5-HT3) as a pharmacodynamic (PD) marker.   
Male and female subjects with schizophrenia, age 18 to 50 years old, inclusive, will be randomized to 1 of 6 
treatment sequences (Table 2.a) to receive 1 of 3 dose regimens in each period: a single oral administration of 
CVN058 (15 mg or 150 mg) or matching placebo. The sequence will determine the order in which a subject will 
take each of the 3 regimens. Discontinued subjects may be replaced at the discretion of the sponsor so that 
approximately 20 completed subjects are available for analysis. 
The study includes three 1-day treatment periods, with a minimum of 7-day washout, maximum 10 day washout 
(2 total washouts, after Periods 1 and 2) between periods, and a 7-10 day follow-up call post dosing of the last 
period. Subjects may be inpatients or outpatients at the discretion of the Investigator. 
Table 2.a Treatment Sequences 
Sequence 
Period 1 
Period 2 
Period 3 
1 
A 
B 
C 
2 
B 
A 
C 
3 
C 
A 
B 
4 
A 
C 
B 
5 
B 
C 
A 
6 
C 
B 
A 
A: Placebo 
B: CVN058 15 mg 
C: CVN058 150 mg  
At each testing session, subjects undergo post dose electroencephalography (EEG) testing including: MMN, P50, 
gamma power, and P300. Study drug will be administered with water. Testing sessions will begin approximately 
1.5 hours post-dose. Prior to dosing and at various time points post dose, blood samples will be collected for the 
assessment of plasma concentrations of CVN058 and biomarkers.  
Study procedures will be conducted at approximately the same times across Treatment Periods to minimize 
diurnal effects on outcomes. The effect of CVN058 on MMN as well as on exploratory measures (e.g., P50 
auditory gating, gamma power, and P300) will be compared to placebo.  
 
A schematic of the study design is presented below: 
  
 
 


CVN058 
 
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CONFIDENTIAL 
 
Primary Objective: 
To determine whether improvement in MMN is demonstrated after administration of CVN058 compared to 
placebo in subjects with schizophrenia. 
Secondary Objective: 
Assess the safety and tolerability of single doses of CVN058 in subjects with schizophrenia. 
Exploratory Objectives: 
• 
To determine whether improvement in P50 auditory gating, gamma power, and P300 is demonstrated 
after administration of CVN058 compared to placebo in subjects with schizophrenia. 
• 
To assess the pharmacokinetics (PK) of CVN058 following a single dose to subjects with 
schizophrenia. 
• 
To explore the exposure-response relationship for CVN058 in subjects with schizophrenia. 
Subject Population:  
Subjects with stable schizophrenia on antipsychotic medication(s).  
Number of Subjects: 
Estimated total: at least 20 evaluable subjects who 
complete the study  
Number of Sites: 
Approximately 2 (United States) 
Dose Level(s): 
Placebo: solution vehicle, oral administration  
CVN058: 15 mg solution, oral administration  
CVN058: 150 mg solution, oral administration 
Route of Administration: 
Oral 
Duration of Treatment: 
Single oral dose in each of the 3 periods.  
Period of Evaluation: 
Screening Days (Part 1): Up to 28 days. 
3 Treatment Periods, each <1 day duration;  
with a 7-10 day washout between periods 
Follow-up call 7-10 days following the last dose of 


CVN058 
 
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                    Page 12 of 72 
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CONFIDENTIAL 
study drug in Treatment Period 3. 
Total Duration: Up to 58 days. 
Main Criteria for Inclusion: 
Subjects 18 to 50 years of age, inclusive, at the time of informed consent. 
The subject weighs at least 50 kg and has a body mass index (BMI) between 18 and 40 kg/m2 inclusive at 
Screening. 
Subject meets schizophrenia criteria as defined by the Diagnostic & Statistical Manual of Mental Disorders, 5th 
Edition (DSM–V).  
Subjects are on a stable dose of antipsychotic medication(s) for at least 2 months prior to Screening as 
documented by medical history and assessed by site staff. 
Subject has a Positive and Negative Syndrome Scale (PANSS) total score of <95. 
Main Criteria for Exclusion: 
Subject currently receiving treatment with any excluded medication or dietary supplement. 
Subjects who have a history of gastrointestinal disease that would influence the absorption of study drug or have 
a history of any surgical intervention known to impact absorption (e.g., bariatric surgery or bowel resection). 
Subjects having clinical laboratory evaluations (including clinical chemistry, hematology and complete 
urinalysis) outside the reference range for the testing laboratory, unless the results are deemed to be not clinically 
significant (NCS) by the investigator at Screening. 
Subjects with moderate to severe substance use disorder, unstable mood or anxiety disorder. 
Subject has a current diagnosis of a significant psychiatric illness other than schizophrenia per DSM-V and is in 
an acute phase/episode. 
Subject has clinically meaningful hearing loss. 
Main Criteria for Evaluation and Analyses: 
Pharmacodynamics: 
MMN will be measured as a PD marker for CVN058. Exploratory measurements include P50 auditory gating, 
gamma power, and P300, which are EEG markers commonly impaired in subjects with schizophrenia.  
Pharmacokinetics:  
Blood samples will be collected for the determination of plasma concentrations of CVN058, and its metabolite if 
appropriate, at the following time points: Pre-dose (within 15 minutes prior to dosing), and at 1 (pre-EEG) and 5 
(post-EEG) hours post dose. The following PK parameters will be determined from concentrations of CVN058, 
and its metabolite if appropriate, in plasma: maximum observed plasma concentration (Cmax), time to reach Cmax 
(tmax), and area under the curve from time 0 to the time of the last quantifiable concentration (AUCt). Other 
parameters may be calculated if appropriate.  
Pharmacogenomics: 
Whole blood will be collected and stored for possible deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) 
isolation and analysis.  
DNA samples will be used to evaluate drug metabolic enzyme and transporter polymorphisms that may 
contribute to variability in the PK of CVN058. Also, since pharmacogenomics is an evolving science, many 
genes and their functions are not yet fully understood. Future data may suggest a role of some gene in drug 
response, which may lead to additional hypothesis-generating exploratory research and diagnostic development 
on stored samples. 
Statistical Considerations: 
Observed values for the PD parameters (MMN and exploratory PD parameters) at each time point and will be 
summarized by treatment and compared to time matched assessments during placebo dosing using summary 
statistics. Comparison of post dose PD parameters to time match placebo period timepoints will be analyzed 
using analysis of covariance (ANCOVA) with baseline value as a covariate and factors for time point, sequence, 
subject nested within sequence, period, and treatment. Two-sided 95% confidence intervals will be constructed 


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CONFIDENTIAL 
for the least squares mean differences between CVN058 and placebo in changes of PD parameters from time-
matched period Baseline to each postdose time point. 
Effect size will be calculated for comparisons of CVN058 to placebo using Cohen’s d which expresses the 
difference between the means of 2 groups as a function of their pooled standard deviation. 
Plasma PK concentrations and parameters of CVN058, and its metabolite if appropriate, will be listed and 
summarized by treatment using descriptive statistics. Exposure-response relationships for CVN058 will be 
explored graphically. 
Adverse events (AEs) will be presented in listings, and treatment-emergent AEs (TEAEs) will be summarized by 
treatment. Individual results of vital signs will be listed and observed values and changes from Baseline in vital 
signs will be summarized by treatment.  
Sample Size Justification:  
Enrollment of 20 subjects with schizophrenia is estimated to provide >80% power to detect a median effect size 
of Cohen’s d=0.5. Discontinued or withdrawn subjects and subjects for whom MMN is not available for all three 
study periods may be replaced. The sample size chosen of 20 completed subjects is expected to be sufficient to 
explore the changes in MMN between CVN058 and placebo as well as safety and tolerability of CVN058 in this 
population. 
 


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3.0 
LIST OF ABBREVIATIONS 
5-HT 
5-hydroxytryptamine (serotonin) 
5-HT3 
5-hydroxytryptamine (serotonin) receptor 3 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
AUCt 
area under the plasma concentration-time curve from 0 to time of last quantifiable 
concentration 
BA 
bioavailability 
BMI 
body mass index 
CIAS 
cognitive impairment associated with schizophrenia 
CL/F 
apparent clearance after extravascular administration 
Cmax 
maximum observed plasma concentration 
CNS 
central nervous system 
CRO 
contract research organization 
CS 
clinically significant 
CSF 
cerebrospinal fluid 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DSM -V 
Diagnostic & Statistical Manual of Mental Disorders, 5th Edition – Text Revision 
eCRF 
electronic case report form  
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
EEG 
electroencephalography 
EMA 
European Medicines Agency  
ERP 
evoked response potential 
FDA 
Food and Drug Administration 
FM 
frequency-modulation 
FSH 
follicle-stimulating hormone 
FSI 
fast-spiking interneurons 
Fz 
frontal electrodes 
Fz,Cz 
frontocentral electrodes 
GABA 
γ-aminobutyric acid 
GCP 
Good Clinical Practice 
GGT 
γ-glutamyl transferase 
HBsAg 
hepatitis B surface antigen 
hCG 
human chorionic gonadotropin 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
ICH 
International Conference on Harmonisation 
IEC 
independent ethics committee 
INR 
international normalized ratio 
IRB 
institutional review board 
IUD 
intrauterine device 


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K2EDTA 
potassium ethylenediamine tetraacetic acid 
LFT 
liver function test 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMN 
mismatch negativity 
NCS 
not clinically significant 
NMDAR 
N-methyl-D-aspartate receptor 
NFSI 
non-fasting spiking interneurons 
OTC 
Over-the-counter 
PANSS 
Positive and Negative Syndrome Scale 
PD 
pharmacodynamic(s) 
PI 
principal investigator 
PK 
pharmacokinetic(s) 
PT 
PTT 
prothrombin time 
partial thromboplastin time 
PTE 
pretreatment event 
PV 
parvalbumin 
Pz 
parietal electrodes  
P50 Ratio 
ratio of S2 to S1  
RNA 
ribonucleic acid 
QTcB 
QT interval with Bazett correction method 
QTcF 
QT interval with Fridericia correction method 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SSR 
steady state response 
SUSAR 
suspected unexpected serious adverse reaction 
t1/2z 
terminal elimination half-life 
CVN058 
also known as ENV8058 and TAK-058 
TEAE 
treatment-emergent adverse event 
tmax 
time to reach Cmax 
ULN 
upper limit of normal 
Vz/F 
apparent volume of distribution during the terminal phase 
WHODRUG  
World Health Organization Drug Dictionary 


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4.0 
INTRODUCTION 
4.1 
Background 
Schizophrenia is a complex disorder comprising several clinical features that are highly variable 
among affected individuals. Probably the most well-known schizophrenia symptom domains are 
the so-called positive symptoms, e.g., hallucinations, delusions, disorganization of thought, 
bizarre behavior, and incongruity of affect. Negative symptoms include avolition (loss of 
motivation), blunt affect, alogia (reduced speech), and anhedonia (reduced ability to experience 
pleasure). Cognitive impairment associated with schizophrenia (CIAS) usually precedes 
psychosis and is observed in most cases involving deficits in a broad range of domains. Finally, 
patients with schizophrenia often experience depression and anxiety, express hostility, and 
become demoralized (Thaker, 2001).  
Cognitive impairment is considered a core feature of schizophrenia and represents an area of 
significant unmet medical need. Cognitive deficits in schizophrenia include problems in speed of 
processing, attention/vigilance, working memory, verbal learning, visual learning, reasoning and 
problem solving, and social cognition (Green, 2006). These cognitive deficits are believed to 
underlie much of the significant functional impairments observed in schizophrenia, such as 
impairment in independent living skills, social functions, vocational functioning, and self-care 
(Harvey, 2007). Thus, the core nature of CIAS and the associations that have been demonstrated 
with functional disability suggest that improving cognitive impairment may lead to improved 
functional outcomes (Heinrichs, 2005). 
The understanding of CIAS has evolved significantly in recent years and led to new therapeutic 
strategies. In postmortem samples from schizophrenic patients, studies consistently reveal 
reduced levels of enzymes that synthesize the inhibitory neurotransmitter γ-aminobutyric acid 
(GABA) in the prefrontal cortex (McNally, 2013) a key center for higher cognitive function. The 
GABAergic neurons deficient in the cortex are termed fast-spiking interneurons (FSIs), and they 
express the marker parvalbumin (PV) (McNally, 2013). These PV+ FSIs are chemically coupled 
and release GABA in a rhythmic pattern that synchronizes the activity of local cortical pyramidal 
neurons (Cardin, 2009). This synchronization, which is essential for cognition, is disrupted in 
patients [(McNally, 2013), (Cardin, 2009)] [(Whittington, 1997), (Rotaru, 2012), (Gonzalez-
Burgos, 2012)]. These and other human and animal model data implicate FSI hypofunction, and 
a resulting imbalance in the excitation/inhibition balance in cortical regions, in CIAS. 
Based on this emerging insight into disease pathophysiology, a therapeutic that restores the 
normal function of the cortical pyramidal neuron/FSI microcircuit would be expected to improve 
cognitive function in patients with schizophrenia. One strategy for boosting the function of this 
circuit is to inhibit a second population of inhibitory GABAergic interneurons, known as non-
fast spiking interneurons (NFSIs), which project locally onto the FSIs and the dendrites of the 
pyramidal neurons. These NFSIs are modulated by a wide variety of inputs, particularly 
excitatory glutamatergic efferents from the thalamus, and noradrenergic, cholinergic, and 
serotonergic efferents from subcortical regions [(Tian, 2010), (Kawaguchi, 1998), (Kawaguchi, 
1997), (Lee, 2010)]. Thus, NFSIs appear to integrate state-dependent information and release 
GABA to regulate pyramidal neuron/FSI microcircuits. 


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Mismatch negativity (MMN) is an established biomarker of cortical function (Javitt, 2015). This 
signal is obtained as an evoked potential during an auditory oddball task, in which a subject is 
repeatedly exposed to auditory tones and a small proportion of those tones (the “deviant” stimuli) 
differ from the others (the “standard” stimuli) in their frequency or duration. Typically, the tones 
are presented and the evoked potentials are recorded while subjects are engaged on a different 
task, such as reading. Normally, the occurrence of a deviant stimulus increases the amplitude of 
the negative component in the evoked potential occurring at around 200 msec. MMN is the 
difference in amplitude between deviant and standard stimuli responses, and is considered to 
represent an aspect of preattentive novelty detection. MMN is consistently reduced in 
schizophrenia patients relative to healthy individuals, a finding extensively replicated and with a 
large effect size (Cohen’s d = 1). MMN reduction in schizophrenia has been shown to reflect 
impaired N-methyl-D-aspartate receptor (NMDAR) function at the level of supratemporal 
auditory cortex, dependent on cortical interneuron modulation of pyramidal cell activity and 
NMDA receptor-dependent (Lee, 2017). 
4.2 
Non-Clinical 
CVN058 (also known as ENV8058 or TAK-058) is a small molecule that potently and 
selectively antagonizes the 5-hydroxytryptamine (5-HT) receptor type 3 (5-HT3). 5-HT3 is a cys-
loop family ligand-gated ion channel that allows cations to pass into the neurons when activated 
by serotonin, and is highly expressed in NFSIs [(Lee, 2010), (Lummis, 2012)]. The receptor is a 
pentamer consisting of at least two 5-HT3a subunits and 3 other subunits; in the central nervous 
system (CNS) the receptor is almost exclusively a homomeric pentamer comprised of 5-HT3a 
(Kawaguchi, 1997). The 5-HT3 channel opens when serotonin molecules interact with the 2 
ligand recognition sites in the extracellular side of the receptor. Influxed calcium and other 
positive ions depolarize the NFSIs, leading to GABA release. CVN058 is orally absorbed and 
readily passes the blood brain barrier, allowing it to occupy cortical 5-HT3 receptors (50% 
occupancy of rat cortical 5-HT3 receptors is achieved at plasma concentrations of approximately 
5.8 ng/mL). CNS 5-HT3 receptor occupancy is correlated with efficacy in a rat model of 
cognition where it reverses deficits in novel object recognition induced by subchronic 
phencyclidine treatment. Thus, CVN058 is a novel therapeutic candidate that may improve 
cognitive function by inhibiting specific subsets of cortical interneurons.  
Additional information from the nonclinical studies can be found in the current Investigator’s 
Brochure. 
4.3 
Clinical 
Two human clinical studies of CVN058 have been completed (ENV8058_101 and TAK-058-
1002). 
CVN058 was well tolerated up to a dose of 150 mg administered orally as a single dose in 
aqueous solution (Study ENV8058_101). There were no deaths or other serious adverse events 
(SAEs) reported in this study and no subject discontinued study due to a treatment-emergent 
adverse event (TEAE). There were no clinically significant (CS) laboratory abnormalities, 
electrocardiogram (ECG) changes or changes in vital signs in the completed single dose study. 


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The mean Cmax and area under the plasma concentration–time curve (AUC) values of CVN058 
increased less than proportionally with increasing CVN058 dose across the dose range of 5 to 
150 mg, but mean Cmax and AUC values increase in an approximately dose proportional manner 
across the 5 to 45 mg dose range. The rate of appearance of CVN058 in plasma was rapid with 
median time to Cmax (tmax) values of 1 to 1.25 hours across the dose range of 5 to 150 mg. The 
mean terminal elimination half-life (t1/2z) values of CVN058 ranged from approximately 2.8 to 
10.5 hours across the cohorts; the lower doses (5 to 30 mg) had lower mean t1/2z values compared 
to the higher doses (45 to 150 mg). There were no trends with mean apparent clearance (CL/F) 
values of CVN058 with increasing dose from 5 to 45 mg, but faster apparent clearance was 
observed at the 75 and 150 mg doses, possibly due to decreased bioavailability (BA) at higher 
doses. The mean apparent volume of distribution (Vz/F) increased as dose increased. Excretion 
of unchanged CVN058 in the urine was ≤2.3% of the administered CVN058 dose over the dose 
range evaluated. 
In the multiple-rising dose study (TAK-058-1002), CVN058 was well-tolerated at daily doses of 
25, 75, and 150 mg for 7 days, and at a single 300 mg dose, in aqueous solution. There were no 
deaths or other SAEs reported in this study and no subject discontinued study due to a TEAE. 
There were no clinically significant laboratory abnormalities, ECG changes or changes in vital 
signs in the completed single dose study. Following single or multiple doses, the mean Cmax and 
AUC values of CVN058 increased less than proportionally with increasing CVN058 dose across 
the dose range of 25 to 300 mg. No accumulation was observed following daily administration. 
CVN058 concentrations in cerebrospinal fluid (CSF) were assessed after daily doses of CVN058 
75 mg for 5 days. The CSF concentrations averaged 17.5 ng/mL, or approximately 1% of the 
concentration in plasma. 
4.4 
Rationale for the Proposed Study 
This study will explore central target engagement and proof of mechanism by measuring 
auditory evoked potential MMN as a pharmacodynamic (PD) marker of CNS response to the 
selective 5-HT3 receptor antagonist CVN058. It has been reported that subjects with 
schizophrenia commonly demonstrate a deficit in neural processing that is manifested as a 
reduction in MMN and impairment of auditory sensory gating (P50) (Javitt and Sweet, 2015). 
Other 5-HT3 receptor antagonists have been reported to improve impairments in auditory evoked 
potentials in schizophrenic subjects. In a study with ondansetron, a 5-HT3 receptor antagonist, 
using P50 auditory gating as the auditory evoked potential measure, subjects were given a single 
dose of ondansetron (16 mg) or placebo in a double-blind, placebo-controlled, randomized and 
balanced crossover design (Adler, 2005). Serial measurements of the P50 evoked potential were 
done at Baseline and 1, 2, and 3 hours after receipt of placebo or ondansetron. The results of the 
study indicated that ondansetron significantly enhanced P50 auditory gating in subjects with 
schizophrenia. Tropisetron, a 5-HT3 antagonist that also has α7 nicotinic cholinergic agonist 
activity, has similarly been shown to improve P50 auditory gating in subjects with schizophrenia 
(Koike, 2005).  
While the P50 signal is likely a reflection of brainstem and thalamic network activity and is 
sensitive to antipsychotic treatment, MMN is thought to reflect excitation-inhibition balance in 
cortical circuits and is not sensitive to antipsychotic treatment (Javitt and Sweet, 2015). 
Therefore, to evaluate the potential for CVN058 to improve cognitive function in schizophrenics, 


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MMN will be used as a PD marker. The study will be performed as a 3-way crossover to assess 
the effect on MMN of CVN058 at two dose levels relative to placebo, with each subject serving 
as his or her own control to reduce variability. P50 auditory gating will also be measured, as an 
exploratory endpoint, along with other potentially informative electrophysiological and 
psychometric parameters. 
Medications that might inhibit or mask the effects of CVN058 will not be permitted as 
concomitant medications. These include serotonin reuptake inhibitors which increase synaptic 
serotonin levels, as well as drugs that bind to 5-HT3 at clinically relevant concentrations or are 
reported to inhibit signaling through 5-HT3 non-competitively, including some antipsychotic 
drugs [(Eisensamer, 2005), (Eisensamer, 2003), (Rammes, 2004)]. Permissible antipsychotic 
medications are risperidone (Risperdal), haloperidol (Haldol), quetiapine (Seroquel), aripiprazole 
(Abilify) and paliperidone (Invega). 


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5.0 
STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Objectives 
5.1.1 Primary Objective 
• To determine whether improvement in MMN is demonstrated after administration of 
CVN058 compared to placebo in subjects with schizophrenia.  
5.1.2 Secondary Objective 
• To assess the safety and tolerability of single doses of CVN058 in subjects with 
schizophrenia. 
5.1.3 Exploratory Objectives  
• To determine whether improvement in P50 auditory gating, gamma power, and P300 is 
demonstrated after administration of CVN058 compared to placebo in subjects with 
schizophrenia. 
• To assess the pharmacokinetics (PK) of CVN058 following a single dose to subjects with 
schizophrenia. 
• To explore the exposure-response relationship for CVN058 in subjects with schizophrenia. 
5.2 
Endpoints 
5.2.1 Primary Endpoints  
• Mean amplitude of duration MMN at 5 electrodes surrounding frontal (Fz) electrodes 
following administration of CVN058 compared to placebo. 
5.2.2 Secondary Endpoint 
• Percentage of subjects who experience at least 1 TEAE  
• Percentage of subjects who experience at least 1 clinically significant abnormal laboratory 
test result 
5.2.3 Exploratory Endpoints 
• Mean P50 ratio (S2/S1) at 5 electrodes surrounding Cz following administration of CVN058 
compared to placebo 
• Mean P50 differences (S2-S1) at 5 electrodes surrounding Cz following administration of 
CVN058 compared to placebo. 
• Pre-stimulus gamma amplitude following administration of CVN058 compared to placebo  
• P300 amplitude and latency at average of 5 centroparietal electrodes around parietal 
electrodes (Pz) following administration of CVN058 compared to placebo 


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• MMN amplitude to additional deviants (frequency, intensity, location, frequency-modulation 
[FM]) and latency to all deviants following administration of CVN058 compared to placebo 
• CVN058, its metabolite if appropriate, Cmax, tmax, and area under the plasma concentration-
time curve from 0 to the last quantifiable concentration (AUCt). 


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6.0 
STUDY DESIGN AND DESCRIPTION 
6.1 
Study Design  
This is a phase 1, double-blind, placebo-controlled, 3 period cross-over study to evaluate 
CVN058 target engagement by measuring auditory evoked potential MMN downstream to 5-
hydroxytryptamine receptor 3 (5-HT3) as a PD marker.  
Male and female subjects with schizophrenia, age 18 to 50 years old, inclusive, will be 
randomized to 1 of 6 treatment sequences (Table 6.a) to receive 1 of 3 dose regimens in each 
period; a single oral administration of CVN058 (15 mg or 150 mg), or a matching placebo. The 
sequence will determine the order in which a subject will receive each of the 3 regimens. 
Discontinued subjects may be replaced so that 20 completed subjects are available for analysis. 
Each treatment period is less than 1 day in duration, with a minimum of 7-day washout, 
maximum 10 day washout between doses. A follow-up telephone call will occur approximately 
7-10 days following the last dose received. Subjects may be inpatients or outpatients at the 
discretion of the Investigator. 
Table 6.a 
Treatment Sequences 
Sequence 
Period 1 
Period 2 
Period 3 
1 
A 
B 
C 
2 
B 
A 
C 
3 
C 
A 
B 
4 
A 
C 
B 
5 
B 
C 
A 
6 
C 
B 
A 
A: Placebo 
B: CVN058 15 mg 
C: CVN058 150 mg 
 
At each testing session, subjects will undergo post dose EEG testing including: MMN, P50, 
gamma power, and P300. Study drug will be administered with water in the morning. Testing 
sessions will begin approximately 1.5 hours post-dose. Prior to dose and at various time points 
postdose, blood samples will be collected for the assessment of plasma concentrations of 
CVN058 and biomarkers.  
Study procedures will be conducted at approximately the same times across Treatment Periods to 
minimize diurnal effects on outcomes.  The effect of CVN058 on MMN as well as on 
exploratory measures (e.g., P50 auditory gating, gamma power, and P300) will be compared to 
placebo.  
A schematic of the study design is presented in Figure 6.a. 


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Figure 6.a 
Schematic of Study Design 
 
6.2 
Justification for Study Design, Dose, and Endpoints 
This study will explore CNS target engagement by measuring alterations in auditory evoked 
potentials, similar to the demonstration of an effect on P50 auditory gating using the 5-HT3 
antagonist, ondansetron (Adler, 2005). The study design was based on that published study, 
adapted for CVN058 as study drug and MMN as the primary endpoint. It has been reported that 
most subjects with schizophrenia demonstrate a deficit in neural processing that is manifested as 
a reduction in MMN and impairment of auditory sensory gating (P50). According to Adler et al., 
ondansetron improves the P50 deficit after a single dose administration (Adler, 2005).  
The study will be a randomized, 3 period crossover study (CVN058 at two dose levels, and 
placebo) in order to evaluate the effect of CVN058 on MMN as well as on exploratory measures 
(i.e., P50 auditory gating, gamma power, and P300) compared to placebo. The study will be 
double-blind and placebo-controlled in order to avoid subjective bias in the assessment of the PD 
markers. In addition, conduct of study procedures for each subject will occur at approximately 
the same time per day across each of the Treatment Periods to avoid diurnal changes that may 
otherwise confound the analysis.  
The 150 mg level of CVN058 is expected to saturate CNS 5-HT3 receptors throughout the EEG 
session, but is 50% lower than the highest dosage for which safety and tolerability has been 
demonstrated in previous phase 1 studies in healthy subjects, thus presumably maximizing the 
PD signal within the established limits of safe use. The lower dose level of 15 mg CVN058 is 
expected to attain a lower CNS 5-HT3 receptor occupancy, decreasing to possibly 70-80% by the 
end of the EEG session. The 10-fold difference in these dosages should help establish a dose-
response relationship for evoked response potential (ERP) effects of CVN058. From a safety 


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perspective, single doses ranging from 5 mg to 300 mg CVN058 have been safe and well-
tolerated. Daily doses of 25, 75, and 150 mg of CVN058 for 7 days have also been studied, and 
were similarly safe and well-tolerated. 
The timing of dosing was selected to allow the EEG assessments to occur at the corresponding 
estimated tmax values of CVN058. The length of the washout periods is considered adequate 
based on the PK profile of CVN058. 
In addition, based on the EEG deficits reported in subjects with schizophrenia, P50 auditory 
gating, gamma frequency, and P300 neurophysiological markers will be measured. 
6.3 
Premature Termination or Suspension of Study or Investigational Site 
6.3.1 Criteria for Premature Termination or Suspension of the Study 
The study will be completed as planned unless new information or other evaluation regarding the 
safety or efficacy of the study medication indicates a change in the known risk/benefit profile for 
the compound, such that the risk/benefit is no longer acceptable for subjects participating in the 
study. 
6.3.2 Criteria for Premature Termination or Suspension of Investigational Sites 
A study site may be terminated prematurely or suspended if the site (including the investigator) 
is found in significant violation of Good Clinical Practice (GCP), protocol, or contractual 
agreement, is unable to ensure adequate performance of the study, or as otherwise permitted by 
the contractual agreement. 
6.3.3 Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s) 
In the event that the sponsor, an institutional review board (IRB) / independent ethics committee 
(IEC), or regulatory authority elects to terminate or suspend the study or the participation of an 
investigational site, a study-specific procedure for early termination or suspension will be 
provided by the sponsor; the procedure will be followed by applicable investigational sites 
during the course of termination or study suspension. 


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7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS 
All entry criteria, including test results, need to be confirmed prior to randomization. Subjects 
who do not initially meet eligibility criteria may be re-screened at investigator’s discretion.  
7.1 
Inclusion Criteria 
Subject eligibility is determined according to the following criteria prior to entry into the study:  
1. In the opinion of the investigator, the subject is capable of understanding and complying with 
protocol requirements. 
2. The subject signs and dates a written, informed consent form and any required privacy 
authorization prior to the initiation of any study procedures. 
3. The subject is aged 18 to 50 years, inclusive, at the time of informed consent. 
4. The subject weighs at least 50 kg and has a body mass index (BMI) between 18 and 40 kg/m2 
inclusive at Screening. 
5. The subject meets schizophrenia criteria as defined by the Diagnostic and Statistical Manual 
of Mental Disorders 5th edition (DSM-V) (American Psychiatric Association, 2013). 
6. The subject is on a stable dose of allowed antipsychotic medication(s) for at least 2 months 
prior to Screening as documented by medical history and assessed by site staff. 
7. The subject has a Positive and Negative Syndrome Scale (PANSS) total score of <95 at 
Screening. 
7.2 
Exclusion Criteria 
Any subject who meets any of the following criteria will not qualify for entry into the study:  
1. A male subject who is nonsterilized* and sexually active with a female partner of 
childbearing potential* does not agree to use adequate contraception* from signing of 
informed consent throughout the duration of the study and for 12 weeks after last dose of 
study drug. 
2. A female subject of childbearing potential* who is sexually active with a nonsterilized* male 
partner does not agree to use acceptable methods of contraception* from signing of informed 
consent throughout the duration of the study and for 12 weeks after last dose of study drug. 
*Definitions and acceptable methods of contraception are defined in 
Section 9.1.9 Contraception and Pregnancy Avoidance Procedure and 
reporting responsibilities are defined in Section 9.1.10 Pregnancy. 
3. If female, the subject is pregnant or lactating or intending to become pregnant before, during, 
or within 12 weeks after the last dose of study medication; or intending to donate ova during 
such time period. 
4. The subject has uncontrolled, clinically significant neurologic, cardiovascular, pulmonary, 
hepatic, renal, metabolic, gastrointestinal, or endocrine disease or other abnormality that may 
impact the ability of the subject to participate or potentially confound the study results.  


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5. The subject has a history of gastrointestinal disease that would influence the absorption of 
study drug, or history of any surgical intervention known to impact absorption (e.g., bariatric 
surgery or bowel resection). 
6. The subject has clinical laboratory evaluations (including clinical chemistry, hematology and 
complete urinalysis) outside the reference range for the testing laboratory, unless the results 
are deemed to be NCS by the investigator at Screening. 
7. The subject has received any investigational compound within 30 days prior to signing of 
informed consent. 
8. The subject has taken any excluded medication or dietary supplement within time frames 
listed in the Excluded Medications table in Section 7.3. 
9. The subject does not have a stable indoor living situation (e.g., living independently, with 
family, or group home)  
10. The subject is an immediate family member, study site employee, or is in a dependent 
relationship with a study site employee who is involved in the conduct of this study 
(e.g., spouse, parent, child, sibling) or may consent under duress. 
11. Subjects with moderate to severe substance use disorder according to DSM-5 criteria. 
12. The subject has a positive urine drug result for drugs of abuse (defined as any illicit drug use, 
including marijuana) at Screening.  
13. The subject has a history of cancer requiring chemotherapy within the past 5 years prior to 
the first dose of study medication. This criterion does not include subjects successfully 
treated for basal cell or stage I squamous cell carcinoma of the skin. 
14. The subject has a positive test result for hepatitis B surface antigen (HBsAg), hepatitis C 
virus (HCV) antibody (unless having completed curative therapy), or known history of 
human immunodeficiency virus (HIV) antibody at Screening.  
15. The subject has a QT interval with Fridericia’s correction method (QTcF) >450 msec (males) 
or >470 msec (females) or PR outside the range of 120 to 220 msec, confirmed by triplicate 
testing at 5 minute intervals, at the Screening Visit. 
16. The subject has poor peripheral venous access.  
17. The subject has hair or scalp condition(s) that would prevent the application of the EEG 
electrodes. 
18. The subject has a current diagnosis of a significant psychiatric illness other than 
schizophrenia, per DSM-V and is in an acute phase/episode. 
19. Subject has clinically meaningful hearing loss per investigator’s judgment. 
20. The subject has donated or lost 450 mL or more of his or her blood volume (including 
plasmapheresis), or had a transfusion of any blood product, within 3 months prior to Day 1. 
21. The subject has an abnormal (clinically significant) Screening ECG. Entry of any subject 
with an abnormal (not clinically significant) ECG must be approved and documented by 
signature of the principal investigator (PI).  


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22. The subject has abnormal Screening laboratory values that suggest a clinically significant 
underlying disease, or subject with the following lab abnormalities: alanine aminotransferase 
(ALT) and/or aspartate aminotransferase (AST) >2x the upper limit of normal (ULN). 
23. The subject has abnormal Screening vital sign values that suggest a clinically significant 
underlying disease. 
24. The subject has a risk of suicide according to the Investigator’s clinical judgment, a 
Screening Visit Columbia-Suicide Severity Rating Scale [C-SSRS]) score of greater than 3, 
or has a history of suicide attempt. 
7.3 
Excluded Medications, Dietary Products, Procedures, and Treatments  
Use of the agents in Table 7.a (prescription or nonprescription) is prohibited from the time points 
specified until completion of all study activities.  
Table 7.a 
Prohibited Medications  
28 Days Prior to Check-in  
1 Days Prior to Check-in  
1 Hour Prior to 
Each EEG 
Assessment  
Nutraceuticals and dietary supplements (e.g., St. John’s wort, 
ginseng, kava kava, ginkgo biloba, Chinese herbs, and melatonin) 
 
Alcohol-containing 
products 
Products containing 
nicotine, caffeine or 
xanthine (e.g., tea) 
Antipsychotic medications, except risperidone (Risperdal), 
haloperidol (Haldol), quetiapine (Seroquel), aripiprazole (Abilify) 
and paliperidone (Invega) 
 
Sedative hypnotic 
medications (barbiturates 
and benzodiazepines) 
 
5-HT3 receptor antagonists, including ondansetron (Zofran, 
Zuplenz), granisetron (Kytril, Sancuso, Granisol, Sustol), 
palonosetron (Aloxi), dolasetron (Anzemet)  
 
 
 
5-HT3 allosteric modulators buproprion (Wellbutrin, Zyban) and 
hydroxybupropion 
 
 
 
Serotonin Reuptake Inhibitors (SSRI, SNRI), including sertraline 
(Zoloft), fluoxetine (Prozac, Sarafem), citalopram (Celexa), 
escitalopram (Lexapro), paroxetine (Paxil, Pexeva, Brisdelle), 
vortioxetine (Trintellix), and fluvoxamine (Luvox) 
 
 
 
Mirtazapine (Remeron), desipramine, imipramine, trimipramine, 
reboxetine 
 
 
  
Subjects must be instructed not to take any medications, including over-the-counter (OTC) 
products, without first consulting with the investigator. Subjects must be instructed to not make 
any changes to their concomitant medications during the course of the study without first 
consulting with the investigator. 


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During study participation, subjects will maintain usual dosing schedule of antipsychotic 
medication(s) and approved concomitant medications. Sedative hypnotics will not be allowed 
after 10 pm the night prior to testing, and until completion of testing the following day. 
7.4 
Diet, Fluid, Activity Control  
Subjects should have their customary meal before each study visit. The contents of the meal 
should be summarized on the electronic case report form (eCRF). 
During EEG and ERP assessments, subjects will remain still in a seated or partially recumbent 
position, according to the EEG acquisition guidelines. Subjects will refrain from strenuous 
exercise from 72 hours before Check-in through check-out, relative to each Treatment Period. 
If subject is a smoker; they must refrain from smoking at least 1 hour prior to the EEG testing at 
all time points. 
On each dosing day, CVN058 or placebo will be administered with approximately 240 mL of 
water.  
7.5 
Criteria for Discontinuation or Withdrawal of a Subject 
The primary reason for discontinuation or withdrawal of the subject from the study or study 
medication should be recorded in the eCRF using the following categories. For screen failure 
subjects, refer to Section 9.1.17. 
1. Pretreatment event (PTE) or AE. The subject has experienced a PTE or AE that requires 
early termination because continued participation imposes an unacceptable risk to the 
subject’s health or the subject is unwilling to continue because of the PTE or AE. 
2. Liver Function Test (LFT) Abnormalities 
Study medication should be discontinued immediately with appropriate clinical follow-up 
(including repeat laboratory tests, until a subject’s laboratory profile has returned to 
normal/baseline status, see Section 9.1.8), if the following circumstances occur at any 
time during study medication treatment: 
– ALT or AST >8 ×ULN, or 
– ALT or AST >5 ×ULN and persists for more than 2 weeks, or 
– ALT or AST >3 ×ULN in conjunction with elevated total bilirubin >2 × ULN or 
international normalized ratio (INR) >1.5, or 
– ALT or AST >3 ×ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%). 
3. Significant protocol deviation. The discovery post randomization or after the first dose of 
study medication that the subject failed to meet protocol entry criteria or did not adhere to 
protocol requirements, and continued participation poses an unacceptable risk to the subject’s 
health. 
4. Lost to follow-up. The subject did not return to the clinic and attempts to contact the subject 
were unsuccessful. Attempts to contact the subject must be documented. 


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5. Voluntary withdrawal. The subject (or subject’s legally acceptable representative) wishes to 
withdraw from the study. The reason for withdrawal, if provided, should be recorded in the 
eCRF. 
Note: All attempts should be made to determine the underlying reason for the withdrawal 
and, where possible, the primary underlying reason should be recorded (i.e., withdrawal due 
to an AE). 
6. Study termination. The sponsor, IRB, IEC, or regulatory agency terminates the study. 
7. Pregnancy. The subject is found to be pregnant. 
Note: If the subject is found to be pregnant, the subject must be withdrawn immediately. The 
procedure is described in Section 9.1.10. 
8. Other. 
Note: The specific reasons should be recorded in the “specify” field of the eCRF. 
7.6 
Procedures for Discontinuation or Withdrawal of a Subject 
The investigator may discontinue a subject’s study participation at any time during the study 
when the subject meets the study termination criteria described in Section 7.5. In addition, a 
subject may discontinue his or her participation without giving a reason at any time during the 
study. Should a subject’s participation be discontinued, the primary criterion for termination 
must be recorded by the investigator. In addition, efforts should be made to perform all 
procedures scheduled for the Early Termination Visit. Discontinued or withdrawn subjects be 
replaced. 


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8.0 
CLINICAL TRIAL MATERIAL MANAGEMENT 
This section contains information regarding all medication and materials provided directly by the 
sponsor, and/or sourced by other means, that are required by the study protocol, including 
important sections describing the management of clinical trial material. 
8.1 
Study Medication and Materials 
8.1.1 Dosage Form, Manufacturing, Packaging, and Labeling 
Study drug refers to CVN058 and matching placebo. Study drug will be provided in bulk supply. 
An unblinded pharmacist will manage and prepare doses as oral solutions, as needed. 
In this protocol, the term study medication refers to all or any of the drugs defined below. 
8.1.1.1 Investigational Drug 
CVN058 and Matching Placebo  
CVN058 drug substance is supplied as bulk powder to the clinical site to be compounded into an 
oral solution. A matching placebo containing all of the components of the active oral suspension 
with the exception of the drug substance will also be compounded by the site. Compounding 
instructions will be outlined in a separate pharmacy manual and provided by the sponsor. 
CVN058 oral solution will be prepared in concentrations of 10 mg/mL. The composition of the 
oral solutions (active and placebo) can be found in Table 8.a. 
The oral solution will be labeled with the appropriate study information and caution statements. 
Table 8.a 
Composition of CVN058 and Matching Placebo 
Component 
10 mg/mL solution 
Placebo 
CVN058 (free base) 
10 g 
Not Applicable 
Citric Acid Monohydrate, USP 
15.76 g 
15.76 g 
Sterile Water for Irrigation, USP 
q.s. to 1,000 mL 
q.s.to 1,000 mL 
q.s.=quantity sufficient, USP= United States Pharmacopeia. 
 
8.1.1.2 Sponsor-Supplied Drug 
CVN058 drug substance is supplied to the clinical site by Cerevance by way of a contract 
manufacturing organization, Johnson-Mathey Pharma Services, Devens, MA. 
8.1.1.3 Ancillary Materials 
Ancillary materials will be provided by either the clinical site and/or sponsor based on 
availability.  
Ancillary material details are provided in the pharmacy manual. 
Unused ancillary materials, if provided by the sponsor, will be accounted for and disposed of as 
directed by the sponsor or their designee.  


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8.1.2 Storage 
All clinical trial material must be kept in an appropriate, limited-access, secure place until it is 
used or returned to the sponsor or designee for destruction. 
All study medication must be stored under the conditions specified on the label, and remain in 
the original container until dispensed. A daily temperature log of the drug storage area must be 
maintained every working day. 
CVN058 powdered drug substance is stored at room temperature. CVN058 oral solution and 
matching placebo can be stored protected from light at 2°C-8°C (35.6°F-46.4°F) for up to 28 
days. CVN058 oral solution and matching placebo are stable at room temperature for up to 24 
hours. 
8.1.3 Dose and Regimen 
The investigator or investigator’s designee will instruct the subject on dosing procedures. 
All dosing will occur while subjects are in the clinic under the supervision of the PI or designee, 
who will be blinded to the dose. 
Subjects will receive CVN058 (15 mg or 150 mg) or matching placebo in each of the 3 periods.  
Table 8.b describes the treatment and medication type that would be provided for each period. 
Table 8.b 
Treatment and Medication Type 
Regimen 
Planned Treatment 
Medication Type 
A 
Placebo 
Placebo  
B 
CVN058 15 mg 
CVN058  
C 
CVN058 150 mg 
CVN058 
 
8.1.4 Overdose 
An overdose is defined as a known deliberate or accidental administration of investigational 
drug, to or by a study subject, at a dose above that which is assigned to that individual subject 
according to the study protocol. 
All cases of overdose (with or without associated AEs) will be documented on an Overdose page 
of the eCRF, in order to capture this important safety information consistently in the database. 
Cases of overdose without manifested signs or symptoms are not considered AEs. AEs 
associated with an overdose will be documented on AE CRF(s) according to Section 10.0, 
Pretreatment Events and Adverse Events. 
The SAEs associated with overdose should be reported according to the procedure outlined in 
Section 10.2.2, Collection and Reporting of SAEs. 
In the event of drug overdose, the subject should be treated, e.g., administration of supportive 
therapy as directed by the subject’s clinical status, removal of unabsorbed material from the 
gastrointestinal tract and initiation of additional clinical monitoring.  


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8.2 
Investigational Drug Assignment and Dispensing Procedures 
Subjects will be assigned a 7-digit subject number in the sequential order in which they are 
randomized beginning with a 3-digit code “NNN-” where NNN represents a site specific 
identifier which will be provided by the Sponsor. Replacement subjects will be assigned a new 
number (e.g. site number followed by subject number). The 7-digit subject number assigned will 
be entered in the subject’s eCRF and noted on any subject specific source record and lab sample 
tubes. 
This 7-digit subject number will also be used by the clinical site to facilitate the prelabeling of 
PK samples, and will be the only subject identifier used on all PK sample collections. It should 
also be contained on the PK transport vials shipped to the bioanalytical laboratory, and will be 
used by the laboratory to report the subject data results. 
8.3 
Randomization Code Creation and Storage  
The randomization schedule will be generated under the direction of Cerevance statistician or 
designee and a copy will be provided to the site pharmacist prior to the start of study. All 
randomization information will be stored in a secured area, accessible only by authorized 
personnel. 
8.4 
Investigational Drug Blind Maintenance  
The investigational drug blind is maintained through a randomization schedule held by the 
dispensing pharmacist.  
8.5 
Unblinding Procedure  
The investigational drug blind shall not be broken by the investigator unless information 
concerning the investigational drug is necessary for the medical treatment of the subject. All 
study assessments and assignment of causality for AEs should be performed, if possible, prior to 
unblinding. In the event of a medical emergency, if possible, the medical monitor should be 
contacted before the investigational drug blind is broken to discuss the need for unblinding. 
For unblinding a subject, the investigational drug blind can be obtained by contacting the 
dispensing pharmacist. 
The sponsor must be notified as soon as possible if the investigational drug blind is broken. The 
date, time, and reason the blind is broken must be recorded in the source documents and the 
same information (except the time) must be recorded on the eCRF. 
If any site personnel are unblinded, investigational drug must be stopped immediately and the 
subject must be withdrawn from the study. 
No change should be made to any assessment of the subject after unblinding. 
8.6 
Accountability and Destruction of Sponsor-Supplied Drugs 
Drug supplies will be counted and reconciled at the site before being returned to the sponsor or 
designee or destroyed per site’s procedures. 


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The investigator or designee must ensure that the sponsor-supplied drug is used in accordance 
with the protocol and is dispensed only to subjects enrolled in the study. To document 
appropriate use of sponsor-supplied drug, the investigator or designee must maintain records of 
all sponsor-supplied drug delivery to the site, site inventory, dispensation and use by each 
subject, and return to the sponsor or designee. 
Upon receipt of sponsor-supplied drug, the investigator or designee must verify the contents of 
the shipments against the packing list. The verifier should ensure that the quantity is correct, and 
the medication is in good condition. If quantity and conditions are acceptable, investigator or 
designee should acknowledge the receipt of the shipment by signing bottom half of the packing 
list and faxing per instructions provided on the form. If there are any discrepancies between the 
packing list versus the actual product received, Cerevance must be contacted to resolve the issue. 
The packing list should be filed in the investigator’s essential document file. 
The investigator or designee must maintain 100% accountability for all sponsor-supplied drugs 
received and dispensed during his or her entire participation in the study. Proper drug 
accountability includes, but is not limited to: 
• Continuously monitoring expiration dates. 
• Frequently verifying that actual inventory matches documented inventory. 
• Verifying that the log is completed for the drug lot used to prepare each dose. 
• Verifying that all containers used are documented accurately on the log. 
• Verifying that required fields are completed accurately and legibly. 
If any dispensing errors or discrepancies are discovered, the sponsor must be notified 
immediately. 
The investigator or designee must record the current inventory of all sponsor-supplied drugs 
CVN058 or placebo on a sponsor-approved drug accountability log. The following information 
will be recorded at a minimum: protocol number and title, name of investigator, site identifier 
and number, description of sponsor-supplied drugs, expiration date and amount dispensed, 
including initials of the person dispensing the drug, and the date and amount returned to the site 
by the subject, including the initials of the person receiving the sponsor-supplied drug. The log 
should include all required information as a separate entry for each subject to whom sponsor-
supplied drug is dispensed. 
All study drug that was not returned to the site by a subject must be investigated by the site and 
appropriately documented on the drug accountability log. 
Prior to site closure or at appropriate intervals, a representative from the sponsor or its designee 
will perform sponsor-supplied drug accountability and reconciliation before sponsor-supplied 
drugs are returned to the sponsor or its designee for destruction. The investigator or designee will 
retain a copy of the documentation regarding sponsor-supplied drug accountability, return, 
and/or destruction, and originals will be sent to the sponsor or designee. 
The investigator will be notified of any expiry date or retest date extension of sponsor-supplied 
drug during the study conduct. On expiry date notification from the sponsor or designee, the site 


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must complete all instructions outlined in the notification, including segregation of expired 
sponsor-supplied drug for return to the sponsor or its designee for destruction. 


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9.0 
STUDY PLAN 
9.1 
Study Procedures 
The following sections describe the study procedures and data to be collected. For each 
procedure, subjects are to be assessed by the same investigator or site personnel whenever 
possible. The Schedule of Study Procedures is located in Appendix A. 
9.1.1 Informed Consent Procedure 
The requirements of the informed consent are described in Section 15.2. 
Informed consent must be obtained prior to the subject entering into the study, and before any 
protocol-directed procedures are performed. 
A unique subject Screening number will be assigned to each subject at the time that the informed 
consent is obtained; this Screening number will be used until the subject has been randomized 
into the study, at which time the Subject number will be primary method of identification on 
study records. 
9.1.1.1 Pharmacogenomic Informed Consent Procedure 
Pharmacogenomics informed consent is a component of the overall study informed consent. The 
requirements are described in Section 15.2. 
The pharmacogenomic sample collection is optional. 
9.1.2 Demographics, Medical History, and Medication History Procedure 
Demographic information to be obtained will include date of birth, sex, Hispanic ethnicity, race 
as described by the subject, height, weight, caffeine consumption, reproductive status (including 
last menstrual period) and smoking status of the subject at Screening.  
Medical history to be obtained will include determining whether the subject has any significant 
conditions or diseases relevant to the disease under study that stopped at or prior to signing of 
informed consent. Ongoing conditions are considered concurrent medical conditions 
(see Section 9.1.7). 
Medication history information to be obtained includes any medication relevant to eligibility 
criteria stopped at or within 45 days (for subjects with schizophrenia) prior to signing of 
informed consent. 
9.1.3 Physical Examination Procedure 
A physical examination will consist of the following body systems: (1) eyes; (2) ears, nose, 
throat; (3) cardiovascular system; (4) respiratory system; (5) gastrointestinal system; 
(6) dermatologic system; (7) extremities; (8) musculoskeletal system; (9) nervous system; 
(10) lymph nodes; and (11) other. 
Any abnormal change from the initial Screening physical examination must be assessed by the 
investigator as not clinically significant (NCS) or clinically significant (CS) and recorded in the 
source document and eCRF. 


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Any CS change, as determined by the investigator, from the baseline physical examination will 
be recorded as an AE or pretreatment event in source documentation and on the Pretreatment 
Event/AE eCRF. 
9.1.4 Weight, Height, and BMI 
A subject should have weight and height measured while wearing indoor clothing and with shoes 
off. The BMI is calculated using metric units with the formula provided below:  
The standard for collecting height is centimeters without decimal places and for weight it is 
kilograms (kg) with 1 decimal place. BMI should be derived as: 
Metric:  
BMI = weight (kg)/height (m)2 
Note that although height is measured in centimeters, the BMI formula uses meters for height; 
meters can be determined by dividing centimeters by 100. Thus, for example, if height=176 cm 
(1.76 m) and weight=79.2 kg, then BMI=79.2/1.762=25.56818 kg/m2. 
Results for BMI will be expressed with 1 decimal place and rounding is allowed. The above 
value should be captured as 25.6 kg/m2 in the database. 
9.1.5 Vital Sign Procedure  
When vital signs are scheduled at the same time as blood draws, the blood draw will take priority 
and vital signs will be obtained within 0.5 hour before or after the scheduled blood draw. 
Vital signs consisting of body temperature (oral), respiration rate, blood pressure and pulse will 
be measured in a seated resting state (>10 minutes). 
9.1.6 Documentation of Concomitant Medications 
Concomitant medication is any drug given in addition to the study medication. These may be 
prescribed by a physician or obtained by the subject over the counter. Concomitant medication is 
not provided by Cerevance. At each study visit, subjects will be asked whether they have taken 
any medication other than the study medication (used from signing of informed consent through 
the end of the study), and all medication including vitamin supplements, OTC medications, and 
oral herbal preparations, must be recorded in the eCRF. Documentation will include generic 
medication name, dose, unit, frequency, route of administration, start and end dates, and reason 
for use.  
9.1.7 Documentation of Concurrent Medical Conditions 
Concurrent medical conditions are those significant ongoing conditions or diseases that are 
present at signing of informed consent. This includes clinically significant laboratory, ECG, or 
physical examination abnormalities noted at the Screening examination. The condition (i.e., 
diagnosis) should be described. 
9.1.8 Procedures for Clinical Laboratory Samples 
All samples will be collected in accordance with acceptable laboratory procedures and as 
stipulated in the Schedule of Study Procedures (Appendix A). Abnormal Screening labs may be 


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repeated once at the discretion of the investigator for assessment of eligibility. Subjects who still 
do not meet eligibility criteria may be re-screened at investigator’s discretion. 
Table 9.a lists the tests that will be obtained for each laboratory specimen  
Table 9.a 
Clinical Laboratory Tests 
Hematology 
Serum Chemistry 
Urinalysis 
 
RBC 
WBC with differential (% 
and absolute) 
Hemoglobin 
Hematocrit 
Platelets 
Prothrombin time 
/INR/Partial thromboplastin 
time (PTT) 
ALT 
Albumin 
Alkaline phosphatase 
AST 
Total bilirubin 
Direct bilirubin 
Total protein 
Creatinine 
Blood urea nitrogen 
Creatine kinase 
GGT 
Potassium 
Sodium 
Glucose 
Chloride 
Bicarbonate 
Calcium 
pH 
Specific gravity 
Protein 
Glucose 
Blood  
Nitrite 
Microscopic Analysis 
(only if positive dipstick 
results):  
RBC/high power field 
WBC/high power field 
Epithelial cells, casts etc 
 
Diagnostic Screening: 
Serum 
Urine 
Saliva (d) 
Serum hCG (a) 
At Screening Only:  
Hepatitis panel, including HBsAg 
and anti-HCV 
FSH (b) 
Drug screen including 
amphetamines, barbiturates, 
benzodiazepines, cannabinoids, 
cocaine, opiates, alcohol, and 
cotinine (c) 
Alcohol 
cotinine 
FSH=follicle-stimulating hormone, GGT=γ-glutamyl transferase, RBC=red blood cells, WBC=white blood cells. 
(a) Serum hCG pregnancy test will be done at Screening. 
(b) FSH level will be obtained for female subjects at Screening if they are postmenopausal (i.e., last regular 
menstrual cycle >2 years) and not surgically sterile. The result must be >40 IU/L to obviate the need for 
contraception.  
(c) To be performed at Screening.  
(d) Alcohol and cotinine saliva samples may be collected, if needed. 
The local laboratory will perform laboratory tests for hematology, serum chemistries, and 
urinalysis. The results of laboratory tests will be returned to the investigator, who is responsible 
for reviewing and filing these results. 
If subjects experience ALT or AST >3 ×ULN, follow-up laboratory tests (at a minimum, serum 
alkaline phosphatase, ALT, AST, total bilirubin, GGT, and INR) should be performed within a 
maximum of 7 days and preferably within 48 to 72 hours after the abnormality was noted. 
(Please refer to Section 7.5 for discontinuation criteria, and Section 10.2.3 for the appropriate 
guidance on Reporting of Abnormal Liver Function Tests in relation to ALT or AST >3 ×ULN 
in conjunction with total bilirubin >2 ×ULN.) 


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If the ALT or AST remains elevated >3 ×ULN on these 2 consecutive occasions, the investigator 
must contact the Medical Monitor for consideration of additional testing, close monitoring, 
possible discontinuation of study medication, discussion of the relevant subject details and 
possible alternative etiologies. The abnormality should be recorded as an AE (please refer to 
Section 10.2.3 Reporting of Abnormal Liver Function Tests for reporting requirements). 
All laboratory safety data will be transferred electronically to Cerevance or designee in the 
format requested by Cerevance. If the laboratory is unable to electronically transfer data, the 
study site coordinator or designee is responsible for transcribing laboratory results into the eCRF. 
The investigator will maintain a copy of the laboratory accreditation and the reference ranges for 
the laboratory used. 
Laboratory reports must be signed and dated by the PI or sub-investigator indicating that the 
report has been reviewed and any abnormalities have been assessed for clinical significance.  
All CS laboratory abnormalities must be recorded as a PTE/AE in the subject’s source 
documents and on the appropriate eCRF. A CS laboratory abnormality that has been verified by 
retesting will be followed until the abnormality returns to an acceptable level or a satisfactory 
explanation has been obtained. 
9.1.9 Contraception and Pregnancy Avoidance Procedure 
During the study and for 12 weeks after last dose of study medication, nonsterilized males and 
female subjects of childbearing potential who are sexually active must agree to use two effective 
methods of contraception.  
From signing of informed consent, throughout the duration of the study, and for 12 weeks after 
last dose of study medication, nonsterilized** male subjects who are sexually active with a 
female partner of childbearing potential* must use barrier contraception (e.g., condom with 
spermicidal cream or jelly). In addition, they must be advised not to donate sperm during this 
period.  
From signing of informed consent, throughout the duration of the study, and for 12 weeks after 
last dose of study medication, female subjects of childbearing potential* who are sexually active 
with a nonsterilized male partner** must use adequate contraception. In addition they must be 
advised not to donate ova during this period. 
*Females NOT of childbearing potential are defined as those who have been surgically sterilized 
(hysterectomy, bilateral oophorectomy or tubal ligation) or who are postmenopausal (e.g., 
defined as at least 2 years since last regular menses with an FSH>40 IU/L or at least 5 years 
since last regular menses, confirmed before any study medication is implemented). 
**Sterilized males should be at least 1 year postvasectomy and have confirmed that they have 
obtained documentation of the absence of sperm in the ejaculate. 
The following are acceptable forms of contraception: 


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Barrier methods (each time the subject has 
intercourse): 
Intrauterine devices (IUDs): 
• Male condom PLUS spermicide. 
• Cap (plus spermicidal cream or jelly). 
• Diaphragm (plus spermicidal cream or 
jelly). 
Hormonal Contraception (stable regimen) 
• Birth control pills or patch. 
• Injected hormonal contraceptive  
(such as Depo-Provera). 
• Vaginal hormonal ring  
(such as NuvaRing). 
• Copper T PLUS condom or spermicide. 
Subjects will be provided with information on acceptable methods of contraception as part of the 
subject informed consent process and will be asked to sign a consent form stating that they 
understand the requirements for avoidance of pregnancy, donation of ova, and sperm donation 
during the course of the study. 
During the course of the study, regular serum human chorionic gonadotropin (hCG) pregnancy 
tests will be performed only for women of childbearing potential, and subjects will receive 
guidance with respect to the avoidance of pregnancy. In addition to a negative serum hCG 
pregnancy test at Screening, subjects also must have a negative urine hCG pregnancy test prior to 
receiving any dose of study medication. Male subjects must be advised not to donate sperm from 
signing of informed consent to 12 weeks after the last dose of study medication. 
9.1.10 Pregnancy 
If any subject is found to be pregnant during the study she should be withdrawn and any sponsor-
supplied drug should be immediately discontinued. In addition, any pregnancies in the partner of 
a male subject during the study or for 12 weeks after the last dose should also be recorded 
following authorization from the subject’s partner.  
If the pregnancy occurs during administration of active study medication, e.g., after Visit 1 or 
within 12 weeks of the last dose of active study medication, the pregnancy should be reported 
immediately, using a pregnancy notification form, to the contact listed in Section 1.0. 
Should the pregnancy occur during or after administration of blinded drug, the investigator must 
inform the subject of their right to receive treatment information. If the subject chooses to 
receive unblinded treatment information, the individual blind should be broken by the 
investigator. Subjects who have only received placebo need not be followed. 
If the female subject and/or female partner of a male subject agrees to the primary care physician 
being informed, the investigator should notify the primary care physician that the subject/female 


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partner of the subject was participating in a clinical study at the time she became pregnant and 
provide details of treatment the subject received (blinded or unblinded, as applicable). 
All reported pregnancies will be followed up to final outcome, using the pregnancy form. The 
outcome, including any premature termination, must be reported to the sponsor. An evaluation 
after the birth of the child will also be conducted. 
9.1.11 ECG Procedure  
A standard 12-lead ECG will be recorded in a supine position resting for at least 10 minutes at 
Screening to assess eligibility. The ECGs will be recorded in triplicate at approximately 5 minute 
intervals. The investigator (or a qualified physician at the investigational site) will interpret the 
ECG using 1 of the following categories: within normal limits, abnormal but NCS, or abnormal 
and CS. A copy of the ECG trace should be kept with the subject’s notes. 
ECGs will be read automatically and also, the investigator or sub-investigator or a suitably 
qualified delegate will manually interpret the ECG using 1 of the following categories: within 
normal limits, abnormal NCS, or abnormal and CS. All 12-lead ECGs will be stored for manual 
measurement of intervals, if necessary.  
Twelve-lead ECGs will be recorded using an ECG machine that automatically calculates the 
heart rate and measures PR interval, RR interval, QRS interval, QT interval, and QTcF and 
QTcB (Fridericia’s and Bazett’s correction) intervals.  
One copy of the 12-lead ECG with the physician’s signature and date of assessment will be filed 
with the source documents and captured in the appropriate eCRF. All ECGs will be recorded at 
the time points detailed in the Schedule of Study Procedures (Appendix A). 
9.1.12 Pharmacogenomic Sample Collection 
Every subject must sign informed consent/be consented in order to participate in the study, but 
consent to participate in the pharmacogenomic sample collection (genetic substudy) is optional. 
Deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) form the basis for the genes that 
make the body produce proteins such as enzymes, drug transporters or drug targets, and may be 
evaluated for the genetic contribution how the drug is broken down, or how the drug affects the 
body. This is called a “pharmacogenomics research study.” Specific purposes of this study 
include: 
• Identifying genetic reasons why certain people respond differently to CVN058. 
• Finding out more information about how CVN058 works. 
• Generating information needed for research, development, and regulatory approval of tests to 
predict response to CVN058. 
• Identifying variations in genes related to the biological target of CVN058. 
This information may be used, for example, to develop a better understanding of the safety and 
efficacy of CVN058 and other study medications, and for improving the efficiency, design and 
study methods of future research studies. 


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The DNA samples will be used to evaluate common variations in genes which encode drug 
metabolizing enzymes and transporters. This could be helpful in understanding why there are 
differences in CVN058 kinetics between subjects. Also, since pharmacogenomics is an evolving 
science, many genes and their functions are not yet fully understood. Future data may suggest a 
role of some of these genes in drug response, which may lead to additional hypothesis-generating 
exploratory research and diagnostic development on stored samples. 
Whole blood will be collected and stored for possible DNA or RNA isolation and analysis.  
DNA sample collection: 
One 6 mL whole blood sample will be collected before study drug dosing on Day 1 of 
Period 1 only from each subject in the study, into plastic potassium ethylenediamine 
tetraacetic acid (K2EDTA) spray-coated tubes, and stored under frozen conditions.  
RNA sample collection: 
Two whole blood samples (2.5 mL per sample) will be collected from each subject into a 
PAXgene tube on Day 1 of each period at pre dose and post EEG for RNA 
pharmacogenomic analysis.  
If isolation of DNA from the first sample was not successful or possible, a second aliquot of 
blood may be taken, if feasible. 
Each pharmacogenomic sample for a study subject should be identifiable on the requisition form 
with the 7-digit subject ID. Detailed instructions for the handling, shipping, and storage of 
pharmacogenomic samples will be provided in the lab manual.  
The samples will be stored for no longer than 15 years after completion of the CVN058 study 
and/or until the drug development of CVN058 is no longer actively pursued by Cerevance or its 
collaborators. No samples will be stored for longer than permitted by the applicable law and 
samples will be destroyed upon notification from Cerevance. 
9.1.13 Pharmacokinetic Sample Collection 
9.1.13.1 Collection of Blood for Pharmacokinetic Sampling 
Blood samples (one 6-mL sample per scheduled time) will be collected for analysis of CVN058, 
and its metabolite if appropriate; plasma will be collected into chilled vacutainers containing 
K2EDTA according to the schedule in Appendix A. Instructions for sample processing and 
shipment will be provided in the lab manual. 
Serial blood samples for determination of CVN058, and its metabolite if appropriate, in plasma 
will be collected according to Table 9.b. 
Table 9.b 
Collection of Blood Samples for CVN058 Pharmacokinetic Analysis 
Sample 
Type 
Dosing Day 
Time Postdose (hours) 
Plasma 
1 
Predose (within 15 minutes prior to dosing), 1 hour post dose (pre-EEG), and 5 hours 
post dose (post-EEG)   
 


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The PK samples will be collected before any other assessments are performed, if scheduled at the 
same time point. The actual time of sample collection will be recorded on the source document 
and eCRF. 
Placebo samples will not be analyzed by the bioanalytical laboratory except 1 sample per subject 
receiving placebo around the expected time at which CVN058 Cmax is expected to occur to 
ensure from a safety perspective that no subjects have inadvertently received active treatment. 
9.1.13.2 Bioanalytical Methods 
Plasma concentrations of CVN058 will be measured by high-performance liquid 
chromatography with tandem mass spectrometry. If appropriate, plasma samples analyzed for 
CVN058 also may be analyzed for the CVN058 metabolite. 
9.1.14 Pharmacokinetic Parameters  
The PK parameters of CVN058, and its metabolite (if appropriate), will be derived using non-
compartmental analysis methods. The PK parameters will be determined from the concentration-
time data for all evaluable subjects. Actual sampling times, rather than scheduled sampling 
times, will be used in all computations involving sampling times. The following PK parameters 
will be determined from concentrations of CVN058, and its metabolite if appropriate, in plasma. 
Other parameters may be calculated as appropriate.  
Symbol/Term 
Definition 
Plasma 
AUCt 
Area under the plasma concentration-time curve from time 0 to time of the last 
quantifiable concentration. 
Cmax 
Maximum observed plasma concentration. 
tmax 
Time to reach Cmax. 
 
9.1.15 Pharmacodynamic Sample Collection  
MMN will be used as a PD assessment. At each testing session, the following PD assessments 
will be performed during the EEG: MMN, P50, gamma power, and P300. Collection of P50 may 
be omitted if the essential equipment is not available. The testing session during each Treatment 
Period will begin approximately 1.5 hours after administration of study drug.  
9.1.16 Pharmacodynamic Parameters  
All EEG parameters will be obtained in accordance with the EEG acquisition guideline provided 
by Cerevance or their designee. It is anticipated that each EEG procedure will take 
approximately 4 hours to complete, including approximately 30 minutes to set up, 3 hours 
acquisition time, and 30 minutes to clean up. 
MMN 
MMN is a pre-attentive auditory component elicited by deviant stimuli in an auditory oddball 
task. MMN predominantly reflects activation of neuronal ensembles within primary auditory 
cortex, and thus indexes sensory level disturbance in schizophrenia. MMN will be obtained 


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independently to pitch and duration deviant stimuli. MMN is maximal at frontocentral electrodes 
(Fz, Cz). Mean peak amplitude at 5 electrodes surrounding Fz within a predefined latency range 
will be the primary outcome measure. 
P50 
P50 auditory evoked potentials will be recorded. Participants will be seated and instructed to 
relax and to focus their eyes on a fixation point. Stimulus signal of 90-dB pulses of 0.1 msec in 
duration will be generated and recorded the event-related potential waveforms.  
32 pairs of auditory clicks will be presented every 10 seconds, with a 500 msec interclick 
interval. 
 
The conditioning P50 wave (S1) and test P50 wave (S2) will be identified as the power in the 
alpha/beta frequency bands as suggested by Smucny et al. (Smucny, 2013). The data from the 
vertex (Cz) and surrounding electrodes will be collected and the P50 gating ratios will be 
calculated as the ratio of the test P50 to the conditioning P50 power. In case the Cz gating ratio is 
>0.2 units above the surrounding electrodes, the value will be discarded and replaced with the 
value from surrounding electrodes. P50 ratio will be defined as the ratio of S2/S1 power. The S2-
S1 difference score as suggested by Smucny et al. (Smucny, 2013) will be used as an exploratory 
outcome measure.  
Quantitative Electroencephalogram, Gamma Power 
Five minute eyes open/close recordings will be obtained during each recording session. Ten 1-
second, artifact-free epochs will be chosen for quantitative analysis. Primary outcome measures 
will consist of power within delta (0.5 – 4 Hz), theta (4-7 Hz), alpha (8-13 Hz), delta (13-20 Hz), 
low gamma (20-40 Hz) and high gamma (40 – 60 Hz) over predesignated frontal, central, 
temporal and occipital sites. In addition, specific measures of 40 Hz activity will be assessed in 
response to repetitive 40 Hz auditory stimulation. 
P300 
As opposed to MMN, which are obtained under passive (i.e., no-task) conditions, auditory P300 
will be obtained only when subjects must attend to and detect novel task-relevant deviant stimuli. 
Generators for P300 are located in distributed frontoparietal networks and so represent an index 
of higher order, “cognitive” processing in schizophrenia. P300 will be obtained to deviant 
auditory stimuli in an auditory “oddball” paradigm. P300 is maximal in amplitude at Fz and Pz 
electrodes. Primary outcome measures will consist of peak amplitude within prespecified latency 
range at the frontal/parietal sites. 
9.1.17 Positive and Negative Syndrome Scale 
The PANSS was developed and standardized for typological and dimensional assessment of 
schizophrenic phenomena. In this study, empirically derived factors are tested excluding those 
items that could not be assessed during the test sessions: positive symptom factor (delusions, 
unusual thoughts, somatic concern, grandiosity, suspiciousness, and hallucinations), negative 
symptom factor (emotional withdrawal, blunted affect, poor rapport, disturbance of volition, 
preoccupation, and motor retardation), cognitive factor (difficulty in abstract thinking, 
stereotyped thinking, cognitive disorganization, lack of judgment and insight, poor attention, 


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tension, mannerisms, and posturing), hostility (excitement, hostility, impulse control, and 
uncooperativeness), emotional discomfort (depression, anxiety, and guilt). PANSS will be 
collected at Screening, Early Termination, and at the Follow-up Visit if clinically significant 
findings were observed upon discharge. In these cases, subjects must then be brought back to the 
clinic for re-evaluation per investigator’s discretion.  
The duration of the PANSS is approximately 30 minutes (Kay, 1990). 
9.1.18 Columbia Suicide Severity Rating Scale 
The determination and management of patients’ suicidality risk is the Investigators’ 
responsibility. For study purposes, suicidality will be assessed by the use of the C-SSRS. The C-
SSRS is a 3-part scale that measures suicidal ideation (e.g., subject endorses thoughts about a 
wish to be dead or has other thoughts of suicide), intensity of ideation (frequency, duration, 
controllability, deterrents, and reasons for ideation), and suicidal behavior (actually, interrupted, 
and aborted attempts at suicide) (Mundt, 2013). 
The C-SSRS is a 2-page questionnaire that prospectively assesses suicidal thoughts and behavior 
using a structured interview for patient responses. Suicidal ideation is classified on a 5-item 
scale: 1 (wish to be dead), 2 (nonspecific active suicidal thoughts), 3 (active suicidal ideation 
with any methods [not plan] without intent to act), 4 (active suicidal ideation with some intent to 
act, without specific plan), and 5 (active suicidal ideation with specific plan and intent). The C-
SSRS also captures information about the intensity of ideation, specifically the frequency, 
duration, controllability, deterrents, and reasons for the most severe types of ideation. Suicidal 
behavior is classified on a 5-item scale: 0 (no suicidal behavior), 1 (preparatory acts or behavior), 
2 (aborted attempt), 3 (interrupted attempt), and 4 (actual attempt). 
Different versions of the scale are available. In this study, “Baseline/Screening” version will be 
used at Screening Visit and “Since last visit” version at all subsequent visits. “Since the last 
visit” should collect information from the last visit where C-SSRS was administered. If the 
patient’s response generates a change in the findings report from negative to positive, the patient 
should be referred for immediate psychiatric evaluation on the same date as the site visit. 
Positive suicidality findings, if confirmed by the PI, is considered to be a serious event. If arising 
after signing informed consent but prior to administration of any study medication, it is 
considered a Pretreatment Event (PTE). If arising after administration of any study medication, it 
is considered an SAE.  
The C-SSRS will be administered by the PI or a trained designee on paper and captured in the 
eCRF. The same interviewer should be used throughout the study for the same subject where 
possible. 
9.1.19 Documentation of Screen Failure 
Investigators must account for all subjects who sign informed consent. If the subject is found to 
be not eligible at this visit, the investigator should complete the eCRF screen failure form. 
The primary reason for screen failure is recorded in the eCRF using the following categories: 
• PTE/AE. 


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• Did not meet inclusion criteria or did meet exclusion criteria. 
• Significant protocol deviation. 
• Lost to follow-up. 
• Voluntary withdrawal. 
• Study termination. 
• Other <specify reason>. 
Subject numbers assigned to subjects who fail Screening should not be reused. 
9.1.20 Documentation of Randomization 
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible 
for randomization into the treatment phase. Randomization will take place on Day 1 of 
Treatment Period 1. 
If the subject is found to be not eligible for randomization, the investigator should record the 
primary reason for failure on the applicable eCRF. 
9.2 
Monitoring Subject Treatment Compliance 
Study medication will be administered while subjects are under observation in the clinical 
research unit. Following administration of the study medication, appropriate mouth and/or hand 
checks will be performed to ensure that the dose is swallowed and noted in the source document. 
The date and time of each dose will be recorded in the source documents and on the eCRFs. An 
inventory of the study medication supplies dispensed will be performed by the site pharmacist or 
authorized study designee and recorded onto the Drug Accountability Log in the subject’s source 
document records or equivalent. The exact dose time of consecutive subjects may be staggered to 
facilitate logistics at the site. 
9.3 
Schedule of Observations and Procedures 
The schedule for all study-related procedures for all evaluations is shown in Appendix A. 
Assessments should be completed at the designated visit/time point(s). 
9.3.1 Screening 
Subjects with schizophrenia will be screened within 28 days prior to enrollment. All subjects will 
be screened in accordance with predefined inclusion and exclusion criteria as described in 
Section 7.0. See Section 9.1.17 for procedures for documenting screen failures.  Following 
written informed consent, Screening procedures may be conducted on different days. 
Assessments to be conducted during the Screening period are outlined in Appendix A. 
9.3.2 Treatment Phase 
The treatment will be administered over 3 Periods, separated by 7-10 days for washout.  
Assessments to be conducted during the screening period are outlined in Appendix A. 


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9.3.3 Final Visit/End of Treatment  
The Final Visit additional assessments will occur prior to Discharge from the clinic at the end of 
Treatment Period 3, Day 1, as outlined in Appendix A. 
For all subjects who received any study medication, the investigator must complete the End of 
Study eCRF page. 
9.3.4 Early Termination 
The reason for discontinuation must be documented in the source document and eCRF. The 
procedures outlined in Appendix A will be performed and documented. 
For all subjects receiving study medication, the investigator must complete the End of Study 
eCRF page. 
9.3.5 Follow-up Visit/Telephone Call  
The Follow-up Visit will occur by telephone approximately 7-10 days after receiving the last 
dose of study medication (Treatment Period 3) unless abnormal, clinically significant findings 
were observed upon discharge. In these cases, subjects must then be brought back to the clinic 
for re-evaluation per investigator’s discretion. 
9.4 
Biological Sample Retention and Destruction  
In this study, specimens for genome/gene analysis will be collected as described in Section 
9.1.12, Pharmacogenomic Sample Collection. The genetic material will be preserved and 
retained by a biorepository contracted by Cerevance for up to but not longer than 15 years or as 
required by applicable law.  
The samples will be sent to a central laboratory that processes the blood sample and serves as a 
secure storage facility. The sponsor and researchers working with the sponsor will have access to 
the samples collected and any test results. All samples collected during the study will be stored 
securely with limited access and the sponsor will require anyone who works with the samples to 
agree to hold the research information and any results in confidence. 
The sample will be labeled with a unique sample identifier similar to labeling in the main study. 
During the “storage” stage, the sample will be used in the analysis of the study drug and related 
disease states. At this stage, sample and data are linked to personal health information with code 
numbers. This link means that patients may be identifiable but only indirectly. The code numbers 
will be kept secure by the sponsor.  
Subjects who consented and provided a pharmacogenomic sample for DNA and RNA analysis 
can withdraw their consent and request disposal of a stored sample at any time prior to analysis. 
Notify sponsor of consent withdrawal. 
9.5 
Blood Volume 
Total blood sampling volume for an individual subject is shown in Table 9.c. 


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Table 9.c 
Approximate Blood Volume 
Sample Type 
Sample 
Volume 
(mL) 
Screening  
(x1) 
 
Number of Samples per 
Period  
(x 3 Periods) 
End of 
Treatment 
Total 
Volume 
(mL) 
Safety 
Laboratory 
Samples (a) 
12.5 
1 
-- 
1 
25 
Hepatitis Panel 
5 
1 
-- 
 
5 
FSH (b) 
3 
1 
-- 
 
3 
PK Samples 
6 
-- 
9 
-- 
54 
DNA Sample 
6 
-- 
1 (c) 
-- 
6 
RNA Samples 
5 
-- 
6 
-- 
30 
 
Total Blood Sampling Volume (per Study) 
 
123 
(a) Includes Hematology, serum chemistry, and coagulation panel. 
(b) FSH level will be obtained for female subjects at Screening if they are postmenopausal (i.e. last regular 
menstrual cycle >2 years) and not surgically sterile. 
(c) Only collected in Day 1, Period 1. 
 
The maximum volume of blood at any single day is approximately 40 mL, and the approximate 
total volume of blood for the study is approximately 123 mL.  
Direct venipuncture is the preferred method of blood collection. Any other method will need to 
be approved by the Sponsor. 


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10.0 
PRETREATMENT EVENTS AND ADVERSE EVENTS 
10.1 
Definitions 
10.1.1 PTEs 
A PTE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study but prior to administration of any study 
medication; it does not necessarily have to have a causal relationship with study participation. 
10.1.2 AEs 
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a drug; it does not necessarily have to have a causal relationship with this 
treatment. 
An AE can therefore be any unfavorable and unintended sign (e.g., a clinically significant 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug 
whether or not it is considered related to the drug. 
10.1.3 Additional Points to Consider for PTEs and AEs 
An untoward finding generally may: 
• Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent 
events for pre existing conditions or underlying disease should not be considered PTEs or 
AEs.) 
• Necessitate therapeutic intervention. 
• Require an invasive diagnostic procedure. 
• Require discontinuation or a change in dose of study medication or a concomitant 
medication. 
• Be considered unfavorable by the investigator for any reason.  
• PTEs/AEs caused by a study procedure (e.g., a bruise after blood draw) should be recorded 
as a PTE/AE. 
Diagnoses vs signs and symptoms: 
• Each event should be recorded to represent a single diagnosis. Accompanying signs 
(including abnormal laboratory values or ECG findings) or symptoms should NOT be 
recorded as additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be 
recorded appropriately as a PTE(s) or as an AE(s). 
Laboratory values and ECG findings: 
• Changes in laboratory values or ECG parameters are only considered to be PTEs or AEs if 
they are judged to be clinically significant (i.e., if some action or intervention is required or if 
the investigator judges the change to be beyond the range of normal physiologic fluctuation). 
A laboratory re-test and/or continued monitoring of an abnormal value are not considered an 


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intervention. In addition, repeated or additional noninvasive testing for verification, 
evaluation or monitoring of an abnormality is not considered an intervention. 
• If abnormal laboratory values or ECG findings are the result of pathology for which there is 
an overall diagnosis (e.g., increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as a PTE or as an AE. 
Pre-existing conditions: 
• Pre-existing conditions (present at the time of signing of informed consent) are considered 
concurrent medical conditions and should NOT be recorded as PTEs or AEs. Baseline 
evaluations (e.g., laboratory tests, ECG, X-rays etc.) should NOT be recorded as PTEs unless 
related to study procedures. However, if the subject experiences a worsening or complication 
of such a concurrent condition, the worsening or complication should be recorded 
appropriately as a PTE (worsening or complication occurs before start of study medication) 
or an AE (worsening or complication occurs after start of study medication). Investigators 
should ensure that the event term recorded captures the change in the condition (e.g., 
“worsening of…”). 
• If a subject has a pre-existing episodic condition (e.g., asthma, epilepsy) any occurrence of an 
episode should only be captured as a PTE/AE if the episodes become more frequent, serious 
or severe in nature, that is, investigators should ensure that the AE term recorded captures the 
change in the condition from Baseline (e.g. “worsening of…”). 
• If a subject has a degenerative concurrent condition (e.g., cataracts, rheumatoid arthritis), 
worsening of the condition should only be captured as a PTE/AE if occurring to a greater 
extent to that which would be expected. Again, investigators should ensure that the AE term 
recorded captures the change in the condition (e.g., “worsening of…”). 
Worsening of PTEs or AEs: 
• If the subject experiences a worsening or complication of a PTE after starting administration 
of the study medication, the worsening or complication should be recorded appropriately as 
an AE. Investigators should ensure that the AE term recorded captures the change in the 
condition (e.g., “worsening of…”). 
• If the subject experiences a worsening or complication of an AE after any change in study 
medication, the worsening or complication should be recorded as a new AE. Investigators 
should ensure that the AE term recorded captures the change in the condition (e.g., 
“worsening of…”). 
Changes in severity of AEs /Serious PTEs: 
• If the subject experiences changes in severity of an AE/serious PTE, the event should be 
captured once with the maximum severity recorded. 
Preplanned surgeries or procedures: 
• Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered PTEs or AEs. However, if a preplanned procedure is 
performed early (e.g., as an emergency) due to a worsening of the pre-existing condition, the 


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worsening of the condition should be captured appropriately as a PTE or an AE. 
Complications resulting from any planned surgery should be reported as AEs. 
Elective surgeries or procedures: 
• Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as PTEs or AEs, but should be documented in the subject’s source 
documents. Complications resulting from an elective surgery should be reported as AEs. 
Overdose: 
• Cases of overdose with any medication without manifested side effects are NOT considered 
PTEs or AEs, but instead will be documented on an Overdose page of the eCRF. Any 
manifested side effects will be considered PTEs or AEs and will be recorded on the AE page 
of the eCRF. 
• Suicidal Ideation and Behavior:  
• A completed suicide is always a SAE based on its fatal outcome. C-SSRS score of 4 (active 
suicidal ideation with some intent to act) or 5 (active suicidal ideation with specific plan and 
intent) would likely indicate serious suicidal ideation and can be used to trigger intervention 
procedures to provide urgent care. Such procedures may include further evaluation and 
appropriate management; and/or immediate contact with (or need for a referral to) the 
subject’s mental health practitioner; and/or possible referral to the emergency room; and/or 
admission to an in-subject unit. For the purpose of this protocol active suicidal ideation level 
4 and 5 should be considered important medical events and reported as serious irrespective of 
whether the subject was hospitalized or not.  
• Unless the event meets other serious criteria, suicidal thoughts or suicidal ideations that do 
not include a definite plan or intention to act will be collected as non-serious adverse events 
in accordance with the standard AE reporting requirements (e.g., if a pre-existing suicidal 
ideation recorded on the screening C-SSRS got worse during the study, it should be reported 
as an AE).  
• A subject presenting with self-mutilation or other types of self-injury should be questioned 
by the investigator to clarify if the action was suicidal in intent. If the event was suicidal in 
intent, the investigator should include suicidal behavior as part of the verbatim term on the 
eCRF, that is, “slit wrists/suicidal behavior”. Such an event will be collected as a serious 
adverse event.  
• Acts of self-mutilation or self-injury without suicidal intention (i.e., self-imposed cigarette 
burns), will be collected as non-serious adverse events, unless they meet other seriousness 
criteria.  
10.1.4 SAEs 
An SAE is defined as any untoward medical occurrence that at any dose: 
1. Results in DEATH. 
2. Is LIFE THREATENING. 


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• The term “life threatening” refers to an event in which the subject was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have caused 
death if it were more severe. 
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization. 
4. Results in persistent or significant DISABILITY/INCAPACITY. 
5. Is a CONGENITAL ANOMALY/BIRTH DEFECT. 
• Report if you suspect that exposure to a medical product prior to conception or during 
pregnancy may have resulted in an adverse outcome in the child. 
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following: 
• May require intervention to prevent items 1 through 5 above. 
• May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization. 
• Includes any event or synonym described in the Medically Significant AE List 
(Table 10.a). 
Table 10.a 
Medically Significant AE List 
Term 
Acute respiratory failure/acute respiratory distress 
syndrome 
Hepatic necrosis 
Torsade de pointes / ventricular fibrillation / ventricular 
tachycardia 
Acute liver failure 
Anaphylactic shock 
Malignant hypertension 
Acute renal failure 
Convulsive seizure 
Pulmonary hypertension 
Agranulocytosis 
Pulmonary fibrosis 
Aplastic anemia 
Confirmed or suspected endotoxin shock 
Toxic epidermal necrolysis/Stevens-Johnson syndrome Confirmed or suspected transmission of infectious agent by 
a medicinal product 
 
Serotonin syndrome 
Neuroleptic malignant syndrome / malignant hyperthermia 
 
Spontaneous abortion / stillbirth and fetal death 
 
PTEs that fulfill 1 or more of the serious criteria above are also to be considered SAEs and 
should be reported and followed up in the same manner (see Sections 10.2.2 and 10.3). 
10.1.5 Severity of PTEs and AEs 
The different categories of intensity (severity) are characterized as follows: 
Mild: 
The event is transient and easily tolerated by the subject. 
Moderate: 
The event causes the subject discomfort and interrupts the subject’s usual activities. 
Severe: 
The event causes considerable interference with the subject’s usual activities. 


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10.1.6 Causality of AEs 
The relationship of each AE to study medication(s) will be assessed using the following 
categories: 
Related: 
An AE that follows a reasonable temporal sequence from administration of a drug (including 
the course after withdrawal of the drug), or for which possible involvement of the drug cannot 
be ruled out, although factors other than the drug, such as underlying diseases, complications, 
concomitant drugs and concurrent treatments, may also be responsible. 
Not Related: 
An AE that does not follow a reasonable temporal sequence from administration of a drug 
and/or that can reasonably be explained by other factors, such as underlying diseases, 
complications, concomitant drugs and concurrent treatments. 
10.1.7 Relationship to Study Procedures 
Relationship (causality) to study procedures should be determined for all PTEs and AEs. 
The relationship should be assessed as Related if the investigator considers that there is 
reasonable possibility that an event is due to a study procedure. Otherwise, the relationship 
should be assessed as Not Related. 
10.1.8 Start Date 
The start date of the AE/PTE is the date that the first signs/symptoms were noted by the subject 
and/or physician. 
10.1.9 
Stop Date  
The stop date of the AE/PTE is the date at which the subject recovered, the event resolved but 
with sequelae or the subject died. 
10.1.10 Frequency  
Episodic AEs/PTE (e.g., vomiting) or those which occur repeatedly over a period of consecutive 
days are intermittent. All other events are continuous. 
10.1.11 Action Concerning Study Medication  
• Drug withdrawn – a study medication is stopped due to the particular AE. 
• Dose not changed – the particular AE did not require stopping a study medication. 
• Unknown – only to be used if it has not been possible to determine what action has been 
taken. 
• Not Applicable – a study medication was stopped for a reason other than the particular AE 
(e.g., the study has been terminated, the subject died, dosing with study medication was 
already stopped before the onset of the AE). 
10.1.12 Outcome 
• Recovered/Resolved – Subject returned to first assessment status with respect to the AE/PTE. 


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• Recovering/Resolving – the intensity is lowered by one or more stages: the diagnosis or 
signs/symptoms has almost disappeared; the abnormal laboratory value improved, but has not 
returned to the normal range or to Baseline; the subject died from a cause other than the 
particular AE/PTE with the condition remaining “recovering/resolving”. 
• Not recovered/not resolved – there is no change in the diagnosis, signs or symptoms; the 
intensity of the diagnosis, signs/ symptoms or laboratory value on the last day of the 
observed study period has got worse than when it started; is an irreversible congenital 
anomaly; the subject died from another cause with the particular AE/PTE state remaining 
“Not recovered/not resolved”. 
• Resolved with sequelae – the subject recovered from an acute AE/PTE but was left with 
permanent/significant impairment (e.g., recovered from a cardiovascular accident but with 
some persisting paresis). 
• Fatal – the AEs/PTEs which are considered as the cause of death. 
• Unknown – the course of the AE/PTE cannot be followed up due to hospital change or 
residence change at the end of the subject’s participation in the study. 
10.2 
Procedures 
10.2.1 Collection and Reporting of AEs 
10.2.1.1 PTE and AE Collection Period 
Collection of PTEs will commence from the time the subject signs the informed consent to 
participate in the study and continue until the subject is first administered study medication on 
Day 1 Period 1 of Part 2 or until screen failure. For subjects who discontinue prior to study 
medication administration, PTEs are collected until the subject discontinues study participation. 
Collection of AEs will commence from the time that the subject is first administered study 
medication Day 1 Treatment Period 1. Routine collection of AEs will continue until 21 days 
following last dose. 
10.2.1.2 PTE and AE Reporting 
At each study visit, the investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Subjects may report AEs occurring at any other time during the study. Subjects experiencing a 
serious PTE must be monitored until the symptoms subside and any clinically relevant changes 
in laboratory values have returned to Baseline or there is a satisfactory explanation for the 
change. Non-serious PTEs, related or unrelated to the study procedure, need not to be followed-
up for the purposes of the protocol. 
All subjects experiencing AEs, whether considered associated with the use of the study 
medication or not, must be monitored until the symptoms subside and any clinically relevant 
changes in laboratory values have returned to Baseline or until there is a satisfactory explanation 
for the changes observed. All PTEs and AEs will be documented in the PTE/AE page of the 


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eCRF, whether or not the investigator concludes that the event is related to the drug treatment. 
The following information will be documented for each event: 
1. Event term. 
2. Start and stop date. 
3. Frequency. 
4. Severity. 
5. Investigator’s opinion of the causal relationship between the event and administration of 
study medication(s) (related or not related) (not completed for PTEs). 
6. Investigator’s opinion of the causal relationship to study procedure(s), including the details 
of the suspected procedure. 
7. Action concerning study medication (not applicable for PTEs). 
8. Outcome of event. 
9. Seriousness. 
10.2.2 Collection and Reporting of SAEs 
When an SAE occurs through the AE collection period it should be reported according to the 
following procedure: 
A Cerevance SAE form must be completed, in English, and signed by the investigator 
immediately or within 24 hours of first onset or notification of the event. The information should 
be completed as fully as possible but contain, at a minimum: 
• A short description of the event and the reason why the event is categorized as serious. 
• Subject identification number. 
• Investigator’s name. 
• Name of the study medication(s). 
• Causality assessment. 
The SAE form should be transmitted within 24 hours to the attention of the contact listed in 
Section 1.0.  
Any SAE spontaneously reported to the investigator following the AE collection period should 
be reported to the sponsor if considered related to study participation. 
Reporting of Serious PTEs will follow the procedure described for SAEs. 
10.2.3 Reporting of Abnormal Liver Function Tests 
If a subject is noted to have ALT or AST elevated >3 ×ULN on 2 consecutive occasions, the 
abnormality should be recorded as an AE. In addition, an LFT Increases eCRF must be 
completed providing additional information on relevant recent history, risk factors, clinical signs 
and symptoms and results of any additional diagnostic tests performed. 


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If a subject is noted to have ALT or AST >3 ×ULN and total bilirubin >2 ×ULN for which an 
alternative etiology has not been identified, the event should be recorded as an SAE and reported 
as per Section 10.2.2. The investigator must contact the Medical Monitor for discussion of the 
relevant subject details and possible alternative etiologies, such as acute viral hepatitis A or B or 
other acute liver disease or medical history/concurrent medical conditions. Follow-up laboratory 
tests as described in Section 9.1.8 must also be performed. In addition, an LFT Increases eCRF 
must be completed and transmitted with the Cerevance SAE form (as per Section 10.2.2). 
10.3 
Follow-up of SAEs 
If information is not available at the time of the first report, but becomes available at a later date, 
the investigator should complete a follow-up SAE form or provide other written documentation 
and fax it immediately within 24 hours of receipt. Copies of any relevant data from the hospital 
notes (e.g., ECGs, laboratory tests, discharge summary, postmortem results) should be sent to the 
addressee, if requested. 
All SAEs should be followed up until resolution or permanent outcome of the event. The 
timelines and procedure for follow-up reports are the same as those for the initial report. 
10.3.1 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities  
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, including the European 
Medicines Agency (EMA), investigators and IRBs or IECs, as applicable, in accordance with 
national regulations in the countries where the study is conducted. Relative to the first awareness 
of the event by/or further provision to the sponsor or sponsor’s designee, SUSARs will be 
submitted to the regulatory authorities as expedited report within 7 days for fatal and life-
threatening events and 15 days for other serious events, unless otherwise required by national 
regulations. The sponsor will also prepare an expedited report for other safety issues where these 
might materially alter the current benefit-risk assessment of an investigational medicinal product 
or that would be sufficient to consider changes in the investigational medicinal products 
administration or in the overall conduct of the trial. The investigational site also will forward a 
copy of all expedited reports to his or her IRB or IEC in accordance with national regulations. 


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11.0 
STUDY-SPECIFIC COMMITTEES 
No steering committee, data safety monitoring committee, or clinical endpoint committee will be 
used in this study. 


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12.0 
DATA HANDLING AND RECORDKEEPING 
The full details of procedures for data handling will be documented in the Data Management 
Plan. AEs, PTEs, medical history, and concurrent conditions will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the World Health 
Organization Drug Dictionary (WHODRUG). 
12.1 
CRFs (Electronic) 
Completed eCRFs are required for each subject who signs an informed consent. 
The sponsor or its designee will supply investigative sites with access to eCRFs. The sponsor 
will make arrangements to train appropriate site staff in the use of the eCRFs. These forms are 
used to transmit the information collected in the performance of this study to the sponsor and 
regulatory authorities. eCRFs must be completed in English. 
After completion of the entry process, computer logic checks will be run to identify items, such 
as inconsistent dates, missing data, and questionable values. Queries may be issued by Cerevance 
personnel (or designees) and will be answered by the site.  
Corrections to eCRFs are recorded in an audit trail that captures the old information, the new 
information, identification of the person making the correction, the date the correction was made, 
and the reason for change. Reasons for significant corrections should additionally be included. 
The PI must review the eCRFs for completeness and accuracy and must sign and date the 
appropriate eCRFs as indicated. Furthermore, the investigator must retain full responsibility for 
the accuracy and authenticity of all data entered on the eCRFs. 
After the lock of the clinical study database, any change of, modification of or addition to the 
data on the eCRFs should be made by the investigator with use of change and modification 
records of the eCRFs. The principle investigator must review the data change for completeness 
and accuracy, and must sign, and date. 
The eCRFs will be reviewed for completeness and acceptability at the study site during periodic 
visits by study monitors. The sponsor or its designee will be permitted to review the subject’s 
medical and hospital records pertinent to the study to ensure accuracy of the eCRFs. The 
completed eCRFs are the sole property of the sponsor and should not be made available in any 
form to third parties, except for authorized representatives of appropriate governmental health or 
regulatory authorities, without written permission of the sponsor. 
12.2 
Record Retention 
The investigator agrees to keep the records stipulated in Section 12.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated informed consent forms, subject authorization forms 
regarding the use of personal health information (if separate from the informed consent forms), 
electronic copy of eCRFs, including the audit trail, and detailed records of drug disposition to 
enable evaluations or audits from regulatory authorities, the sponsor or its designees. Any source 
documentation printed on degradable thermal sensitive paper should be photocopied by the site 


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and filed with the original in the subject’s chart to ensure long-term legibility. Furthermore, 
International Conference on Harmonisation (ICH) E6 Section 4.9.5 requires the investigator to 
retain essential documents specified in ICH E6 (Section 8) until at least 2 years after the last 
approval of a marketing application for a specified drug indication being investigated or, if an 
application is not approved, until at least 2 years after the investigation is discontinued and 
regulatory authorities are notified. In addition, ICH E6 Section 4.9.5 states that the study records 
should be retained until an amount of time specified by applicable regulatory requirements or for 
a time specified in the Clinical Study Site Agreement between the investigator and sponsor. 
Refer to the Phase 1 Site Specifications document for the sponsor’s requirements on record 
retention. The investigator should contact and receive written approval from the sponsor before 
disposing of any such documents. 


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13.0 
STATISTICAL METHODS 
13.1 
Statistical and Analytical Plans 
A statistical analysis plan (SAP) will be prepared and finalized prior to the beginning of Part 2. 
This document will provide further details regarding the definition of analysis variables and 
analysis methodology to address all study objectives. 
A targeted data review will be conducted prior to database lock. This review will assess the 
accuracy and completeness of the study database, subject evaluability, and appropriateness of the 
planned statistical methods. 
13.1.1 Analysis Sets 
Safety Set 
The Safety Set will consist of all subjects who are randomized and receive study drug. Subjects 
in this analysis set will be used for demographic, baseline characteristics and safety summaries. 
Pharmacokinetic Set 
The PK Set will consist of all subjects who receive study drug and have at least 1 measurable 
plasma concentration of CVN058. 
Pharmacodynamic Set 
The PD Set will consist of all subjects who receive study drug and have at least 1 postdose PD 
measurement. 
If any subjects are found to be noncompliant in dosing schedule or with incomplete data, a 
decision will be made on a case-by-case basis as to their inclusion in the PK and PD endpoint 
analyses, but data for all subjects will be presented in the subject listings. 
13.1.2 Analysis of Demographics and Other Baseline Characteristics 
Demographic and baseline characteristics will be summarized by sequence and overall. 
Summary statistics (number of subjects, mean, median, standard deviation, minimum and 
maximum) will be generated for continuous variables (e.g., age and weight) and the number and 
percentage of subjects within each category will be presented for categorical variables (e.g., 
gender, ethnicity, race, smoking status, and caffeine consumption). 
13.1.3 Pharmacokinetic Analysis 
The concentration of CVN058, and its metabolite if appropriate, in plasma will be summarized 
over each scheduled sampling interval using descriptive statistics (arithmetic mean, SD, median, 
minimum and maximum). Individual plasma concentration data versus time will be presented in 
a data listing. 
Descriptive statistics will be used to summarize the plasma PK parameters for CVN058, and its 
metabolite if appropriate. In addition, geometric mean and percent coefficient of variation will be 
computed for Cmax and AUCt. 
A more detailed analysis will be presented in the SAP. 


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13.1.4 Pharmacodynamic Analysis  
Observed values for the PD parameters (MMN and exploratory PD parameters) at each time 
point will summarized by treatment and compared to placebo using summary statistics. 
Comparison of post dose PD parameters from time-matched placebo period timepoints will be 
analyzed using analysis of covariance (ANCOVA) with baseline value as a covariate and factors 
for time point, sequence, subject nested within sequence, period, and treatment. Two-sided 95% 
confidence intervals will be constructed for the LS mean differences between CVN058 and 
placebo in changes of PD parameters from time-matched period baseline to each postdose time 
point. 
Effect size will be calculated for comparisons of CVN058 to placebo using Cohen’s d which 
expresses the difference between the means of 2 groups as a function of their pooled standard 
deviation. 
Exposure-response relationships for CVN058 will be explored graphically. 
13.1.5 Safety Analysis 
The Safety Set will be used for all summaries of TEAEs, laboratory tests, and vital signs. All 
safety data will be summarized by treatment. 
AEs will be presented in listings. TEAEs will be classified according to system organ class and 
preferred term and will be tabulated with a breakdown by treatment and by event severity. 
Similar TEAE tabulations will be performed on those events assessed by the investigator as 
related to study drug. 
Individual results of vital signs will be listed and observed values and changes from Baseline in 
vital signs will be summarized by treatment. 
Physical exam findings, suicidality assessments (C-SSRS), and PANSS scores will be presented 
in data listings. 
13.2 
Determination of Sample Size 
Enrollment of 20 subjects with schizophrenia is estimated to provide >80% power to detect a 
median effect size of Cohen’s d=0.5. Discontinued or withdrawn subjects and subjects for whom 
MMN is not available for all three study periods may be replaced. The sample size chosen of 20 
completed subjects is considered to be sufficient to explore the changes in MMN between 
CVN058 and placebo as well as safety and tolerability of CVN058 in this population. 


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14.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
14.1 
Study-Site Monitoring Visits 
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and institution guarantee access to source documents by the sponsor or its 
designee contract research organization (CRO) and by the IRB or IEC. 
All aspects of the study and its documentation will be subject to review by the sponsor or 
designee (as long as blinding is not jeopardized), including but not limited to the Investigator’s 
Binder, study medication, subject medical records, informed consent documentation, 
documentation of subject authorization to use personal health information (if separate from the 
informed consent forms), and review of eCRFs and associated source documents. It is important 
that the investigator and other study personnel are available during the monitoring visits and that 
sufficient time is devoted to the process. 
14.2 
Protocol Deviations 
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will 
require deviation from protocol-specified procedures, the investigator should consult with the 
sponsor or designee (and IRB or IEC, as required) to determine the appropriate course of action. 
There will be no exemptions (a prospectively approved deviation) from the inclusion or 
exclusion criteria. 
The site should document all protocol deviations in the subject’s source documents. In the event 
of a significant deviation, the site should notify the sponsor or its designee (and IRB or EC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the subject, or confound interpretation of primary study 
assessment. PK samples collected outside of the intervals (listed in Table 14.a), ECGs, vital 
signs, and RNA pharmacogenomic samples collected outside of the listed intervals are minor 
deviations and do not require the Protocol Deviation Form to be completed but must be 
documented in the subject’s source documents. A Protocol Deviation eCRF should be completed 
by the site and signed by the sponsor or designee for any significant deviation from the protocol.  
Every attempt will be made to collect each PK blood sample at the designated time point, and the 
actual time of each blood sample will be recorded on the source document and eCRF. Table 14.a 
defines the windows allowed for sample collections.  
Protocol Deviations should be captured in the site source document for PK samples collected 
outside of the following intervals: 


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Table 14.a 
Windows for Pharmacokinetic Blood Sample Collection 
Minutes 
Nominal Sampling Time 
no more than 15 minutes predose 
Pre-dose (-0.25 hour) 
±5 
Postdose 1 hour 
±15 
Postdose 5 hours  
 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections 
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, 
including those of foreign governments (e.g., the Food and Drug Administration (FDA), the 
United Kingdom Medicines and Healthcare products Regulatory Agency, the Pharmaceuticals 
and Medical Devices Agency of Japan). If the study site is contacted for an inspection by a 
regulatory body, the sponsor should be notified immediately. The investigator and institution 
guarantee access for quality assurance auditors to all study documents as described in Section 
14.1. 


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15.0 
ETHICAL ASPECTS OF THE STUDY 
This study will be conducted with the highest respect for the individual participants (i.e., 
subjects) according to the protocol, the ethical principles that have their origin in the Declaration 
of Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will 
conduct the study according to applicable local or regional regulatory requirements and align his 
or her conduct in accordance with the “Responsibilities of the Investigator” that are listed in 
Appendix B. The principles of Helsinki are addressed through the protocol and through 
appendices containing requirements for informed consent and investigator responsibilities. 
15.1 
IRB and/or IEC Approval 
IRBs and IECs must be constituted according to the applicable state and federal/local 
requirements of each participating region.  
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of 
the informed consent form, and, if applicable, subject recruitment materials and/or 
advertisements and other documents required by all applicable laws and regulations, must be 
submitted to a central or local IRB or IEC for approval. The IRB’s or IEC’s written approval of 
the protocol and subject informed consent must be obtained and submitted to the sponsor or 
designee before commencement of the study (i.e., before shipment of the sponsor-supplied drug 
or study specific Screening activity). The IRB or IEC approval must refer to the study by exact 
protocol title, number, and version date; identify versions of other documents (e.g., ICF) 
reviewed; and state the approval date. The sponsor will ship drug/notify site once the sponsor has 
confirmed the adequacy of site regulatory documentation and, when applicable, the sponsor has 
received permission from competent authority to begin the trial. Until the site receives 
drug/notification no protocol activities, including screening may occur. 
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the informed consent 
form, recruitment materials intended for viewing by subjects, local safety reporting requirements, 
reports and updates regarding the ongoing review of the study at intervals specified by the 
respective IRB or IEC, and submission of the investigator’s final status report to IRB or IEC. All 
IRB and IEC approvals and relevant documentation for these items must be provided to the 
sponsor or its designee. 
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor. 
15.2 
Subject Information, Informed Consent, and Subject Authorization 
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The informed consent form, subject authorization form (if 
applicable), and subject information sheet (if applicable) describe the planned and permitted 
uses, transfers, and disclosures of the subject’s personal and personal health information for 
purposes of conducting the study. The informed consent form and the subject information sheet 


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(if applicable) further explain the nature of the study, its objectives, and potential risks and 
benefits, as well as the date informed consent is given. The informed consent form will detail the 
requirements of the participant and the fact that he or she is free to withdraw at any time without 
giving a reason and without prejudice to his or her further medical care. 
The investigator is responsible for the preparation, content, and IRB or IEC approval of the 
informed consent form and if applicable, the subject authorization form. The informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) 
must be approved by both the IRB or IEC and the sponsor prior to use. 
The informed consent form, subject authorization form (if applicable), and subject information 
sheet (if applicable) must be written in a language fully comprehensible to the prospective 
subject. It is the responsibility of the investigator to explain the detailed elements of the informed 
consent form, subject authorization form (if applicable), and subject information sheet (if 
applicable) to the subject. Information should be given in both oral and written form whenever 
possible and in the manner deemed appropriate by the IRB or IEC. In the event the subject is not 
capable of rendering adequate written informed consent, then the subject’s legally acceptable 
representative may provide such consent for the subject in accordance with applicable laws and 
regulations. 
The subject, or the subject’s legally acceptable representative, must be given ample opportunity 
to: (1) inquire about details of the study and (2) decide whether or not to participate in the study. 
If the subject, or the subject’s legally acceptable representative, determines he or she will 
participate in the study, then the informed consent form and subject authorization form (if 
applicable) must be signed and dated by the subject, or the subject’s legally acceptable 
representative, at the time of consent and prior to the subject entering into the study. The subject 
or the subject’s legally acceptable representative should be instructed to sign using their legal 
names, not nicknames, using blue or black ballpoint ink. The investigator must also sign and date 
the informed consent form and subject authorization (if applicable) at the time of consent and 
prior to subject entering into the study; however, the sponsor may allow a designee of the 
investigator to sign to the extent permitted by applicable law. 
Once signed, the original informed consent form, subject authorization form (if applicable), and 
subject information sheet (if applicable) will be stored in the investigator’s site file. The 
investigator must document the date the subject signs the informed consent in the subject’s 
medical record. Copies of the signed informed consent form, the signed subject authorization 
form (if applicable), and subject information sheet (if applicable) shall be given to the subject. 
All revised informed consent forms must be reviewed and signed by relevant subjects or the 
relevant subject’s legally acceptable representative in the same manner as the original informed 
consent. The date the revised consent was obtained should be recorded in the subject’s medical 
record, and the subject should receive a copy of the revised informed consent form. 
Subjects who consented and provided a pharmacogenomic sample for DNA and RNA analysis 
can withdraw their consent and request disposal of a stored sample at any time prior to analysis. 
Notify sponsor of consent withdrawal. 


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15.3 
Subject Confidentiality 
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or 
date of birth, and subject initials may be used to verify the subject and accuracy of the subject’s 
unique identification number. 
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the 
sponsor requires the investigator to permit its monitor or designee’s monitor, representatives 
from any regulatory authority (e.g., FDA, Medicines and Healthcare products Regulatory 
Agency, Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and 
the appropriate IRBs and IECs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a subject’s study 
participation, and autopsy reports. Access to a subject’s original medical records requires the 
specific authorization of the subject as part of the informed consent process (see Section 15.2). 
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (i.e., subject name, address, and other identifier 
fields not collected on the subject’s eCRF). 
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy 
15.4.1 Publication and Disclosure 
The investigator is obliged to provide the sponsor with complete test results and all data derived 
by the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor. 
The sponsor may publish any data and information from the study (including data and 
information generated by the investigator) without the consent of the investigator. Manuscript 
authorship for any peer-reviewed publication will appropriately reflect contributions to the 
production and review of the document. All publications and presentations must be prepared in 
accordance with this section and the Clinical Study Site Agreement. In the event of any 
discrepancy between the protocol and the Clinical Study Site Agreement, the Clinical Study Site 
Agreement will prevail. 
15.4.2 Clinical Trial Registration  
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations, and guidance, Cerevance will, at a minimum register 
interventional clinical trials it sponsors on ClinicalTrials.gov or other publicly accessible 
websites before start of study. Cerevance contact information, along with investigator’s city, 
state (for American investigators), country, and recruiting status will be registered and available 


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for public viewing. For some registries, Cerevance will assist callers in locating trial sites closest 
to their homes by providing the investigator name, address, and phone number to the callers 
requesting trial information. Once subjects receive investigator contact information, they may 
call the site requesting enrollment into the trial. The investigative sites are encouraged to handle 
the trial inquiries according to their established subject Screening process. If the caller asks 
additional questions beyond the topic of trial enrollment, they should be referred to the sponsor. 
Any investigator who objects to Cerevance providing this information to callers must provide 
Cerevance with a written notice requesting that their information not be listed on the registry site. 
15.4.3 Clinical Trial Results Disclosure  
Cerevance may post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites, as required by applicable laws and/or regulations. 
15.5 
Insurance and Compensation for Injury 
Each subject in the study must be insured in accordance with the regulations applicable to the 
site where the subject is participating. If a local underwriter is required, then the sponsor or 
sponsor’s designee will obtain clinical study insurance against the risk of injury to clinical study 
subjects. Refer to the Clinical Study Site Agreement regarding the sponsor’s policy on subject 
compensation and treatment for injury. If the investigator has questions regarding this policy, he 
or she should contact the sponsor or sponsor’s designee. 


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16.0 
REFERENCES 
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17. Adler LE, Cawthra EM, Donovan KA, Harris JG, Nagamoto HT, Olincy A, et al. Improved 
p50 auditory gating with ondansetron in medicated schizophrenia patients. Am J Psychiatry 
2005;162(2):386-8. 
18. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders 
(DSM-5). 5th ed. Arlington, VA: American Psychiatric Association; 2013. 
19. Smucny J, Wylie K, Rojas D, Stevens K, Olincy A, Kronberg E, et al. Evidence for gamma 
and beta sensory gating deficits as translational endophenotypes for schizophrenia. 
Psychiatry Res 2013;214(2):169-74. 
20. Kay SR. Positive-negative symptom assessment in schizophrenia: psychometric issues and 
scale comparison. Psychiatr Q 1990;61(3):163-78. 
21. Mundt JC, Greist JH, Jefferson JW, Federico M, Mann JJ, Posner K. Prediction of suicidal 
behavior in clinical research by lifetime suicidal ideation and behavior ascertained by the 
electronic Columbia-Suicide Severity Rating Scale. J Clin Psychiatry 2013;74(9):887-93. 
22. Javitt D. Neurophysiological models for new treatment development in schizophrenia: early 
sensory approaches. The New York Academy of Sciences. 2015;1344: 92-104.  
23. Lee M, Sehatpour P, Hoptman MJ, Lakatos P, Dias EC, Kantrowitz JT, Martinez AM, Javitt 
DC. Neural mechanisms of mismatch negativity dysfunction in schizophrenia. Mol 
Psychiatry. 2017;22(11):1585-1593. doi: 10.1038/mp.2017.3. 
24. Javitt D and Sweet R. Auditory dysfunction in schizophrenia: integrating clinical and basic 
features. Nat Rev Neurosci. 2015; 16(9): 535–550. doi:10.1038/nrn4002. 
25. Eisensamer B, Uhr M, Meyr S, Gimpl G, Deiml T, Rammes G, Lambert JJ, Zieglgänsberger 
W, Holsboer F, Rupprecht R. Antidepressants and antipsychotic drugs colocalize with 5-HT3 
receptors in raft-like domains. J Neurosci. 2005 Nov  2;25(44):10198-206. PubMed PMID: 
16267227. 
26. Eisensamer B, Rammes G, Gimpl G, Shapa M, Ferrari U, Hapfelmeier G, Bondy B, Parsons 
C, Gilling K, Zieglgänsberger W, Holsboer F, Rupprecht R. Antidepressants are functional 
antagonists at the serotonin type 3 (5-HT3) receptor. Mol Psychiatry. 2003 Nov;8(12):994-
1007. PubMed PMID: 14647397. 
27. Rammes G, Eisensamer B, Ferrari U, Shapa M, Gimpl G, Gilling K, Parsons C, Riering K, 
Hapfelmeier G, Bondy B, Zieglgänsberger W, Holsboer F, Rupprecht R. Antipsychotic drugs 
antagonize human serotonin type 3 receptor currents in a noncompetitive manner. Mol 
Psychiatry. 2004 Sep;9(9):846-58, 818. PubMed PMID: 15024394. 
 
 


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Appendix A Schedule of Study Procedures 
 
 
 
CVN058 and Placebo 
Treatment Periods 1, 2, and 3 
(a) 
End of 
Treatment 
 
Follow-up  
Study Day: 
Visit 1: 
Screening 
 
Day 1 
pre-dose 
Day 1 
post-dose 
Period 3, 
End Day 1  
Early 
Termination 
(c)  
Day 7-10 
After End of 
Treatment 
(b) 
Informed consent 
X 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
X 
 
 
 
 
Demographics and 
medical history 
X 
 
 
 
 
 
Medication history 
X 
 
 
 
 
 
Physical examination  
X 
X 
 
X 
X 
 
Vital signs (d) 
X 
X 
X 
 
X 
 
Weight, height, and BMI 
(e) 
X 
 
 
X 
X 
 
Concomitant medications 
(f) 
X 
X 
X 
 
X 
X 
Concurrent medical 
conditions (g) 
X 
 
 
 
 
 
Clinical laboratory tests 
(h) 
X 
 
 
X 
X 
 
Hepatitis panel 
X 
 
 
 
 
 
Audiometric Screening 
and Tone Matching test 
(i) 
X 
 
 
 
 
 
FSH (j) 
X 
 
 
 
 
 
Pregnancy test (hCG), 
serum except as noted 
X 
X (urine) 
 
 
X 
 
Urine drug and saliva 
alcohol screen 
X 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
EEG battery (k) 
 
 
X 
 
 
 
MMN (l) 
 
 
X 
 
 
 
DNA sample collection 
(m) 
 
X 
 
 
 
 
RNA sample collection 
(n) 
 
X 
X 
 
 
 
PK blood collection (o) 
 
X 
X 
 
X 
 
Study drug dosing (p) 
 
 
X 
 
 
 
PTE assessment (q) 
X 
X 
 
 
 
 
AE assessment (r) 
 
 
X 
 
X 
X 
C-SSRS (s) 
X 
 
X 
 
X 
 
PANSS (t) 
X 
 
X 
 
X 
 
Footnotes are on last table page. 


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(a) Minimum 7-day and maximum 10-day washout period is required in between Treatment Periods 1, 2 and 3.  
(b) The Follow-up Visit will occur by telephone 7-10 days after End of Treatment unless abnormal, clinically significant findings 
were observed upon discharge. In these cases, subjects must then be brought back to the clinic for re-evaluation per investigator’s 
discretion. 
(c) Conduct procedures for subjects discontinued early per Protocol Section 7.6. The PK sample should be collected at the Early 
Termination Visit, if within 1 hour of a scheduled PK time point. 
(d) Vital signs (oral temperature, respiration, pulse, and blood pressure) will be obtained at Screening, and in Periods 1, 2, and 3 
(pre dose [within 30 minutes prior to dosing], and at 1 and 5 hours post dose), and at Early Termination (if applicable), and if 
clinically indicated according to Investigator discretion at the Follow-up visit.  
(e) Height and BMI will be collected at Screening only. 
(f) Record all patient medications from Screening and throughout the study. 
(g) All new concurrent medical conditions arising post-oi should be recorded as PTE or AE.  
(h) Clinical laboratory tests (hematology, serum chemistry, and urinalysis) will be collected at Screening and prior to check-out at 
End of Treatment or Early Termination, and at the Investigator discretion if a Follow-up Visit is indicated.  
(i) Audiometric Screening assessment conducted according to local practice.  
(j) A FSH level will be obtained on post menopausal women (defined as continuous amenorrhea of at least 2 years and not 
surgically sterile). 
(k) For the EEG battery, testing will be done at Day 1 starting approximately 1.5 hours post dose for each period and will last 
approximately 3 hours. NOTE: Subjects should refrain from drinking coffee and smoking approximately 1 hour prior to the EEG 
assessment until discharge from clinic at the end of the afternoon. 
(l) MMN will be the first EEG assessment conducted in the battery.  
(m) One blood sample (6 mL) will be collected for pharmacogenomic analysis prior to study drug administration on Day 1 of 
Period 1 only. If isolation of DNA from the first sample was not successful or possible, a second aliquot of blood may 
be taken, if feasible. 
(n) Two 2.5 mL whole blood samples will be collected for each Period (Periods 1, 2, and 3) on Day 1 at pre-dose, and 5 hours 
post- dose  
(o) Blood samples (6 mL) for PK analyses will be collected at pre -dose (within 15 minutes prior to dosing), and 1 and 5 hours 
post dose. 
(p) Dosing will only occur on Day 1 of each period, and signals the start of the post-dose Day 1 visit assessments. 
(q) PTEs will be collected from signing of informed consent up until dosing on Day 1. 
(r) Any adverse event with onset or exacerbation after dosing on Day 1 of Period 1 will be captured as an AE or SAE. 
(s) The Screening/Baseline C-SSRS will be administered at Screening and the Since Last Visit C-SSRS will be administered after 
EEG/ERP collection on each dosing day, and End of Treatment or Early Termination (if applicable). 
(t) The Screening/Baseline PANSS will be collected at Screening, approximately 5 hours after each dose (post EEG) and at Early 
Termination (if applicable). 
 


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Appendix B Responsibilities of the Investigator 
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on investigators by the FDA are 
summarized in the “Statement of Investigator” (Form 1572) which must be completed and 
signed before the investigator may participate in this study. 
The investigator agrees to assume the following responsibilities by signing a Form 1572.  
1. Conduct the study in accordance with the protocol. 
2. Personally conduct or supervise the staff who will assist in the protocol. 
3. Ensure that study related procedures; including study specific (non-routine/non- standard 
panel) Screening assessments are NOT performed on potential subjects prior to the receipt of 
written approval from relevant governing bodies/authorities. 
4. Ensure that all colleagues and employees assisting in the conduct of the study are informed 
of these obligations. 
5. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform 
to 21 CFR Part 56 ICH, and local regulatory requirements. 
6. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and 
approval of the protocol. Promptly report to the IRB/IEC all changes in research activity and 
all anticipated risks to subjects. Make at least yearly reports on the progress of the study to 
the IRB/IEC, and issue a final report within 3 months of study completion. 
7. Ensure that requirements for informed consent, as outlined in 21 CRF Part 50 ICH and local 
regulations, are met. 
8. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each informed consent form should contain a subject 
authorization section that describes the uses and disclosures of a subject’s personal 
information (including personal health information) that will take place in connection with 
the study. If an informed consent form does not include such a subject authorization, then the 
investigator must obtain a separate subject authorization form from each subject or the 
subject’s legally acceptable representative. 
9. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc., and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents. 
10. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents. 
11. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor. 


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CONFIDENTIAL 
12. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours. 
 


 
 
 
PROTOCOL  
A Placebo-Controlled Study to Evaluate the Effect of a Single Dose of CVN058 on 
Mismatch Negativity in Subjects with Stable Schizophrenia 
 
Short title: CVN058 Effect on Mismatch Negativity in Schizophrenics 
 
Sponsor: 
Cerevance Alpha (hereafter, “Cerevance”) 
One Marina Park Drive, suite 1410 
Boston, MA 02210 
Study Number: 
CVN058-103 
IND Number: 
121,520 
EudraCT 
Number: 
N/A 
Compound: 
 
CVN058  
Date: 
27 Mar 2019 
Amendment Number:  
3 
 
 
 
 
Previous Versions: 
 
28 Sep 2018 
Amendment Number:         2 
 
02 Jul 2018 
Amendment Number:         1 
 
21 May 2018 
Original 
 
 
CONFIDENTIAL PROPERTY OF CEREVANCE 
This document is a confidential communication of Cerevance. Acceptance of this document constitutes the 
agreement by the recipient that no information contained herein will be published or disclosed without written 
authorization from Cerevance except to the extent necessary to obtain informed consent from those persons to whom 
the drug may be administered. Furthermore, the information is only meant for review and compliance by the 
recipient, his or her staff, and applicable institutional review committee and regulatory agencies to enable conduct of 
the study. 


CVN058 
 
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CONFIDENTIAL 
1.0 
ADMINISTRATIVE INFORMATION 
1.1 
Contacts  
 
Contact Type / Role 
Contact 
Serious adverse event and pregnancy reporting 
CliniLabs 
Fax: 919-591-0004 
Email: safety@safeharborpv.com 
 
Medical Monitor 
(carries overall responsibility for the conduct of the study) 
, MD, CPI 
Director of Medical Affairs, CliniLabs 
 
Responsible Medical Officer  
(medical advice on protocol and compound) 
, MD PhD 
Senior Vice President  
Cerevance, Inc. 
 




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INVESTIGATOR AGREEMENT  
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, and 
any other product information provided by the sponsor. I agree to conduct this study in 
accordance with the requirements of this protocol and also to protect the rights, safety, privacy, 
and well-being of study subjects in accordance with the following: 
 The ethical principles that have their origin in the Declaration of Helsinki. 
 International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline. 
 All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations. 
 Regulatory requirements for reporting serious adverse events defined in Section 10.2 of this 
protocol. 
 Terms outlined in the Clinical Study Site Agreement. 
 Appendix B – Responsibilities of the Investigator. 
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in the clinical trial agreement with Cerevance. 
Signature of Investigator 
Date 
Investigator Name (print or type) 
Investigator’s Title 
Location of Facility (City, State/Provence) 
Location of Facility (Country) 


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TABLE OF CONTENTS 
1.0 
ADMINISTRATIVE INFORMATION ..............................................................................2 
1.1 
Contacts..........................................................................................................................2 
1.2 
Approval ........................................................................................................................3 
2.0 
STUDY SUMMARY.........................................................................................................10 
3.0 
LIST OF ABBREVIATIONS ............................................................................................15 
4.0 
INTRODUCTION .............................................................................................................17 
4.1 
Background ..................................................................................................................17 
4.2 
Non-Clinical .................................................................................................................18 
4.3 
Clinical .........................................................................................................................18 
4.4 
Rationale for the Proposed Study ................................................................................19 
5.0 
STUDY OBJECTIVES AND ENDPOINTS .....................................................................21 
5.1 
Objectives ....................................................................................................................21 
5.1.1 Primary Objective ..................................................................................................21 
5.1.2 Secondary Objective ..............................................................................................21 
5.1.3 Exploratory Objectives ..........................................................................................21 
5.2 
Endpoints .....................................................................................................................21 
5.2.1 Primary Endpoints .................................................................................................21 
5.2.2 Secondary Endpoint ...............................................................................................21 
5.2.3 Exploratory Endpoints ...........................................................................................21 
6.0 
STUDY DESIGN AND DESCRIPTION ..........................................................................23 
6.1 
Study Design ................................................................................................................23 
6.2 
Justification for Study Design, Dose, and Endpoints ..................................................24 
6.3 
Premature Termination or Suspension of Study or Investigational Site ......................25 
6.3.1 Criteria for Premature Termination or Suspension of the Study ...........................25 
6.3.2 Criteria for Premature Termination or Suspension of Investigational Sites ..........25 
6.3.3 Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s)...................................................................25 
7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS ...............26 
7.1 
Inclusion Criteria .........................................................................................................26 
7.2 
Exclusion Criteria ........................................................................................................26 
7.3 
Excluded Medications, Dietary Products, Procedures, and Treatments ......................28 
7.4 
Diet, Fluid, Activity Control ........................................................................................29 
7.5 
Criteria for Discontinuation or Withdrawal of a Subject .............................................29 
7.6 
Procedures for Discontinuation or Withdrawal of a Subject .......................................30 
8.0 
CLINICAL TRIAL MATERIAL MANAGEMENT.........................................................31 
8.1 
Study Medication and Materials ..................................................................................31 


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8.1.1 Dosage Form, Manufacturing, Packaging, and Labeling ......................................31 
8.1.1.1 Investigational Drug .........................................................................................31 
8.1.1.2 Sponsor-Supplied Drug ....................................................................................31 
8.1.1.3 Ancillary Materials ..........................................................................................31 
8.1.2 Storage ...................................................................................................................32 
8.1.3 Dose and Regimen .................................................................................................32 
8.1.4 Overdose ................................................................................................................32 
8.2 
Investigational Drug Assignment and Dispensing Procedures ....................................33 
8.3 
Randomization Code Creation and Storage .................................................................33 
8.4 
Investigational Drug Blind Maintenance .....................................................................33 
8.5 
Unblinding Procedure ..................................................................................................33 
8.6 
Accountability and Destruction of Sponsor-Supplied Drugs .......................................33 
9.0 
STUDY PLAN ...................................................................................................................36 
9.1 
Study Procedures .........................................................................................................36 
9.1.1 Informed Consent Procedure .................................................................................36 
9.1.1.1 Pharmacogenomic Informed Consent Procedure .............................................36 
9.1.2 Demographics, Medical History, and Medication History Procedure ...................36 
9.1.3 Physical Examination Procedure ...........................................................................36 
9.1.4 Weight, Height, and BMI.......................................................................................37 
9.1.5 Vital Sign Procedure ..............................................................................................37 
9.1.6 Documentation of Concomitant Medications ........................................................37 
9.1.7 Documentation of Concurrent Medical Conditions ...............................................37 
9.1.8 Procedures for Clinical Laboratory Samples .........................................................38 
9.1.9 Contraception and Pregnancy Avoidance Procedure .............................................39 
9.1.10 Pregnancy ...............................................................................................................40 
9.1.11 ECG Procedure ......................................................................................................41 
9.1.12 Pharmacogenomic Sample Collection ...................................................................41 
9.1.13 Pharmacokinetic Sample Collection ......................................................................42 
9.1.13.1 
Collection of Blood for Pharmacokinetic Sampling ..................................42 
9.1.13.2 
Bioanalytical Methods ...............................................................................43 
9.1.14 Pharmacokinetic Parameters ..................................................................................43 
9.1.15 Pharmacodynamic Sample Collection ...................................................................43 
9.1.16 Pharmacodynamic Parameters ...............................................................................44 
9.1.17 Positive and Negative Syndrome Scale .................................................................45 
9.1.18 Columbia Suicide Severity Rating Scale ...............................................................45 
9.1.19 Documentation of Screen Failure ..........................................................................46 
9.1.20 Documentation of Randomization .........................................................................46 


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9.2 
Monitoring Subject Treatment Compliance .................................................................46 
9.3 
Schedule of Observations and Procedures ...................................................................46 
9.3.1 Screening................................................................................................................47 
9.3.2 Treatment Phase .....................................................................................................47 
9.3.3 Final Visit/End of Treatment .................................................................................47 
9.3.4 Early Termination ..................................................................................................47 
9.3.5 Follow-up Visit/Telephone Call ............................................................................47 
9.4 
Biological Sample Retention and Destruction .............................................................47 
9.5 
Blood Volume ..............................................................................................................48 
10.0 
PRETREATMENT EVENTS AND ADVERSE EVENTS ..............................................49 
10.1 
Definitions....................................................................................................................49 
10.1.1 PTEs .......................................................................................................................49 
10.1.2 AEs .........................................................................................................................49 
10.1.3 Additional Points to Consider for PTEs and AEs ..................................................49 
10.1.4 SAEs ......................................................................................................................51 
10.1.5 Severity of PTEs and AEs......................................................................................52 
10.1.6 Causality of AEs ....................................................................................................53 
10.1.7 Relationship to Study Procedures ..........................................................................53 
10.1.8 Start Date ...............................................................................................................53 
10.1.9 Stop Date ................................................................................................................53 
10.1.10 
Frequency .........................................................................................................53 
10.1.11 
Action Concerning Study Medication .............................................................53 
10.1.12 
Outcome ...........................................................................................................53 
10.2 
Procedures ....................................................................................................................54 
10.2.1 Collection and Reporting of AEs ...........................................................................54 
10.2.1.1 
PTE and AE Collection Period ..................................................................54 
10.2.1.2 
PTE and AE Reporting ..............................................................................54 
10.2.2 Collection and Reporting of SAEs .........................................................................55 
10.2.3 Reporting of Abnormal Liver Function Tests ........................................................55 
10.3 
Follow-up of SAEs ......................................................................................................56 
10.3.1 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities .....56 
11.0 
STUDY-SPECIFIC COMMITTEES .................................................................................57 
12.0 
DATA HANDLING AND RECORDKEEPING ..............................................................58 
12.1 
CRFs (Electronic) ........................................................................................................58 
12.2 
Record Retention .........................................................................................................58 
13.0 
STATISTICAL METHODS ..............................................................................................60 
13.1 
Statistical and Analytical Plans ....................................................................................60 


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13.1.1 Analysis Sets ..........................................................................................................60 
13.1.2 Analysis of Demographics and Other Baseline Characteristics ............................60 
13.1.3 Pharmacokinetic Analysis ......................................................................................60 
13.1.4 Pharmacodynamic Analysis ...................................................................................61 
13.1.5 Safety Analysis ......................................................................................................61 
13.2 
Determination of Sample Size .....................................................................................61 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................62 
14.1 
Study-Site Monitoring Visits .......................................................................................62 
14.2 
Protocol Deviations ......................................................................................................62 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections ..................................63 
15.0 
ETHICAL ASPECTS OF THE STUDY ...........................................................................64 
15.1 
IRB and/or IEC Approval ............................................................................................64 
15.2 
Subject Information, Informed Consent, and Subject Authorization ..........................64 
15.3 
Subject Confidentiality ................................................................................................66 
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy ..................................66 
15.4.1 Publication and Disclosure ....................................................................................66 
15.4.2 Clinical Trial Registration ......................................................................................66 
15.4.3 Clinical Trial Results Disclosure ...........................................................................67 
15.5 
Insurance and Compensation for Injury .......................................................................67 
16.0 
REFERENCES ..................................................................................................................68 
 
LIST OF IN-TEXT TABLES 
Table 6.a 
Treatment Sequences .............................................................................................23 
Table 7.a 
Prohibited Medications ..........................................................................................28 
Table 8.a 
Composition of CVN058 and Matching Placebo ..................................................31 
Table 8.b 
Treatment and Medication Type ............................................................................32 
Table 9.a 
Clinical Laboratory Tests .......................................................................................38 
Table 9.b 
Collection of Blood Samples for CVN058 Pharmacokinetic Analysis .................43 
Table 9.c 
Approximate Blood Volume ..................................................................................48 
Table 10.a 
Medically Significant AE List ...............................................................................52 
Table 14.a 
Windows for Pharmacokinetic Blood Sample Collection .....................................63 
 
LIST OF IN-TEXT FIGURES 
Figure 6.a 
Schematic of Study Design ....................................................................................24 
 


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LIST OF APPENDICES 
Appendix A 
Schedule of Study Procedures ...............................................................................70 
Appendix B 
Responsibilities of the Investigator ........................................................................72 
 


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2.0 
STUDY SUMMARY 
Name of Sponsor(s): 
Cerevance Alpha, Inc.  
(hereafter referred to as “Cerevance”) 
Compound: 
CVN058 
Title of Protocol: A Placebo-Controlled Study to 
Evaluate the Effect of a Single Dose of CVN058 on 
Mismatch Negativity in Subjects with Stable 
Schizophrenia 
IND No.: 121,520 
EudraCT No.: 
Not Applicable 
Study Number: CVN058-103 
Phase: 1 
Study Design: 
This is a phase 1, double-blind, placebo-controlled, 3 period cross-over study to evaluate CVN058 target 
engagement by measuring auditory evoked potential mismatch negativity (MMN) downstream to 5-
hydroxytryptamine receptor 3 (5-HT3) as a pharmacodynamic (PD) marker.   
Male and female subjects with schizophrenia (including schizoaffective disorder), age 18 to 50 years old, 
inclusive, will be randomized to 1 of 6 treatment sequences (Table 2.a) to receive 1 of 3 dose regimens in each 
period: a single oral administration of CVN058 (15 mg or 150 mg) or matching placebo. The sequence will 
determine the order in which a subject will take each of the 3 regimens. Discontinued subjects may be replaced 
at the discretion of the sponsor so that approximately 20 completed subjects are available for analysis. Sample 
size re-estimation may occur when blinded MMN data from all 3 periods are available for 12 subjects, or when 
20 subjects have been dosed and are expected to complete the study.  
The study includes three 1-day treatment periods, with a minimum of 7-day washout, maximum 10-day washout 
(2 total washouts, after Periods 1 and 2) between periods, and a 7-10 day follow-up call post dosing of the last 
period. Subjects may be inpatients or outpatients at the discretion of the Investigator. 
Table 2.a Treatment Sequences 
Sequence 
Period 1 
Period 2 
Period 3 
1 
A 
B 
C 
2 
B 
A 
C 
3 
C 
A 
B 
4 
A 
C 
B 
5 
B 
C 
A 
6 
C 
B 
A 
A: Placebo 
B: CVN058 15 mg 
C: CVN058 150 mg  
At each testing session, subjects undergo post dose electroencephalography (EEG) testing including: MMN, P50, 
gamma power, and P300. Study drug will be administered with water. Testing sessions will begin approximately 
1.5 hours post-dose. Prior to dosing and at various time points post dose, blood samples will be collected for the 
assessment of plasma concentrations of CVN058 and biomarkers.  
Study procedures will be conducted at approximately the same times across Treatment Periods to minimize 
diurnal effects on outcomes. The effect of CVN058 on MMN as well as on exploratory measures (e.g., P50 
auditory gating, gamma power, and P300) will be compared to placebo.  
 
A schematic of the study design is presented below: 
  
 
 


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Primary Objective: 
To determine whether improvement in MMN is demonstrated after administration of CVN058 compared to 
placebo in subjects with schizophrenia. 
Secondary Objective: 
Assess the safety and tolerability of single doses of CVN058 in subjects with schizophrenia. 
Exploratory Objectives: 
 
To determine whether improvement in P50 auditory gating, gamma power, and P300 is demonstrated 
after administration of CVN058 compared to placebo in subjects with schizophrenia. 
 
To assess the pharmacokinetics (PK) of CVN058 following a single dose to subjects with 
schizophrenia. 
 
To explore the exposure-response relationship for CVN058 in subjects with schizophrenia. 
Subject Population:  
Subjects with stable schizophrenia including schizoaffective disorder on antipsychotic medication(s).  
Number of Subjects: 
Estimated total: at least 20 evaluable subjects who 
complete the study. 
Sample size is subject to re-estimation based on blinded 
preliminary data.  
Number of Sites: 
Approximately 3 (United States) 
Dose Level(s): 
Placebo: solution vehicle, oral administration  
CVN058: 15 mg solution, oral administration  
CVN058: 150 mg solution, oral administration 
Route of Administration: 
Oral 
Duration of Treatment: 
Single oral dose in each of the 3 periods.  
Period of Evaluation: 
Screening Days: Up to 28 days. 
3 Treatment Periods, each <1 day duration;  


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with a 7-10 day washout between periods 
Follow-up call 7-10 days following the last dose of 
study drug in Treatment Period 3. 
Total Duration: Up to 58 days. 
Main Criteria for Inclusion: 
Subjects 18 to 50 years of age, inclusive, at the time of informed consent. 
The subject weighs at least 50 kg and has a body mass index (BMI) between 18 and 40 kg/m2 inclusive at 
Screening. 
Subject meets schizophrenia or schizoaffective disorder criteria as defined by the Diagnostic & Statistical 
Manual of Mental Disorders, 5th Edition (DSM–V).  
Subjects are on a stable dose of antipsychotic medication(s) for at least 2 months prior to Screening as 
documented by medical history and assessed by site staff. 
Subject has a Positive and Negative Syndrome Scale (PANSS) total score of <95. 
Main Criteria for Exclusion: 
Subject currently receiving treatment with any excluded medication or dietary supplement. 
Subjects who have a history of gastrointestinal disease that would influence the absorption of study drug or have 
a history of any surgical intervention known to impact absorption (e.g., bariatric surgery or bowel resection). 
Subjects having clinical laboratory evaluations (including clinical chemistry, hematology and complete 
urinalysis) outside the reference range for the testing laboratory, unless the results are deemed to be not clinically 
significant (NCS) by the investigator at Screening. 
Subjects with moderate to severe substance use disorder, unstable mood or anxiety disorder. 
Subject has a current diagnosis of a significant psychiatric illness other than schizophrenia or schizoaffective 
disorder per DSM-V and is in an acute phase/episode. 
Subject has clinically meaningful hearing loss. 


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Main Criteria for Evaluation and Analyses: 
Pharmacodynamics: 
MMN will be measured as a PD marker for CVN058. Exploratory measurements include P50 auditory gating, 
gamma power, and P300, which are EEG markers commonly impaired in subjects with schizophrenia including 
schizoaffective disorder.  
Pharmacokinetics:  
Blood samples will be collected for the determination of plasma concentrations of CVN058, and its metabolite if 
appropriate, at the following time points: Pre-dose (within 15 minutes prior to dosing), and at 1 (pre-EEG) and 5 
(post-EEG) hours post dose. Analysis of these samples will confirm drug exposure during EEG data collection 
and will support basic PK/PD response correlations. The following PK parameters will be determined from 
concentrations of CVN058, and its metabolite if appropriate, in plasma: maximum observed plasma 
concentration (Cmax), time to reach Cmax (tmax), and area under the curve from time 0 to 5 hours post dose (AUCt). 
Other parameters may be calculated if appropriate.  
Pharmacogenomics: 
Whole blood will be collected and stored for possible deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) 
isolation and analysis.  
DNA samples will be used to evaluate drug metabolic enzyme and transporter polymorphisms that may 
contribute to variability in the PK of CVN058. Also, since pharmacogenomics is an evolving science, many 
genes and their functions are not yet fully understood. Future data may suggest a role of some gene in drug 
response, which may lead to additional hypothesis-generating exploratory research and diagnostic development 
on stored samples. 
Statistical Considerations: 
Observed values for the PD parameters (MMN and exploratory PD parameters) in each period will be 
summarized by treatment and compared to time matched assessments during placebo dosing using summary 
statistics. Comparison of post dose PD parameters to time matched placebo period timepoints will be analyzed 
using analysis of covariance (ANCOVA) with baseline value as a covariate and factors for sequence, subject 
nested within sequence, period, and treatment. Two-sided 95% confidence intervals will be constructed for the 
least squares mean differences between CVN058 and placebo in changes of PD parameters, comparing CVN058 
and placebo at a time-matched post-dose time point. 
Effect size will be calculated for comparisons of CVN058 to placebo using Cohen’s d which expresses the 
difference between the means of 2 groups as a function of their pooled standard deviation. 
Plasma PK concentrations and parameters of CVN058, and its metabolite if appropriate, will be listed and 
summarized by treatment using descriptive statistics. Exposure-response relationships for CVN058 will be 
explored graphically. 
Adverse events (AEs) will be presented in listings, and treatment-emergent AEs (TEAEs) will be summarized by 
treatment. Individual results of vital signs will be listed and observed values and changes from Baseline in vital 
signs will be summarized by treatment.  
Sample size re-estimation will occur after twelve (12) subjects have completed all study visits, or when 20 
subjects have been dosed and are expected to complete the study, whichever is sooner. The sample size re-
estimation will be performed using SAS PROC POWER for Paired-Sample Means and specifications of power 
= 80%, alpha=0.10 and the blinded group standard deviation values attained from the twelve study subjects.  


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Sample Size Justification:  
Enrollment of 20 subjects is estimated to provide >80% power to detect a median effect size of Cohen’s d=0.5. 
Discontinued or withdrawn subjects and subjects for whom MMN is not available for all three study periods may 
be replaced. The sample size chosen of 20 completed subjects is expected to be sufficient to explore the changes 
in MMN between CVN058 and placebo as well as safety and tolerability of CVN058 in this population. 
Sample size re-estimation may occur when blinded MMN data from all 3 periods are available for 12 subjects, or 
when 20 subjects have been dosed and are expected to complete the study, whichever is sooner. Sample size may 
be increased up to a total of 40 subjects to ensure adequate study power if the lowest MMN values for already 
studied subjects show less impairment than is expected for a schizophrenic population.  
 


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3.0 
LIST OF ABBREVIATIONS 
5-HT 
5-hydroxytryptamine (serotonin) 
5-HT3 
5-hydroxytryptamine (serotonin) receptor 3 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
AUCt 
area under the plasma concentration-time curve from 0 to 5 hours post dose  
BA 
bioavailability 
BMI 
body mass index 
CIAS 
cognitive impairment associated with schizophrenia 
CL/F 
apparent clearance after extravascular administration 
Cmax 
maximum observed plasma concentration 
CNS 
central nervous system 
CRO 
contract research organization 
CS 
clinically significant 
CSF 
cerebrospinal fluid 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DSM -V 
Diagnostic & Statistical Manual of Mental Disorders, 5th Edition – Text Revision 
eCRF 
electronic case report form  
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
EEG 
electroencephalography 
EMA 
European Medicines Agency  
ERP 
evoked response potential 
FDA 
Food and Drug Administration 
FM 
frequency-modulation 
FSH 
follicle-stimulating hormone 
FSI 
fast-spiking interneurons 
Fz 
frontal electrodes 
Fz,Cz 
frontocentral electrodes 
GABA 
γ-aminobutyric acid 
GCP 
Good Clinical Practice 
GGT 
-glutamyl transferase 
HBsAg 
hepatitis B surface antigen 
hCG 
human chorionic gonadotropin 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
ICH 
International Conference on Harmonisation 
IEC 
independent ethics committee 
INR 
international normalized ratio 
IRB 
institutional review board 
IUD 
intrauterine device 
K2EDTA 
potassium ethylenediamine tetraacetic acid 


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LFT 
liver function test 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMN 
mismatch negativity 
NCS 
not clinically significant 
NMDAR 
N-methyl-D-aspartate receptor 
NFSI 
non-fasting spiking interneurons 
OTC 
Over-the-counter 
PANSS 
Positive and Negative Syndrome Scale 
PD 
pharmacodynamic(s) 
PI 
principal investigator 
PK 
pharmacokinetic(s) 
PT 
PTT 
prothrombin time 
partial thromboplastin time 
PTE 
pretreatment event 
PV 
parvalbumin 
Pz 
parietal electrodes  
P50 Ratio 
ratio of S2 to S1  
RNA 
ribonucleic acid 
QTcB 
QT interval with Bazett correction method 
QTcF 
QT interval with Fridericia correction method 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SSR 
steady state response 
SUSAR 
suspected unexpected serious adverse reaction 
t1/2z 
terminal elimination half-life 
CVN058 
also known as ENV8058 and TAK-058 
TEAE 
treatment-emergent adverse event 
tmax 
time to reach Cmax 
ULN 
upper limit of normal 
Vz/F 
apparent volume of distribution during the terminal phase 
WHODRUG  
World Health Organization Drug Dictionary 


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4.0 
INTRODUCTION 
4.1 
Background 
Schizophrenia is a complex disorder comprising several clinical features that are highly variable 
among affected individuals. Probably the most well-known schizophrenia symptom domains are 
the so-called positive symptoms, e.g., hallucinations, delusions, disorganization of thought, 
bizarre behavior, and incongruity of affect. Negative symptoms include avolition (loss of 
motivation), blunt affect, alogia (reduced speech), and anhedonia (reduced ability to experience 
pleasure). Symptoms of a mood disorder, such as mania and depression, are prominent in a 
subset of patients; those patients are considered to have schizoaffective disorder. There is a well-
established cognitive impairment associated with schizophrenia (CIAS) including schizoaffective 
disorder (Hartman, 2019). CIAS is observed in most cases involving deficits in a broad range of 
domains.  
Cognitive impairment is considered a core feature of schizophrenia and represents an area of 
significant unmet medical need. Cognitive deficits in schizophrenia include problems in speed of 
processing, attention/vigilance, working memory, verbal learning, visual learning, reasoning and 
problem solving, and social cognition (Green, 2006). These cognitive deficits are believed to 
underlie much of the significant functional impairments observed in schizophrenia, such as 
impairment in independent living skills, social functions, vocational functioning, and self-care 
(Harvey, 2007). Thus, the core nature of CIAS and the associations that have been demonstrated 
with functional disability suggest that improving cognitive impairment may lead to improved 
functional outcomes (Heinrichs, 2005). 
The understanding of CIAS has evolved significantly in recent years and led to new therapeutic 
strategies. In postmortem samples from schizophrenic patients, studies consistently reveal 
reduced levels of enzymes that synthesize the inhibitory neurotransmitter γ-aminobutyric acid 
(GABA) in the prefrontal cortex (McNally, 2013) a key center for higher cognitive function. The 
GABAergic neurons deficient in the cortex are termed fast-spiking interneurons (FSIs), and they 
express the marker parvalbumin (PV) (McNally, 2013). These PV+ FSIs are chemically coupled 
and release GABA in a rhythmic pattern that synchronizes the activity of local cortical pyramidal 
neurons (Cardin, 2009). This synchronization, which is essential for cognition, is disrupted in 
patients [(McNally, 2013), (Cardin, 2009)] [(Whittington, 1997), (Rotaru, 2012), (Gonzalez-
Burgos, 2012)]. These and other human and animal model data implicate FSI hypofunction, and 
a resulting imbalance in the excitation/inhibition balance in cortical regions, in CIAS. 
Based on this emerging insight into disease pathophysiology, a therapeutic that restores the 
normal function of the cortical pyramidal neuron/FSI microcircuit would be expected to improve 
cognitive function in patients with schizophrenia. One strategy for boosting the function of this 
circuit is to inhibit a second population of inhibitory GABAergic interneurons, known as non-
fast spiking interneurons (NFSIs), which project locally onto the FSIs and the dendrites of the 
pyramidal neurons. These NFSIs are modulated by a wide variety of inputs, particularly 
excitatory glutamatergic efferents from the thalamus, and noradrenergic, cholinergic, and 
serotonergic efferents from subcortical regions [(Tian, 2010), (Kawaguchi, 1998), (Kawaguchi, 
1997), (Lee, 2010)]. Thus, NFSIs appear to integrate state-dependent information and release 
GABA to regulate pyramidal neuron/FSI microcircuits. 


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Mismatch negativity (MMN) is an established biomarker of cortical function (Javitt, 2015). This 
signal is obtained as an evoked potential during an auditory oddball task, in which a subject is 
repeatedly exposed to auditory tones and a small proportion of those tones (the “deviant” stimuli) 
differ from the others (the “standard” stimuli) in their frequency or duration. Typically, the tones 
are presented and the evoked potentials are recorded while subjects are engaged on a different 
task, such as reading. Normally, the occurrence of a deviant stimulus increases the amplitude of 
the negative component in the evoked potential occurring at around 200 msec. MMN is the 
difference in amplitude between deviant and standard stimuli responses, and is considered to 
represent an aspect of preattentive novelty detection. MMN is consistently reduced in 
schizophrenia patients relative to healthy individuals, a finding extensively replicated and with a 
large effect size (Cohen’s d = 1). MMN reduction in schizophrenia has been shown to reflect 
impaired N-methyl-D-aspartate receptor (NMDAR) function at the level of supratemporal 
auditory cortex, dependent on cortical interneuron modulation of pyramidal cell activity and 
NMDA receptor-dependent (Lee, 2017). 
4.2 
Non-Clinical 
CVN058 (also known as ENV8058 or TAK-058) is a small molecule that potently and 
selectively antagonizes the 5-hydroxytryptamine (5-HT) receptor type 3 (5-HT3). 5-HT3 is a cys-
loop family ligand-gated ion channel that allows cations to pass into the neurons when activated 
by serotonin, and is highly expressed in NFSIs [(Lee, 2010), (Lummis, 2012)]. The receptor is a 
pentamer consisting of at least two 5-HT3a subunits and 3 other subunits; in the central nervous 
system (CNS) the receptor is almost exclusively a homomeric pentamer comprised of 5-HT3a 
(Kawaguchi, 1997). The 5-HT3 channel opens when serotonin molecules interact with the 2 
ligand recognition sites in the extracellular side of the receptor. Influxed calcium and other 
positive ions depolarize the NFSIs, leading to GABA release. CVN058 is orally absorbed and 
readily passes the blood brain barrier, allowing it to occupy cortical 5-HT3 receptors. CNS 5-HT3 
receptor occupancy is correlated with efficacy in a rat model of cognition where it reverses 
deficits in novel object recognition induced by subchronic phencyclidine treatment. Thus, 
CVN058 is a novel therapeutic candidate that may improve cognitive function by inhibiting 
specific subsets of cortical interneurons.  
Additional information from the nonclinical studies can be found in the current Investigator’s 
Brochure. 
4.3 
Clinical 
Two human clinical studies of CVN058 have been completed (ENV8058_101 and TAK-058-
1002). 
CVN058 was well tolerated up to a dose of 150 mg administered orally as a single dose in 
aqueous solution (Study ENV8058_101). There were no deaths or other serious adverse events 
(SAEs) reported in this study and no subject discontinued study due to a treatment-emergent 
adverse event (TEAE). There were no clinically significant (CS) laboratory abnormalities, 
electrocardiogram (ECG) changes or changes in vital signs in the completed single dose study. 
The mean Cmax and area under the plasma concentration–time curve (AUC) values of CVN058 
increased less than proportionally with increasing CVN058 dose across the dose range of 5 to 


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150 mg, but mean Cmax and AUC values increase in an approximately dose proportional manner 
across the 5 to 45 mg dose range. The rate of appearance of CVN058 in plasma was rapid with 
median time to Cmax (tmax) values of 1 to 1.25 hours across the dose range of 5 to 150 mg. The 
mean terminal elimination half-life (t1/2z) values of CVN058 ranged from approximately 2.8 to 
10.5 hours across the cohorts; the lower doses (5 to 30 mg) had lower mean t1/2z values compared 
to the higher doses (45 to 150 mg). There were no trends with mean apparent clearance (CL/F) 
values of CVN058 with increasing dose from 5 to 45 mg, but faster apparent clearance was 
observed at the 75 and 150 mg doses, possibly due to decreased bioavailability (BA) at higher 
doses. The mean apparent volume of distribution (Vz/F) increased as dose increased. Excretion 
of unchanged CVN058 in the urine was ≤2.3% of the administered CVN058 dose over the dose 
range evaluated. 
In the multiple-rising dose study (TAK-058-1002), CVN058 was well-tolerated at daily doses of 
25, 75, and 150 mg for 7 days, and at a single 300 mg dose, in aqueous solution. There were no 
deaths or other SAEs reported in this study and no subject discontinued study due to a TEAE. 
There were no clinically significant laboratory abnormalities, ECG changes or changes in vital 
signs in the completed single dose study. Following single or multiple doses, the mean Cmax and 
AUC values of CVN058 increased less than proportionally with increasing CVN058 dose across 
the dose range of 25 to 300 mg. No accumulation was observed following daily administration. 
CVN058 concentrations in cerebrospinal fluid (CSF) were assessed after daily doses of CVN058 
75 mg for 5 days. The CSF concentrations averaged 17.5 ng/mL, or approximately 1% of the 
concentration in plasma. 
4.4 
Rationale for the Proposed Study 
This study will explore central target engagement and proof of mechanism by measuring 
auditory evoked potential MMN as a pharmacodynamic (PD) marker of CNS response to the 
selective 5-HT3 receptor antagonist CVN058. It has been reported that subjects with 
schizophrenia including schizoaffective disorder commonly demonstrate a deficit in neural 
processing that is manifested as a reduction in MMN (Avissar, 2018); impairment of auditory 
sensory gating (P50) is also observed (Javitt and Sweet, 2015). Other 5-HT3 receptor antagonists 
have been reported to improve impairments in auditory evoked potentials in schizophrenic 
subjects. In a study with ondansetron, a 5-HT3 receptor antagonist, using P50 auditory gating as 
the auditory evoked potential measure, subjects were given a single dose of ondansetron (16 mg) 
or placebo in a double-blind, placebo-controlled, randomized and balanced crossover design 
(Adler, 2005). Serial measurements of the P50 evoked potential were done at Baseline and 1, 2, 
and 3 hours after receipt of placebo or ondansetron. The results of the study indicated that 
ondansetron significantly enhanced P50 auditory gating in subjects with schizophrenia. 
Tropisetron, a 5-HT3 antagonist that also has 7 nicotinic cholinergic agonist activity, has 
similarly been shown to improve P50 auditory gating in subjects with schizophrenia (Koike, 
2005).  
While the P50 signal is likely a reflection of brainstem and thalamic network activity and is 
sensitive to antipsychotic treatment, MMN is thought to reflect excitation-inhibition balance in 
cortical circuits and is not sensitive to antipsychotic treatment (Javitt and Sweet, 2015). 
Therefore, to evaluate the potential for CVN058 to improve cognitive function in schizophrenics, 
MMN will be used as a PD marker. The study will be performed as a 3-way crossover to assess 


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the effect on MMN of CVN058 at two dose levels relative to placebo, with each subject serving 
as his or her own control to reduce variability. P50 auditory gating will also be measured, as an 
exploratory endpoint, along with other potentially informative electrophysiological and 
psychometric parameters. 
Medications that might inhibit or mask the effects of CVN058 will not be permitted as 
concomitant medications. These include serotonin reuptake inhibitors which increase synaptic 
serotonin levels, as well as drugs that bind to 5-HT3 at clinically relevant concentrations or are 
reported to inhibit signaling through 5-HT3 non-competitively, including some antipsychotic 
drugs [( Eisensamer, 2005), (Eisensamer, 2003), (Rammes, 2004)]. Permissible antipsychotic 
medications are risperidone (Risperdal), haloperidol (Haldol), quetiapine (Seroquel), aripiprazole 
(Abilify) and paliperidone (Invega). 


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5.0 
STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Objectives 
5.1.1 Primary Objective 
 To determine whether improvement in MMN is demonstrated after administration of 
CVN058 compared to placebo in subjects with schizophrenia.  
5.1.2 Secondary Objective 
 To assess the safety and tolerability of single doses of CVN058 in subjects with 
schizophrenia. 
5.1.3 Exploratory Objectives  
 To determine whether improvement in P50 auditory gating, gamma power, and P300 is 
demonstrated after administration of CVN058 compared to placebo in subjects with 
schizophrenia. 
 To assess the pharmacokinetics (PK) of CVN058 following a single dose to subjects with 
schizophrenia. 
 To explore the exposure-response relationship for CVN058 in subjects with schizophrenia. 
5.2 
Endpoints 
5.2.1 Primary Endpoints  
 Mean amplitude of duration MMN at 5 electrodes surrounding frontal (Fz) electrodes 
following administration of CVN058 compared to placebo. 
5.2.2 Secondary Endpoint 
 Percentage of subjects who experience at least 1 TEAE  
 Percentage of subjects who experience at least 1 clinically significant abnormal laboratory 
test result 
5.2.3 Exploratory Endpoints 
 Mean P50 ratio (S2/S1) at 5 electrodes surrounding Cz following administration of CVN058 
compared to placebo 
 Mean P50 differences (S2-S1) at 5 electrodes surrounding Cz following administration of 
CVN058 compared to placebo. 
 Pre-stimulus gamma amplitude following administration of CVN058 compared to placebo  
 P300 amplitude and latency at average of 5 centroparietal electrodes around parietal 
electrodes (Pz) following administration of CVN058 compared to placebo 


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 MMN amplitude to additional deviants (frequency, intensity, location, frequency-modulation 
[FM]) and latency to all deviants following administration of CVN058 compared to placebo 
 CVN058, its metabolite if appropriate, Cmax, tmax, and area under the plasma concentration-
time curve from 0 to 5 hours post dose (AUCt). 


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6.0 
STUDY DESIGN AND DESCRIPTION 
6.1 
Study Design  
This is a phase 1, double-blind, placebo-controlled, 3 period cross-over study to evaluate 
CVN058 target engagement by measuring auditory evoked potential MMN downstream to 5-
hydroxytryptamine receptor 3 (5-HT3) as a PD marker.  
Male and female subjects with schizophrenia including schizoaffective disorder, age 18 to 50 
years old, inclusive, will be randomized to 1 of 6 treatment sequences (Table 6.a) to receive 1 of 
3 dose regimens in each period; a single oral administration of CVN058 (15 mg or 150 mg), or a 
matching placebo. The sequence will determine the order in which a subject will receive each of 
the 3 regimens. Discontinued subjects may be replaced so that 20 completed subjects are 
available for analysis. Sample size re-estimation may occur when blinded MMN data from all 3 
periods are available for 12 subjects, or when 20 subjects have been dosed and are expected to 
complete the study. 
Each treatment period is less than 1 day in duration, with a minimum of 7-day washout, 
maximum 10-day washout between doses. A follow-up telephone call will occur approximately 
7-10 days following the last dose received. Subjects may be inpatients or outpatients at the 
discretion of the Investigator. 
Table 6.a 
Treatment Sequences 
Sequence 
Period 1 
Period 2 
Period 3 
1 
A 
B 
C 
2 
B 
A 
C 
3 
C 
A 
B 
4 
A 
C 
B 
5 
B 
C 
A 
6 
C 
B 
A 
A: Placebo 
B: CVN058 15 mg 
C: CVN058 150 mg 
 
At each testing session, subjects will undergo post dose EEG testing including: MMN, P50, 
gamma power, and P300. Study drug will be administered with water in the morning. Testing 
sessions will begin approximately 1.5 hours post-dose. Prior to dose and at various time points 
postdose, blood samples will be collected for the assessment of plasma concentrations of 
CVN058 and biomarkers. Analysis of these samples will confirm drug exposure during EEG 
data collection and will support basic PK/PD response correlations. 
Study procedures will be conducted at approximately the same times across Treatment Periods to 
minimize diurnal effects on outcomes.  The effect of CVN058 on MMN as well as on 
exploratory measures (e.g., P50 auditory gating, gamma power, and P300) will be compared to 
placebo.  
A schematic of the study design is presented in Figure 6.a. 


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Figure 6.a 
Schematic of Study Design 
 
6.2 
Justification for Study Design, Dose, and Endpoints 
This study will explore CNS target engagement by measuring alterations in auditory evoked 
potentials, similar to the demonstration of an effect on P50 auditory gating using the 5-HT3 
antagonist, ondansetron (Adler, 2005). The study design was based on that published study, 
adapted for CVN058 as study drug and MMN as the primary endpoint. It has been reported that 
most subjects with schizophrenia demonstrate a deficit in neural processing that is manifested as 
a reduction in MMN and impairment of auditory sensory gating (P50). According to Adler et al., 
ondansetron improves the P50 deficit after a single dose administration (Adler, 2005).  
The study will be a randomized, 3 period crossover study (CVN058 at two dose levels, and 
placebo) in order to evaluate the effect of CVN058 on MMN as well as on exploratory measures 
(i.e., P50 auditory gating, gamma power, and P300) compared to placebo. The study will be 
double-blind and placebo-controlled in order to avoid subjective bias in the assessment of the PD 
markers. In addition, conduct of study procedures for each subject will occur at approximately 
the same time per day across each of the Treatment Periods to avoid diurnal changes that may 
otherwise confound the analysis.  
The 150 mg level of CVN058 is expected to saturate CNS 5-HT3 receptors throughout the EEG 
session, but is 50% lower than the highest dosage for which safety and tolerability has been 
demonstrated in previous phase 1 studies in healthy subjects, thus presumably maximizing the 
PD signal within the established limits of safe use. The lower dose level of 15 mg CVN058 is 
expected to attain a lower CNS 5-HT3 receptor occupancy, decreasing to possibly 70-80% by the 
end of the EEG session. The 10-fold difference in these dosages should help establish a dose-
response relationship for evoked response potential (ERP) effects of CVN058. From a safety 


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perspective, single doses ranging from 5 mg to 300 mg CVN058 have been safe and well-
tolerated. Daily doses of 25, 75, and 150 mg of CVN058 for 7 days have also been studied, and 
were similarly safe and well-tolerated. 
The timing of dosing was selected to allow the EEG assessments to occur at the corresponding 
estimated tmax values of CVN058. The length of the washout periods is considered adequate 
based on the PK profile of CVN058. 
In addition, based on the EEG deficits reported in subjects with schizophrenia including 
schizoaffective disorder, P50 auditory gating, gamma frequency, and P300 neurophysiological 
markers will be measured. 
6.3 
Premature Termination or Suspension of Study or Investigational Site 
6.3.1 Criteria for Premature Termination or Suspension of the Study 
The study will be completed as planned unless new information or other evaluation regarding the 
safety or efficacy of the study medication indicates a change in the known risk/benefit profile for 
the compound, such that the risk/benefit is no longer acceptable for subjects participating in the 
study. 
6.3.2 Criteria for Premature Termination or Suspension of Investigational Sites 
A study site may be terminated prematurely or suspended if the site (including the investigator) 
is found in significant violation of Good Clinical Practice (GCP), protocol, or contractual 
agreement, is unable to ensure adequate performance of the study, or as otherwise permitted by 
the contractual agreement. 
6.3.3 Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s) 
In the event that the sponsor, an institutional review board (IRB) / independent ethics committee 
(IEC), or regulatory authority elects to terminate or suspend the study or the participation of an 
investigational site, a study-specific procedure for early termination or suspension will be 
provided by the sponsor; the procedure will be followed by applicable investigational sites 
during the course of termination or study suspension. 


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7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS 
All entry criteria, including test results, need to be confirmed prior to randomization. Subjects 
who do not initially meet eligibility criteria may be re-screened at investigator’s discretion.  
7.1 
Inclusion Criteria 
Subject eligibility is determined according to the following criteria prior to entry into the study:  
1. In the opinion of the investigator, the subject is capable of understanding and complying with 
protocol requirements. 
2. The subject signs and dates a written, informed consent form and any required privacy 
authorization prior to the initiation of any study procedures. 
3. The subject is aged 18 to 50 years, inclusive, at the time of informed consent. 
4. The subject weighs at least 50 kg and has a body mass index (BMI) between 18 and 40 kg/m2 
inclusive at Screening. 
5. The subject meets schizophrenia or schizoaffective disorder criteria as defined by the 
Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-V) (American 
Psychiatric Association, 2013). 
6. The subject is on a stable dose of allowed antipsychotic medication(s) for at least 2 months 
prior to Screening as documented by medical history and assessed by site staff. 
7. The subject has a Positive and Negative Syndrome Scale (PANSS) total score of <95 at 
Screening. 
7.2 
Exclusion Criteria 
Any subject who meets any of the following criteria will not qualify for entry into the study:  
1. A male subject who is nonsterilized* and sexually active with a female partner of 
childbearing potential* does not agree to use adequate contraception* from signing of 
informed consent throughout the duration of the study and for 12 weeks after last dose of 
study drug. 
2. A female subject of childbearing potential* who is sexually active with a nonsterilized* male 
partner does not agree to use acceptable methods of contraception* from signing of informed 
consent throughout the duration of the study and for 12 weeks after last dose of study drug. 
*Definitions and acceptable methods of contraception are defined in 
Section 9.1.9 Contraception and Pregnancy Avoidance Procedure and 
reporting responsibilities are defined in Section 9.1.10 Pregnancy. 
3. If female, the subject is pregnant or lactating or intending to become pregnant before, during, 
or within 12 weeks after the last dose of study medication; or intending to donate ova during 
such time period. 


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4. The subject has uncontrolled, clinically significant neurologic, cardiovascular, pulmonary, 
hepatic, renal, metabolic, gastrointestinal, or endocrine disease or other abnormality that may 
impact the ability of the subject to participate or potentially confound the study results.  
5. The subject has a history of gastrointestinal disease that would influence the absorption of 
study drug, or history of any surgical intervention known to impact absorption (e.g., bariatric 
surgery or bowel resection). 
6. The subject has clinical laboratory evaluations (including clinical chemistry, hematology and 
complete urinalysis) outside the reference range for the testing laboratory, unless the results 
are deemed to be NCS by the investigator at Screening. 
7. The subject has received any investigational compound within 30 days prior to signing of 
informed consent. 
8. The subject has taken any excluded medication or dietary supplement within time frames 
listed in the Excluded Medications table in Section 7.3. 
9. The subject does not have a stable indoor living situation (e.g., living independently, with 
family, or group home)  
10. The subject is an immediate family member, study site employee, or is in a dependent 
relationship with a study site employee who is involved in the conduct of this study 
(e.g., spouse, parent, child, sibling) or may consent under duress. 
11. Subjects with moderate to severe substance use disorder according to DSM-5 criteria. 
12. The subject has a positive urine drug result for drugs of abuse (defined as any illicit drug use, 
including marijuana) at Screening.  
13. The subject has a history of cancer requiring chemotherapy within the past 5 years prior to 
the first dose of study medication. This criterion does not include subjects successfully 
treated for basal cell or stage I squamous cell carcinoma of the skin. 
14. The subject has a positive test result for hepatitis B surface antigen (HBsAg), hepatitis C 
virus (HCV) antibody (unless having completed curative therapy), or known history of 
human immunodeficiency virus (HIV) antibody at Screening.  
15. The subject has a QT interval with Fridericia’s correction method (QTcF) >450 msec (males) 
or >470 msec (females) or PR outside the range of 120 to 220 msec, confirmed by triplicate 
testing at 5-minute intervals, at the Screening Visit. 
16. The subject has poor peripheral venous access.  
17. The subject has hair or scalp condition(s) that would prevent the application of the EEG 
electrodes. 
18. The subject has a current diagnosis of a significant psychiatric illness other than 
schizophrenia or schizoaffective disorder, per DSM-V and is in an acute phase/episode. 
19. Subject has clinically meaningful hearing loss per investigator’s judgment. 
20. The subject has donated or lost 450 mL or more of his or her blood volume (including 
plasmapheresis), or had a transfusion of any blood product, within 3 months prior to Day 1. 


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21. The subject has an abnormal (clinically significant) Screening ECG. Entry of any subject 
with an abnormal (not clinically significant) ECG must be approved and documented by 
signature of the principal investigator (PI).  
22. The subject has abnormal Screening laboratory values that suggest a clinically significant 
underlying disease, or subject with the following lab abnormalities: alanine aminotransferase 
(ALT) and/or aspartate aminotransferase (AST) >2x the upper limit of normal (ULN). 
23. The subject has abnormal Screening vital sign values that suggest a clinically significant 
underlying disease. 
24. The subject has a risk of suicide according to the Investigator’s clinical judgment, a 
Screening Visit Columbia-Suicide Severity Rating Scale [C-SSRS]) score of greater than 3, 
or has a history of suicide attempt in the past 3 years. 
7.3 
Excluded Medications, Dietary Products, Procedures, and Treatments  
Use of the agents in Table 7.a (prescription or nonprescription) is prohibited from the time points 
specified until completion of all study activities.  
Table 7.a 
Prohibited Medications  
28 Days Prior to Check-in  
1 Days Prior to Check-in  
1 Hour Prior to 
Each EEG 
Assessment  
Nutraceuticals and dietary supplements (e.g., St. John’s wort, 
ginseng, kava kava, ginkgo biloba, Chinese herbs, and melatonin) 
 
Alcohol-containing 
products 
Products containing 
nicotine, caffeine or 
xanthine (e.g., tea) 
Antipsychotic medications, except risperidone (Risperdal), 
haloperidol (Haldol), quetiapine (Seroquel), aripiprazole (Abilify) 
and paliperidone (Invega) 
 
Sedative hypnotic 
medications (barbiturates 
and benzodiazepines) 
 
5-HT3 receptor antagonists, including ondansetron (Zofran, 
Zuplenz), granisetron (Kytril, Sancuso, Granisol, Sustol), 
palonosetron (Aloxi), dolasetron (Anzemet)  
 
 
 
5-HT3 allosteric modulators buproprion (Wellbutrin, Zyban) and 
hydroxybupropion 
 
 
 
Serotonin Reuptake Inhibitors (SSRI, SNRI), including sertraline 
(Zoloft), fluoxetine (Prozac, Sarafem), citalopram (Celexa), 
escitalopram (Lexapro), paroxetine (Paxil, Pexeva, Brisdelle), 
vortioxetine (Trintellix), and fluvoxamine (Luvox) 
 
 
 
Mirtazapine (Remeron), desipramine, imipramine, trimipramine, 
reboxetine 
 
 
  
Subjects must be instructed not to take any medications, including over-the-counter (OTC) 
products, without first consulting with the investigator. Subjects must be instructed to not make 


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any changes to their concomitant medications during the course of the study without first 
consulting with the investigator. 
During study participation, subjects will maintain usual dosing schedule of antipsychotic 
medication(s) and approved concomitant medications. Sedative hypnotics will not be allowed 
after 10 pm the night prior to testing, and until completion of testing the following day. 
7.4 
Diet, Fluid, Activity Control  
Subjects should have their customary meal before each study visit. The contents of the meal 
should be summarized on the electronic case report form (eCRF). 
During EEG and ERP assessments, subjects will remain still in a seated or partially recumbent 
position, according to the EEG acquisition guidelines. Subjects will refrain from strenuous 
exercise from 72 hours before Check-in through check-out, relative to each Treatment Period. 
If subject is a smoker; they must refrain from smoking at least 1 hour prior to the EEG testing at 
all time points. 
On each dosing day, CVN058 or placebo will be administered with approximately 240 mL of 
water.  
7.5 
Criteria for Discontinuation or Withdrawal of a Subject 
The primary reason for discontinuation or withdrawal of the subject from the study or study 
medication should be recorded in the eCRF using the following categories. For screen failure 
subjects, refer to Section 9.1.17. 
1. Pretreatment event (PTE) or AE. The subject has experienced a PTE or AE that requires 
early termination because continued participation imposes an unacceptable risk to the 
subject’s health or the subject is unwilling to continue because of the PTE or AE. 
2. Liver Function Test (LFT) Abnormalities 
Study medication should be discontinued immediately with appropriate clinical follow-up 
(including repeat laboratory tests, until a subject’s laboratory profile has returned to 
normal/baseline status, see Section 9.1.8), if the following circumstances occur at any 
time during study medication treatment: 
– ALT or AST >8 ×ULN, or 
– ALT or AST >5 ×ULN and persists for more than 2 weeks, or 
– ALT or AST >3 ×ULN in conjunction with elevated total bilirubin >2 × ULN or 
international normalized ratio (INR) >1.5, or 
– ALT or AST >3 ×ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%). 
3. Significant protocol deviation. The discovery post randomization or after the first dose of 
study medication that the subject failed to meet protocol entry criteria or did not adhere to 
protocol requirements, and continued participation poses an unacceptable risk to the subject’s 
health. 


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4. Lost to follow-up. The subject did not return to the clinic and attempts to contact the subject 
were unsuccessful. Attempts to contact the subject must be documented. 
5. Voluntary withdrawal. The subject (or subject’s legally acceptable representative) wishes to 
withdraw from the study. The reason for withdrawal, if provided, should be recorded in the 
eCRF. 
Note: All attempts should be made to determine the underlying reason for the withdrawal 
and, where possible, the primary underlying reason should be recorded (i.e., withdrawal due 
to an AE). 
6. Study termination. The sponsor, IRB, IEC, or regulatory agency terminates the study. 
7. Pregnancy. The subject is found to be pregnant. 
Note: If the subject is found to be pregnant, the subject must be withdrawn immediately. The 
procedure is described in Section 9.1.10. 
8. Other. 
Note: The specific reasons should be recorded in the “specify” field of the eCRF. 
7.6 
Procedures for Discontinuation or Withdrawal of a Subject 
The investigator may discontinue a subject’s study participation at any time during the study 
when the subject meets the study termination criteria described in Section 7.5. In addition, a 
subject may discontinue his or her participation without giving a reason at any time during the 
study. Should a subject’s participation be discontinued, the primary criterion for termination 
must be recorded by the investigator. In addition, efforts should be made to perform all 
procedures scheduled for the Early Termination Visit. Discontinued or withdrawn subjects be 
replaced. 


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8.0 
CLINICAL TRIAL MATERIAL MANAGEMENT 
This section contains information regarding all medication and materials provided directly by the 
sponsor, and/or sourced by other means, that are required by the study protocol, including 
important sections describing the management of clinical trial material. 
8.1 
Study Medication and Materials 
8.1.1 Dosage Form, Manufacturing, Packaging, and Labeling 
Study drug refers to CVN058 and matching placebo. Study drug will be provided in bulk supply. 
An unblinded pharmacist will manage and prepare doses as oral solutions, as needed. 
In this protocol, the term study medication refers to all or any of the drugs defined below. 
8.1.1.1 Investigational Drug 
CVN058 and Matching Placebo  
CVN058 drug substance is supplied as bulk powder to the clinical site to be compounded into an 
oral solution. A matching placebo containing all of the components of the active oral suspension 
with the exception of the drug substance will also be compounded by the site. Compounding 
instructions will be outlined in a separate pharmacy manual and provided by the sponsor. 
CVN058 oral solution will be prepared in concentrations of 10 mg/mL. The composition of the 
oral solutions (active and placebo) can be found in Table 8.a. 
The oral solution will be labeled with the appropriate study information and caution statements. 
Table 8.a 
Composition of CVN058 and Matching Placebo 
Component 
10 mg/mL solution 
Placebo 
CVN058 (free base) 
10 g 
Not Applicable 
Citric Acid Monohydrate, USP 
15.76 g 
15.76 g 
Sterile Water for Irrigation, USP 
q.s. to 1,000 mL 
q.s.to 1,000 mL 
q.s.=quantity sufficient, USP= United States Pharmacopeia. 
 
8.1.1.2 Sponsor-Supplied Drug 
CVN058 drug substance is supplied to the clinical site by Cerevance by way of a contract 
manufacturing organization, Johnson-Matthey Pharma Services, Devens, MA. 
8.1.1.3 Ancillary Materials 
Ancillary materials will be provided by either the clinical site and/or sponsor based on 
availability.  
Ancillary material details are provided in the pharmacy manual. 
Unused ancillary materials, if provided by the sponsor, will be accounted for and disposed of as 
directed by the sponsor or their designee.  


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8.1.2 Storage 
All clinical trial material must be kept in an appropriate, limited-access, secure place until it is 
used or returned to the sponsor or designee for destruction. 
All study medication must be stored under the conditions specified on the label, and remain in 
the original container until dispensed. A daily temperature log of the drug storage area must be 
maintained every working day. 
CVN058 powdered drug substance is stored at room temperature. CVN058 oral solution and 
matching placebo can be stored protected from light at 2°C-8°C (35.6°F-46.4°F) for up to 28 
days. CVN058 oral solution and matching placebo are stable at room temperature for up to 24 
hours. 
8.1.3 Dose and Regimen 
The investigator or investigator’s designee will instruct the subject on dosing procedures. 
All dosing will occur while subjects are in the clinic under the supervision of the PI or designee, 
who will be blinded to the dose. 
Subjects will receive CVN058 (15 mg or 150 mg) or matching placebo in each of the 3 periods.  
Table 8.b describes the treatment and medication type that would be provided for each period. 
Table 8.b 
Treatment and Medication Type 
Regimen 
Planned Treatment 
Medication Type 
A 
Placebo 
Placebo  
B 
CVN058 15 mg 
CVN058  
C 
CVN058 150 mg 
CVN058 
 
8.1.4 Overdose 
An overdose is defined as a known deliberate or accidental administration of investigational 
drug, to or by a study subject, at a dose above that which is assigned to that individual subject 
according to the study protocol. 
All cases of overdose (with or without associated AEs) will be documented on an Overdose page 
of the eCRF, in order to capture this important safety information consistently in the database. 
Cases of overdose without manifested signs or symptoms are not considered AEs. AEs 
associated with an overdose will be documented on AE CRF(s) according to Section 10.0, 
Pretreatment Events and Adverse Events. 
The SAEs associated with overdose should be reported according to the procedure outlined in 
Section 10.2.2, Collection and Reporting of SAEs. 
In the event of drug overdose, the subject should be treated, e.g., administration of supportive 
therapy as directed by the subject’s clinical status, removal of unabsorbed material from the 
gastrointestinal tract and initiation of additional clinical monitoring.  


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8.2 
Investigational Drug Assignment and Dispensing Procedures 
Subjects will be assigned a 7-digit subject number in the sequential order in which they are 
randomized beginning with a 3-digit code “NNN-” where NNN represents a site-specific 
identifier which will be provided by the Sponsor. Replacement subjects will be assigned a new 
number (e.g. site number followed by subject number). The 7-digit subject number assigned will 
be entered in the subject’s eCRF and noted on any subject specific source record and lab sample 
tubes. 
This 7-digit subject number will also be used by the clinical site to facilitate the prelabeling of 
PK samples, and will be the only subject identifier used on all PK sample collections. It should 
also be contained on the PK transport vials shipped to the bioanalytical laboratory, and will be 
used by the laboratory to report the subject data results. 
8.3 
Randomization Code Creation and Storage  
The randomization schedule will be generated under the direction of Cerevance statistician or 
designee and a copy will be provided to the site pharmacist prior to the start of study. All 
randomization information will be stored in a secured area, accessible only by authorized 
personnel. 
8.4 
Investigational Drug Blind Maintenance  
The investigational drug blind is maintained through a randomization schedule held by the 
dispensing pharmacist.  
8.5 
Unblinding Procedure  
The investigational drug blind shall not be broken by the investigator unless information 
concerning the investigational drug is necessary for the medical treatment of the subject. All 
study assessments and assignment of causality for AEs should be performed, if possible, prior to 
unblinding. In the event of a medical emergency, if possible, the medical monitor should be 
contacted before the investigational drug blind is broken to discuss the need for unblinding. 
For unblinding a subject, the investigational drug blind can be obtained by contacting the 
dispensing pharmacist. 
The sponsor must be notified as soon as possible if the investigational drug blind is broken. The 
date, time, and reason the blind is broken must be recorded in the source documents and the 
same information (except the time) must be recorded on the eCRF. 
If any site personnel are unblinded, investigational drug must be stopped immediately and the 
subject must be withdrawn from the study. 
No change should be made to any prior assessments or data of the subject after unblinding. 
8.6 
Accountability and Destruction of Sponsor-Supplied Drugs 
Drug supplies will be counted and reconciled at the site before being returned to the sponsor or 
designee or destroyed per site’s procedures. 


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The investigator or designee must ensure that the sponsor-supplied drug is used in accordance 
with the protocol and is dispensed only to subjects enrolled in the study. To document 
appropriate use of sponsor-supplied drug, the investigator or designee must maintain records of 
all sponsor-supplied drug delivery to the site, site inventory, dispensation and use by each 
subject, and return to the sponsor or designee. 
Upon receipt of sponsor-supplied drug, the investigator or designee must verify the contents of 
the shipments against the packing list. The verifier should ensure that the quantity is correct, and 
the medication is in good condition. If quantity and conditions are acceptable, investigator or 
designee should acknowledge the receipt of the shipment by signing bottom half of the packing 
list and faxing per instructions provided on the form. If there are any discrepancies between the 
packing list versus the actual product received, Cerevance must be contacted to resolve the issue. 
The packing list should be filed in the investigator’s essential document file. 
The investigator or designee must maintain 100% accountability for all sponsor-supplied drugs 
received and dispensed during his or her entire participation in the study. Proper drug 
accountability includes, but is not limited to: 
 Continuously monitoring expiration dates. 
 Frequently verifying that actual inventory matches documented inventory. 
 Verifying that the log is completed for the drug lot used to prepare each dose. 
 Verifying that all containers used are documented accurately on the log. 
 Verifying that required fields are completed accurately and legibly. 
If any dispensing errors or discrepancies are discovered, the sponsor must be notified 
immediately. 
The investigator or designee must record the current inventory of all sponsor-supplied drugs 
CVN058 or placebo on a sponsor-approved drug accountability log. The following information 
will be recorded at a minimum: protocol number and title, name of investigator, site identifier 
and number, description of sponsor-supplied drugs, expiration date and amount dispensed, 
including initials of the person dispensing the drug, and the date and amount returned to the site 
by the subject, including the initials of the person receiving the sponsor-supplied drug. The log 
should include all required information as a separate entry for each subject to whom sponsor-
supplied drug is dispensed. 
All study drug that was not returned to the site by a subject must be investigated by the site and 
appropriately documented on the drug accountability log. 
Prior to site closure or at appropriate intervals, a representative from the sponsor or its designee 
will perform sponsor-supplied drug accountability and reconciliation before sponsor-supplied 
drugs are returned to the sponsor or its designee for destruction. The investigator or designee will 
retain a copy of the documentation regarding sponsor-supplied drug accountability, return, 
and/or destruction, and originals will be sent to the sponsor or designee. 
The investigator will be notified of any expiry date or retest date extension of sponsor-supplied 
drug during the study conduct. On expiry date notification from the sponsor or designee, the site 


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must complete all instructions outlined in the notification, including segregation of expired 
sponsor-supplied drug for return to the sponsor or its designee for destruction. 


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9.0 
STUDY PLAN 
9.1 
Study Procedures 
The following sections describe the study procedures and data to be collected. For each 
procedure, subjects are to be assessed by the same investigator or site personnel whenever 
possible. The Schedule of Study Procedures is located in Appendix A. 
9.1.1 Informed Consent Procedure 
The requirements of the informed consent are described in Section 15.2. 
Informed consent must be obtained prior to the subject entering into the study, and before any 
protocol-directed procedures are performed. 
A unique subject Screening number will be assigned to each subject at the time that the informed 
consent is obtained; this Screening number will be used until the subject has been randomized 
into the study, at which time the Subject number will be primary method of identification on 
study records. 
9.1.1.1 Pharmacogenomic Informed Consent Procedure 
Pharmacogenomics informed consent is a component of the overall study informed consent. The 
requirements are described in Section 15.2. 
The pharmacogenomic sample collection is optional. 
9.1.2 Demographics, Medical History, and Medication History Procedure 
Demographic information to be obtained will include date of birth, sex, Hispanic ethnicity, race 
as described by the subject, height, weight, caffeine consumption, reproductive status (including 
last menstrual period) and smoking status of the subject at Screening.  
Medical history to be obtained will include determining whether the subject has any significant 
conditions or diseases relevant to the disease under study that stopped at or prior to signing of 
informed consent. Ongoing conditions are considered concurrent medical conditions 
(see Section 9.1.7). 
Medication history information to be obtained includes any medication relevant to eligibility 
criteria stopped at or within 45 days prior to signing of informed consent. 
9.1.3 Physical Examination Procedure 
A physical examination will consist of the following body systems: (1) eyes; (2) ears, nose, 
throat; (3) cardiovascular system; (4) respiratory system; (5) gastrointestinal system; 
(6) dermatologic system; (7) extremities; (8) musculoskeletal system; (9) nervous system; 
(10) lymph nodes; and (11) other. 
Any abnormal change from the initial Screening physical examination must be assessed by the 
investigator as not clinically significant (NCS) or clinically significant (CS) and recorded in the 
source document and eCRF. 


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Any CS change, as determined by the investigator, from the baseline physical examination will 
be recorded as an AE or pretreatment event in source documentation and on the Pretreatment 
Event/AE eCRF. 
9.1.4 Weight, Height, and BMI 
A subject should have weight and height measured while wearing indoor clothing and with shoes 
off. The BMI is calculated using metric units with the formula provided below:  
The standard for collecting height is centimeters without decimal places and for weight it is 
kilograms (kg) with 1 decimal place. BMI should be derived as: 
Metric:  
BMI = weight (kg)/height (m)2 
Note that although height is measured in centimeters, the BMI formula uses meters for height; 
meters can be determined by dividing centimeters by 100. Thus, for example, if height=176 cm 
(1.76 m) and weight=79.2 kg, then BMI=79.2/1.762=25.56818 kg/m2. 
Results for BMI will be expressed with 1 decimal place and rounding is allowed. The above 
value should be captured as 25.6 kg/m2 in the database. 
9.1.5 Vital Sign Procedure  
When vital signs are scheduled at the same time as blood draws, the blood draw will take priority 
and vital signs will be obtained within 0.5 hour before or after the scheduled blood draw. Vital 
signs assessments will be collected with a window of ±15 minutes. 
Vital signs consisting of body temperature (oral), respiration rate, blood pressure and pulse will 
be measured in a seated resting state (>10 minutes). 
9.1.6 Documentation of Concomitant Medications 
Concomitant medication is any drug given in addition to the study medication. These may be 
prescribed by a physician or obtained by the subject over the counter. Concomitant medication is 
not provided by Cerevance. At each study visit, subjects will be asked whether they have taken 
any medication other than the study medication (used from signing of informed consent through 
the end of the study), and all medication including vitamin supplements, OTC medications, and 
oral herbal preparations, must be recorded in the eCRF. Documentation will include generic 
medication name, dose, unit, frequency, route of administration, start and end dates, and reason 
for use.  
9.1.7 Documentation of Concurrent Medical Conditions 
Concurrent medical conditions are those significant ongoing conditions or diseases that are 
present at signing of informed consent. This includes clinically significant laboratory, ECG, or 
physical examination abnormalities noted at the Screening examination. The condition (i.e., 
diagnosis) should be described. 


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9.1.8 Procedures for Clinical Laboratory Samples 
All samples will be collected in accordance with acceptable laboratory procedures and as 
stipulated in the Schedule of Study Procedures (Appendix A). Abnormal Screening labs may be 
repeated once at the discretion of the investigator for assessment of eligibility. Subjects who still 
do not meet eligibility criteria may be re-screened at investigator’s discretion. 
Table 9.a lists the tests that will be obtained for each laboratory specimen. Additional laboratory 
assessments may be performed at the Investigator’s discretion and entered in the database for 
Randomized Subjects only, if the results are deemed Clinically Significant by Investigator. 
Table 9.a 
Clinical Laboratory Tests 
Hematology 
Serum Chemistry 
Urinalysis 
 
RBC 
WBC with differential (% 
and absolute) 
Hemoglobin 
Hematocrit 
Platelets 
Prothrombin time 
/INR/Partial thromboplastin 
time (PTT) 
ALT 
Albumin 
Alkaline phosphatase 
AST 
Total bilirubin 
Direct bilirubin 
Total protein 
Creatinine 
Blood urea nitrogen 
Creatine kinase 
GGT 
Potassium 
Sodium 
Glucose 
Chloride 
Bicarbonate 
Calcium 
pH 
Specific gravity 
Protein 
Glucose 
Blood  
Nitrite 
Microscopic Analysis 
(only if positive dipstick 
results):  
RBC/high power field 
WBC/high power field 
Epithelial cells, casts etc 
 
Diagnostic Screening: 
Serum 
Urine 
Saliva (d) 
Serum hCG (a) 
At Screening Only:  
Hepatitis panel, including HBsAg 
and anti-HCV 
FSH (b) 
Drug screen including 
amphetamines, barbiturates, 
benzodiazepines, cannabinoids, 
cocaine, opiates, alcohol, and 
cotinine (c) 
Alcohol 
cotinine 
FSH=follicle-stimulating hormone, GGT=-glutamyl transferase, RBC=red blood cells, WBC=white blood cells. 
(a) Serum hCG pregnancy test will be done at Screening. 
(b) FSH level will be obtained for female subjects at Screening if they are postmenopausal (i.e., last regular 
menstrual cycle >2 years) and not surgically sterile. The result must be >40 IU/L to obviate the need for 
contraception.  
(c) To be performed at Screening.  
(d) Alcohol and cotinine saliva samples may be collected, if needed. 
The local laboratory will perform laboratory tests for hematology, serum chemistries, and 
urinalysis. The results of laboratory tests will be returned to the investigator, who is responsible 
for reviewing and filing these results. 


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If subjects experience ALT or AST >3 ×ULN, follow-up laboratory tests (at a minimum, serum 
alkaline phosphatase, ALT, AST, total bilirubin, GGT, and INR) should be performed within a 
maximum of 7 days and preferably within 48 to 72 hours after the abnormality was noted. 
(Please refer to Section 7.5 for discontinuation criteria, and Section 10.2.3 for the appropriate 
guidance on Reporting of Abnormal Liver Function Tests in relation to ALT or AST >3 ×ULN 
in conjunction with total bilirubin >2 ×ULN.) 
If the ALT or AST remains elevated >3 ×ULN on these 2 consecutive occasions, the investigator 
must contact the Medical Monitor for consideration of additional testing, close monitoring, 
possible discontinuation of study medication, discussion of the relevant subject details and 
possible alternative etiologies. The abnormality should be recorded as an AE (please refer to 
Section 10.2.3 Reporting of Abnormal Liver Function Tests for reporting requirements). 
All laboratory safety data will be transferred electronically to Cerevance or designee in the 
format requested by Cerevance. If the laboratory is unable to electronically transfer data, the 
study site coordinator or designee is responsible for transcribing laboratory results into the eCRF. 
The investigator will maintain a copy of the laboratory accreditation and the reference ranges for 
the laboratory used. 
Laboratory reports must be signed and dated by the PI or sub-investigator indicating that the 
report has been reviewed and any abnormalities have been assessed for clinical significance.  
All CS laboratory abnormalities must be recorded as a PTE/AE in the subject’s source 
documents and on the appropriate eCRF. A CS laboratory abnormality that has been verified by 
retesting will be followed until the abnormality returns to an acceptable level or a satisfactory 
explanation has been obtained. 
9.1.9 Contraception and Pregnancy Avoidance Procedure 
During the study and for 12 weeks after last dose of study medication, nonsterilized males and 
female subjects of childbearing potential who are sexually active must agree to use two effective 
methods of contraception.  
From signing of informed consent, throughout the duration of the study, and for 12 weeks after 
last dose of study medication, nonsterilized** male subjects who are sexually active with a 
female partner of childbearing potential* must use barrier contraception (e.g., condom with 
spermicidal cream or jelly). In addition, they must be advised not to donate sperm during this 
period.  
From signing of informed consent, throughout the duration of the study, and for 12 weeks after 
last dose of study medication, female subjects of childbearing potential* who are sexually active 
with a nonsterilized male partner** must use adequate contraception. In addition they must be 
advised not to donate ova during this period. 


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*Females NOT of childbearing potential are defined as those who have been surgically sterilized 
(hysterectomy, bilateral oophorectomy or tubal ligation) or who are postmenopausal (e.g., 
defined as at least 2 years since last regular menses with an FSH>40 IU/L or at least 5 years 
since last regular menses, confirmed before any study medication is implemented). 
**Sterilized males should be at least 1 year postvasectomy and have confirmed that they have 
obtained documentation of the absence of sperm in the ejaculate. 
The following are acceptable forms of contraception: 
Barrier methods (each time the subject has 
intercourse): 
Intrauterine devices (IUDs): 
 Male condom PLUS spermicide. 
 Cap (plus spermicidal cream or jelly). 
 Diaphragm (plus spermicidal cream or 
jelly). 
Hormonal Contraception (stable regimen) 
 Birth control pills or patch. 
 Injected hormonal contraceptive  
(such as Depo-Provera). 
 Vaginal hormonal ring  
(such as NuvaRing). 
 Copper T PLUS condom or spermicide. 
Subjects will be provided with information on acceptable methods of contraception as part of the 
subject informed consent process and will be asked to sign a consent form stating that they 
understand the requirements for avoidance of pregnancy, donation of ova, and sperm donation 
during the course of the study. 
During the course of the study, regular serum human chorionic gonadotropin (hCG) pregnancy 
tests will be performed only for women of childbearing potential, and subjects will receive 
guidance with respect to the avoidance of pregnancy. In addition to a negative serum hCG 
pregnancy test at Screening, subjects also must have a negative urine hCG pregnancy test prior to 
receiving any dose of study medication. Male subjects must be advised not to donate sperm from 
signing of informed consent to 12 weeks after the last dose of study medication. 
9.1.10 Pregnancy 
If any subject is found to be pregnant during the study she should be withdrawn and any sponsor-
supplied drug should be immediately discontinued. In addition, any pregnancies in the partner of 
a male subject during the study or for 12 weeks after the last dose should also be recorded 
following authorization from the subject’s partner.  


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If the pregnancy occurs during administration of active study medication, e.g., after Visit 1 or 
within 12 weeks of the last dose of active study medication, the pregnancy should be reported 
immediately, using a pregnancy notification form, to the contact listed in Section 1.0. 
Should the pregnancy occur during or after administration of blinded drug, the investigator must 
inform the subject of their right to receive treatment information. If the subject chooses to 
receive unblinded treatment information, the individual blind should be broken by the 
investigator. Subjects who have only received placebo need not be followed. 
If the female subject and/or female partner of a male subject agrees to the primary care physician 
being informed, the investigator should notify the primary care physician that the subject/female 
partner of the subject was participating in a clinical study at the time she became pregnant and 
provide details of treatment the subject received (blinded or unblinded, as applicable). 
All reported pregnancies will be followed up to final outcome, using the pregnancy form. The 
outcome, including any premature termination, must be reported to the sponsor. An evaluation 
after the birth of the child will also be conducted. 
9.1.11 ECG Procedure  
A standard 12-lead ECG will be recorded in a supine position resting for at least 10 minutes at 
Screening to assess eligibility. The ECGs will be recorded in triplicate at approximately 5-minute 
intervals, with a window of ±2 minutes. The investigator (or a qualified physician at the 
investigational site) will interpret the ECG using 1 of the following categories: within normal 
limits, abnormal but NCS, or abnormal and CS. A copy of the ECG trace should be kept with the 
subject’s notes. 
ECGs will be read automatically and also, the investigator or sub-investigator or a suitably 
qualified delegate will manually interpret the ECG using 1 of the following categories: within 
normal limits, abnormal NCS, or abnormal and CS. All 12-lead ECGs will be stored for manual 
measurement of intervals, if necessary.  
Twelve-lead ECGs will be recorded using an ECG machine that automatically calculates the 
heart rate and measures PR interval, RR interval, QRS interval, QT interval, and QTcF and 
QTcB (Fridericia’s and Bazett’s correction) intervals.  
One copy of the 12-lead ECG with the physician’s signature and date of assessment will be filed 
with the source documents and captured in the appropriate eCRF. All ECGs will be recorded at 
the time points detailed in the Schedule of Study Procedures (Appendix A). 
9.1.12 Pharmacogenomic Sample Collection 
Every subject must sign informed consent/be consented in order to participate in the study, but 
consent to participate in the pharmacogenomic sample collection (genetic substudy) is optional. 
Deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) form the basis for the genes that 
make the body produce proteins such as enzymes, drug transporters or drug targets, and may be 
evaluated for the genetic contribution how the drug is broken down, or how the drug affects the 
body. This is called a “pharmacogenomics research study.” Specific purposes of this study 
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 Identifying genetic reasons why certain people respond differently to CVN058. 
 Finding out more information about how CVN058 works. 
 Generating information needed for research, development, and regulatory approval of tests to 
predict response to CVN058. 
 Identifying variations in genes related to the biological target of CVN058. 
This information may be used, for example, to develop a better understanding of the safety and 
efficacy of CVN058 and other study medications, and for improving the efficiency, design and 
study methods of future research studies. 
The DNA samples will be used to evaluate common variations in genes which encode drug 
metabolizing enzymes and transporters. This could be helpful in understanding why there are 
differences in CVN058 kinetics between subjects. Also, since pharmacogenomics is an evolving 
science, many genes and their functions are not yet fully understood. Future data may suggest a 
role of some of these genes in drug response, which may lead to additional hypothesis-generating 
exploratory research and diagnostic development on stored samples. 
Whole blood will be collected and stored for possible DNA or RNA isolation and analysis.  
DNA sample collection: 
One 6 mL whole blood sample will be collected before study drug dosing on Day 1 of 
Period 1 only from each subject in the study, into plastic potassium ethylenediamine 
tetraacetic acid (K2EDTA) spray-coated tubes, and stored under frozen conditions.  
RNA sample collection: 
Two whole blood samples (2.5 mL per sample) will be collected from each subject into a 
PAXgene tube on Day 1 of each period at pre-dose and post EEG for RNA 
pharmacogenomic analysis.  
If isolation of DNA from the first sample was not successful or possible, a second aliquot of 
blood may be taken, if feasible. 
Each pharmacogenomic sample for a study subject should be identifiable on the requisition form 
with the 7-digit subject ID. Detailed instructions for the handling, shipping, and storage of 
pharmacogenomic samples will be provided in the lab manual.  
The samples will be stored for no longer than 15 years after completion of the CVN058 study 
and/or until the drug development of CVN058 is no longer actively pursued by Cerevance or its 
collaborators. No samples will be stored for longer than permitted by the applicable law and 
samples will be destroyed upon notification from Cerevance. 
9.1.13 Pharmacokinetic Sample Collection 
9.1.13.1 Collection of Blood for Pharmacokinetic Sampling 
Blood samples (one 6-mL sample per scheduled time) will be collected for analysis of CVN058, 
and its metabolite if appropriate; plasma will be collected into chilled vacutainers containing 


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K2EDTA according to the schedule in Appendix A. Instructions for sample processing and 
shipment will be provided in the lab manual. 
Serial blood samples for determination of CVN058, and its metabolite if appropriate, in plasma 
will be collected according to Table 9.b. 
Table 9.b 
Collection of Blood Samples for CVN058 Pharmacokinetic Analysis 
Sample 
Type 
Dosing Day 
Time Post-dose (hours) 
Plasma 
1 
Pre-dose (within 15 minutes prior to dosing), 1 hour post dose (pre-EEG), and 5 hours 
post dose (post-EEG)   
 
The PK samples will be collected before any other assessments are performed, if scheduled at the 
same time point. The actual time of sample collection will be recorded on the source document 
and eCRF. 
Placebo samples will not be analyzed by the bioanalytical laboratory except 1 sample per subject 
receiving placebo around the expected time at which CVN058 Cmax is expected to occur to 
ensure from a safety perspective that no subjects have inadvertently received active treatment. 
9.1.13.2 Bioanalytical Methods 
Plasma concentrations of CVN058 will be measured by high-performance liquid 
chromatography with tandem mass spectrometry. If appropriate, plasma samples analyzed for 
CVN058 also may be analyzed for the CVN058 metabolite. 
9.1.14 Pharmacokinetic Parameters  
The PK parameters of CVN058, and its metabolite (if appropriate), will be derived using non-
compartmental analysis methods. The PK parameters will be determined from the concentration-
time data for all evaluable subjects. Actual sampling times, rather than scheduled sampling 
times, will be used in all computations involving sampling times. The following PK parameters 
will be determined from concentrations of CVN058, and its metabolite if appropriate, in plasma. 
Other parameters may be calculated as appropriate.  
Symbol/Term 
Definition 
Plasma 
AUCt 
Area under the plasma concentration-time curve from time 0 to 5 hours post dose. 
Cmax 
Maximum observed plasma concentration. 
tmax 
Time to reach Cmax. 
 
9.1.15 Pharmacodynamic Sample Collection  
MMN will be used as a PD assessment. At each testing session, the following PD assessments 
will be performed during the EEG: MMN, P50, gamma power, and P300. Collection of P50 may 
be omitted if the essential equipment is not available. The testing session during each Treatment 
Period will begin approximately 1.5 hours after administration of study drug.  


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9.1.16 Pharmacodynamic Parameters  
All EEG parameters will be obtained in accordance with the EEG acquisition guideline provided 
by Cerevance or their designee. It is anticipated that each EEG procedure will take 
approximately 4 hours to complete, including approximately 30 minutes to set up, 3 hours 
acquisition time, and 30 minutes to clean up. 
MMN 
MMN is a pre-attentive auditory component elicited by deviant stimuli in an auditory oddball 
task. MMN predominantly reflects activation of neuronal ensembles within primary auditory 
cortex, and thus indexes sensory level disturbance in schizophrenia. MMN will be obtained 
independently to pitch and duration deviant stimuli. MMN is maximal at frontocentral electrodes 
(Fz, Cz). Mean peak amplitude at 5 electrodes surrounding Fz within a predefined latency range 
will be the primary outcome measure. 
P50 
P50 auditory evoked potentials will be recorded. Participants will be seated and instructed to 
relax and to focus their eyes on a fixation point. Stimulus signal of 90-dB pulses of 0.1 msec in 
duration will be generated and recorded the event-related potential waveforms.  
32 pairs of auditory clicks will be presented every 10 seconds, with a 500 msec interclick 
interval. 
 
The conditioning P50 wave (S1) and test P50 wave (S2) will be identified as the power in the 
alpha/beta frequency bands as suggested by Smucny et al. (Smucny, 2013). The data from the 
vertex (Cz) and surrounding electrodes will be collected and the P50 gating ratios will be 
calculated as the ratio of the test P50 to the conditioning P50 power. In case the Cz gating ratio is 
>0.2 units above the surrounding electrodes, the value will be discarded and replaced with the 
value from surrounding electrodes. P50 ratio will be defined as the ratio of S2/S1 power. The S2-
S1 difference score as suggested by Smucny et al. (Smucny, 2013) will be used as an exploratory 
outcome measure.  
Quantitative Electroencephalogram, Gamma Power 
Five-minute eyes open/close recordings will be obtained during each recording session. Ten 1-
second, artifact-free epochs will be chosen for quantitative analysis. Primary outcome measures 
will consist of power within delta (0.5 – 4 Hz), theta (4-7 Hz), alpha (8-13 Hz), delta (13-20 Hz), 
low gamma (20-40 Hz) and high gamma (40 – 60 Hz) over predesignated frontal, central, 
temporal and occipital sites. In addition, specific measures of 40 Hz activity will be assessed in 
response to repetitive 40 Hz auditory stimulation. 
P300 
As opposed to MMN, which are obtained under passive (i.e., no-task) conditions, auditory P300 
will be obtained only when subjects must attend to and detect novel task-relevant deviant stimuli. 
Generators for P300 are located in distributed frontoparietal networks and so represent an index 
of higher order, “cognitive” processing in schizophrenia. P300 will be obtained to deviant 
auditory stimuli in an auditory “oddball” paradigm. P300 is maximal in amplitude at Fz and Pz 


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electrodes. Primary outcome measures will consist of peak amplitude within prespecified latency 
range at the frontal/parietal sites. 
9.1.17 Positive and Negative Syndrome Scale 
The PANSS was developed and standardized for typological and dimensional assessment of 
schizophrenic phenomena. In this study, empirically derived factors are tested excluding those 
items that could not be assessed during the test sessions: positive symptom factor (delusions, 
unusual thoughts, somatic concern, grandiosity, suspiciousness, and hallucinations), negative 
symptom factor (emotional withdrawal, blunted affect, poor rapport, disturbance of volition, 
preoccupation, and motor retardation), cognitive factor (difficulty in abstract thinking, 
stereotyped thinking, cognitive disorganization, lack of judgment and insight, poor attention, 
tension, mannerisms, and posturing), hostility (excitement, hostility, impulse control, and 
uncooperativeness), emotional discomfort (depression, anxiety, and guilt). PANSS will be 
collected at Screening, Early Termination, and at the Follow-up Visit if clinically significant 
findings were observed upon discharge. In these cases, subjects must then be brought back to the 
clinic for re-evaluation per investigator’s discretion.  
The duration of the PANSS is approximately 30 minutes (Kay, 1990). 
9.1.18 Columbia Suicide Severity Rating Scale 
The determination and management of subjects’ suicidality risk is the Investigators’ 
responsibility. For study purposes, suicidality will be assessed by the use of the C-SSRS. The C-
SSRS is a 3-part scale that measures suicidal ideation (e.g., subject endorses thoughts about a 
wish to be dead or has other thoughts of suicide), intensity of ideation (frequency, duration, 
controllability, deterrents, and reasons for ideation), and suicidal behavior (actually, interrupted, 
and aborted attempts at suicide) (Mundt, 2013). 
The C-SSRS is a 2-page questionnaire that prospectively assesses suicidal thoughts and behavior 
using a structured interview for patient responses. Suicidal ideation is classified on a 5-item 
scale: 1 (wish to be dead), 2 (nonspecific active suicidal thoughts), 3 (active suicidal ideation 
with any methods [not plan] without intent to act), 4 (active suicidal ideation with some intent to 
act, without specific plan), and 5 (active suicidal ideation with specific plan and intent). The C-
SSRS also captures information about the intensity of ideation, specifically the frequency, 
duration, controllability, deterrents, and reasons for the most severe types of ideation. Suicidal 
behavior is classified on a 5-item scale: 0 (no suicidal behavior), 1 (preparatory acts or behavior), 
2 (aborted attempt), 3 (interrupted attempt), and 4 (actual attempt). 
Different versions of the scale are available. In this study, “Baseline/Screening” version will be 
used at Screening Visit and “Since last visit” version at all subsequent visits. “Since the last 
visit” should collect information from the last visit where C-SSRS was administered. If the 
patient’s response generates a change in the findings report from negative to positive, the patient 
should be referred for immediate psychiatric evaluation on the same date as the site visit. 
Positive suicidality findings, if confirmed by the PI, is considered to be a serious event. If arising 
after signing informed consent but prior to administration of any study medication, it is 
considered a Pretreatment Event (PTE). If arising after administration of any study medication, it 
is considered an SAE.  


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The C-SSRS will be administered by the PI or a trained designee on paper and captured in the 
eCRF. The same interviewer should be used throughout the study for the same subject where 
possible. 
9.1.19 Documentation of Screen Failure 
Investigators must account for all subjects who sign informed consent. If the subject is found to 
be not eligible at this visit, the investigator should complete the eCRF screen failure form. 
The primary reason for screen failure is recorded in the eCRF using the following categories: 
 PTE/AE. 
 Did not meet inclusion criteria or did meet exclusion criteria. 
 Significant protocol deviation. 
 Lost to follow-up. 
 Voluntary withdrawal. 
 Study termination. 
 Other <specify reason>. 
Subject numbers assigned to subjects who fail Screening should not be reused. 
9.1.20 Documentation of Randomization 
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible 
for randomization into the treatment phase. Randomization will take place on Day 1 of 
Treatment Period 1. 
If the subject is found to be not eligible for randomization, the investigator should record the 
primary reason for failure on the applicable eCRF. 
9.2 
Monitoring Subject Treatment Compliance 
Study medication will be administered while subjects are under observation in the clinical 
research unit. Following administration of the study medication, appropriate mouth and/or hand 
checks will be performed to ensure that the dose is swallowed and noted in the source document. 
The date and time of each dose will be recorded in the source documents and on the eCRFs. An 
inventory of the study medication supplies dispensed will be performed by the site pharmacist or 
authorized study designee and recorded onto the Drug Accountability Log in the subject’s source 
document records or equivalent. The exact dose time of consecutive subjects may be staggered to 
facilitate logistics at the site. 
9.3 
Schedule of Observations and Procedures 
The schedule for all study-related procedures for all evaluations is shown in Appendix A. 
Assessments should be completed at the designated visit/time point(s). 


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9.3.1 Screening 
Subjects with schizophrenia including schizoaffective disorder will be screened within 28 days 
prior to enrollment. All subjects will be screened in accordance with predefined inclusion and 
exclusion criteria as described in Section 7.0. See Section 9.1.17 for procedures for documenting 
screen failures.  Following written informed consent, Screening procedures may be conducted on 
different days. Assessments to be conducted during the Screening period are outlined in 
Appendix A. 
9.3.2 Treatment Phase 
The treatment will be administered over 3 Periods, separated by 7-10 days for washout.  
Assessments to be conducted during the screening period are outlined in Appendix A. 
9.3.3 Final Visit/End of Treatment  
The Final Visit additional assessments will occur prior to Discharge from the clinic at the end of 
Treatment Period 3, Day 1, as outlined in Appendix A. 
For all subjects who received any study medication, the investigator must complete the End of 
Study eCRF page. 
9.3.4 Early Termination 
The reason for discontinuation must be documented in the source document and eCRF. The 
procedures outlined in Appendix A will be performed and documented. 
For all subjects receiving study medication, the investigator must complete the End of Study 
eCRF page. 
9.3.5 Follow-up Visit/Telephone Call  
The Follow-up Visit will occur by telephone approximately 7-10 days after receiving the last 
dose of study medication (Treatment Period 3) unless abnormal, clinically significant findings 
were observed upon discharge. In these cases, subjects must then be brought back to the clinic 
for re-evaluation per investigator’s discretion. 
9.4 
Biological Sample Retention and Destruction  
In this study, specimens for genome/gene analysis will be collected as described in Section 
9.1.12, Pharmacogenomic Sample Collection. The genetic material will be preserved and 
retained by a biorepository contracted by Cerevance for up to but not longer than 15 years or as 
required by applicable law.  
The samples will be sent to a central laboratory that processes the blood sample and serves as a 
secure storage facility. The sponsor and researchers working with the sponsor will have access to 
the samples collected and any test results. All samples collected during the study will be stored 
securely with limited access and the sponsor will require anyone who works with the samples to 
agree to hold the research information and any results in confidence. 


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The sample will be labeled with a unique sample identifier similar to labeling in the main study. 
During the “storage” stage, the sample will be used in the analysis of the study drug and related 
disease states. At this stage, sample and data are linked to personal health information with code 
numbers. This link means that subjects may be identifiable but only indirectly. The code 
numbers will be kept secure by the sponsor.  
Subjects who consented and provided a pharmacogenomic sample for DNA and RNA analysis 
can withdraw their consent and request disposal of a stored sample at any time prior to analysis. 
Notify sponsor of consent withdrawal. 
9.5 
Blood Volume 
Total blood sampling volume for an individual subject is shown in Table 9.c. 
Table 9.c 
Approximate Blood Volume 
Sample Type 
Sample 
Volume 
(mL) 
Screening  
(x1) 
 
Number of Samples per 
Period  
(x 3 Periods) 
End of 
Treatment 
Total 
Volume 
(mL) 
Safety 
Laboratory 
Samples (a) 
12.5 
1 
-- 
1 
25 
Hepatitis Panel 
5 
1 
-- 
 
5 
FSH (b) 
3 
1 
-- 
 
3 
PK Samples 
6 
-- 
9 
-- 
54 
DNA Sample 
6 
-- 
1 (c) 
-- 
6 
RNA Samples 
5 
-- 
6 
-- 
30 
 
Total Blood Sampling Volume (per Study) 
 
123 
(a) Includes Hematology, serum chemistry, and coagulation panel. 
(b) FSH level will be obtained for female subjects at Screening if they are postmenopausal (i.e. last regular 
menstrual cycle >2 years) and not surgically sterile. 
(c) Only collected in Day 1, Period 1. 
 
The maximum volume of blood at any single day is approximately 40 mL, and the approximate 
total volume of blood for the study is approximately 123 mL.  
Direct venipuncture is the preferred method of blood collection. Any other method will need to 
be approved by the Sponsor. 


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10.0 
PRETREATMENT EVENTS AND ADVERSE EVENTS 
10.1 
Definitions 
10.1.1 PTEs 
A PTE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study but prior to administration of any study 
medication; it does not necessarily have to have a causal relationship with study participation. 
10.1.2 AEs 
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a drug; it does not necessarily have to have a causal relationship with this 
treatment. 
An AE can therefore be any unfavorable and unintended sign (e.g., a clinically significant 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug 
whether or not it is considered related to the drug. 
10.1.3 Additional Points to Consider for PTEs and AEs 
An untoward finding generally may: 
 Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent 
events for pre-existing conditions or underlying disease should not be considered PTEs or 
AEs.) 
 Necessitate therapeutic intervention. 
 Require an invasive diagnostic procedure. 
 Require discontinuation or a change in dose of study medication or a concomitant 
medication. 
 Be considered unfavorable by the investigator for any reason.  
 PTEs/AEs caused by a study procedure (e.g., a bruise after blood draw) should be recorded 
as a PTE/AE. 
Diagnoses vs signs and symptoms: 
 Each event should be recorded to represent a single diagnosis. Accompanying signs 
(including abnormal laboratory values or ECG findings) or symptoms should NOT be 
recorded as additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be 
recorded appropriately as a PTE(s) or as an AE(s). 
Laboratory values and ECG findings: 
 Changes in laboratory values or ECG parameters are only considered to be PTEs or AEs if 
they are judged to be clinically significant (i.e., if some action or intervention is required or if 
the investigator judges the change to be beyond the range of normal physiologic fluctuation). 
A laboratory re-test and/or continued monitoring of an abnormal value are not considered an 


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intervention. In addition, repeated or additional noninvasive testing for verification, 
evaluation or monitoring of an abnormality is not considered an intervention. 
 If abnormal laboratory values or ECG findings are the result of pathology for which there is 
an overall diagnosis (e.g., increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as a PTE or as an AE. 
Pre-existing conditions: 
 Pre-existing conditions (present at the time of signing of informed consent) are considered 
concurrent medical conditions and should NOT be recorded as PTEs or AEs. Baseline 
evaluations (e.g., laboratory tests, ECG, X-rays etc.) should NOT be recorded as PTEs unless 
related to study procedures. However, if the subject experiences a worsening or complication 
of such a concurrent condition, the worsening or complication should be recorded 
appropriately as a PTE (worsening or complication occurs before start of study medication) 
or an AE (worsening or complication occurs after start of study medication). Investigators 
should ensure that the event term recorded captures the change in the condition (e.g., 
“worsening of…”). 
 If a subject has a pre-existing episodic condition (e.g., asthma, epilepsy) any occurrence of an 
episode should only be captured as a PTE/AE if the episodes become more frequent, serious 
or severe in nature, that is, investigators should ensure that the AE term recorded captures the 
change in the condition from Baseline (e.g. “worsening of…”). 
 If a subject has a degenerative concurrent condition (e.g., cataracts, rheumatoid arthritis), 
worsening of the condition should only be captured as a PTE/AE if occurring to a greater 
extent to that which would be expected. Again, investigators should ensure that the AE term 
recorded captures the change in the condition (e.g., “worsening of…”). 
Worsening of PTEs or AEs: 
 If the subject experiences a worsening or complication of a PTE after starting administration 
of the study medication, the worsening or complication should be recorded appropriately as 
an AE. Investigators should ensure that the AE term recorded captures the change in the 
condition (e.g., “worsening of…”). 
 If the subject experiences a worsening or complication of an AE after any change in study 
medication, the worsening or complication should be recorded as a new AE. Investigators 
should ensure that the AE term recorded captures the change in the condition (e.g., 
“worsening of…”). 
Changes in severity of AEs /Serious PTEs: 
 If the subject experiences changes in severity of an AE/serious PTE, the event should be 
captured once with the maximum severity recorded. 
Preplanned surgeries or procedures: 
 Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered PTEs or AEs. However, if a preplanned procedure is 
performed early (e.g., as an emergency) due to a worsening of the pre-existing condition, the 


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worsening of the condition should be captured appropriately as a PTE or an AE. 
Complications resulting from any planned surgery should be reported as AEs. 
Elective surgeries or procedures: 
 Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as PTEs or AEs, but should be documented in the subject’s source 
documents. Complications resulting from an elective surgery should be reported as AEs. 
Overdose: 
 Cases of overdose with any medication without manifested side effects are NOT considered 
PTEs or AEs, but instead will be documented on an Overdose page of the eCRF. Any 
manifested side effects will be considered PTEs or AEs and will be recorded on the AE page 
of the eCRF. 
 Suicidal Ideation and Behavior:  
 A completed suicide is always a SAE based on its fatal outcome. C-SSRS score of 4 (active 
suicidal ideation with some intent to act) or 5 (active suicidal ideation with specific plan and 
intent) would likely indicate serious suicidal ideation and can be used to trigger intervention 
procedures to provide urgent care. Such procedures may include further evaluation and 
appropriate management; and/or immediate contact with (or need for a referral to) the 
subject’s mental health practitioner; and/or possible referral to the emergency room; and/or 
admission to an in-subject unit. For the purpose of this protocol active suicidal ideation level 
4 and 5 should be considered important medical events and reported as serious irrespective of 
whether the subject was hospitalized or not.  
 Unless the event meets other serious criteria, suicidal thoughts or suicidal ideations that do 
not include a definite plan or intention to act will be collected as non-serious adverse events 
in accordance with the standard AE reporting requirements (e.g., if a pre-existing suicidal 
ideation recorded on the screening C-SSRS got worse during the study, it should be reported 
as an AE).  
 A subject presenting with self-mutilation or other types of self-injury should be questioned 
by the investigator to clarify if the action was suicidal in intent. If the event was suicidal in 
intent, the investigator should include suicidal behavior as part of the verbatim term on the 
eCRF, that is, “slit wrists/suicidal behavior”. Such an event will be collected as a serious 
adverse event.  
 Acts of self-mutilation or self-injury without suicidal intention (i.e., self-imposed cigarette 
burns), will be collected as non-serious adverse events, unless they meet other seriousness 
criteria.  
10.1.4 SAEs 
An SAE is defined as any untoward medical occurrence that at any dose: 
1. Results in DEATH. 
2. Is LIFE THREATENING. 


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 The term “life threatening” refers to an event in which the subject was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have caused 
death if it were more severe. 
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization. 
4. Results in persistent or significant DISABILITY/INCAPACITY. 
5. Is a CONGENITAL ANOMALY/BIRTH DEFECT. 
 Report if you suspect that exposure to a medical product prior to conception or during 
pregnancy may have resulted in an adverse outcome in the child. 
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following: 
 May require intervention to prevent items 1 through 5 above. 
 May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization. 
 Includes any event or synonym described in the Medically Significant AE List 
(Table 10.a). 
Table 10.a 
Medically Significant AE List 
Term 
Acute respiratory failure/acute respiratory distress 
syndrome 
Hepatic necrosis 
Torsade de pointes / ventricular fibrillation / ventricular 
tachycardia 
Acute liver failure 
Anaphylactic shock 
Malignant hypertension 
Acute renal failure 
Convulsive seizure 
Pulmonary hypertension 
Agranulocytosis 
Pulmonary fibrosis 
Aplastic anemia 
Confirmed or suspected endotoxin shock 
Toxic epidermal necrolysis/Stevens-Johnson syndrome Confirmed or suspected transmission of infectious agent by 
a medicinal product 
 
Serotonin syndrome 
Neuroleptic malignant syndrome / malignant hyperthermia 
 
Spontaneous abortion / stillbirth and fetal death 
 
PTEs that fulfill 1 or more of the serious criteria above are also to be considered SAEs and 
should be reported and followed up in the same manner (see Sections 10.2.2 and 10.3). 
10.1.5 Severity of PTEs and AEs 
The different categories of intensity (severity) are characterized as follows: 
Mild: 
The event is transient and easily tolerated by the subject. 
Moderate: 
The event causes the subject discomfort and interrupts the subject’s usual activities. 
Severe: 
The event causes considerable interference with the subject’s usual activities. 


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10.1.6 Causality of AEs 
The relationship of each AE to study medication(s) will be assessed using the following 
categories: 
Related: 
An AE that follows a reasonable temporal sequence from administration of a drug (including 
the course after withdrawal of the drug), or for which possible involvement of the drug cannot 
be ruled out, although factors other than the drug, such as underlying diseases, complications, 
concomitant drugs and concurrent treatments, may also be responsible. 
Not Related: 
An AE that does not follow a reasonable temporal sequence from administration of a drug 
and/or that can reasonably be explained by other factors, such as underlying diseases, 
complications, concomitant drugs and concurrent treatments. 
10.1.7 Relationship to Study Procedures 
Relationship (causality) to study procedures should be determined for all PTEs and AEs. 
The relationship should be assessed as Related if the investigator considers that there is 
reasonable possibility that an event is due to a study procedure. Otherwise, the relationship 
should be assessed as Not Related. 
10.1.8 Start Date 
The start date of the AE/PTE is the date that the first signs/symptoms were noted by the subject 
and/or physician. 
10.1.9 
Stop Date  
The stop date of the AE/PTE is the date at which the subject recovered, the event resolved but 
with sequelae or the subject died. 
10.1.10 Frequency  
Episodic AEs/PTE (e.g., vomiting) or those which occur repeatedly over a period of consecutive 
days are intermittent. All other events are continuous. 
10.1.11 Action Concerning Study Medication  
 Drug withdrawn – a study medication is stopped due to the particular AE. 
 Dose not changed – the particular AE did not require stopping a study medication. 
 Unknown – only to be used if it has not been possible to determine what action has been 
taken. 
 Not Applicable – a study medication was stopped for a reason other than the particular AE 
(e.g., the study has been terminated, the subject died, dosing with study medication was 
already stopped before the onset of the AE). 
10.1.12 Outcome 
 Recovered/Resolved – Subject returned to first assessment status with respect to the AE/PTE. 


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 Recovering/Resolving – the intensity is lowered by one or more stages: the diagnosis or 
signs/symptoms has almost disappeared; the abnormal laboratory value improved, but has not 
returned to the normal range or to Baseline; the subject died from a cause other than the 
particular AE/PTE with the condition remaining “recovering/resolving”. 
 Not recovered/not resolved – there is no change in the diagnosis, signs or symptoms; the 
intensity of the diagnosis, signs/ symptoms or laboratory value on the last day of the 
observed study period has got worse than when it started; is an irreversible congenital 
anomaly; the subject died from another cause with the particular AE/PTE state remaining 
“Not recovered/not resolved”. 
 Resolved with sequelae – the subject recovered from an acute AE/PTE but was left with 
permanent/significant impairment (e.g., recovered from a cardiovascular accident but with 
some persisting paresis). 
 Fatal – the AEs/PTEs which are considered as the cause of death. 
 Unknown – the course of the AE/PTE cannot be followed up due to hospital change or 
residence change at the end of the subject’s participation in the study. 
10.2 
Procedures 
10.2.1 Collection and Reporting of AEs 
10.2.1.1 PTE and AE Collection Period 
Collection of PTEs will commence from the time the subject signs the informed consent to 
participate in the study and continue until the subject is first administered study medication on 
Day 1 Period 1 or until screen failure. For subjects who discontinue prior to study medication 
administration, PTEs are collected until the subject discontinues study participation. 
Collection of AEs will commence from the time that the subject is first administered study 
medication Day 1 Treatment Period 1. Routine collection of AEs will continue until 21 days 
following last dose. 
10.2.1.2 PTE and AE Reporting 
At each study visit, the investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Subjects may report AEs occurring at any other time during the study. Subjects experiencing a 
serious PTE must be monitored until the symptoms subside and any clinically relevant changes 
in laboratory values have returned to Baseline or there is a satisfactory explanation for the 
change. Non-serious PTEs, related or unrelated to the study procedure, need not to be followed-
up for the purposes of the protocol. 
All subjects experiencing AEs, whether considered associated with the use of the study 
medication or not, must be monitored until the symptoms subside and any clinically relevant 
changes in laboratory values have returned to Baseline or until there is a satisfactory explanation 
for the changes observed. All PTEs and AEs will be documented in the PTE/AE page of the 


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eCRF, whether or not the investigator concludes that the event is related to the drug treatment. 
The following information will be documented for each event: 
1. Event term. 
2. Start and stop date. 
3. Frequency. 
4. Severity. 
5. Investigator’s opinion of the causal relationship between the event and administration of 
study medication(s) (related or not related) (not completed for PTEs). 
6. Investigator’s opinion of the causal relationship to study procedure(s), including the details 
of the suspected procedure. 
7. Action concerning study medication (not applicable for PTEs). 
8. Outcome of event. 
9. Seriousness. 
10.2.2 Collection and Reporting of SAEs 
When an SAE occurs through the AE collection period it should be reported according to the 
following procedure: 
A Cerevance SAE form must be completed, in English, and signed by the investigator 
immediately or within 24 hours of first onset or notification of the event. The information should 
be completed as fully as possible but contain, at a minimum: 
 A short description of the event and the reason why the event is categorized as serious. 
 Subject identification number. 
 Investigator’s name. 
 Name of the study medication(s). 
 Causality assessment. 
The SAE form should be transmitted within 24 hours to the attention of the contact listed in 
Section 1.0.  
Any SAE spontaneously reported to the investigator following the AE collection period should 
be reported to the sponsor if considered related to study participation. 
Reporting of Serious PTEs will follow the procedure described for SAEs. 
10.2.3 Reporting of Abnormal Liver Function Tests 
If a subject is noted to have ALT or AST elevated >3 ×ULN on 2 consecutive occasions, the 
abnormality should be recorded as an AE. In addition, an LFT Increases eCRF must be 
completed providing additional information on relevant recent history, risk factors, clinical signs 
and symptoms and results of any additional diagnostic tests performed. 


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If a subject is noted to have ALT or AST >3 ×ULN and total bilirubin >2 ×ULN for which an 
alternative etiology has not been identified, the event should be recorded as an SAE and reported 
as per Section 10.2.2. The investigator must contact the Medical Monitor for discussion of the 
relevant subject details and possible alternative etiologies, such as acute viral hepatitis A or B or 
other acute liver disease or medical history/concurrent medical conditions. Follow-up laboratory 
tests as described in Section 9.1.8 must also be performed. In addition, an LFT Increases eCRF 
must be completed and transmitted with the Cerevance SAE form (as per Section 10.2.2). 
10.3 
Follow-up of SAEs 
If information is not available at the time of the first report, but becomes available at a later date, 
the investigator should complete a follow-up SAE form or provide other written documentation 
and fax it immediately within 24 hours of receipt. Copies of any relevant data from the hospital 
notes (e.g., ECGs, laboratory tests, discharge summary, postmortem results) should be sent to the 
addressee, if requested. 
All SAEs should be followed up until resolution or permanent outcome of the event. The 
timelines and procedure for follow-up reports are the same as those for the initial report. 
10.3.1 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities  
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, including the European 
Medicines Agency (EMA), investigators and IRBs or IECs, as applicable, in accordance with 
national regulations in the countries where the study is conducted. Relative to the first awareness 
of the event by/or further provision to the sponsor or sponsor’s designee, SUSARs will be 
submitted to the regulatory authorities as expedited report within 7 days for fatal and life-
threatening events and 15 days for other serious events, unless otherwise required by national 
regulations. The sponsor will also prepare an expedited report for other safety issues where these 
might materially alter the current benefit-risk assessment of an investigational medicinal product 
or that would be sufficient to consider changes in the investigational medicinal products 
administration or in the overall conduct of the trial. The investigational site also will forward a 
copy of all expedited reports to his or her IRB or IEC in accordance with national regulations. 


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11.0 
STUDY-SPECIFIC COMMITTEES 
No steering committee, data safety monitoring committee, or clinical endpoint committee will be 
used in this study. 


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12.0 
DATA HANDLING AND RECORDKEEPING 
The full details of procedures for data handling will be documented in the Data Management 
Plan. AEs, PTEs, medical history, and concurrent conditions will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the World Health 
Organization Drug Dictionary (WHODRUG). 
12.1 
CRFs (Electronic) 
Completed eCRFs are required for each subject who signs an informed consent. 
The sponsor or its designee will supply investigative sites with access to eCRFs. The sponsor 
will make arrangements to train appropriate site staff in the use of the eCRFs. These forms are 
used to transmit the information collected in the performance of this study to the sponsor and 
regulatory authorities. eCRFs must be completed in English. 
After completion of the entry process, computer logic checks will be run to identify items, such 
as inconsistent dates, missing data, and questionable values. Queries may be issued by Cerevance 
personnel (or designees) and will be answered by the site.  
Corrections to eCRFs are recorded in an audit trail that captures the old information, the new 
information, identification of the person making the correction, the date the correction was made, 
and the reason for change. Reasons for significant corrections should additionally be included. 
The PI must review the eCRFs for completeness and accuracy and must sign and date the 
appropriate eCRFs as indicated. Furthermore, the investigator must retain full responsibility for 
the accuracy and authenticity of all data entered on the eCRFs. 
After the lock of the clinical study database, any change of, modification of or addition to the 
data on the eCRFs should be made by the investigator with use of change and modification 
records of the eCRFs. The principle investigator must review the data change for completeness 
and accuracy, and must sign, and date. 
The eCRFs will be reviewed for completeness and acceptability at the study site during periodic 
visits by study monitors. The sponsor or its designee will be permitted to review the subject’s 
medical and hospital records pertinent to the study to ensure accuracy of the eCRFs. The 
completed eCRFs are the sole property of the sponsor and should not be made available in any 
form to third parties, except for authorized representatives of appropriate governmental health or 
regulatory authorities, without written permission of the sponsor. 
12.2 
Record Retention 
The investigator agrees to keep the records stipulated in Section 12.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated informed consent forms, subject authorization forms 
regarding the use of personal health information (if separate from the informed consent forms), 
electronic copy of eCRFs, including the audit trail, and detailed records of drug disposition to 
enable evaluations or audits from regulatory authorities, the sponsor or its designees. Any source 
documentation printed on degradable thermal sensitive paper should be photocopied by the site 


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and filed with the original in the subject’s chart to ensure long-term legibility. Furthermore, 
International Conference on Harmonisation (ICH) E6 Section 4.9.5 requires the investigator to 
retain essential documents specified in ICH E6 (Section 8) until at least 2 years after the last 
approval of a marketing application for a specified drug indication being investigated or, if an 
application is not approved, until at least 2 years after the investigation is discontinued and 
regulatory authorities are notified. In addition, ICH E6 Section 4.9.5 states that the study records 
should be retained until an amount of time specified by applicable regulatory requirements or for 
a time specified in the Clinical Study Site Agreement between the investigator and sponsor. 
Refer to the Phase 1 Site Specifications document for the sponsor’s requirements on record 
retention. The investigator should contact and receive written approval from the sponsor before 
disposing of any such documents. 


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13.0 
STATISTICAL METHODS 
13.1 
Statistical and Analytical Plans 
A statistical analysis plan (SAP) will be prepared and finalized prior to interim analysis and 
database lock. This document will provide further details regarding the definition of analysis 
variables and analysis methodology to address all study objectives.  Included in the SAP will be 
details for a blinded interim analysis and a sample size re-assessment.   
A targeted data review will be conducted prior to database lock. This review will assess the 
accuracy and completeness of the study database, subject evaluability, and appropriateness of the 
planned statistical methods. 
13.1.1 Analysis Sets 
Safety Set 
The Safety Set will consist of all subjects who are randomized and receive study drug. Subjects 
in this analysis set will be used for demographic, baseline characteristics and safety summaries. 
Pharmacokinetic Set 
The PK Set will consist of all subjects who receive study drug and have at least 1 measurable 
plasma concentration of CVN058. 
Pharmacodynamic Set 
The PD Set will consist of all subjects who receive study drug and have at least 1 post-dose PD 
measurement. 
If any subjects are found to be noncompliant in dosing schedule or with incomplete data, a 
decision will be made on a case-by-case basis as to their inclusion in the PK and PD endpoint 
analyses, but data for all subjects will be presented in the subject listings. 
13.1.2 Analysis of Demographics and Other Baseline Characteristics 
Demographic and baseline characteristics will be summarized by sequence and overall. 
Summary statistics (number of subjects, mean, median, standard deviation, minimum and 
maximum) will be generated for continuous variables (e.g., age and weight) and the number and 
percentage of subjects within each category will be presented for categorical variables (e.g., 
gender, ethnicity, race, smoking status, and caffeine consumption). 
13.1.3 Pharmacokinetic Analysis 
The concentration of CVN058, and its metabolite if appropriate, in plasma will be summarized 
over each scheduled sampling interval using descriptive statistics (arithmetic mean, SD, median, 
minimum and maximum). Individual plasma concentration data versus time will be presented in 
a data listing. 
Descriptive statistics will be used to summarize the plasma PK parameters for CVN058, and its 
metabolite if appropriate. In addition, geometric mean and percent coefficient of variation will be 
computed for Cmax and AUCt. 


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A more detailed analysis will be presented in the SAP. 
13.1.4 Pharmacodynamic Analysis  
Observed values for the PD parameters (MMN and exploratory PD parameters) will be 
summarized by treatment and compared to placebo using summary statistics. Comparison of 
post-dose PD parameters from a time-matched placebo period timepoint will be analyzed using 
analysis of covariance (ANCOVA) with factors for sequence, subject nested within sequence, 
period, and treatment. Two-sided 95% confidence intervals will be constructed for the LS mean 
of observed differences in PD parameters, comparing CVN058 and placebo at a time-matched 
post-dose time point. 
Effect size will be calculated for comparisons of CVN058 to placebo using Cohen’s d which 
expresses the difference between the means of 2 groups as a function of their pooled standard 
deviation. 
Exposure-response relationships for CVN058 will be explored graphically. 
13.1.5 Safety Analysis 
The Safety Set will be used for all summaries of TEAEs, laboratory tests, and vital signs. All 
safety data will be summarized by treatment. 
AEs will be presented in listings. TEAEs will be classified according to system organ class and 
preferred term and will be tabulated with a breakdown by treatment and by event severity. 
Similar TEAE tabulations will be performed on those events assessed by the investigator as 
related to study drug. 
Individual results of vital signs will be listed and observed values and changes from Baseline in 
vital signs will be summarized by treatment. 
Physical exam findings, suicidality assessments (C-SSRS), and PANSS scores will be presented 
in data listings. 
Baseline values will be the latest observation prior to dosing in the first study period. Thus, for 
most assessments, the Baseline value will be the Day 1 pre-dose observation; for Clinical 
Laboratory assessments, the Baseline values will be from the Screening Visit (Day -28). 
13.2 
Determination of Sample Size 
Enrollment of 20 subjects with schizophrenia is estimated to provide approximately 80% power 
to detect a mean effect size of Cohen’s d=0.5 with an error rate of alpha=0.10.  Discontinued or 
withdrawn subjects and subjects for whom MMN is not available for all three study periods may 
be replaced. The sample size chosen of 20 completed subjects is considered to be sufficient to 
explore the changes in MMN between CVN058 and placebo as well as safety and tolerability of 
CVN058 in this population. 
Sample size re-estimation may occur when blinded MMN data from all 3 periods are available 
for 12 subjects, or when 20 subjects have been dosed and are expected to complete the study, 
whichever is sooner. To ensure adequate study power, sample size may be increased based on 
this re-estimation procedure.  Further details will be included in the SAP.   


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14.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
14.1 
Study-Site Monitoring Visits 
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and institution guarantee access to source documents by the sponsor or its 
designee contract research organization (CRO) and by the IRB or IEC. 
All aspects of the study and its documentation will be subject to review by the sponsor or 
designee (as long as blinding is not jeopardized), including but not limited to the Investigator’s 
Binder, study medication, subject medical records, informed consent documentation, 
documentation of subject authorization to use personal health information (if separate from the 
informed consent forms), and review of eCRFs and associated source documents. It is important 
that the investigator and other study personnel are available during the monitoring visits and that 
sufficient time is devoted to the process. 
14.2 
Protocol Deviations 
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will 
require deviation from protocol-specified procedures, the investigator should consult with the 
sponsor or designee (and IRB or IEC, as required) to determine the appropriate course of action. 
There will be no exemptions (a prospectively approved deviation) from the inclusion or 
exclusion criteria. 
The site should document all protocol deviations in the subject’s source documents. In the event 
of a significant deviation, the site should notify the sponsor or its designee (and IRB or EC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the subject, or confound interpretation of primary study 
assessment. PK samples collected outside of the intervals (listed in Table 14.a), ECGs, vital 
signs, and RNA pharmacogenomic samples collected outside of the listed intervals are minor 
deviations and do not require the Protocol Deviation Form to be completed but must be 
documented in the subject’s source documents. A Protocol Deviation eCRF should be completed 
by the site and signed by the sponsor or designee for any significant deviation from the protocol.  
Every attempt will be made to collect each PK blood sample at the designated time point, and the 
actual time of each blood sample will be recorded on the source document and eCRF. Table 14.a 
defines the windows allowed for sample collections.  
Protocol Deviations should be captured in the site source document for PK samples collected 
outside of the following intervals: 


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Table 14.a 
Windows for Pharmacokinetic Blood Sample Collection 
Minutes 
Nominal Sampling Time 
no more than 15 minutes predose 
Pre-dose (-0.25 hour) 
±5 
Postdose 1 hour 
±15 
Postdose 5 hours  
 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections 
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, 
including those of foreign governments (e.g., the Food and Drug Administration (FDA), the 
United Kingdom Medicines and Healthcare products Regulatory Agency, the Pharmaceuticals 
and Medical Devices Agency of Japan). If the study site is contacted for an inspection by a 
regulatory body, the sponsor should be notified immediately. The investigator and institution 
guarantee access for quality assurance auditors to all study documents as described in Section 
14.1. 


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15.0 
ETHICAL ASPECTS OF THE STUDY 
This study will be conducted with the highest respect for the individual participants (i.e., 
subjects) according to the protocol, the ethical principles that have their origin in the Declaration 
of Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will 
conduct the study according to applicable local or regional regulatory requirements and align his 
or her conduct in accordance with the “Responsibilities of the Investigator” that are listed in 
Appendix B. The principles of Helsinki are addressed through the protocol and through 
appendices containing requirements for informed consent and investigator responsibilities. 
15.1 
IRB and/or IEC Approval 
IRBs and IECs must be constituted according to the applicable state and federal/local 
requirements of each participating region.  
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of 
the informed consent form, and, if applicable, subject recruitment materials and/or 
advertisements and other documents required by all applicable laws and regulations, must be 
submitted to a central or local IRB or IEC for approval. The IRB’s or IEC’s written approval of 
the protocol and subject informed consent must be obtained and submitted to the sponsor or 
designee before commencement of the study (i.e., before shipment of the sponsor-supplied drug 
or study specific Screening activity). The IRB or IEC approval must refer to the study by exact 
protocol title, number, and version date; identify versions of other documents (e.g., ICF) 
reviewed; and state the approval date. The sponsor will ship drug/notify site once the sponsor has 
confirmed the adequacy of site regulatory documentation and, when applicable, the sponsor has 
received permission from competent authority to begin the trial. Until the site receives 
drug/notification no protocol activities, including screening may occur. 
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the informed consent 
form, recruitment materials intended for viewing by subjects, local safety reporting requirements, 
reports and updates regarding the ongoing review of the study at intervals specified by the 
respective IRB or IEC, and submission of the investigator’s final status report to IRB or IEC. All 
IRB and IEC approvals and relevant documentation for these items must be provided to the 
sponsor or its designee. 
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor. 
15.2 
Subject Information, Informed Consent, and Subject Authorization 
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The informed consent form, subject authorization form (if 
applicable), and subject information sheet (if applicable) describe the planned and permitted 
uses, transfers, and disclosures of the subject’s personal and personal health information for 
purposes of conducting the study. The informed consent form and the subject information sheet 


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(if applicable) further explain the nature of the study, its objectives, and potential risks and 
benefits, as well as the date informed consent is given. The informed consent form will detail the 
requirements of the participant and the fact that he or she is free to withdraw at any time without 
giving a reason and without prejudice to his or her further medical care. 
The investigator is responsible for the preparation, content, and IRB or IEC approval of the 
informed consent form and if applicable, the subject authorization form. The informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) 
must be approved by both the IRB or IEC and the sponsor prior to use. 
The informed consent form, subject authorization form (if applicable), and subject information 
sheet (if applicable) must be written in a language fully comprehensible to the prospective 
subject. It is the responsibility of the investigator to explain the detailed elements of the informed 
consent form, subject authorization form (if applicable), and subject information sheet (if 
applicable) to the subject. Information should be given in both oral and written form whenever 
possible and in the manner deemed appropriate by the IRB or IEC. In the event the subject is not 
capable of rendering adequate written informed consent, then the subject’s legally acceptable 
representative may provide such consent for the subject in accordance with applicable laws and 
regulations. 
The subject, or the subject’s legally acceptable representative, must be given ample opportunity 
to: (1) inquire about details of the study and (2) decide whether or not to participate in the study. 
If the subject, or the subject’s legally acceptable representative, determines he or she will 
participate in the study, then the informed consent form and subject authorization form (if 
applicable) must be signed and dated by the subject, or the subject’s legally acceptable 
representative, at the time of consent and prior to the subject entering into the study. The subject 
or the subject’s legally acceptable representative should be instructed to sign using their legal 
names, not nicknames, using blue or black ballpoint ink. The investigator must also sign and date 
the informed consent form and subject authorization (if applicable) at the time of consent and 
prior to subject entering into the study; however, the sponsor may allow a designee of the 
investigator to sign to the extent permitted by applicable law. 
Once signed, the original informed consent form, subject authorization form (if applicable), and 
subject information sheet (if applicable) will be stored in the investigator’s site file. The 
investigator must document the date the subject signs the informed consent in the subject’s 
medical record. Copies of the signed informed consent form, the signed subject authorization 
form (if applicable), and subject information sheet (if applicable) shall be given to the subject. 
All revised informed consent forms must be reviewed and signed by relevant subjects or the 
relevant subject’s legally acceptable representative in the same manner as the original informed 
consent. The date the revised consent was obtained should be recorded in the subject’s medical 
record, and the subject should receive a copy of the revised informed consent form. 
Subjects who consented and provided a pharmacogenomic sample for DNA and RNA analysis 
can withdraw their consent and request disposal of a stored sample at any time prior to analysis. 
Notify sponsor of consent withdrawal. 


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15.3 
Subject Confidentiality 
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or 
date of birth, and subject initials may be used to verify the subject and accuracy of the subject’s 
unique identification number. 
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the 
sponsor requires the investigator to permit its monitor or designee’s monitor, representatives 
from any regulatory authority (e.g., FDA, Medicines and Healthcare products Regulatory 
Agency, Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and 
the appropriate IRBs and IECs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a subject’s study 
participation, and autopsy reports. Access to a subject’s original medical records requires the 
specific authorization of the subject as part of the informed consent process (see Section 15.2). 
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (i.e., subject name, address, and other identifier 
fields not collected on the subject’s eCRF). 
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy 
15.4.1 Publication and Disclosure 
The investigator is obliged to provide the sponsor with complete test results and all data derived 
by the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor. 
The sponsor may publish any data and information from the study (including data and 
information generated by the investigator) without the consent of the investigator. Manuscript 
authorship for any peer-reviewed publication will appropriately reflect contributions to the 
production and review of the document. All publications and presentations must be prepared in 
accordance with this section and the Clinical Study Site Agreement. In the event of any 
discrepancy between the protocol and the Clinical Study Site Agreement, the Clinical Study Site 
Agreement will prevail. 
15.4.2 Clinical Trial Registration  
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations, and guidance, Cerevance will, at a minimum register 
interventional clinical trials it sponsors on ClinicalTrials.gov or other publicly accessible 
websites before start of study. Cerevance contact information, along with investigator’s city, 
state (for American investigators), country, and recruiting status will be registered and available 


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for public viewing. For some registries, Cerevance will assist callers in locating trial sites closest 
to their homes by providing the investigator name, address, and phone number to the callers 
requesting trial information. Once subjects receive investigator contact information, they may 
call the site requesting enrollment into the trial. The investigative sites are encouraged to handle 
the trial inquiries according to their established subject Screening process. If the caller asks 
additional questions beyond the topic of trial enrollment, they should be referred to the sponsor. 
Any investigator who objects to Cerevance providing this information to callers must provide 
Cerevance with a written notice requesting that their information not be listed on the registry site. 
15.4.3 Clinical Trial Results Disclosure  
Cerevance may post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites, as required by applicable laws and/or regulations. 
15.5 
Insurance and Compensation for Injury 
Each subject in the study must be insured in accordance with the regulations applicable to the 
site where the subject is participating. If a local underwriter is required, then the sponsor or 
sponsor’s designee will obtain clinical study insurance against the risk of injury to clinical study 
subjects. Refer to the Clinical Study Site Agreement regarding the sponsor’s policy on subject 
compensation and treatment for injury. If the investigator has questions regarding this policy, he 
or she should contact the sponsor or sponsor’s designee. 


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16.0 
REFERENCES 
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2. Green MF. Cognitive impairment and functional outcome in schizophrenia and bipolar 
disorder. J Clin Psychiatry 2006;67 Suppl 9:3-8; discussion 36-42. 
3. Harvey PD, Velligan DI, Bellack AS. Performance-based measures of functional skills: 
usefulness in clinical treatment studies. Schizophr Bull 2007;33(5):1138-48. 
4. Heinrichs RW. The primacy of cognition in schizophrenia. Am Psychol 2005;60(3):229-42. 
5. McNally JM, McCarley RW, Brown RE. Impaired GABAergic neurotransmission in 
schizophrenia underlies impairments in cortical gamma band oscillations. Curr Psychiatry 
Rep 2013;15(3):346. 
6. Cardin JA, Carlen M, Meletis K, Knoblich U, Zhang F, Deisseroth K, et al. Driving fast-
spiking cells induces gamma rhythm and controls sensory responses. Nature 
2009;459(7247):663-7. 
7. Whittington MA, Traub RD, Faulkner HJ, Stanford IM, Jefferys JG. Recurrent excitatory 
postsynaptic potentials induced by synchronized fast cortical oscillations. Proc Natl Acad Sci 
U S A 1997;94(22):12198-203. 
8. Rotaru DC, Lewis DA, Gonzalez-Burgos G. The role of glutamatergic inputs onto 
parvalbumin-positive interneurons: relevance for schizophrenia. Rev Neurosci 
2012;23(1):97-109. 
9. Gonzalez-Burgos G, Lewis DA. NMDA receptor hypofunction, parvalbumin-positive 
neurons, and cortical gamma oscillations in schizophrenia. Schizophr Bull 2012;38(5):950-7. 
10. Curley AA, Lewis DA. Cortical basket cell dysfunction in schizophrenia. J Physiol 
2012;590(Pt 4):715-24. 
11. Tian G, Kong Q, Lai L, Ray-Chaudhury A, Lin CG. Increased expression of cholesterol 24S-
hydroxylase results in disruption of glial glutamate transporter EAAT2 association with lipid 
rafts: a potential role in Alzheimer's disease. J Neurochem 2010;113(4):978-89. 
12. Kawaguchi Y, Shindou T. Noradrenergic excitation and inhibition of GABAergic cell types 
in rat frontal cortex. J Neurosci 1998;18(17):6963-76. 
13. Kawaguchi Y. Selective cholinergic modulation of cortical GABAergic cell subtypes. J 
Neurophysiol 1997;78(3):1743-7. 
14. Lee S, Hjerling-Leffler J, Zagha E, Fishell G, Rudy B. The largest group of superficial 
neocortical GABAergic interneurons expresses ionotropic serotonin receptors. J Neurosci 
2010;30(50):16796-808. 
15. Koike K, Hashimoto K, Takai N, Shimizu E, Komatsu N, Watanabe H, et al. Tropisetron 
improves deficits in auditory P50 suppression in schizophrenia. Schizophr Res 
2005;76(1):67-72. 
16. Lummis SC. 5-HT3 receptors. J Biol Chem 2012;287(48):40239-45. 


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        27 MAR 2019
 
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17. Adler LE, Cawthra EM, Donovan KA, Harris JG, Nagamoto HT, Olincy A, et al. Improved 
p50 auditory gating with ondansetron in medicated schizophrenia patients. Am J Psychiatry 
2005;162(2):386-8. 
18. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders 
(DSM-5). 5th ed. Arlington, VA: American Psychiatric Association; 2013. 
19. Smucny J, Wylie K, Rojas D, Stevens K, Olincy A, Kronberg E, et al. Evidence for gamma 
and beta sensory gating deficits as translational endophenotypes for schizophrenia. 
Psychiatry Res 2013;214(2):169-74. 
20. Kay SR. Positive-negative symptom assessment in schizophrenia: psychometric issues and 
scale comparison. Psychiatr Q 1990;61(3):163-78. 
21. Mundt JC, Greist JH, Jefferson JW, Federico M, Mann JJ, Posner K. Prediction of suicidal 
behavior in clinical research by lifetime suicidal ideation and behavior ascertained by the 
electronic Columbia-Suicide Severity Rating Scale. J Clin Psychiatry 2013;74(9):887-93. 
22. Javitt D. Neurophysiological models for new treatment development in schizophrenia: early 
sensory approaches. The New York Academy of Sciences. 2015;1344: 92-104.  
23. Lee M, Sehatpour P, Hoptman MJ, Lakatos P, Dias EC, Kantrowitz JT, Martinez AM, Javitt 
DC. Neural mechanisms of mismatch negativity dysfunction in schizophrenia. Mol 
Psychiatry. 2017;22(11):1585-1593. doi: 10.1038/mp.2017.3. 
24. Javitt D and Sweet R. Auditory dysfunction in schizophrenia: integrating clinical and basic 
features. Nat Rev Neurosci. 2015; 16(9): 535–550. doi:10.1038/nrn4002. 
25. Eisensamer B, Uhr M, Meyr S, Gimpl G, Deiml T, Rammes G, Lambert JJ, Zieglgänsberger 
W, Holsboer F, Rupprecht R. Antidepressants and antipsychotic drugs colocalize with 5-HT3 
receptors in raft-like domains. J Neurosci. 2005 Nov  2;25(44):10198-206. PubMed PMID: 
16267227. 
26. Eisensamer B, Rammes G, Gimpl G, Shapa M, Ferrari U, Hapfelmeier G, Bondy B, Parsons 
C, Gilling K, Zieglgänsberger W, Holsboer F, Rupprecht R. Antidepressants are functional 
antagonists at the serotonin type 3 (5-HT3) receptor. Mol Psychiatry. 2003 Nov;8(12):994-
1007. PubMed PMID: 14647397. 
27. Rammes G, Eisensamer B, Ferrari U, Shapa M, Gimpl G, Gilling K, Parsons C, Riering K, 
Hapfelmeier G, Bondy B, Zieglgänsberger W, Holsboer F, Rupprecht R. Antipsychotic drugs 
antagonize human serotonin type 3 receptor currents in a noncompetitive manner. Mol 
Psychiatry. 2004 Sep;9(9):846-58, 818. PubMed PMID: 15024394. 
28. Hartman LI, Heinrichs RW, Mashhadi F. The continuing story of schizophrenia and 
schizoaffective disorder: One condition or two? Schizophr Res Cogn. 2019. 16:36-42. 
29. Avissar M, Xie S, Vail B, Lopez-Calderon J, Wang Y, Javitt DC. Meta-analysis of mismatch 
negativity to simple versus complex deviants in schizophrenia. Schizophr Res. 2018. 191:25-
34. 
 
 


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Appendix A Schedule of Study Procedures 
 
 
 
CVN058 and Placebo 
Treatment Periods 1, 2, and 3 
(a) 
End of 
Treatment 
 
Follow-up  
Study Day: 
Visit 1: 
Screening 
 
Day 1 
pre-dose 
Day 1 
post-dose 
Period 3, 
End Day 1  
Early 
Termination 
(c)  
Day 7-10 
After End of 
Treatment 
(b) 
Informed consent 
X 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
X 
 
 
 
 
Demographics and 
medical history 
X 
 
 
 
 
 
Reproductive Status 
X 
 
 
 
 
 
Social History 
X 
 
 
 
 
 
Medication history 
X 
 
 
 
 
 
Physical examination  
X 
X 
 
X 
X 
 
Vital signs (d) 
X 
X 
X 
 
X 
 
Weight, height, and BMI 
(e) 
X 
 
 
X 
X 
 
Concomitant medications 
(f) 
X 
X 
X 
 
X 
X 
Medical history (g) 
X 
 
 
 
 
 
Clinical laboratory tests 
(h) 
X 
 
 
X 
X 
 
Hepatitis panel 
X 
 
 
 
 
 
Audiometric Screening 
and Tone Matching test 
(i) 
X 
 
 
 
 
 
FSH (j) 
X 
 
 
 
 
 
Pregnancy test (hCG), 
serum except as noted 
X 
X (urine) 
 
 
X 
 
Urine drug and saliva 
alcohol screen 
X 
 
 
 
 
 
ECG (k) 
X 
 
 
 
 
 
EEG battery (l) 
 
 
X 
 
 
 
MMN (m) 
 
 
X 
 
 
 
DNA sample collection 
(n) 
 
X 
 
 
 
 
RNA sample collection 
(o) 
 
X 
X 
 
 
 
PK blood collection (p) 
 
X 
X 
 
X 
 
Study drug dosing (q) 
 
 
X 
 
 
 
PTE assessment (r) 
X 
X 
 
 
 
 
AE assessment (s) 
 
 
X 
 
X 
X 
C-SSRS (t) 
X 
 
X 
 
X 
 
PANSS (u) 
X 
 
X 
 
X 
 
Footnotes are on last table page. 


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(a) Minimum 7-day and maximum 10-day washout period is required in between Treatment Periods 1, 2 and 3.  
(b) The Follow-up Visit will occur by telephone 7-10 days after End of Treatment unless abnormal, clinically significant findings 
were observed upon discharge. In these cases, subjects must then be brought back to the clinic for re-evaluation per investigator’s 
discretion. 
(c) Conduct procedures for subjects discontinued early per Protocol Section 7.6. The PK sample should be collected at the Early 
Termination Visit, if within 1 hour of a scheduled PK time point. 
(d) Vital signs (oral temperature, respiration, pulse, and blood pressure) will be obtained at Screening, and in Periods 1, 2, and 3 
(pre dose [within 30 minutes prior to dosing], and at 1 and 5 hours post dose), and at Early Termination (if applicable), and if 
clinically indicated according to Investigator discretion at the Follow-up visit. Vital signs will be collected with a window of ±15 
minutes. 
(e) Height and BMI will be collected at Screening only. 
(f) Record all patient medications from Screening and throughout the study. 
(g) All new medical history arising after signing ICF should be recorded as PTE or AE.  
(h) Clinical laboratory tests (hematology, serum chemistry, and urinalysis) will be collected at Screening and prior to check-out at 
End of Treatment or Early Termination, and at the Investigator discretion if a Follow-up Visit is indicated.  
(i) Audiometric Screening assessment conducted according to local practice.  
(j) A FSH level will be obtained on post-menopausal women (defined as continuous amenorrhea of at least 2 years and not 
surgically sterile). 
(k) ECGs will be collected with a window of ±2 minutes. 
(l) For the EEG battery, testing will be done at Day 1 starting approximately 1.5 hours post dose for each period and will last 
approximately 3 hours. NOTE: Subjects should refrain from drinking coffee and smoking approximately 1 hour prior to the EEG 
assessment until discharge from clinic at the end of the afternoon.  
(m) MMN will be the first EEG assessment conducted in the battery. EEG (MMN) assessment will be collected with a window of 
±60 minutes. 
(n) One blood sample (6 mL) will be collected for pharmacogenomic analysis prior to study drug administration on Day 1 of 
Period 1 only. If isolation of DNA from the first sample was not successful or possible, a second aliquot of blood may 
be taken, if feasible. 
(o) Two 2.5 mL whole blood samples will be collected for each Period (Periods 1, 2, and 3) on Day 1 at pre-dose, and 5 hours 
post- dose  
(p) Blood samples (6 mL) for PK analyses will be collected at pre -dose (within 15 minutes prior to dosing), and 1 and 5 hours 
post dose. PK collection for pre-dose will be (within 15 minutes prior to dosing), ±15 minutes at the 1 hour post-dose time point, 
and ±30 minutes at the 5 hour post-dose time point. 
(q) Dosing will only occur on Day 1 of each period, and signals the start of the post-dose Day 1 visit assessments. 
(r) PTEs will be collected from signing of informed consent up until dosing on Day 1. 
(s) Any adverse event with onset or exacerbation after dosing on Day 1 of Period 1 will be captured as an AE or SAE. 
(t) The Screening/Baseline C-SSRS will be administered at Screening and the Since Last Visit C-SSRS will be administered after 
EEG/ERP collection on each dosing day, and End of Treatment or Early Termination (if applicable). 
(u) The Screening/Baseline PANSS will be collected at Screening, approximately 5 hours after each dose (post EEG) and at Early 
Termination (if applicable). PANSS will be collected with a window of ±45 minutes. 
 


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Appendix B Responsibilities of the Investigator 
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on investigators by the FDA are 
summarized in the “Statement of Investigator” (Form 1572) which must be completed and 
signed before the investigator may participate in this study. 
The investigator agrees to assume the following responsibilities by signing a Form 1572.  
1. Conduct the study in accordance with the protocol. 
2. Personally conduct or supervise the staff who will assist in the protocol. 
3. Ensure that study related procedures; including study specific (non-routine/non- standard 
panel) Screening assessments are NOT performed on potential subjects prior to the receipt of 
written approval from relevant governing bodies/authorities. 
4. Ensure that all colleagues and employees assisting in the conduct of the study are informed 
of these obligations. 
5. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform 
to 21 CFR Part 56 ICH, and local regulatory requirements. 
6. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and 
approval of the protocol. Promptly report to the IRB/IEC all changes in research activity and 
all anticipated risks to subjects. Make at least yearly reports on the progress of the study to 
the IRB/IEC, and issue a final report within 3 months of study completion. 
7. Ensure that requirements for informed consent, as outlined in 21 CRF Part 50 ICH and local 
regulations, are met. 
8. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each informed consent form should contain a subject 
authorization section that describes the uses and disclosures of a subject’s personal 
information (including personal health information) that will take place in connection with 
the study. If an informed consent form does not include such a subject authorization, then the 
investigator must obtain a separate subject authorization form from each subject or the 
subject’s legally acceptable representative. 
9. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc., and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents. 
10. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents. 
11. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor. 


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12. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours. 
 


 
 
 
PROTOCOL  
A Placebo-Controlled Study to Evaluate the Effect of a Single Dose of CVN058 on 
Mismatch Negativity in Subjects with Stable Schizophrenia 
 
Short title: CVN058 Effect on Mismatch Negativity in Schizophrenics 
 
Sponsor: 
Cerevance Alpha (hereafter, “Cerevance”) 
One Marina Park Drive, suite 1410 
Boston, MA 02210 
Study Number: 
CVN058-103 
IND Number: 
121,520 
EudraCT 
Number: 
N/A 
Compound: 
 
CVN058  
Date: 
24 Sep 2019 
Amendment Number:  
4 
 
 
 
 
Previous Versions: 
 
27 Mar 2019 
Amendment Number:         3 
 
28 Sep 2018 
Amendment Number:         2 
 
02 Jul 2018 
Amendment Number:         1 
 
21 May 2018 
Original 
 
 
CONFIDENTIAL PROPERTY OF CEREVANCE 
This document is a confidential communication of Cerevance. Acceptance of this document constitutes the 
agreement by the recipient that no information contained herein will be published or disclosed without written 
authorization from Cerevance except to the extent necessary to obtain informed consent from those persons to whom 
the drug may be administered. Furthermore, the information is only meant for review and compliance by the 
recipient, his or her staff, and applicable institutional review committee and regulatory agencies to enable conduct of 
the study. 


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CONFIDENTIAL 
1.0 
ADMINISTRATIVE INFORMATION 
1.1 
Contacts  
 
Contact Type / Role 
Contact 
Serious adverse event and pregnancy reporting 
 
 
   
 
Medical Monitor 
(carries overall responsibility for the conduct of the study) 
, MD, CPI 
Director of Medical Affairs, CliniLabs 
 
Responsible Medical Officer  
(medical advice on protocol and compound) 
, MD PhD 
Senior Vice President  
Cerevance, Inc. 
 
 




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CONFIDENTIAL 
INVESTIGATOR AGREEMENT  
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, and 
any other product information provided by the sponsor. I agree to conduct this study in 
accordance with the requirements of this protocol and also to protect the rights, safety, privacy, 
and well-being of study subjects in accordance with the following: 
 The ethical principles that have their origin in the Declaration of Helsinki. 
 International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline. 
 All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations. 
 Regulatory requirements for reporting serious adverse events defined in Section 10.2 of this 
protocol. 
 Terms outlined in the Clinical Study Site Agreement. 
 Appendix B – Responsibilities of the Investigator. 
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in the clinical trial agreement with Cerevance. 
Signature of Investigator 
Date 
Investigator Name (print or type) 
Investigator’s Title 
Location of Facility (City, State/Provence) 
Location of Facility (Country) 


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CONFIDENTIAL 
TABLE OF CONTENTS 
1.0 
ADMINISTRATIVE INFORMATION ..............................................................................2 
1.1 
Contacts..........................................................................................................................2 
1.2 
Approval ........................................................................................................................3 
2.0 
STUDY SUMMARY...........................................................................................................9 
3.0 
LIST OF ABBREVIATIONS ............................................................................................14 
4.0 
INTRODUCTION .............................................................................................................16 
4.1 
Background ..................................................................................................................16 
4.2 
Non-Clinical .................................................................................................................17 
4.3 
Clinical .........................................................................................................................17 
4.4 
Rationale for the Proposed Study ................................................................................18 
5.0 
STUDY OBJECTIVES AND ENDPOINTS .....................................................................20 
5.1 
Objectives ....................................................................................................................20 
5.1.1 Primary Objective ..................................................................................................20 
5.1.2 Secondary Objective ..............................................................................................20 
5.1.3 Exploratory Objectives ..........................................................................................20 
5.2 
Endpoints .....................................................................................................................20 
5.2.1 Primary Endpoints .................................................................................................20 
5.2.2 Secondary Endpoint ...............................................................................................20 
5.2.3 Exploratory Endpoints ...........................................................................................20 
6.0 
STUDY DESIGN AND DESCRIPTION ..........................................................................22 
6.1 
Study Design ................................................................................................................22 
6.2 
Justification for Study Design, Dose, and Endpoints ..................................................23 
6.2.1 Dose Modification .................................................................................................24 
6.3 
Premature Termination or Suspension of Study or Investigational Site ......................24 
6.3.1 Criteria for Premature Termination or Suspension of the Study ...........................24 
6.3.2 Criteria for Premature Termination or Suspension of Investigational Sites ..........24 
6.3.3 Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s)...................................................................24 
7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS ...............25 
7.1 
Inclusion Criteria .........................................................................................................25 
7.2 
Exclusion Criteria ........................................................................................................25 
7.3 
Excluded Medications, Dietary Products, Procedures, and Treatments ......................27 
7.4 
Diet, Fluid, Activity Control ........................................................................................28 
7.5 
Criteria for Discontinuation or Withdrawal of a Subject .............................................28 
7.6 
Procedures for Discontinuation or Withdrawal of a Subject .......................................29 
8.0 
CLINICAL TRIAL MATERIAL MANAGEMENT.........................................................30 


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8.1 
Study Medication and Materials ..................................................................................30 
8.1.1 Dosage Form, Manufacturing, Packaging, and Labeling ......................................30 
8.1.2 Storage ...................................................................................................................31 
8.1.3 Dose and Regimen .................................................................................................31 
8.1.4 Overdose ................................................................................................................31 
8.2 
Investigational Drug Assignment and Dispensing Procedures ....................................32 
8.3 
Randomization Code Creation and Storage .................................................................32 
8.4 
Investigational Drug Blind Maintenance .....................................................................32 
8.5 
Unblinding Procedure ..................................................................................................32 
8.6 
Accountability and Destruction of Sponsor-Supplied Drugs .......................................33 
9.0 
STUDY PLAN ...................................................................................................................35 
9.1 
Study Procedures .........................................................................................................35 
9.1.1 Informed Consent Procedure .................................................................................35 
9.1.2 Demographics, Medical History, Medication History Procedure, Reproductive 
Status ......................................................................................................................35 
9.1.3 Physical Examination Procedure ...........................................................................35 
9.1.4 Weight, Height, and BMI.......................................................................................36 
9.1.5 Vital Sign Procedure ..............................................................................................36 
9.1.6 Documentation of Concomitant Medications ........................................................36 
9.1.7 Documentation of Concurrent Medical Conditions ...............................................36 
9.1.8 Procedures for Clinical Laboratory Samples .........................................................37 
9.1.9 Contraception and Pregnancy Avoidance Procedure .............................................38 
9.1.10 Pregnancy ...............................................................................................................39 
9.1.11 ECG Procedure ......................................................................................................40 
9.1.12 Pharmacogenomic Sample Collection ...................................................................40 
9.1.13 Pharmacokinetic Sample Collection ......................................................................41 
9.1.14 Pharmacokinetic Parameters ..................................................................................42 
9.1.15 Pharmacodynamic Sample Collection ...................................................................42 
9.1.16 Pharmacodynamic Parameters ...............................................................................43 
9.1.17 Positive and Negative Syndrome Scale .................................................................44 
9.1.18 Columbia Suicide Severity Rating Scale ...............................................................44 
9.1.19 Documentation of Screen Failure ..........................................................................45 
9.1.20 Documentation of Randomization .........................................................................45 
9.2 
Monitoring Subject Treatment Compliance .................................................................45 
9.3 
Schedule of Observations and Procedures ...................................................................45 
9.3.1 Screening................................................................................................................46 
9.3.2 Treatment Phase .....................................................................................................46 


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9.3.3 Final Visit/End of Treatment .................................................................................46 
9.3.4 Early Termination ..................................................................................................46 
9.3.5 Follow-up Visit/Telephone Call ............................................................................46 
9.4 
Biological Sample Retention and Destruction .............................................................46 
9.5 
Blood Volume ..............................................................................................................47 
10.0 
PRETREATMENT EVENTS AND ADVERSE EVENTS ..............................................48 
10.1 
Definitions....................................................................................................................48 
10.1.1 PTEs .......................................................................................................................48 
10.1.2 AEs .........................................................................................................................48 
10.1.3 Additional Points to Consider for PTEs and AEs ..................................................48 
10.1.4 SAEs ......................................................................................................................50 
10.1.5 Severity of PTEs and AEs......................................................................................51 
10.1.6 Causality of AEs ....................................................................................................52 
10.1.7 Relationship to Study Procedures ..........................................................................52 
10.1.8 Start Date ...............................................................................................................52 
10.1.9 Stop Date ................................................................................................................52 
10.1.10 
Frequency .........................................................................................................52 
10.1.11 
Action Concerning Study Medication .............................................................52 
10.1.12 
Outcome ...........................................................................................................52 
10.2 
Procedures ....................................................................................................................53 
10.2.1 Collection and Reporting of AEs ...........................................................................53 
10.2.2 Collection and Reporting of SAEs .........................................................................54 
10.2.3 Reporting of Abnormal Liver Function Tests ........................................................54 
10.3 
Follow-up of SAEs ......................................................................................................55 
10.3.1 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities .....55 
11.0 
STUDY-SPECIFIC COMMITTEES .................................................................................56 
12.0 
DATA HANDLING AND RECORDKEEPING ..............................................................57 
12.1 
CRFs (Electronic) ........................................................................................................57 
12.2 
Record Retention .........................................................................................................57 
13.0 
STATISTICAL METHODS ..............................................................................................59 
13.1 
Statistical and Analytical Plans ....................................................................................59 
13.1.1 Blinded Interim Analysis .......................................................................................59 
13.1.2 Unblinded Interim Analysis ...................................................................................59 
13.1.3 Analysis Sets ..........................................................................................................60 
13.1.4 Analysis of Demographics and Other Baseline Characteristics ............................60 
13.1.5 Pharmacokinetic Analysis ......................................................................................60 
13.1.6 Pharmacodynamic Analysis ...................................................................................60 


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13.1.7 Safety Analysis ......................................................................................................61 
13.2 
Determination of Sample Size .....................................................................................61 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................62 
14.1 
Study-Site Monitoring Visits .......................................................................................62 
14.2 
Protocol Deviations ......................................................................................................62 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections ..................................63 
15.0 
ETHICAL ASPECTS OF THE STUDY ...........................................................................64 
15.1 
IRB and/or IEC Approval ............................................................................................64 
15.2 
Subject Information, Informed Consent, and Subject Authorization ..........................64 
15.3 
Subject Confidentiality ................................................................................................66 
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy ..................................66 
15.4.1 Publication and Disclosure ....................................................................................66 
15.4.2 Clinical Trial Registration ......................................................................................66 
15.4.3 Clinical Trial Results Disclosure ...........................................................................67 
15.5 
Insurance and Compensation for Injury .......................................................................67 
16.0 
REFERENCES ..................................................................................................................68 
 
LIST OF IN-TEXT TABLES 
Table 6.a 
Treatment Sequences .............................................................................................22 
Table 7.a 
Prohibited Medications ..........................................................................................27 
Table 8.a 
Composition of CVN058 and Matching Placebo ..................................................30 
Table 8.b 
Treatment and Medication Type ............................................................................31 
Table 9.a 
Clinical Laboratory Tests .......................................................................................37 
Table 9.b 
Collection of Blood Samples for CVN058 Pharmacokinetic Analysis .................42 
Table 9.c 
Approximate Blood Volume ..................................................................................47 
Table 10.a 
Medically Significant AE List ...............................................................................51 
Table 14.a 
Windows for Pharmacokinetic Blood Sample Collection .....................................63 
 
LIST OF IN-TEXT FIGURES 
Figure 6.a 
Schematic of Study Design ....................................................................................23 
 
LIST OF APPENDICES 
Appendix A 
Schedule of Study Procedures ...............................................................................70 
Appendix B 
Responsibilities of the Investigator ........................................................................72 
 


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2.0 
STUDY SUMMARY 
Name of Sponsor(s): 
Cerevance Alpha, Inc.  
(hereafter referred to as “Cerevance”) 
Compound: 
CVN058 
Title of Protocol: A Placebo-Controlled Study to 
Evaluate the Effect of a Single Dose of CVN058 on 
Mismatch Negativity in Subjects with Stable 
Schizophrenia 
IND No.: 121,520 
EudraCT No.: 
Not Applicable 
Study Number: CVN058-103 
Phase: 1 
Study Design: 
This is a phase 1, double-blind, placebo-controlled, 3 period cross-over study to evaluate CVN058 target 
engagement by measuring auditory evoked potential mismatch negativity (MMN) downstream to 5-
hydroxytryptamine receptor 3 (5-HT3) as a pharmacodynamic (PD) marker.   
Male and female subjects with schizophrenia (including schizoaffective disorder), age 18 to 50 years old, 
inclusive, will be randomized to 1 of 6 treatment sequences (Table 2.a) to receive 1 of 3 dose regimens in each 
period: a single oral administration of CVN058 (15 mg or 150 mg initially; one or both dosages may be revised 
after interim analysis) or matching placebo. The sequence will determine the order in which a subject will take 
each of the 3 regimens. Discontinued subjects may be replaced at the discretion of the sponsor so that 
approximately 20 completed subjects are available for analysis. Sample size re-estimation may occur when 
MMN data from all 3 periods are available for 12 subjects, or when 20 subjects have been dosed and are 
expected to complete the study.  
The study includes three 1-day treatment periods, with a minimum of 7-day washout, maximum 10-day washout 
(2 total washouts, after Periods 1 and 2) between periods, and a 7-10 day follow-up call post dosing of the last 
period. Subjects may be inpatients or outpatients at the discretion of the Investigator. 
Table 2.a Treatment Sequences 
Sequence 
Period 1 
Period 2 
Period 3 
1 
A 
B 
C 
2 
B 
A 
C 
3 
C 
A 
B 
4 
A 
C 
B 
5 
B 
C 
A 
6 
C 
B 
A 
A: Placebo 
B: CVN058 15 mg initially; dosage may be revised after interim analysis 
C: CVN058 150 mg initially; dosage may be revised after interim analysis  
At each testing session, subjects undergo post dose electroencephalography (EEG) testing including: MMN, P50, 
gamma power, and P300. Study drug will be administered with water. Testing sessions will begin approximately 
1.5 hours post-dose. Prior to dosing and at various time points post dose, blood samples will be collected for the 
assessment of plasma concentrations of CVN058 and biomarkers.  
Study procedures will be conducted at approximately the same times across Treatment Periods to minimize 
diurnal effects on outcomes. The effect of CVN058 on MMN as well as on exploratory measures (e.g., P50 
auditory gating, gamma power, and P300) will be compared to placebo.  
 
A schematic of the study design is presented below: 
  
 


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Note: CVN058 dosages will be 15 mg and 150 mg initially; one or both dosages may be revised after interim 
analysis. 
Primary Objective: 
To determine whether improvement in MMN is demonstrated after administration of CVN058 compared to 
placebo in subjects with schizophrenia. 
Secondary Objective: 
Assess the safety and tolerability of single doses of CVN058 in subjects with schizophrenia. 
Exploratory Objectives: 
 
To determine whether improvement in P50 auditory gating, gamma power, and P300 is demonstrated 
after administration of CVN058 compared to placebo in subjects with schizophrenia. 
 
To assess the pharmacokinetics (PK) of CVN058 following a single dose to subjects with 
schizophrenia. 
 
To explore the exposure-response relationship for CVN058 in subjects with schizophrenia. 
Subject Population:  
Subjects with stable schizophrenia including schizoaffective disorder on antipsychotic medication(s).  
Number of Subjects: 
Estimated total: at least 20 evaluable subjects who 
complete the study. 
Sample size is subject to re-estimation based on 
preliminary data from an interim analysis.  
Number of Sites: 
Approximately 3 (United States) 


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Dose Level(s): 
Placebo: solution vehicle, oral administration  
CVN058: 15 mg solution, oral administration  
CVN058: 150 mg solution, oral administration 
 
The CVN058 dosages above will be used from study 
start; one or both dosages may be revised after interim 
analysis. 
Route of Administration: 
Oral 
Duration of Treatment: 
Single oral dose in each of the 3 periods.  
Period of Evaluation: 
Screening Days: Up to 28 days. 
3 Treatment Periods, each <1 day duration;  
with a 7-10 day washout between periods 
Follow-up call 7-10 days following the last dose of 
study drug in Treatment Period 3. 
Total Duration: Up to 58 days. 
Main Criteria for Inclusion: 
Subjects 18 to 50 years of age, inclusive, at the time of informed consent. 
The subject weighs at least 50 kg and has a body mass index (BMI) between 18 and 40 kg/m2 inclusive at 
Screening. 
Subject meets schizophrenia or schizoaffective disorder criteria as defined by the Diagnostic & Statistical 
Manual of Mental Disorders, 5th Edition (DSM–V).  
Subjects are on a stable dose of antipsychotic medication(s) for at least 2 months prior to Screening as 
documented by medical history and assessed by site staff. 
Subject has a Positive and Negative Syndrome Scale (PANSS) total score of <95. 
Main Criteria for Exclusion: 
Subject currently receiving treatment with any excluded medication or dietary supplement. 
Subjects who have a history of gastrointestinal disease that would influence the absorption of study drug or have 
a history of any surgical intervention known to impact absorption (e.g., bariatric surgery or bowel resection). 
Subjects having clinical laboratory evaluations (including clinical chemistry, hematology and complete 
urinalysis) outside the reference range for the testing laboratory, unless the results are deemed to be not clinically 
significant (NCS) by the investigator at Screening. 
Subjects with moderate to severe substance use disorder, unstable mood or anxiety disorder. 
Subject has a current diagnosis of a significant psychiatric illness other than schizophrenia or schizoaffective 
disorder per DSM-V and is in an acute phase/episode. 
Subject has clinically meaningful hearing loss. 


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Main Criteria for Evaluation and Analyses: 
Pharmacodynamics: 
MMN will be measured as a PD marker for CVN058. Exploratory measurements include P50 auditory gating, 
gamma power, and P300, which are EEG markers commonly impaired in subjects with schizophrenia including 
schizoaffective disorder.  
Pharmacokinetics:  
Blood samples will be collected for the determination of plasma concentrations of CVN058, and its metabolite if 
appropriate, at the following time points: Pre-dose (within 15 minutes prior to dosing), and at 1 (pre-EEG) and 5 
(post-EEG) hours post dose. Analysis of these samples will confirm drug exposure during EEG data collection 
and will support basic PK/PD response correlations. The following PK parameters will be determined from 
concentrations of CVN058, and its metabolite if appropriate, in plasma: maximum observed plasma 
concentration (Cmax), time to reach Cmax (tmax), and area under the curve from time 0 to 5 hours post dose (AUCt). 
Other parameters may be calculated if appropriate.  
Pharmacogenomics: 
Whole blood will be collected and stored for possible deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) 
isolation and analysis.  
DNA samples will be used to evaluate drug metabolic enzyme and transporter polymorphisms that may 
contribute to variability in the PK of CVN058. Also, since pharmacogenomics is an evolving science, many 
genes and their functions are not yet fully understood. Future data may suggest a role of some gene in drug 
response, which may lead to additional hypothesis-generating exploratory research and diagnostic development 
on stored samples. 
Statistical Considerations: 
Observed values for the PD parameters (MMN and exploratory PD parameters) in each period will be 
summarized by treatment and compared to time matched assessments during placebo dosing using summary 
statistics. Comparison of post dose PD parameters to time matched placebo period timepoints will be analyzed 
using analysis of covariance (ANCOVA) with baseline value as a covariate and factors for sequence, subject 
nested within sequence, period, and treatment. Two-sided 95% confidence intervals will be constructed for the 
least squares mean differences between CVN058 and placebo in changes of PD parameters, comparing CVN058 
and placebo at a time-matched post-dose time point. 
Effect size will be calculated for comparisons of CVN058 to placebo using Cohen’s d which expresses the 
difference between the means of 2 groups as a function of their pooled standard deviation. 
Plasma PK concentrations and parameters of CVN058, and its metabolite if appropriate, will be listed and 
summarized by treatment using descriptive statistics. Exposure-response relationships for CVN058 will be 
explored graphically. 
Adverse events (AEs) will be presented in listings, and treatment-emergent AEs (TEAEs) will be summarized by 
treatment. Individual results of vital signs will be listed and observed values and changes from Baseline in vital 
signs will be summarized by treatment.  
Sample size re-estimation will occur after twelve (12) subjects have completed all study visits, or when 20 
subjects have been dosed and are expected to complete the study, whichever is sooner. The sample size re-
estimation will be performed using SAS PROC POWER for Paired-Sample Means and specifications of power 
= 80%, alpha=0.10 and the unblinded group standard deviation values attained from the twelve study subjects.  


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Sample Size Justification:  
Enrollment of 20 subjects is estimated to provide >80% power to detect a median effect size of Cohen’s d=0.5. 
Discontinued or withdrawn subjects and subjects for whom MMN is not available for all three study periods may 
be replaced. The sample size chosen of 20 completed subjects is expected to be sufficient to explore the changes 
in MMN between CVN058 and placebo as well as safety and tolerability of CVN058 in this population. 
Sample size re-estimation may occur when MMN data from all 3 periods are available for 12 subjects, or when 
20 subjects have been dosed and are expected to complete the study, whichever is sooner. Sample size may be 
increased up to a total of 40 subjects to ensure adequate study power to achieve its scientific objectives.  
 


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3.0 
LIST OF ABBREVIATIONS 
5-HT 
5-hydroxytryptamine (serotonin) 
5-HT3 
5-hydroxytryptamine (serotonin) receptor 3 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
AUCt 
area under the plasma concentration-time curve from 0 to 5 hours post dose  
BA 
bioavailability 
BMI 
body mass index 
CIAS 
cognitive impairment associated with schizophrenia 
CL/F 
apparent clearance after extravascular administration 
Cmax 
maximum observed plasma concentration 
CNS 
central nervous system 
CRO 
contract research organization 
CS 
clinically significant 
CSF 
cerebrospinal fluid 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DSM -V 
Diagnostic & Statistical Manual of Mental Disorders, 5th Edition – Text Revision 
eCRF 
electronic case report form  
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
EEG 
electroencephalography 
EMA 
European Medicines Agency  
ERP 
evoked response potential 
FDA 
Food and Drug Administration 
FM 
frequency-modulation 
FSH 
follicle-stimulating hormone 
FSI 
fast-spiking interneurons 
Fz 
frontal electrodes 
Fz,Cz 
frontocentral electrodes 
GABA 
γ-aminobutyric acid 
GCP 
Good Clinical Practice 
GGT 
-glutamyl transferase 
HBsAg 
hepatitis B surface antigen 
hCG 
human chorionic gonadotropin 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
ICH 
International Conference on Harmonisation 
IEC 
independent ethics committee 
INR 
international normalized ratio 
IRB 
institutional review board 
IUD 
intrauterine device 
K2EDTA 
potassium ethylenediamine tetraacetic acid 


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LFT 
liver function test 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMN 
mismatch negativity 
NCS 
not clinically significant 
NMDAR 
N-methyl-D-aspartate receptor 
NFSI 
non-fasting spiking interneurons 
OTC 
Over-the-counter 
PANSS 
Positive and Negative Syndrome Scale 
PD 
pharmacodynamic(s) 
PI 
principal investigator 
PK 
pharmacokinetic(s) 
PT 
PTT 
prothrombin time 
partial thromboplastin time 
PTE 
pretreatment event 
PV 
parvalbumin 
Pz 
parietal electrodes  
P50 Ratio 
ratio of S2 to S1  
RNA 
ribonucleic acid 
QTcB 
QT interval with Bazett correction method 
QTcF 
QT interval with Fridericia correction method 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SSR 
steady state response 
SUSAR 
suspected unexpected serious adverse reaction 
t1/2z 
terminal elimination half-life 
CVN058 
also known as ENV8058 and TAK-058 
TEAE 
treatment-emergent adverse event 
tmax 
time to reach Cmax 
ULN 
upper limit of normal 
Vz/F 
apparent volume of distribution during the terminal phase 
WHODRUG  
World Health Organization Drug Dictionary 


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4.0 
INTRODUCTION 
4.1 
Background 
Schizophrenia is a complex disorder comprising several clinical features that are highly variable 
among affected individuals. Probably the most well-known schizophrenia symptom domains are 
the so-called positive symptoms, e.g., hallucinations, delusions, disorganization of thought, 
bizarre behavior, and incongruity of affect. Negative symptoms include avolition (loss of 
motivation), blunt affect, alogia (reduced speech), and anhedonia (reduced ability to experience 
pleasure). Symptoms of a mood disorder, such as mania and depression, are prominent in a 
subset of patients; those patients are considered to have schizoaffective disorder. There is a well-
established cognitive impairment associated with schizophrenia (CIAS) including schizoaffective 
disorder (Hartman, 2019). CIAS is observed in most cases involving deficits in a broad range of 
domains.  
Cognitive impairment is considered a core feature of schizophrenia and represents an area of 
significant unmet medical need. Cognitive deficits in schizophrenia include problems in speed of 
processing, attention/vigilance, working memory, verbal learning, visual learning, reasoning and 
problem solving, and social cognition (Green, 2006). These cognitive deficits are believed to 
underlie much of the significant functional impairments observed in schizophrenia, such as 
impairment in independent living skills, social functions, vocational functioning, and self-care 
(Harvey, 2007). Thus, the core nature of CIAS and the associations that have been demonstrated 
with functional disability suggest that improving cognitive impairment may lead to improved 
functional outcomes (Heinrichs, 2005). 
The understanding of CIAS has evolved significantly in recent years and led to new therapeutic 
strategies. In postmortem samples from schizophrenic patients, studies consistently reveal 
reduced levels of enzymes that synthesize the inhibitory neurotransmitter γ-aminobutyric acid 
(GABA) in the prefrontal cortex (McNally, 2013) a key center for higher cognitive function. The 
GABAergic neurons deficient in the cortex are termed fast-spiking interneurons (FSIs), and they 
express the marker parvalbumin (PV) (McNally, 2013). These PV+ FSIs are chemically coupled 
and release GABA in a rhythmic pattern that synchronizes the activity of local cortical pyramidal 
neurons (Cardin, 2009). This synchronization, which is essential for cognition, is disrupted in 
patients [(McNally, 2013), (Cardin, 2009)] [(Whittington, 1997), (Rotaru, 2012), (Gonzalez-
Burgos, 2012)]. These and other human and animal model data implicate FSI hypofunction, and 
a resulting imbalance in the excitation/inhibition balance in cortical regions, in CIAS. 
Based on this emerging insight into disease pathophysiology, a therapeutic that restores the 
normal function of the cortical pyramidal neuron/FSI microcircuit would be expected to improve 
cognitive function in patients with schizophrenia. One strategy for boosting the function of this 
circuit is to inhibit a second population of inhibitory GABAergic interneurons, known as non-
fast spiking interneurons (NFSIs), which project locally onto the FSIs and the dendrites of the 
pyramidal neurons. These NFSIs are modulated by a wide variety of inputs, particularly 
excitatory glutamatergic efferents from the thalamus, and noradrenergic, cholinergic, and 
serotonergic efferents from subcortical regions [(Tian, 2010), (Kawaguchi, 1998), (Kawaguchi, 
1997), (Lee, 2010)]. Thus, NFSIs appear to integrate state-dependent information and release 
GABA to regulate pyramidal neuron/FSI microcircuits. 


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Mismatch negativity (MMN) is an established biomarker of cortical function (Javitt, 2015). This 
signal is obtained as an evoked potential during an auditory oddball task, in which a subject is 
repeatedly exposed to auditory tones and a small proportion of those tones (the “deviant” stimuli) 
differ from the others (the “standard” stimuli) in their frequency or duration. Typically, the tones 
are presented and the evoked potentials are recorded while subjects are engaged on a different 
task, such as reading. Normally, the occurrence of a deviant stimulus increases the amplitude of 
the negative component in the evoked potential occurring at around 200 msec. MMN is the 
difference in amplitude between deviant and standard stimuli responses, and is considered to 
represent an aspect of preattentive novelty detection. MMN is consistently reduced in 
schizophrenia patients relative to healthy individuals, a finding extensively replicated and with a 
large effect size (Cohen’s d = 1). MMN reduction in schizophrenia has been shown to reflect 
impaired N-methyl-D-aspartate receptor (NMDAR) function at the level of supratemporal 
auditory cortex, dependent on cortical interneuron modulation of pyramidal cell activity and 
NMDA receptor-dependent (Lee, 2017). 
4.2 
Non-Clinical 
CVN058 (also known as ENV8058 or TAK-058) is a small molecule that potently and 
selectively antagonizes the 5-hydroxytryptamine (5-HT) receptor type 3 (5-HT3). 5-HT3 is a cys-
loop family ligand-gated ion channel that allows cations to pass into the neurons when activated 
by serotonin, and is highly expressed in NFSIs [(Lee, 2010), (Lummis, 2012)]. The receptor is a 
pentamer consisting of at least two 5-HT3a subunits and 3 other subunits; in the central nervous 
system (CNS) the receptor is almost exclusively a homomeric pentamer comprised of 5-HT3a 
(Kawaguchi, 1997). The 5-HT3 channel opens when serotonin molecules interact with the 2 
ligand recognition sites in the extracellular side of the receptor. Influxed calcium and other 
positive ions depolarize the NFSIs, leading to GABA release. CVN058 is orally absorbed and 
readily passes the blood brain barrier, allowing it to occupy cortical 5-HT3 receptors. CNS 5-HT3 
receptor occupancy is correlated with efficacy in a rat model of cognition where it reverses 
deficits in novel object recognition induced by subchronic phencyclidine treatment. Thus, 
CVN058 is a novel therapeutic candidate that may improve cognitive function by inhibiting 
specific subsets of cortical interneurons.  
Additional information from the nonclinical studies can be found in the current Investigator’s 
Brochure. 
4.3 
Clinical 
Two human clinical studies of CVN058 have been completed (ENV8058_101 and TAK-058-
1002). 
CVN058 was well tolerated up to a dose of 150 mg administered orally as a single dose in 
aqueous solution (Study ENV8058_101). There were no deaths or other serious adverse events 
(SAEs) reported in this study and no subject discontinued study due to a treatment-emergent 
adverse event (TEAE). There were no clinically significant (CS) laboratory abnormalities, 
electrocardiogram (ECG) changes or changes in vital signs in the completed single dose study. 
The mean Cmax and area under the plasma concentration–time curve (AUC) values of CVN058 
increased less than proportionally with increasing CVN058 dose across the dose range of 5 to 


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150 mg, but mean Cmax and AUC values increase in an approximately dose proportional manner 
across the 5 to 45 mg dose range. The rate of appearance of CVN058 in plasma was rapid with 
median time to Cmax (tmax) values of 1 to 1.25 hours across the dose range of 5 to 150 mg. The 
mean terminal elimination half-life (t1/2z) values of CVN058 ranged from approximately 2.8 to 
10.5 hours across the cohorts; the lower doses (5 to 30 mg) had lower mean t1/2z values compared 
to the higher doses (45 to 150 mg). There were no trends with mean apparent clearance (CL/F) 
values of CVN058 with increasing dose from 5 to 45 mg, but faster apparent clearance was 
observed at the 75 and 150 mg doses, possibly due to decreased bioavailability (BA) at higher 
doses. The mean apparent volume of distribution (Vz/F) increased as dose increased. Excretion 
of unchanged CVN058 in the urine was ≤2.3% of the administered CVN058 dose over the dose 
range evaluated. 
In the multiple-rising dose study (TAK-058-1002), CVN058 was well-tolerated at daily doses of 
25, 75, and 150 mg for 7 days, and at a single 300 mg dose, in aqueous solution. There were no 
deaths or other SAEs reported in this study and no subject discontinued study due to a TEAE. 
There were no clinically significant laboratory abnormalities, ECG changes or changes in vital 
signs in the completed single dose study. Following single or multiple doses, the mean Cmax and 
AUC values of CVN058 increased less than proportionally with increasing CVN058 dose across 
the dose range of 25 to 300 mg. No accumulation was observed following daily administration. 
CVN058 concentrations in cerebrospinal fluid (CSF) were assessed after daily doses of CVN058 
75 mg for 5 days. The CSF concentrations averaged 17.5 ng/mL, or approximately 1% of the 
concentration in plasma. 
4.4 
Rationale for the Proposed Study 
This study will explore central target engagement and proof of mechanism by measuring 
auditory evoked potential MMN as a pharmacodynamic (PD) marker of CNS response to the 
selective 5-HT3 receptor antagonist CVN058. It has been reported that subjects with 
schizophrenia including schizoaffective disorder commonly demonstrate a deficit in neural 
processing that is manifested as a reduction in MMN (Avissar, 2018); impairment of auditory 
sensory gating (P50) is also observed (Javitt and Sweet, 2015). Other 5-HT3 receptor antagonists 
have been reported to improve impairments in auditory evoked potentials in schizophrenic 
subjects. In a study with ondansetron, a 5-HT3 receptor antagonist, using P50 auditory gating as 
the auditory evoked potential measure, subjects were given a single dose of ondansetron (16 mg) 
or placebo in a double-blind, placebo-controlled, randomized and balanced crossover design 
(Adler, 2005). Serial measurements of the P50 evoked potential were done at Baseline and 1, 2, 
and 3 hours after receipt of placebo or ondansetron. The results of the study indicated that 
ondansetron significantly enhanced P50 auditory gating in subjects with schizophrenia. 
Tropisetron, a 5-HT3 antagonist that also has 7 nicotinic cholinergic agonist activity, has 
similarly been shown to improve P50 auditory gating in subjects with schizophrenia (Koike, 
2005).  
While the P50 signal is likely a reflection of brainstem and thalamic network activity and is 
sensitive to antipsychotic treatment, MMN is thought to reflect excitation-inhibition balance in 
cortical circuits and is not sensitive to antipsychotic treatment (Javitt and Sweet, 2015). 
Therefore, to evaluate the potential for CVN058 to improve cognitive function in schizophrenics, 
MMN will be used as a PD marker. The study will be performed as a 3-way crossover to assess 


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the effect on MMN of CVN058 at two dose levels relative to placebo, with each subject serving 
as his or her own control to reduce variability. P50 auditory gating will also be measured, as an 
exploratory endpoint, along with other potentially informative electrophysiological and 
psychometric parameters. 
Medications that might inhibit or mask the effects of CVN058 will not be permitted as 
concomitant medications. These include serotonin reuptake inhibitors which increase synaptic 
serotonin levels, as well as drugs that bind to 5-HT3 at clinically relevant concentrations or are 
reported to inhibit signaling through 5-HT3 non-competitively, including some antipsychotic 
drugs [( Eisensamer, 2005), (Eisensamer, 2003), (Rammes, 2004)]. Permissible antipsychotic 
medications are risperidone (Risperdal), haloperidol (Haldol), quetiapine (Seroquel), aripiprazole 
(Abilify), paliperidone (Invega), lurasidone (Latuda), and ziprasidone (Geodon). 


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5.0 
STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Objectives 
5.1.1 Primary Objective 
 To determine whether improvement in MMN is demonstrated after administration of 
CVN058 compared to placebo in subjects with schizophrenia.  
5.1.2 Secondary Objective 
 To assess the safety and tolerability of single doses of CVN058 in subjects with 
schizophrenia. 
5.1.3 Exploratory Objectives  
 To determine whether improvement in P50 auditory gating, gamma power, and P300 is 
demonstrated after administration of CVN058 compared to placebo in subjects with 
schizophrenia. 
 
 
 
 To explore the exposure-response relationship for CVN058 in subjects with schizophrenia. 
5.2 
Endpoints 
5.2.1 Primary Endpoints  
 Mean amplitude of duration MMN at 5 electrodes surrounding frontal (Fz) electrodes 
following administration of CVN058 compared to placebo. 
5.2.2 Secondary Endpoint 
 Percentage of subjects who experience at least 1 TEAE  
 Percentage of subjects who experience at least 1 clinically significant abnormal laboratory 
test result 
5.2.3 Exploratory Endpoints 
 
 
 Pre-stimulus gamma amplitude following administration of CVN058 compared to placebo  
 P300 amplitude and latency at average 
 
 following administration of CVN058 compared to placebo 


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 MMN amplitude to additional deviants (frequency, intensity, location, frequency-modulation 
[FM]) and latency to all deviants following administration of CVN058 compared to placebo 
 


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6.0 
STUDY DESIGN AND DESCRIPTION 
6.1 
Study Design  
This is a phase 1, double-blind, placebo-controlled, 3 period cross-over study to evaluate 
CVN058 target engagement by measuring auditory evoked potential MMN downstream to 5-
hydroxytryptamine receptor 3 (5-HT3) as a PD marker.  
Male and female subjects with schizophrenia including schizoaffective disorder, age 18 to 50 
years old, inclusive, will be randomized to 1 of 6 treatment sequences (Table 6.a) to receive 1 of 
3 dose regimens in each period; a single oral administration of CVN058 (15 mg or 150 mg 
initially; one or both dosages may be revised after interim analysis), or a matching placebo. The 
sequence will determine the order in which a subject will receive each of the 3 regimens. 
Discontinued subjects may be replaced so that 20 completed subjects are available for analysis. 
Sample size re-estimation may occur when MMN data from all 3 periods are available for 12 
subjects, or when 20 subjects have been dosed and are expected to complete the study. 
Each treatment period is less than 1 day in duration, with a minimum of 7-day washout, 
maximum 10-day washout between doses. A follow-up telephone call will occur approximately 
7-10 days following the last dose received. Subjects may be inpatients or outpatients at the 
discretion of the Investigator. 
Table 6.a 
Treatment Sequences 
Sequence 
Period 1 
Period 2 
Period 3 
1 
A 
B 
C 
2 
B 
A 
C 
3 
C 
A 
B 
4 
A 
C 
B 
5 
B 
C 
A 
6 
C 
B 
A 
A: Placebo 
B: CVN058 15 mg initially; dosage may be revised after interim analysis 
C: CVN058 150 mg initially; dosage may be revised after interim analysis 
 
 
 
At each testing session, subjects will undergo post dose EEG testing including: MMN, P50, 
gamma power, and P300. Study drug will be administered with water in the morning. Testing 
sessions will begin approximately 1.5 hours post-dose. Prior to dose and at various time points 
post-dose, blood samples will be collected for the assessment of plasma concentrations of 
CVN058 and biomarkers. Analysis of these samples will confirm drug exposure during EEG 
data collection and will support basic PK/PD response correlations. 
Study procedures will be conducted at approximately the same times across Treatment Periods to 
minimize diurnal effects on outcomes. The effect of CVN058 on MMN as well as on exploratory 
measures (e.g., P50 auditory gating, gamma power, and P300) will be compared to placebo.  


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A schematic of the study design is presented in Figure 6.a. 
Figure 6.a 
Schematic of Study Design 
 
Note: CVN058 dosages will be 15 mg and 150 mg initially; one or both dosages may be revised after interim 
analysis. 
6.2 
Justification for Study Design, Dose, and Endpoints 
This study will explore CNS target engagement by measuring alterations in auditory evoked 
potentials, similar to the demonstration of an effect on P50 auditory gating using the 5-HT3 
antagonist, ondansetron (Adler, 2005). The study design was based on that published study, 
adapted for CVN058 as study drug and MMN as the primary endpoint. It has been reported that 
most subjects with schizophrenia demonstrate a deficit in neural processing that is manifested as 
a reduction in MMN and impairment of auditory sensory gating (P50). According to Adler et al., 
ondansetron improves the P50 deficit after a single dose administration (Adler, 2005).  
The study will be a randomized, 3 period crossover study (CVN058 at two dose levels, and 
placebo) in order to evaluate the effect of CVN058 on MMN as well as on exploratory 
measures (i.e., P50 auditory gating, gamma power, and P300) compared to placebo. The 
study will be double-blind and placebo-controlled in order to avoid subjective bias in the 
assessment of the PD markers. In addition, conduct of study procedures for each subject 
will occur at approximately the same time per day across each of the Treatment Periods 
to avoid diurnal changes that may otherwise confound the analysis.  
The 150 mg level of CVN058 is expected to saturate CNS 5-HT3 receptors throughout the EEG 
session, but is 50% lower than the highest dosage for which safety and tolerability has been 
demonstrated in previous phase 1 studies in healthy subjects, thus presumably maximizing the 


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PD signal within the established limits of safe use. The lower dose level of 15 mg CVN058 is 
expected to attain a lower CNS 5-HT3 receptor occupancy, decreasing to possibly 70-80% by the 
end of the EEG session. The 10-fold difference in these dosages should help establish a dose-
response relationship for evoked response potential (ERP) effects of CVN058. From a safety 
perspective, single doses ranging from 5 mg to 300 mg CVN058 have been safe and well-
tolerated. Daily doses of 25, 75, and 150 mg of CVN058 for 7 days have also been studied and 
were similarly safe and well-tolerated. Following interim analysis, one or both CVN058 dosages 
may be revised, but will not exceed 150 mg. 
The timing of dosing was selected to allow the EEG assessments to occur at the corresponding 
estimated tmax values of CVN058. The length of the washout periods is considered adequate 
based on the PK profile of CVN058. 
In addition, based on the EEG deficits reported in subjects with schizophrenia including 
schizoaffective disorder, P50 auditory gating, gamma frequency, and P300 neurophysiological 
markers will be measured. 
6.2.1 Dose Modification 
The dosages chosen at study outset, 15 mg and 150 mg, span a 10-fold range, with a large gap in 
between. If unblinded interim data suggest that either dosage is ineffective or poorly tolerated, 
the Sponsor may elect to discontinue use of that dosage and to replace it with another. The new 
dosage will not exceed 150 mg.  
6.3 
Premature Termination or Suspension of Study or Investigational Site 
6.3.1 Criteria for Premature Termination or Suspension of the Study 
The study will be completed as planned unless new information or other evaluation regarding the 
safety or efficacy of the study medication indicates a change in the known risk/benefit profile for 
the compound, such that the risk/benefit is no longer acceptable for subjects participating in the 
study. 
6.3.2 Criteria for Premature Termination or Suspension of Investigational Sites 
A study site may be terminated prematurely or suspended if the site (including the investigator) 
is found in significant violation of Good Clinical Practice (GCP), protocol, or contractual 
agreement, is unable to ensure adequate performance of the study, or as otherwise permitted by 
the contractual agreement. 
6.3.3 Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s) 
In the event that the sponsor, an institutional review board (IRB) / independent ethics committee 
(IEC), or regulatory authority elects to terminate or suspend the study or the participation of an 
investigational site, a study-specific procedure for early termination or suspension will be 
provided by the sponsor; the procedure will be followed by applicable investigational sites 
during the course of termination or study suspension. 


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7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS 
All entry criteria, including test results, need to be confirmed prior to randomization. Subjects 
who do not initially meet eligibility criteria may be re-screened at investigator’s discretion.  
7.1 
Inclusion Criteria 
Subject eligibility is determined according to the following criteria prior to entry into the study:  
1. In the opinion of the investigator, the subject is capable of understanding and complying with 
protocol requirements. 
2. The subject signs and dates a written, informed consent form and any required privacy 
authorization prior to the initiation of any study procedures. 
3. The subject is aged 18 to 50 years, inclusive, at the time of informed consent. 
4. The subject weighs at least 50 kg and has a body mass index (BMI) between 18 and 40 kg/m2 
inclusive at Screening. 
5. The subject meets schizophrenia or schizoaffective disorder criteria as defined by the 
Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-V) (American 
Psychiatric Association, 2013). 
6. The subject is on a stable dose of allowed antipsychotic medication(s) for at least 2 months 
prior to Screening as documented by medical history and assessed by site staff. 
7. The subject has a Positive and Negative Syndrome Scale (PANSS) total score of <95 at 
Screening. 
7.2 
Exclusion Criteria 
Any subject who meets any of the following criteria will not qualify for entry into the study:  
1. A male subject who is nonsterilized* and sexually active with a female partner of 
childbearing potential* does not agree to use adequate contraception* from signing of 
informed consent throughout the duration of the study and for 12 weeks after last dose of 
study drug. 
2. A female subject of childbearing potential* who is sexually active with a nonsterilized* male 
partner does not agree to use acceptable methods of contraception* from signing of informed 
consent throughout the duration of the study and for 12 weeks after last dose of study drug. 
*Definitions and acceptable methods of contraception are defined in 
Section 9.1.9 Contraception and Pregnancy Avoidance Procedure and 
reporting responsibilities are defined in Section 9.1.10 Pregnancy. 
3. If female, the subject is pregnant or lactating or intending to become pregnant before, during, 
or within 12 weeks after the last dose of study medication; or intending to donate ova during 
such time period. 


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4. The subject has uncontrolled, clinically significant neurologic, cardiovascular, pulmonary, 
hepatic, renal, metabolic, gastrointestinal, or endocrine disease or other abnormality that may 
impact the ability of the subject to participate or potentially confound the study results.  
5. The subject has a history of gastrointestinal disease that would influence the absorption of 
study drug, or history of any surgical intervention known to impact absorption (e.g., bariatric 
surgery or bowel resection). 
6. The subject has clinical laboratory evaluations (including clinical chemistry, hematology and 
complete urinalysis) outside the reference range for the testing laboratory, unless the results 
are deemed to be NCS by the investigator at Screening. 
7. The subject has received any investigational compound within 30 days prior to signing of 
informed consent. 
8. The subject has taken any excluded medication or dietary supplement within time frames 
listed in the Excluded Medications table in Section 7.3. 
9. The subject does not have a stable indoor living situation (e.g., living independently, with 
family, or group home)  
10. The subject is an immediate family member, study site employee, or is in a dependent 
relationship with a study site employee who is involved in the conduct of this study 
(e.g., spouse, parent, child, sibling) or may consent under duress. 
11. Subjects with moderate to severe substance use disorder according to DSM-5 criteria. 
12. The subject has a positive urine drug result for drugs of abuse (defined as any illicit drug use, 
except marijuana) at Screening.  
13. The subject has a history of cancer requiring chemotherapy within the past 5 years prior to 
the first dose of study medication. This criterion does not include subjects successfully 
treated for basal cell or stage I squamous cell carcinoma of the skin. 
14. The subject has a positive test result for hepatitis B surface antigen (HBsAg), hepatitis C 
virus (HCV) antibody (unless having completed curative therapy), or known history of 
human immunodeficiency virus (HIV) antibody at Screening.  
15. The subject has a QT interval with Fridericia’s correction method (QTcF) >450 msec (males) 
or >470 msec (females) or PR outside the range of 120 to 220 msec, confirmed by triplicate 
testing at 5-minute intervals, at the Screening Visit. 
16. The subject has poor peripheral venous access.  
17. The subject has hair or scalp condition(s) that would prevent the application of the EEG 
electrodes. 
18. The subject has a current diagnosis of a significant psychiatric illness other than 
schizophrenia or schizoaffective disorder, per DSM-V and is in an acute phase/episode. 
19. Subject has clinically meaningful hearing loss per investigator’s judgment. 
20. The subject has donated or lost 450 mL or more of his or her blood volume (including 
plasmapheresis), or had a transfusion of any blood product, within 3 months prior to Day 1. 


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21. The subject has an abnormal (clinically significant) Screening ECG. Entry of any subject 
with an abnormal (not clinically significant) ECG must be approved and documented by 
signature of the principal investigator (PI).  
22. The subject has abnormal Screening laboratory values that suggest a clinically significant 
underlying disease, or subject with the following lab abnormalities: alanine aminotransferase 
(ALT) and/or aspartate aminotransferase (AST) >2x the upper limit of normal (ULN). 
23. The subject has abnormal Screening vital sign values that suggest a clinically significant 
underlying disease. 
24. The subject has a risk of suicide according to the Investigator’s clinical judgment, a 
Screening Visit Columbia-Suicide Severity Rating Scale [C-SSRS]) score of greater than 3, 
or has a history of suicide attempt in the past 3 years. 
7.3 
Excluded Medications, Dietary Products, Procedures, and Treatments  
Use of the agents in Table 7.a (prescription or nonprescription) is prohibited from the time points 
specified until completion of all study activities.  
Table 7.a 
Prohibited Medications  
28 Days Prior to Check-in  
1 Days Prior to Check-in  
1 Hour Prior to 
Each EEG 
Assessment  
Nutraceuticals and dietary supplements (e.g., St. John’s wort, 
ginseng, kava kava, ginkgo biloba, Chinese herbs, and melatonin) 
 
Alcohol-containing 
products 
Products containing 
nicotine, caffeine or 
xanthine (e.g., tea) 
Antipsychotic medications, except risperidone (Risperdal), 
haloperidol (Haldol), quetiapine (Seroquel), aripiprazole (Abilify), 
paliperidone (Invega), lurasidone (Latuda), and ziprasidone 
(Geodon) 
 
Sedative hypnotic 
medications (barbiturates 
and benzodiazepines) 
 
5-HT3 receptor antagonists, including ondansetron (Zofran, 
Zuplenz), granisetron (Kytril, Sancuso, Granisol, Sustol), 
palonosetron (Aloxi), dolasetron (Anzemet)  
 
 
 
5-HT3 allosteric modulators buproprion (Wellbutrin, Zyban) and 
hydroxybupropion 
 
 
 
Serotonin Reuptake Inhibitors (SSRI, SNRI), including sertraline 
(Zoloft), fluoxetine (Prozac, Sarafem), citalopram (Celexa), 
escitalopram (Lexapro), paroxetine (Paxil, Pexeva, Brisdelle), 
vortioxetine (Trintellix), and fluvoxamine (Luvox) 
 
 
 
Mirtazapine (Remeron), desipramine, imipramine, trimipramine, 
reboxetine 
 
 
  


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Subjects must be instructed not to take any medications, including over-the-counter (OTC) 
products, without first consulting with the investigator. Subjects must be instructed to not make 
any changes to their concomitant medications during the course of the study without first 
consulting with the investigator. 
During study participation, subjects will maintain usual dosing schedule of antipsychotic 
medication(s) and approved concomitant medications. Sedative hypnotics will not be allowed 
after 10 pm the night prior to testing, and until completion of testing the following day. 
7.4 
Diet, Fluid, Activity Control  
Subjects should have their customary meal before each study visit. The contents of the meal 
should be summarized on the electronic case report form (eCRF). 
During EEG and ERP assessments, subjects will remain still in a seated or partially recumbent 
position, according to the EEG acquisition guidelines. Subjects will refrain from strenuous 
exercise from 72 hours before Check-in through check-out, relative to each Treatment Period. 
If subject is a smoker; they must refrain from smoking at least 1 hour prior to the EEG testing at 
all time points. 
On each dosing day, CVN058 or placebo will be administered with approximately 240 mL of 
water.  
7.5 
Criteria for Discontinuation or Withdrawal of a Subject 
The primary reason for discontinuation or withdrawal of the subject from the study or study 
medication should be recorded in the eCRF using the following categories. For screen failure 
subjects, refer to Section 9.1.17. 
1. Pretreatment event (PTE) or AE. The subject has experienced a PTE or AE that requires 
early termination because continued participation imposes an unacceptable risk to the 
subject’s health or the subject is unwilling to continue because of the PTE or AE. 
2. Liver Function Test (LFT) Abnormalities 
Study medication should be discontinued immediately with appropriate clinical follow-up 
(including repeat laboratory tests, until a subject’s laboratory profile has returned to 
normal/baseline status, see Section 9.1.8), if the following circumstances occur at any 
time during study medication treatment: 
– ALT or AST >8 ×ULN, or 
– ALT or AST >5 ×ULN and persists for more than 2 weeks, or 
– ALT or AST >3 ×ULN in conjunction with elevated total bilirubin >2 × ULN or 
international normalized ratio (INR) >1.5, or 
– ALT or AST >3 ×ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%). 
3. Significant protocol deviation. The discovery post randomization or after the first dose of 
study medication that the subject failed to meet protocol entry criteria or did not adhere to 


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protocol requirements, and continued participation poses an unacceptable risk to the subject’s 
health. 
4. Lost to follow-up. The subject did not return to the clinic and attempts to contact the subject 
were unsuccessful. Attempts to contact the subject must be documented. 
5. Voluntary withdrawal. The subject (or subject’s legally acceptable representative) wishes to 
withdraw from the study. The reason for withdrawal, if provided, should be recorded in the 
eCRF. 
Note: All attempts should be made to determine the underlying reason for the withdrawal 
and, where possible, the primary underlying reason should be recorded (i.e., withdrawal due 
to an AE). 
6. Study termination. The sponsor, IRB, IEC, or regulatory agency terminates the study. 
7. Pregnancy. The subject is found to be pregnant. 
Note: If the subject is found to be pregnant, the subject must be withdrawn immediately. The 
procedure is described in Section 9.1.10. 
8. Other. 
Note: The specific reasons should be recorded in the “specify” field of the eCRF. 
7.6 
Procedures for Discontinuation or Withdrawal of a Subject 
The investigator may discontinue a subject’s study participation at any time during the study 
when the subject meets the study termination criteria described in Section 7.5. In addition, a 
subject may discontinue his or her participation without giving a reason at any time during the 
study. Should a subject’s participation be discontinued, the primary criterion for termination 
must be recorded by the investigator. In addition, efforts should be made to perform all 
procedures scheduled for the Early Termination Visit. Discontinued or withdrawn subjects be 
replaced. 


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8.0 
CLINICAL TRIAL MATERIAL MANAGEMENT 
This section contains information regarding all medication and materials provided directly by the 
sponsor, and/or sourced by other means, that are required by the study protocol, including 
important sections describing the management of clinical trial material. 
8.1 
Study Medication and Materials 
8.1.1 Dosage Form, Manufacturing, Packaging, and Labeling 
Study drug refers to CVN058 and matching placebo. Study drug will be provided in bulk supply. 
An unblinded pharmacist will manage and prepare doses as oral solutions, as needed. 
In this protocol, the term study medication refers to all or any of the drugs defined below. 
8.1.1.1 Investigational Drug 
CVN058 and Matching Placebo  
CVN058 drug substance is supplied as bulk powder to the clinical site to be compounded into an 
oral solution. A matching placebo containing all of the components of the active oral suspension 
with the exception of the drug substance will also be compounded by the site. Compounding 
instructions will be outlined in a separate pharmacy manual and provided by the sponsor. 
CVN058 oral solution will be prepared in concentrations of 10 mg/mL. The composition of the 
oral solutions (active and placebo) can be found in Table 8.a. 
The oral solution will be labeled with the appropriate study information and caution statements. 
Table 8.a 
Composition of CVN058 and Matching Placebo 
Component 
10 mg/mL solution 
Placebo 
CVN058 (free base) 
10 g 
Not Applicable 
Citric Acid Monohydrate, USP 
15.76 g 
15.76 g 
Sterile Water for Irrigation, USP 
q.s. to 1,000 mL 
q.s.to 1,000 mL 
q.s.=quantity sufficient, USP= United States Pharmacopeia. 
 
8.1.1.2 Sponsor-Supplied Drug 
CVN058 drug substance is supplied to the clinical site by Cerevance by way of a contract 
manufacturing organization, Johnson-Matthey Pharma Services, Devens, MA. 
8.1.1.3 Ancillary Materials 
Ancillary materials will be provided by either the clinical site and/or sponsor based on 
availability.  
Ancillary material details are provided in the pharmacy manual. 
Unused ancillary materials, if provided by the sponsor, will be accounted for and disposed of as 
directed by the sponsor or their designee.  


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8.1.2 Storage 
All clinical trial material must be kept in an appropriate, limited-access, secure place until it is 
used or returned to the sponsor or designee for destruction. 
All study medication must be stored under the conditions specified on the label, and remain in 
the original container until dispensed. A daily temperature log of the drug storage area must be 
maintained every working day. 
CVN058 powdered drug substance is stored at room temperature. CVN058 oral solution and 
matching placebo can be stored protected from light at 2°C-8°C (35.6°F-46.4°F) for up to 28 
days. CVN058 oral solution and matching placebo are stable at room temperature for up to 24 
hours. 
8.1.3 Dose and Regimen 
The investigator or investigator’s designee will instruct the subject on dosing procedures. 
All dosing will occur while subjects are in the clinic under the supervision of the PI or designee, 
who will be blinded to the dose. 
Subjects will be randomized to 1 of 6 treatment sequences (Table 6.a) to receive 1 of 3 dose 
regimens in each period.  
Table 8.b describes the treatment and medication type that would be provided for each period. 
Table 8.b 
Treatment and Medication Type 
Regimen 
Planned Treatment 
Medication Type 
A 
Placebo 
Placebo  
B 
CVN058 15 mg initially; dosage may be revised after interim analysis 
CVN058  
C 
CVN058 150 mg initially; dosage may be revised after interim analysis 
CVN058 
 
8.1.4 Overdose 
An overdose is defined as a known deliberate or accidental administration of investigational 
drug, to or by a study subject, at a dose above that which is assigned to that individual subject 
according to the study protocol. 
All cases of overdose (with or without associated AEs) will be documented on an Overdose page 
of the eCRF, in order to capture this important safety information consistently in the database. 
Cases of overdose without manifested signs or symptoms are not considered AEs. AEs 
associated with an overdose will be documented on AE CRF(s) according to Section 10.0, 
Pretreatment Events and Adverse Events. 
The SAEs associated with overdose should be reported according to the procedure outlined in 
Section 10.2.2, Collection and Reporting of SAEs. 
In the event of drug overdose, the subject should be treated, e.g., administration of supportive 
therapy as directed by the subject’s clinical status, removal of unabsorbed material from the 
gastrointestinal tract and initiation of additional clinical monitoring.  


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8.2 
Investigational Drug Assignment and Dispensing Procedures 
Subjects will be assigned a 7-digit subject number in the sequential order in which they are 
randomized beginning with a 3-digit code “NNN-” where NNN represents a site-specific 
identifier which will be provided by the Sponsor. Replacement subjects will be assigned a new 
number (e.g. site number followed by subject number). The 7-digit subject number assigned will 
be entered in the subject’s eCRF and noted on any subject specific source record and lab sample 
tubes. 
This 7-digit subject number will also be used by the clinical site to facilitate the prelabeling of 
PK samples, and will be the only subject identifier used on all PK sample collections. It should 
also be contained on the PK transport vials shipped to the bioanalytical laboratory, and will be 
used by the laboratory to report the subject data results. 
8.3 
Randomization Code Creation and Storage  
The randomization schedule will be generated under the direction of Cerevance statistician or 
designee and a copy will be provided to the site pharmacist prior to the start of study. All 
randomization information will be stored in a secured area, accessible only by authorized 
personnel. 
8.4 
Investigational Drug Blind Maintenance  
The investigational drug blind is maintained through a randomization schedule held by the 
dispensing pharmacist.  
8.5 
Unblinding Procedure  
The investigational drug blind shall not be broken by the investigator unless information 
concerning the investigational drug is necessary for the medical treatment of the subject. All 
study assessments and assignment of causality for AEs should be performed, if possible, prior to 
unblinding. In the event of a medical emergency, if possible, the medical monitor should be 
contacted before the investigational drug blind is broken to discuss the need for unblinding. 
For unblinding a subject, the investigational drug blind can be obtained by contacting the 
dispensing pharmacist. 
The sponsor must be notified as soon as possible if the investigational drug blind is broken. The 
date, time, and reason the blind is broken must be recorded in the source documents and the 
same information (except the time) must be recorded on the eCRF. 
If any site personnel are unblinded, investigational drug must be stopped immediately and the 
subject must be withdrawn from the study. 
Having completed a blinded interim analysis of data for the first 12 completed subjects, the 
Sponsor has determined that those data will be unblinded per a change to the study plan 
introduced in Protocol Amendment 4. All data from subsequently enrolled subjects will remain 
blinded until the study is concluded.  
No change should be made to any prior assessments or data of any subject after unblinding of 
his/her treatment assignment. 


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8.6 
Accountability and Destruction of Sponsor-Supplied Drugs 
Drug supplies will be counted and reconciled at the site before being returned to the sponsor or 
designee or destroyed per site’s procedures. 
The investigator or designee must ensure that the sponsor-supplied drug is used in accordance 
with the protocol and is dispensed only to subjects enrolled in the study. To document 
appropriate use of sponsor-supplied drug, the investigator or designee must maintain records of 
all sponsor-supplied drug delivery to the site, site inventory, dispensation and use by each 
subject, and return to the sponsor or designee. 
Upon receipt of sponsor-supplied drug, the investigator or designee must verify the contents of 
the shipments against the packing list. The verifier should ensure that the quantity is correct, and 
the medication is in good condition. If quantity and conditions are acceptable, investigator or 
designee should acknowledge the receipt of the shipment by signing bottom half of the packing 
list and faxing per instructions provided on the form. If there are any discrepancies between the 
packing list versus the actual product received, Cerevance must be contacted to resolve the issue. 
The packing list should be filed in the investigator’s essential document file. 
The investigator or designee must maintain 100% accountability for all sponsor-supplied drugs 
received and dispensed during his or her entire participation in the study. Proper drug 
accountability includes, but is not limited to: 
 Continuously monitoring expiration dates. 
 Frequently verifying that actual inventory matches documented inventory. 
 Verifying that the log is completed for the drug lot used to prepare each dose. 
 Verifying that all containers used are documented accurately on the log. 
 Verifying that required fields are completed accurately and legibly. 
If any dispensing errors or discrepancies are discovered, the sponsor must be notified 
immediately. 
The investigator or designee must record the current inventory of all sponsor-supplied drugs 
CVN058 or placebo on a sponsor-approved drug accountability log. The following information 
will be recorded at a minimum: protocol number and title, name of investigator, site identifier 
and number, description of sponsor-supplied drugs, expiration date and amount dispensed, 
including initials of the person dispensing the drug, and the date and amount returned to the site 
by the subject, including the initials of the person receiving the sponsor-supplied drug. The log 
should include all required information as a separate entry for each subject to whom sponsor-
supplied drug is dispensed. 
All study drug that was not returned to the site by a subject must be investigated by the site and 
appropriately documented on the drug accountability log. 
Prior to site closure or at appropriate intervals, a representative from the sponsor or its designee 
will perform sponsor-supplied drug accountability and reconciliation before sponsor-supplied 
drugs are returned to the sponsor or its designee for destruction. The investigator or designee will 


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retain a copy of the documentation regarding sponsor-supplied drug accountability, return, 
and/or destruction, and originals will be sent to the sponsor or designee. 
The investigator will be notified of any expiry date or retest date extension of sponsor-supplied 
drug during the study conduct. On expiry date notification from the sponsor or designee, the site 
must complete all instructions outlined in the notification, including segregation of expired 
sponsor-supplied drug for return to the sponsor or its designee for destruction. 


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9.0 
STUDY PLAN 
9.1 
Study Procedures 
The following sections describe the study procedures and data to be collected. For each 
procedure, subjects are to be assessed by the same investigator or site personnel whenever 
possible. The Schedule of Study Procedures is located in Appendix A. 
9.1.1 Informed Consent Procedure 
The requirements of the informed consent are described in Section 15.2. 
Informed consent must be obtained prior to the subject entering into the study, and before any 
protocol-directed procedures are performed. 
A unique subject Screening number will be assigned to each subject at the time that the informed 
consent is obtained; this Screening number will be used until the subject has been randomized 
into the study, at which time the Subject number will be primary method of identification on 
study records. 
9.1.1.1 Pharmacogenomic Informed Consent Procedure 
Pharmacogenomics informed consent is a component of the overall study informed consent. The 
requirements are described in Section 15.2. 
The pharmacogenomic sample collection is optional. 
9.1.2 Demographics, Medical History, Medication History Procedure, Reproductive 
Status 
Demographic information to be obtained will include date of birth, sex, Hispanic ethnicity, race 
as described by the subject, height, weight, caffeine consumption, and smoking status of the 
subject at Screening. 
Reproductive status will be collected including last menstrual period. 
Medical history to be obtained will include determining whether the subject has any significant 
conditions or diseases relevant to the disease under study that stopped at or prior to signing of 
informed consent. Ongoing conditions are considered concurrent medical conditions 
(see Section 9.1.7). 
Medication history information to be obtained includes any medication relevant to eligibility 
criteria stopped at or within 45 days prior to signing of informed consent. 
9.1.3 Physical Examination Procedure 
A physical examination will consist of the following body systems: (1) eyes; (2) ears, nose, 
throat; (3) cardiovascular system; (4) respiratory system; (5) gastrointestinal system; 
(6) dermatologic system; (7) extremities; (8) musculoskeletal system; (9) nervous system; 
(10) lymph nodes; and (11) other. 


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Any abnormal change from the initial Screening physical examination must be assessed by the 
investigator as not clinically significant (NCS) or clinically significant (CS) and recorded in the 
source document and eCRF. 
Any CS change, as determined by the investigator, from the baseline physical examination will 
be recorded as an AE or pretreatment event in source documentation and on the Pretreatment 
Event/AE eCRF. 
9.1.4 Weight, Height, and BMI 
A subject should have weight and height measured while wearing indoor clothing and with shoes 
off. The BMI is calculated using metric units with the formula provided below:  
The standard for collecting height is centimeters without decimal places and for weight it is 
kilograms (kg) with 1 decimal place. BMI should be derived as: 
Metric:  
BMI = weight (kg)/height (m)2 
Note that although height is measured in centimeters, the BMI formula uses meters for height; 
meters can be determined by dividing centimeters by 100. Thus, for example, if height=176 cm 
(1.76 m) and weight=79.2 kg, then BMI=79.2/1.762=25.56818 kg/m2. 
Results for BMI will be expressed with 1 decimal place and rounding is allowed. The above 
value should be captured as 25.6 kg/m2 in the database. 
9.1.5 Vital Sign Procedure  
When vital signs are scheduled at the same time as blood draws, the blood draw will take priority 
and vital signs will be obtained within 0.5 hour before or after the scheduled blood draw. Vital 
signs assessments will be collected with a window of ±15 minutes. 
Vital signs consisting of body temperature (oral), respiration rate, blood pressure and pulse will 
be measured in a seated resting state (>10 minutes). 
9.1.6 Documentation of Concomitant Medications 
Concomitant medication is any drug given in addition to the study medication. These may be 
prescribed by a physician or obtained by the subject over the counter. Concomitant medication is 
not provided by Cerevance. At each study visit, subjects will be asked whether they have taken 
any medication other than the study medication (used from signing of informed consent through 
the end of the study), and all medication including vitamin supplements, OTC medications, and 
oral herbal preparations, must be recorded in the eCRF. Documentation will include generic 
medication name, dose, unit, frequency, route of administration, start and end dates, and reason 
for use.  
9.1.7 Documentation of Concurrent Medical Conditions 
Concurrent medical conditions are those significant ongoing conditions or diseases that are 
present at signing of informed consent. This includes clinically significant laboratory, ECG, or 
physical examination abnormalities noted at the Screening examination. The condition (i.e., 
diagnosis) should be described. 


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9.1.8 Procedures for Clinical Laboratory Samples 
All samples will be collected in accordance with acceptable laboratory procedures and as 
stipulated in the Schedule of Study Procedures (Appendix A). Abnormal Screening labs may be 
repeated once at the discretion of the investigator for assessment of eligibility. Subjects who still 
do not meet eligibility criteria may be re-screened at investigator’s discretion. 
Table 9.a lists the tests that will be obtained for each laboratory specimen. Additional laboratory 
assessments may be performed at the Investigator’s discretion and entered in the database for 
Randomized Subjects only, if the results are deemed Clinically Significant by Investigator. 
Table 9.a 
Clinical Laboratory Tests 
Hematology 
Serum Chemistry 
Urinalysis 
 
RBC 
WBC with differential (% 
and absolute) 
Hemoglobin 
Hematocrit 
Platelets 
Prothrombin time 
/INR/Partial thromboplastin 
time (PTT) 
ALT 
Albumin 
Alkaline phosphatase 
AST 
Total bilirubin 
Direct bilirubin 
Total protein 
Creatinine 
Blood urea nitrogen 
Creatine kinase 
GGT 
Potassium 
Sodium 
Glucose 
Chloride 
Bicarbonate 
Calcium 
pH 
Specific gravity 
Protein 
Glucose 
Blood  
Nitrite 
Microscopic Analysis 
(only if positive dipstick 
results):  
RBC/high power field 
WBC/high power field 
Epithelial cells, casts etc 
 
Diagnostic Screening: 
Serum 
Urine 
Saliva (d) 
Serum hCG (a) 
At Screening Only:  
Hepatitis panel, including HBsAg 
and anti-HCV 
FSH (b) 
Drug screen including 
amphetamines, barbiturates, 
benzodiazepines, cannabinoids, 
cocaine, opiates, alcohol, and 
cotinine (c) 
Alcohol 
cotinine 
FSH=follicle-stimulating hormone, GGT=-glutamyl transferase, RBC=red blood cells, WBC=white blood cells. 
(a) Serum hCG pregnancy test will be done at Screening. 
(b) FSH level will be obtained for female subjects at Screening if they are postmenopausal (i.e., last regular 
menstrual cycle >2 years) and not surgically sterile. The result must be >40 IU/L to obviate the need for 
contraception.  
(c) To be performed at Screening.  
(d) Alcohol and cotinine saliva samples may be collected, if needed. 
The local laboratory will perform laboratory tests for hematology, serum chemistries, and 
urinalysis. The results of laboratory tests will be returned to the investigator, who is responsible 
for reviewing and filing these results. 


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If subjects experience ALT or AST >3 ×ULN, follow-up laboratory tests (at a minimum, serum 
alkaline phosphatase, ALT, AST, total bilirubin, GGT, and INR) should be performed within a 
maximum of 7 days and preferably within 48 to 72 hours after the abnormality was noted. 
(Please refer to Section 7.5 for discontinuation criteria, and Section 10.2.3 for the appropriate 
guidance on Reporting of Abnormal Liver Function Tests in relation to ALT or AST >3 ×ULN 
in conjunction with total bilirubin >2 ×ULN.) 
If the ALT or AST remains elevated >3 ×ULN on these 2 consecutive occasions, the investigator 
must contact the Medical Monitor for consideration of additional testing, close monitoring, 
possible discontinuation of study medication, discussion of the relevant subject details and 
possible alternative etiologies. The abnormality should be recorded as an AE (please refer to 
Section 10.2.3 Reporting of Abnormal Liver Function Tests for reporting requirements). 
All laboratory safety data will be transferred electronically to Cerevance or designee in the 
format requested by Cerevance. If the laboratory is unable to electronically transfer data, the 
study site coordinator or designee is responsible for transcribing laboratory results into the eCRF. 
The investigator will maintain a copy of the laboratory accreditation and the reference ranges for 
the laboratory used. 
Laboratory reports must be signed and dated by the PI or sub-investigator indicating that the 
report has been reviewed and any abnormalities have been assessed for clinical significance.  
All CS laboratory abnormalities must be recorded as a PTE/AE in the subject’s source 
documents and on the appropriate eCRF. A CS laboratory abnormality that has been verified by 
retesting will be followed until the abnormality returns to an acceptable level or a satisfactory 
explanation has been obtained. 
9.1.9 Contraception and Pregnancy Avoidance Procedure 
During the study and for 12 weeks after last dose of study medication, nonsterilized males and 
female subjects of childbearing potential who are sexually active must agree to use two effective 
methods of contraception.  
From signing of informed consent, throughout the duration of the study, and for 12 weeks after 
last dose of study medication, nonsterilized** male subjects who are sexually active with a 
female partner of childbearing potential* must use barrier contraception (e.g., condom with 
spermicidal cream or jelly). In addition, they must be advised not to donate sperm during this 
period.  
From signing of informed consent, throughout the duration of the study, and for 12 weeks after 
last dose of study medication, female subjects of childbearing potential* who are sexually active 
with a nonsterilized male partner** must use adequate contraception. In addition, they must be 
advised not to donate ova during this period. 


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*Females NOT of childbearing potential are defined as those who have been surgically sterilized 
(hysterectomy, bilateral oophorectomy or tubal ligation) or who are postmenopausal (e.g., 
defined as at least 2 years since last regular menses with an FSH>40 IU/L or at least 5 years 
since last regular menses, confirmed before any study medication is implemented). 
**Sterilized males should be at least 1-year post-vasectomy and have confirmed that they have 
obtained documentation of the absence of sperm in the ejaculate. 
The following are acceptable forms of contraception: 
Barrier methods (each time the subject has 
intercourse): 
Intrauterine devices (IUDs): 
 Male condom PLUS spermicide. 
 Cap (plus spermicidal cream or jelly). 
 Diaphragm (plus spermicidal cream or 
jelly). 
Hormonal Contraception (stable regimen) 
 Birth control pills or patch. 
 Injected hormonal contraceptive  
(such as Depo-Provera). 
 Vaginal hormonal ring  
(such as NuvaRing). 
 Copper T PLUS condom or spermicide. 
Subjects will be provided with information on acceptable methods of contraception as part of the 
subject informed consent process and will be asked to sign a consent form stating that they 
understand the requirements for avoidance of pregnancy, donation of ova, and sperm donation 
during the course of the study. 
During the course of the study, regular serum human chorionic gonadotropin (hCG) pregnancy 
tests will be performed only for women of childbearing potential, and subjects will receive 
guidance with respect to the avoidance of pregnancy. In addition to a negative serum hCG 
pregnancy test at Screening, subjects also must have a negative urine hCG pregnancy test prior to 
receiving any dose of study medication. Male subjects must be advised not to donate sperm from 
signing of informed consent to 12 weeks after the last dose of study medication. 
9.1.10 Pregnancy 
If any subject is found to be pregnant during the study she should be withdrawn and any sponsor-
supplied drug should be immediately discontinued. In addition, any pregnancies in the partner of 
a male subject during the study or for 12 weeks after the last dose should also be recorded 
following authorization from the subject’s partner.  


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If the pregnancy occurs during administration of active study medication, e.g., after Visit 1 or 
within 12 weeks of the last dose of active study medication, the pregnancy should be reported 
immediately, using a pregnancy notification form, to the contact listed in Section 1.0. 
Should the pregnancy occur during or after administration of blinded drug, the investigator must 
inform the subject of their right to receive treatment information. If the subject chooses to 
receive unblinded treatment information, the individual blind should be broken by the 
investigator. Subjects who have only received placebo need not be followed. 
If the female subject and/or female partner of a male subject agrees to the primary care physician 
being informed, the investigator should notify the primary care physician that the subject/female 
partner of the subject was participating in a clinical study at the time she became pregnant and 
provide details of treatment the subject received (blinded or unblinded, as applicable). 
All reported pregnancies will be followed up to final outcome, using the pregnancy form. The 
outcome, including any premature termination, must be reported to the sponsor. An evaluation 
after the birth of the child will also be conducted. 
9.1.11 ECG Procedure  
A standard 12-lead ECG will be recorded in a supine position resting for at least 10 minutes at 
Screening to assess eligibility. The ECGs will be recorded in triplicate at approximately 5-minute 
intervals, with a window of ±2 minutes. The investigator (or a qualified physician at the 
investigational site) will interpret the ECG using 1 of the following categories: within normal 
limits, abnormal but NCS, or abnormal and CS. A copy of the ECG trace should be kept with the 
subject’s notes. 
ECGs will be read automatically and also, the investigator or sub-investigator or a suitably 
qualified delegate will manually interpret the ECG using 1 of the following categories: within 
normal limits, abnormal NCS, or abnormal and CS. All 12-lead ECGs will be stored for manual 
measurement of intervals, if necessary.  
Twelve-lead ECGs will be recorded using an ECG machine that automatically calculates the 
heart rate and measures PR interval, RR interval, QRS interval, QT interval, and QTcF and 
QTcB (Fridericia’s and Bazett’s correction) intervals.  
One copy of the 12-lead ECG with the physician’s signature and date of assessment will be filed 
with the source documents and captured in the appropriate eCRF. All ECGs will be recorded at 
the time points detailed in the Schedule of Study Procedures (Appendix A). 
9.1.12 Pharmacogenomic Sample Collection 
Every subject must sign informed consent/be consented in order to participate in the study, but 
consent to participate in the pharmacogenomic sample collection (genetic substudy) is optional. 
Deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) form the basis for the genes that 
make the body produce proteins such as enzymes, drug transporters or drug targets, and may be 
evaluated for the genetic contribution how the drug is broken down, or how the drug affects the 
body. This is called a “pharmacogenomics research study.” Specific purposes of this study 
include: 


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 Identifying genetic reasons why certain people respond differently to CVN058. 
 Finding out more information about how CVN058 works. 
 Generating information needed for research, development, and regulatory approval of tests to 
predict response to CVN058. 
 Identifying variations in genes related to the biological target of CVN058. 
This information may be used, for example, to develop a better understanding of the safety and 
efficacy of CVN058 and other study medications, and for improving the efficiency, design and 
study methods of future research studies. 
The DNA samples will be used to evaluate common variations in genes which encode drug 
metabolizing enzymes and transporters. This could be helpful in understanding why there are 
differences in CVN058 kinetics between subjects. Also, since pharmacogenomics is an evolving 
science, many genes and their functions are not yet fully understood. Future data may suggest a 
role of some of these genes in drug response, which may lead to additional hypothesis-generating 
exploratory research and diagnostic development on stored samples. 
Whole blood will be collected and stored for possible DNA or RNA isolation and analysis.  
DNA sample collection: 
One 6 mL whole blood sample will be collected before study drug dosing on Day 1 of 
Period 1 only from each subject in the study, into plastic potassium ethylenediamine 
tetraacetic acid (K2EDTA) spray-coated tubes, and stored under frozen conditions.  
RNA sample collection: 
Two whole blood samples (2.5 mL per sample) will be collected from each subject into a 
PAXgene tube on Day 1 of each period at pre-dose and post EEG for RNA 
pharmacogenomic analysis.  
If isolation of DNA from the first sample was not successful or possible, a second aliquot of 
blood may be taken, if feasible. 
Each pharmacogenomic sample for a study subject should be identifiable on the requisition form 
with the 7-digit subject ID. Detailed instructions for the handling, shipping, and storage of 
pharmacogenomic samples will be provided in the lab manual.  
The samples will be stored for no longer than 15 years after completion of the CVN058 study 
and/or until the drug development of CVN058 is no longer actively pursued by Cerevance or its 
collaborators. No samples will be stored for longer than permitted by the applicable law and 
samples will be destroyed upon notification from Cerevance. 
9.1.13 Pharmacokinetic Sample Collection 
9.1.13.1 Collection of Blood for Pharmacokinetic Sampling 
Blood samples (one 6-mL sample per scheduled time) will be collected for analysis of CVN058, 
and its metabolite if appropriate; plasma will be collected into chilled vacutainers containing 


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K2EDTA according to the schedule in Appendix A. Instructions for sample processing and 
shipment will be provided in the lab manual. 
Serial blood samples for determination of CVN058, and its metabolite if appropriate, in plasma 
will be collected according to Table 9.b. 
Table 9.b 
Collection of Blood Samples for CVN058 Pharmacokinetic Analysis 
Sample 
Type 
Dosing Day 
Time Post-dose (hours) 
Plasma 
1 
Pre-dose (within 15 minutes prior to dosing), 1hour post-dose (pre-EEG), and 5 hours 
post-dose (post-EEG)   
 
The PK samples will be collected before any other assessments are performed, if scheduled at the 
same time point. The actual time of sample collection will be recorded on the source document 
and eCRF. 
Placebo samples will not be analyzed by the bioanalytical laboratory except 1 sample per subject 
receiving placebo around the expected time at which CVN058 Cmax is expected to occur to 
ensure from a safety perspective that no subjects have inadvertently received active treatment. 
9.1.13.2 Bioanalytical Methods 
Plasma concentrations of CVN058 will be measured by high-performance liquid 
chromatography with tandem mass spectrometry. If appropriate, plasma samples analyzed for 
CVN058 also may be analyzed for the CVN058 metabolite. 
9.1.14 Pharmacokinetic Parameters  
The PK parameters of CVN058, and its metabolite (if appropriate), will be derived using non-
compartmental analysis methods. The PK parameters will be determined from the concentration-
time data for all evaluable subjects. Actual sampling times, rather than scheduled sampling 
times, will be used in all computations involving sampling times. The following PK parameters 
will be determined from concentrations of CVN058, and its metabolite if appropriate, in plasma. 
Other parameters may be calculated as appropriate.  
Symbol/Term 
Definition 
Plasma 
AUCt 
Area under the plasma concentration-time curve from time 0 to 5 hours post dose. 
Cmax 
Maximum observed plasma concentration. 
tmax 
Time to reach Cmax. 
 
9.1.15 Pharmacodynamic Sample Collection  
MMN will be used as a PD assessment. At each testing session, the following PD assessments 
will be performed during the EEG: MMN, P50, gamma power, and P300. Collection of P50 may 
be omitted if the essential equipment is not available. The testing session during each Treatment 
Period will begin approximately 1.5 hours after administration of study drug.  


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9.1.16 Pharmacodynamic Parameters  
All EEG parameters will be obtained in accordance with the EEG acquisition guideline provided 
by Cerevance or their designee. It is anticipated that each EEG procedure will take 
approximately 4 hours to complete, including approximately 30 minutes to set up, 3 hours 
acquisition time, and 30 minutes to clean up. 
MMN 
MMN is a pre-attentive auditory component elicited by deviant stimuli in an auditory oddball 
task. MMN predominantly reflects activation of neuronal ensembles within primary auditory 
cortex, and thus indexes sensory level disturbance in schizophrenia. MMN will be obtained 
independently to pitch and duration deviant stimuli. MMN is maximal at frontocentral electrodes 
(Fz, Cz). Mean peak amplitude at 5 electrodes surrounding Fz within a predefined latency range 
will be the primary outcome measure. 
P50 
P50 auditory evoked potentials will be recorded. Participants will be seated and instructed to 
relax and to focus their eyes on a fixation point. Stimulus signal of 90-dB pulses of 0.1 msec in 
duration will be generated and recorded the event-related potential waveforms.  
32 pairs of auditory clicks will be presented every 10 seconds, with a 500 msec interclick 
interval. 
 
Quantitative Electroencephalogram, Gamma Power 
Five-minute eyes open/close recordings will be obtained during each recording session. Ten 1-
second, artifact-free epochs will be chosen for quantitative analysis. Primary outcome measures 
will consist of power within delta (0.5 – 4 Hz), theta (4-7 Hz), alpha (8-13 Hz), beta (13-20 Hz), 
low gamma (20-40 Hz) and high gamma (40 – 60 Hz) over predesignated frontal, central, 
temporal and occipital sites. In addition, specific measures of 40 Hz activity will be assessed in 
response to repetitive 40 Hz auditory stimulation. 
P300 
As opposed to MMN, which are obtained under passive (i.e., no-task) conditions, auditory P300 
will be obtained only when subjects must attend to and detect novel task-relevant deviant stimuli. 
Generators for P300 are located in distributed frontoparietal networks and so represent an index 
of higher order, “cognitive” processing in schizophrenia. P300 will be obtained to deviant 
auditory stimuli in an auditory “oddball” paradigm. P300 is maximal in amplitude at Fz and Pz 


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electrodes. Primary outcome measures will consist of peak amplitude within prespecified latency 
range at the frontal/parietal sites. 
9.1.17 Positive and Negative Syndrome Scale 
The PANSS was developed and standardized for typological and dimensional assessment of 
schizophrenic phenomena. In this study, empirically derived factors are tested excluding those 
items that could not be assessed during the test sessions: positive symptom factor (delusions, 
unusual thoughts, somatic concern, grandiosity, suspiciousness, and hallucinations), negative 
symptom factor (emotional withdrawal, blunted affect, poor rapport, disturbance of volition, 
preoccupation, and motor retardation), cognitive factor (difficulty in abstract thinking, 
stereotyped thinking, cognitive disorganization, lack of judgment and insight, poor attention, 
tension, mannerisms, and posturing), hostility (excitement, hostility, impulse control, and 
uncooperativeness), emotional discomfort (depression, anxiety, and guilt). PANSS will be 
collected at Screening, Early Termination, and at the Follow-up Visit if clinically significant 
findings were observed upon discharge. In these cases, subjects must then be brought back to the 
clinic for re-evaluation per investigator’s discretion.  
The duration of the PANSS is approximately 30 minutes (Kay, 1990). 
9.1.18 Columbia Suicide Severity Rating Scale 
The determination and management of subjects’ suicidality risk is the Investigators’ 
responsibility. For study purposes, suicidality will be assessed by the use of the C-SSRS. The C-
SSRS is a 3-part scale that measures suicidal ideation (e.g., subject endorses thoughts about a 
wish to be dead or has other thoughts of suicide), intensity of ideation (frequency, duration, 
controllability, deterrents, and reasons for ideation), and suicidal behavior (actually, interrupted, 
and aborted attempts at suicide) (Mundt, 2013). 
The C-SSRS is a 2-page questionnaire that prospectively assesses suicidal thoughts and behavior 
using a structured interview for patient responses. Suicidal ideation is classified on a 5-item 
scale: 1 (wish to be dead), 2 (nonspecific active suicidal thoughts), 3 (active suicidal ideation 
with any methods [not plan] without intent to act), 4 (active suicidal ideation with some intent to 
act, without specific plan), and 5 (active suicidal ideation with specific plan and intent). The C-
SSRS also captures information about the intensity of ideation, specifically the frequency, 
duration, controllability, deterrents, and reasons for the most severe types of ideation. Suicidal 
behavior is classified on a 5-item scale: 0 (no suicidal behavior), 1 (preparatory acts or behavior), 
2 (aborted attempt), 3 (interrupted attempt), and 4 (actual attempt). 
Different versions of the scale are available. In this study, “Baseline/Screening” version will be 
used at Screening Visit and “Since last visit” version at all subsequent visits. “Since the last 
visit” should collect information from the last visit where C-SSRS was administered. If the 
patient’s response generates a change in the findings report from negative to positive, the patient 
should be referred for immediate psychiatric evaluation on the same date as the site visit. 
Positive suicidality findings, if confirmed by the PI, is considered to be a serious event. If arising 
after signing informed consent but prior to administration of any study medication, it is 
considered a Pretreatment Event (PTE). If arising after administration of any study medication, it 
is considered an SAE.  


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The C-SSRS will be administered by the PI or a trained designee on paper and captured in the 
eCRF. The same interviewer should be used throughout the study for the same subject where 
possible. 
9.1.19 Documentation of Screen Failure 
Investigators must account for all subjects who sign informed consent. If the subject is found to 
be not eligible at this visit, the investigator should complete the eCRF screen failure form. 
The primary reason for screen failure is recorded in the eCRF using the following categories: 
 PTE/AE. 
 Did not meet inclusion criteria or did meet exclusion criteria. 
 Significant protocol deviation. 
 Lost to follow-up. 
 Voluntary withdrawal. 
 Study termination. 
 Other <specify reason>. 
Subject numbers assigned to subjects who fail Screening should not be reused. 
9.1.20 Documentation of Randomization 
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible 
for randomization into the treatment phase. Randomization will take place on Day 1 of 
Treatment Period 1. 
If the subject is found to be not eligible for randomization, the investigator should record the 
primary reason for failure on the applicable eCRF. 
9.2 
Monitoring Subject Treatment Compliance 
Study medication will be administered while subjects are under observation in the clinical 
research unit. Following administration of the study medication, appropriate mouth and/or hand 
checks will be performed to ensure that the dose is swallowed and noted in the source document. 
The date and time of each dose will be recorded in the source documents and on the eCRFs. An 
inventory of the study medication supplies dispensed will be performed by the site pharmacist or 
authorized study designee and recorded onto the Drug Accountability Log in the subject’s source 
document records or equivalent. The exact dose time of consecutive subjects may be staggered to 
facilitate logistics at the site. 
9.3 
Schedule of Observations and Procedures 
The schedule for all study-related procedures for all evaluations is shown in Appendix A. 
Assessments should be completed at the designated visit/time point(s). 


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9.3.1 Screening 
Subjects with schizophrenia including schizoaffective disorder will be screened within 28 days 
prior to enrollment. All subjects will be screened in accordance with predefined inclusion and 
exclusion criteria as described in Section 7.0. See Section 9.1.17 for procedures for documenting 
screen failures.  Following written informed consent, Screening procedures may be conducted on 
different days. Assessments to be conducted during the Screening period are outlined in 
Appendix A. 
9.3.2 Treatment Phase 
The treatment will be administered over 3 Periods, separated by 7-10 days for washout.  
Assessments to be conducted during the screening period are outlined in Appendix A. 
9.3.3 Final Visit/End of Treatment  
The Final Visit additional assessments will occur prior to Discharge from the clinic at the end of 
Treatment Period 3, Day 1, as outlined in Appendix A. 
For all subjects who received any study medication, the investigator must complete the End of 
Study eCRF page. 
9.3.4 Early Termination 
The reason for discontinuation must be documented in the source document and eCRF. The 
procedures outlined in Appendix A will be performed and documented. 
For all subjects receiving study medication, the investigator must complete the End of Study 
eCRF page. 
9.3.5 Follow-up Visit/Telephone Call  
The Follow-up Visit will occur by telephone approximately 7-10 days after receiving the last 
dose of study medication (Treatment Period 3) unless abnormal, clinically significant findings 
were observed upon discharge. In these cases, subjects must then be brought back to the clinic 
for re-evaluation per investigator’s discretion. 
9.4 
Biological Sample Retention and Destruction  
In this study, specimens for genome/gene analysis will be collected as described in Section 
9.1.12, Pharmacogenomic Sample Collection. The genetic material will be preserved and 
retained by a biorepository contracted by Cerevance for up to but not longer than 15 years or as 
required by applicable law.  
The samples will be sent to a central laboratory that processes the blood sample and serves as a 
secure storage facility. The sponsor and researchers working with the sponsor will have access to 
the samples collected and any test results. All samples collected during the study will be stored 
securely with limited access and the sponsor will require anyone who works with the samples to 
agree to hold the research information and any results in confidence. 


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The sample will be labeled with a unique sample identifier similar to labeling in the main study. 
During the “storage” stage, the sample will be used in the analysis of the study drug and related 
disease states. At this stage, sample and data are linked to personal health information with code 
numbers. This link means that subjects may be identifiable but only indirectly. The code 
numbers will be kept secure by the sponsor.  
Subjects who consented and provided a pharmacogenomic sample for DNA and RNA analysis 
can withdraw their consent and request disposal of a stored sample at any time prior to analysis. 
Notify sponsor of consent withdrawal. 
9.5 
Blood Volume 
Total blood sampling volume for an individual subject is shown in Table 9.c. 
Table 9.c 
Approximate Blood Volume 
Sample Type 
Sample 
Volume 
(mL) 
Screening  
(x1) 
 
Number of Samples per 
Period  
(x 3 Periods) 
End of 
Treatment 
Total 
Volume 
(mL) 
Safety 
Laboratory 
Samples (a) 
12.5 
1 
-- 
1 
25 
Hepatitis Panel 
5 
1 
-- 
 
5 
FSH (b) 
3 
1 
-- 
 
3 
PK Samples 
6 
-- 
9 
-- 
54 
DNA Sample 
6 
-- 
1 (c) 
-- 
6 
RNA Samples 
5 
-- 
6 
-- 
30 
 
Total Blood Sampling Volume (per Study) 
 
123 
(a) Includes Hematology, serum chemistry, and coagulation panel. 
(b) FSH level will be obtained for female subjects at Screening if they are postmenopausal (i.e. last regular 
menstrual cycle >2 years) and not surgically sterile. 
(c) Only collected in Day 1, Period 1. 
 
The maximum volume of blood at any single day is approximately 40 mL, and the approximate 
total volume of blood for the study is approximately 123 mL.  
Direct venipuncture is the preferred method of blood collection. Any other method will need to 
be approved by the Sponsor. 


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10.0 
PRETREATMENT EVENTS AND ADVERSE EVENTS 
10.1 
Definitions 
10.1.1 PTEs 
A PTE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study but prior to administration of any study 
medication; it does not necessarily have to have a causal relationship with study participation. 
10.1.2 AEs 
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a drug; it does not necessarily have to have a causal relationship with this 
treatment. 
An AE can therefore be any unfavorable and unintended sign (e.g., a clinically significant 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug 
whether or not it is considered related to the drug. 
10.1.3 Additional Points to Consider for PTEs and AEs 
An untoward finding generally may: 
 Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent 
events for pre-existing conditions or underlying disease should not be considered PTEs or 
AEs.) 
 Necessitate therapeutic intervention. 
 Require an invasive diagnostic procedure. 
 Require discontinuation or a change in dose of study medication or a concomitant 
medication. 
 Be considered unfavorable by the investigator for any reason.  
 PTEs/AEs caused by a study procedure (e.g., a bruise after blood draw) should be recorded 
as a PTE/AE. 
Diagnoses vs signs and symptoms: 
 Each event should be recorded to represent a single diagnosis. Accompanying signs 
(including abnormal laboratory values or ECG findings) or symptoms should NOT be 
recorded as additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be 
recorded appropriately as a PTE(s) or as an AE(s). 
Laboratory values and ECG findings: 
 Changes in laboratory values or ECG parameters are only considered to be PTEs or AEs if 
they are judged to be clinically significant (i.e., if some action or intervention is required or if 
the investigator judges the change to be beyond the range of normal physiologic fluctuation). 
A laboratory re-test and/or continued monitoring of an abnormal value are not considered an 


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intervention. In addition, repeated or additional noninvasive testing for verification, 
evaluation or monitoring of an abnormality is not considered an intervention. 
 If abnormal laboratory values or ECG findings are the result of pathology for which there is 
an overall diagnosis (e.g., increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as a PTE or as an AE. 
Pre-existing conditions: 
 Pre-existing conditions (present at the time of signing of informed consent) are considered 
concurrent medical conditions and should NOT be recorded as PTEs or AEs. Baseline 
evaluations (e.g., laboratory tests, ECG, X-rays etc.) should NOT be recorded as PTEs unless 
related to study procedures. However, if the subject experiences a worsening or complication 
of such a concurrent condition, the worsening or complication should be recorded 
appropriately as a PTE (worsening or complication occurs before start of study medication) 
or an AE (worsening or complication occurs after start of study medication). Investigators 
should ensure that the event term recorded captures the change in the condition (e.g., 
“worsening of…”). 
 If a subject has a pre-existing episodic condition (e.g., asthma, epilepsy) any occurrence of an 
episode should only be captured as a PTE/AE if the episodes become more frequent, serious 
or severe in nature, that is, investigators should ensure that the AE term recorded captures the 
change in the condition from Baseline (e.g. “worsening of…”). 
 If a subject has a degenerative concurrent condition (e.g., cataracts, rheumatoid arthritis), 
worsening of the condition should only be captured as a PTE/AE if occurring to a greater 
extent to that which would be expected. Again, investigators should ensure that the AE term 
recorded captures the change in the condition (e.g., “worsening of…”). 
Worsening of PTEs or AEs: 
 If the subject experiences a worsening or complication of a PTE after starting administration 
of the study medication, the worsening or complication should be recorded appropriately as 
an AE. Investigators should ensure that the AE term recorded captures the change in the 
condition (e.g., “worsening of…”). 
 If the subject experiences a worsening or complication of an AE after any change in study 
medication, the worsening or complication should be recorded as a new AE. Investigators 
should ensure that the AE term recorded captures the change in the condition (e.g., 
“worsening of…”). 
Changes in severity of AEs /Serious PTEs: 
 If the subject experiences changes in severity of an AE/serious PTE, the event should be 
captured once with the maximum severity recorded. 
Preplanned surgeries or procedures: 
 Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered PTEs or AEs. However, if a preplanned procedure is 
performed early (e.g., as an emergency) due to a worsening of the pre-existing condition, the 


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worsening of the condition should be captured appropriately as a PTE or an AE. 
Complications resulting from any planned surgery should be reported as AEs. 
Elective surgeries or procedures: 
 Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as PTEs or AEs, but should be documented in the subject’s source 
documents. Complications resulting from an elective surgery should be reported as AEs. 
Overdose: 
 Cases of overdose with any medication without manifested side effects are NOT considered 
PTEs or AEs, but instead will be documented on an Overdose page of the eCRF. Any 
manifested side effects will be considered PTEs or AEs and will be recorded on the AE page 
of the eCRF. 
 Suicidal Ideation and Behavior:  
 A completed suicide is always a SAE based on its fatal outcome. C-SSRS score of 4 (active 
suicidal ideation with some intent to act) or 5 (active suicidal ideation with specific plan and 
intent) would likely indicate serious suicidal ideation and can be used to trigger intervention 
procedures to provide urgent care. Such procedures may include further evaluation and 
appropriate management; and/or immediate contact with (or need for a referral to) the 
subject’s mental health practitioner; and/or possible referral to the emergency room; and/or 
admission to an in-subject unit. For the purpose of this protocol active suicidal ideation level 
4 and 5 should be considered important medical events and reported as serious irrespective of 
whether the subject was hospitalized or not.  
 Unless the event meets other serious criteria, suicidal thoughts or suicidal ideations that do 
not include a definite plan or intention to act will be collected as non-serious adverse events 
in accordance with the standard AE reporting requirements (e.g., if a pre-existing suicidal 
ideation recorded on the screening C-SSRS got worse during the study, it should be reported 
as an AE).  
 A subject presenting with self-mutilation or other types of self-injury should be questioned 
by the investigator to clarify if the action was suicidal in intent. If the event was suicidal in 
intent, the investigator should include suicidal behavior as part of the verbatim term on the 
eCRF, that is, “slit wrists/suicidal behavior”. Such an event will be collected as a serious 
adverse event.  
 Acts of self-mutilation or self-injury without suicidal intention (i.e., self-imposed cigarette 
burns), will be collected as non-serious adverse events, unless they meet other seriousness 
criteria.  
10.1.4 SAEs 
An SAE is defined as any untoward medical occurrence that at any dose: 
1. Results in DEATH. 
2. Is LIFE THREATENING. 


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 The term “life threatening” refers to an event in which the subject was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have caused 
death if it were more severe. 
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization. 
4. Results in persistent or significant DISABILITY/INCAPACITY. 
5. Is a CONGENITAL ANOMALY/BIRTH DEFECT. 
 Report if you suspect that exposure to a medical product prior to conception or during 
pregnancy may have resulted in an adverse outcome in the child. 
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following: 
 May require intervention to prevent items 1 through 5 above. 
 May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization. 
 Includes any event or synonym described in the Medically Significant AE List 
(Table 10.a). 
Table 10.a 
Medically Significant AE List 
Term 
Acute respiratory failure/acute respiratory distress 
syndrome 
Hepatic necrosis 
Torsade de pointes / ventricular fibrillation / ventricular 
tachycardia 
Acute liver failure 
Anaphylactic shock 
Malignant hypertension 
Acute renal failure 
Convulsive seizure 
Pulmonary hypertension 
Agranulocytosis 
Pulmonary fibrosis 
Aplastic anemia 
Confirmed or suspected endotoxin shock 
Toxic epidermal necrolysis/Stevens-Johnson syndrome Confirmed or suspected transmission of infectious agent by 
a medicinal product 
 
Serotonin syndrome 
Neuroleptic malignant syndrome / malignant hyperthermia 
 
Spontaneous abortion / stillbirth and fetal death 
 
PTEs that fulfill 1 or more of the serious criteria above are also to be considered SAEs and 
should be reported and followed up in the same manner (see Sections 10.2.2 and 10.3). 
10.1.5 Severity of PTEs and AEs 
The different categories of intensity (severity) are characterized as follows: 
Mild: 
The event is transient and easily tolerated by the subject. 
Moderate: 
The event causes the subject discomfort and interrupts the subject’s usual activities. 
Severe: 
The event causes considerable interference with the subject’s usual activities. 


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10.1.6 Causality of AEs 
The relationship of each AE to study medication(s) will be assessed using the following 
categories: 
Related: 
An AE that follows a reasonable temporal sequence from administration of a drug (including 
the course after withdrawal of the drug), or for which possible involvement of the drug cannot 
be ruled out, although factors other than the drug, such as underlying diseases, complications, 
concomitant drugs and concurrent treatments, may also be responsible. 
Not Related: 
An AE that does not follow a reasonable temporal sequence from administration of a drug 
and/or that can reasonably be explained by other factors, such as underlying diseases, 
complications, concomitant drugs and concurrent treatments. 
10.1.7 Relationship to Study Procedures 
Relationship (causality) to study procedures should be determined for all PTEs and AEs. 
The relationship should be assessed as Related if the investigator considers that there is 
reasonable possibility that an event is due to a study procedure. Otherwise, the relationship 
should be assessed as Not Related. 
10.1.8 Start Date 
The start date of the AE/PTE is the date that the first signs/symptoms were noted by the subject 
and/or physician. 
10.1.9 
Stop Date  
The stop date of the AE/PTE is the date at which the subject recovered, the event resolved but 
with sequelae or the subject died. 
10.1.10 Frequency  
Episodic AEs/PTE (e.g., vomiting) or those which occur repeatedly over a period of consecutive 
days are intermittent. All other events are continuous. 
10.1.11 Action Concerning Study Medication  
 Drug withdrawn – a study medication is stopped due to the particular AE. 
 Dose not changed – the particular AE did not require stopping a study medication. 
 Unknown – only to be used if it has not been possible to determine what action has been 
taken. 
 Not Applicable – a study medication was stopped for a reason other than the particular AE 
(e.g., the study has been terminated, the subject died, dosing with study medication was 
already stopped before the onset of the AE). 
10.1.12 Outcome 
 Recovered/Resolved – Subject returned to first assessment status with respect to the AE/PTE. 


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 Recovering/Resolving – the intensity is lowered by one or more stages: the diagnosis or 
signs/symptoms has almost disappeared; the abnormal laboratory value improved, but has not 
returned to the normal range or to Baseline; the subject died from a cause other than the 
particular AE/PTE with the condition remaining “recovering/resolving”. 
 Not recovered/not resolved – there is no change in the diagnosis, signs or symptoms; the 
intensity of the diagnosis, signs/ symptoms or laboratory value on the last day of the 
observed study period has got worse than when it started; is an irreversible congenital 
anomaly; the subject died from another cause with the particular AE/PTE state remaining 
“Not recovered/not resolved”. 
 Resolved with sequelae – the subject recovered from an acute AE/PTE but was left with 
permanent/significant impairment (e.g., recovered from a cardiovascular accident but with 
some persisting paresis). 
 Fatal – the AEs/PTEs which are considered as the cause of death. 
 Unknown – the course of the AE/PTE cannot be followed up due to hospital change or 
residence change at the end of the subject’s participation in the study. 
10.2 
Procedures 
10.2.1 Collection and Reporting of AEs 
10.2.1.1 PTE and AE Collection Period 
Collection of PTEs will commence from the time the subject signs the informed consent to 
participate in the study and continue until the subject is first administered study medication on 
Day 1 Period 1 or until screen failure. For subjects who discontinue prior to study medication 
administration, PTEs are collected until the subject discontinues study participation. 
Collection of AEs will commence from the time that the subject is first administered study 
medication Day 1 Treatment Period 1. Routine collection of AEs will continue until 21 days 
following last dose. 
10.2.1.2 PTE and AE Reporting 
At each study visit, the investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Subjects may report AEs occurring at any other time during the study. Subjects experiencing a 
serious PTE must be monitored until the symptoms subside and any clinically relevant changes 
in laboratory values have returned to Baseline or there is a satisfactory explanation for the 
change. Non-serious PTEs, related or unrelated to the study procedure, need not to be followed-
up for the purposes of the protocol. 
All subjects experiencing AEs, whether considered associated with the use of the study 
medication or not, must be monitored until the symptoms subside and any clinically relevant 
changes in laboratory values have returned to Baseline or until there is a satisfactory explanation 
for the changes observed. All PTEs and AEs will be documented in the PTE/AE page of the 


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eCRF, whether or not the investigator concludes that the event is related to the drug treatment. 
The following information will be documented for each event: 
1. Event term. 
2. Start and stop date. 
3. Frequency. 
4. Severity. 
5. Investigator’s opinion of the causal relationship between the event and administration of 
study medication(s) (related or not related) (not completed for PTEs). 
6. Investigator’s opinion of the causal relationship to study procedure(s), including the details 
of the suspected procedure. 
7. Action concerning study medication (not applicable for PTEs). 
8. Outcome of event. 
9. Seriousness. 
10.2.2 Collection and Reporting of SAEs 
When an SAE occurs through the AE collection period it should be reported according to the 
following procedure: 
A Cerevance SAE form must be completed, in English, and signed by the investigator 
immediately or within 24 hours of first onset or notification of the event. The information should 
be completed as fully as possible but contain, at a minimum: 
 A short description of the event and the reason why the event is categorized as serious. 
 Subject identification number. 
 Investigator’s name. 
 Name of the study medication(s). 
 Causality assessment. 
The SAE form should be transmitted within 24 hours to the attention of the contact listed in 
Section 1.0.  
Any SAE spontaneously reported to the investigator following the AE collection period should 
be reported to the sponsor if considered related to study participation. 
Reporting of Serious PTEs will follow the procedure described for SAEs. 
10.2.3 Reporting of Abnormal Liver Function Tests 
If a subject is noted to have ALT or AST elevated >3 ×ULN on 2 consecutive occasions, the 
abnormality should be recorded as an AE. In addition, an LFT Increases eCRF must be 
completed providing additional information on relevant recent history, risk factors, clinical signs 
and symptoms and results of any additional diagnostic tests performed. 


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If a subject is noted to have ALT or AST >3 ×ULN and total bilirubin >2 ×ULN for which an 
alternative etiology has not been identified, the event should be recorded as an SAE and reported 
as per Section 10.2.2. The investigator must contact the Medical Monitor for discussion of the 
relevant subject details and possible alternative etiologies, such as acute viral hepatitis A or B or 
other acute liver disease or medical history/concurrent medical conditions. Follow-up laboratory 
tests as described in Section 9.1.8 must also be performed. In addition, an LFT Increases eCRF 
must be completed and transmitted with the Cerevance SAE form (as per Section 10.2.2). 
10.3 
Follow-up of SAEs 
If information is not available at the time of the first report, but becomes available at a later date, 
the investigator should complete a follow-up SAE form or provide other written documentation 
and fax it immediately within 24 hours of receipt. Copies of any relevant data from the hospital 
notes (e.g., ECGs, laboratory tests, discharge summary, postmortem results) should be sent to the 
addressee, if requested. 
All SAEs should be followed up until resolution or permanent outcome of the event. The 
timelines and procedure for follow-up reports are the same as those for the initial report. 
10.3.1 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities  
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, including the European 
Medicines Agency (EMA), investigators and IRBs or IECs, as applicable, in accordance with 
national regulations in the countries where the study is conducted. Relative to the first awareness 
of the event by/or further provision to the sponsor or sponsor’s designee, SUSARs will be 
submitted to the regulatory authorities as expedited report within 7 days for fatal and life-
threatening events and 15 days for other serious events, unless otherwise required by national 
regulations. The sponsor will also prepare an expedited report for other safety issues where these 
might materially alter the current benefit-risk assessment of an investigational medicinal product 
or that would be sufficient to consider changes in the investigational medicinal products 
administration or in the overall conduct of the trial. The investigational site also will forward a 
copy of all expedited reports to his or her IRB or IEC in accordance with national regulations. 


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11.0 
STUDY-SPECIFIC COMMITTEES 
No steering committee, data safety monitoring committee, or clinical endpoint committee will be 
used in this study. 


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12.0 
DATA HANDLING AND RECORDKEEPING 
The full details of procedures for data handling will be documented in the Data Management 
Plan. AEs, PTEs, medical history, and concurrent conditions will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the World Health 
Organization Drug Dictionary (WHODRUG). 
12.1 
CRFs (Electronic) 
Completed eCRFs are required for each subject who signs an informed consent. 
The sponsor or its designee will supply investigative sites with access to eCRFs. The sponsor 
will make arrangements to train appropriate site staff in the use of the eCRFs. These forms are 
used to transmit the information collected in the performance of this study to the sponsor and 
regulatory authorities. eCRFs must be completed in English. 
After completion of the entry process, computer logic checks will be run to identify items, such 
as inconsistent dates, missing data, and questionable values. Queries may be issued by Cerevance 
personnel (or designees) and will be answered by the site.  
Corrections to eCRFs are recorded in an audit trail that captures the old information, the new 
information, identification of the person making the correction, the date the correction was made, 
and the reason for change. Reasons for significant corrections should additionally be included. 
The PI must review the eCRFs for completeness and accuracy and must sign and date the 
appropriate eCRFs as indicated. Furthermore, the investigator must retain full responsibility for 
the accuracy and authenticity of all data entered on the eCRFs. 
After the lock of the clinical study database, any change of, modification of or addition to the 
data on the eCRFs should be made by the investigator with use of change and modification 
records of the eCRFs. The principle investigator must review the data change for completeness 
and accuracy, and must sign, and date. 
The eCRFs will be reviewed for completeness and acceptability at the study site during periodic 
visits by study monitors. The sponsor or its designee will be permitted to review the subject’s 
medical and hospital records pertinent to the study to ensure accuracy of the eCRFs. The 
completed eCRFs are the sole property of the sponsor and should not be made available in any 
form to third parties, except for authorized representatives of appropriate governmental health or 
regulatory authorities, without written permission of the sponsor. 
12.2 
Record Retention 
The investigator agrees to keep the records stipulated in Section 12.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated informed consent forms, subject authorization forms 
regarding the use of personal health information (if separate from the informed consent forms), 
electronic copy of eCRFs, including the audit trail, and detailed records of drug disposition to 
enable evaluations or audits from regulatory authorities, the sponsor or its designees. Any source 
documentation printed on degradable thermal sensitive paper should be photocopied by the site 


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and filed with the original in the subject’s chart to ensure long-term legibility. Furthermore, 
International Conference on Harmonisation (ICH) E6 Section 4.9.5 requires the investigator to 
retain essential documents specified in ICH E6 (Section 8) until at least 2 years after the last 
approval of a marketing application for a specified drug indication being investigated or, if an 
application is not approved, until at least 2 years after the investigation is discontinued and 
regulatory authorities are notified. In addition, ICH E6 Section 4.9.5 states that the study records 
should be retained until an amount of time specified by applicable regulatory requirements or for 
a time specified in the Clinical Study Site Agreement between the investigator and sponsor. 
Refer to the Phase 1 Site Specifications document for the sponsor’s requirements on record 
retention. The investigator should contact and receive written approval from the sponsor before 
disposing of any such documents. 


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13.0 
STATISTICAL METHODS 
13.1 
Statistical and Analytical Plans 
A statistical analysis plan (SAP) will be prepared to describe and direct study data analyses. The 
SAP will provide details regarding the definition of analysis variables and analysis methodology 
to address all study objectives, and will be finalized prior to data analysis. 
A targeted data review will be conducted prior to database lock. This review will assess the 
accuracy and completeness of the study database, subject evaluability, and appropriateness of the 
planned statistical methods. 
13.1.1 Blinded Interim Analysis 
The original study SAP describes a blinded interim analysis and sample size re-assessment to 
occur when blinded MMN data from all 3 periods are available for 12 subjects, or when 20 
subjects have been dosed and are expected to complete the study, whichever is sooner. An 
analysis structured identically to the Primary Analysis but blinded to treatment, will be 
performed. For this interim analysis, the MMN negative values closest to zero (i.e., most 
impaired) and the negative values farthest from zero (i.e., least impaired) for each subject will be 
selected and compared. This analysis will utilize the O’Brien-Fleming group-sequential stopping 
boundary to control alpha. SAS Proc SEQTEST will be employed to perform the conditional 
power analysis for one interim analysis.  Study stoppage for futility may occur if conditional 
power is very low. 
Additionally, prior to study stoppage, an assessment will be performed to calculate the 
conditional power values associated with protocol-permissible increases in the sample size (i.e., 
up to N=40), based on the observed blinded data at the time of the interim analysis 
13.1.2 Unblinded Interim Analysis 
During the study, upon review of the outputs from the blinded interim analysis (which included 
data only from the first 12 subjects, who had already completed the study), the Sponsor 
determined that an unblinded analysis of those interim data is necessary to properly inform 
decisions about study continuation and dose selection. Unblinding of the interim analysis data is 
thus introduced in Protocol Amendment 4, and the SAP will be modified accordingly and 
finalized prior to the unblinded interim analysis.  
An analysis unblinded to treatment and structured identically to the Primary Analysis will be 
performed using data only from the first 12 subjects, who have already completed the study. The 
analysis will consist of a comparison of the post dose PD parameter Mean Amplitude of 
Duration MMN versus the same parameter at time-matched placebo period timepoints. This 
analysis will utilize the O’Brien-Fleming group-sequential stopping boundary to control alpha. 
SAS Proc SEQTEST will be employed to perform the conditional power analysis.  Study 
stoppage for futility may occur if conditional power is very low. 
Additionally, prior to study stoppage, the unblinded interim data will be used to calculate the 
conditional power values associated with protocol-permissible increases in the sample size (i.e., 
up to N=40), based on the observed unblinded data at the time of the interim analysis. 


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13.1.3 Analysis Sets 
Safety Set 
The Safety Set will consist of all subjects who are randomized and receive study drug. Subjects 
in this analysis set will be used for demographic, baseline characteristics and safety summaries. 
Pharmacokinetic Set 
The PK Set will consist of all subjects who receive study drug and have at least 1 measurable 
plasma concentration of CVN058. 
Pharmacodynamic Set 
The PD Set will consist of all subjects who receive study drug and have at least 1 post-dose PD 
measurement. 
If any subjects are found to be noncompliant in dosing schedule or with incomplete data, a 
decision will be made on a case-by-case basis as to their inclusion in the PK and PD endpoint 
analyses, but data for all subjects will be presented in the subject listings. 
13.1.4 Analysis of Demographics and Other Baseline Characteristics 
Demographic and baseline characteristics will be summarized by sequence and overall. 
Summary statistics (number of subjects, mean, median, standard deviation, minimum and 
maximum) will be generated for continuous variables (e.g., age and weight) and the number and 
percentage of subjects within each category will be presented for categorical variables (e.g., 
gender, ethnicity, race, smoking status, and caffeine consumption). 
13.1.5 Pharmacokinetic Analysis 
The concentration of CVN058, and its metabolite if appropriate, in plasma will be summarized 
over each scheduled sampling interval using descriptive statistics (arithmetic mean, SD, median, 
minimum and maximum). Individual plasma concentration data versus time will be presented in 
a data listing. 
Descriptive statistics will be used to summarize the plasma PK parameters for CVN058, and its 
metabolite if appropriate. In addition, geometric mean and percent coefficient of variation will be 
computed for Cmax and AUCt. 
A more detailed analysis will be presented in the SAP. 
13.1.6 Pharmacodynamic Analysis  
Observed values for the PD parameters (MMN and exploratory PD parameters) will be 
summarized by treatment and compared to placebo using summary statistics. Comparison of 
post-dose PD parameters from a time-matched placebo period timepoint will be analyzed using 
analysis of covariance (ANCOVA) with factors for sequence, subject nested within sequence, 
period, and treatment. Two-sided 95% confidence intervals will be constructed for the LS mean 
of observed differences in PD parameters, comparing CVN058 and placebo at a time-matched 
post-dose time point. 


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Effect size will be calculated for comparisons of CVN058 to placebo using Cohen’s d which 
expresses the difference between the means of 2 groups as a function of their pooled standard 
deviation. 
Exposure-response relationships for CVN058 will be explored graphically. 
13.1.7 Safety Analysis 
The Safety Set will be used for all summaries of TEAEs, laboratory tests, and vital signs. An 
increase in weight by 7% should be indicated as Clinically Significant or Not Clinically 
Significant and assessed on a case by case basis. All safety data will be summarized by 
treatment. 
AEs will be presented in listings. TEAEs will be classified according to system organ class and 
preferred term and will be tabulated with a breakdown by treatment and by event severity. 
Similar TEAE tabulations will be performed on those events assessed by the investigator as 
related to study drug. 
Individual results of vital signs will be listed and observed values and changes from Baseline in 
vital signs will be summarized by treatment. 
Physical exam findings, suicidality assessments (C-SSRS), and PANSS scores will be presented 
in data listings. 
Baseline values will be the latest observation prior to dosing in the first study period. Thus, for 
most assessments, the Baseline value will be the Day 1 pre-dose observation; for Clinical 
Laboratory assessments, the Baseline values will be from the Screening Visit (Day -28). 
13.2 
Determination of Sample Size 
Enrollment of 20 subjects with schizophrenia is estimated to provide approximately 80% power 
to detect a mean effect size of Cohen’s d=0.5 with an error rate of alpha=0.10.  Discontinued or 
withdrawn subjects and subjects for whom MMN is not available for all three study periods may 
be replaced. The sample size chosen of 20 completed subjects is considered to be sufficient to 
explore the changes in MMN between CVN058 and placebo as well as safety and tolerability of 
CVN058 in this population. 
Sample size re-estimation may occur when MMN data from all 3 periods are available for 12 
subjects, or when 20 subjects have been dosed and are expected to complete the study, 
whichever is sooner. To ensure adequate study power, sample size may be increased based on 
this re-estimation procedure.  Further details will be included in the SAP.   


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14.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
14.1 
Study-Site Monitoring Visits 
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and institution guarantee access to source documents by the sponsor or its 
designee contract research organization (CRO) and by the IRB or IEC. 
All aspects of the study and its documentation will be subject to review by the sponsor or 
designee (as long as blinding is not jeopardized), including but not limited to the Investigator’s 
Binder, study medication, subject medical records, informed consent documentation, 
documentation of subject authorization to use personal health information (if separate from the 
informed consent forms), and review of eCRFs and associated source documents. It is important 
that the investigator and other study personnel are available during the monitoring visits and that 
sufficient time is devoted to the process. 
14.2 
Protocol Deviations 
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will 
require deviation from protocol-specified procedures, the investigator should consult with the 
sponsor or designee (and IRB or IEC, as required) to determine the appropriate course of action. 
There will be no exemptions (a prospectively approved deviation) from the inclusion or 
exclusion criteria. 
The site should document all protocol deviations in the subject’s source documents. In the event 
of a significant deviation, the site should notify the sponsor or its designee (and IRB or EC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the subject, or confound interpretation of primary study 
assessment. PK samples collected outside of the intervals (listed in Table 14.a), ECGs, vital 
signs, and RNA pharmacogenomic samples collected outside of the listed intervals are minor 
deviations and do not require the Protocol Deviation Form to be completed but must be 
documented in the subject’s source documents. A Protocol Deviation eCRF should be completed 
by the site and signed by the sponsor or designee for any significant deviation from the protocol.  
Every attempt will be made to collect each PK blood sample at the designated time point, and the 
actual time of each blood sample will be recorded on the source document and eCRF. Table 14.a 
defines the windows allowed for sample collections.  
Protocol Deviations should be captured in the site source document for PK samples collected 
outside of the following intervals: 


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Table 14.a 
Windows for Pharmacokinetic Blood Sample Collection 
Minutes 
Nominal Sampling Time 
no more than 15 minutes predose 
Pre-dose (-0.25 hour) 
±5 
Postdose 1 hour 
±15 
Postdose 5 hours  
 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections 
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, 
including those of foreign governments (e.g., the Food and Drug Administration (FDA), the 
United Kingdom Medicines and Healthcare products Regulatory Agency, the Pharmaceuticals 
and Medical Devices Agency of Japan). If the study site is contacted for an inspection by a 
regulatory body, the sponsor should be notified immediately. The investigator and institution 
guarantee access for quality assurance auditors to all study documents as described in Section 
14.1. 


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15.0 
ETHICAL ASPECTS OF THE STUDY 
This study will be conducted with the highest respect for the individual participants (i.e., 
subjects) according to the protocol, the ethical principles that have their origin in the Declaration 
of Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will 
conduct the study according to applicable local or regional regulatory requirements and align his 
or her conduct in accordance with the “Responsibilities of the Investigator” that are listed in 
Appendix B. The principles of Helsinki are addressed through the protocol and through 
appendices containing requirements for informed consent and investigator responsibilities. 
15.1 
IRB and/or IEC Approval 
IRBs and IECs must be constituted according to the applicable state and federal/local 
requirements of each participating region.  
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of 
the informed consent form, and, if applicable, subject recruitment materials and/or 
advertisements and other documents required by all applicable laws and regulations, must be 
submitted to a central or local IRB or IEC for approval. The IRB’s or IEC’s written approval of 
the protocol and subject informed consent must be obtained and submitted to the sponsor or 
designee before commencement of the study (i.e., before shipment of the sponsor-supplied drug 
or study specific Screening activity). The IRB or IEC approval must refer to the study by exact 
protocol title, number, and version date; identify versions of other documents (e.g., ICF) 
reviewed; and state the approval date. The sponsor will ship drug/notify site once the sponsor has 
confirmed the adequacy of site regulatory documentation and, when applicable, the sponsor has 
received permission from competent authority to begin the trial. Until the site receives 
drug/notification no protocol activities, including screening may occur. 
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the informed consent 
form, recruitment materials intended for viewing by subjects, local safety reporting requirements, 
reports and updates regarding the ongoing review of the study at intervals specified by the 
respective IRB or IEC, and submission of the investigator’s final status report to IRB or IEC. All 
IRB and IEC approvals and relevant documentation for these items must be provided to the 
sponsor or its designee. 
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor. 
15.2 
Subject Information, Informed Consent, and Subject Authorization 
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The informed consent form, subject authorization form (if 
applicable), and subject information sheet (if applicable) describe the planned and permitted 
uses, transfers, and disclosures of the subject’s personal and personal health information for 
purposes of conducting the study. The informed consent form and the subject information sheet 


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(if applicable) further explain the nature of the study, its objectives, and potential risks and 
benefits, as well as the date informed consent is given. The informed consent form will detail the 
requirements of the participant and the fact that he or she is free to withdraw at any time without 
giving a reason and without prejudice to his or her further medical care. 
The investigator is responsible for the preparation, content, and IRB or IEC approval of the 
informed consent form and if applicable, the subject authorization form. The informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) 
must be approved by both the IRB or IEC and the sponsor prior to use. 
The informed consent form, subject authorization form (if applicable), and subject information 
sheet (if applicable) must be written in a language fully comprehensible to the prospective 
subject. It is the responsibility of the investigator to explain the detailed elements of the informed 
consent form, subject authorization form (if applicable), and subject information sheet (if 
applicable) to the subject. Information should be given in both oral and written form whenever 
possible and in the manner deemed appropriate by the IRB or IEC. In the event the subject is not 
capable of rendering adequate written informed consent, then the subject’s legally acceptable 
representative may provide such consent for the subject in accordance with applicable laws and 
regulations. 
The subject, or the subject’s legally acceptable representative, must be given ample opportunity 
to: (1) inquire about details of the study and (2) decide whether or not to participate in the study. 
If the subject, or the subject’s legally acceptable representative, determines he or she will 
participate in the study, then the informed consent form and subject authorization form (if 
applicable) must be signed and dated by the subject, or the subject’s legally acceptable 
representative, at the time of consent and prior to the subject entering into the study. The subject 
or the subject’s legally acceptable representative should be instructed to sign using their legal 
names, not nicknames, using blue or black ballpoint ink. The investigator must also sign and date 
the informed consent form and subject authorization (if applicable) at the time of consent and 
prior to subject entering into the study; however, the sponsor may allow a designee of the 
investigator to sign to the extent permitted by applicable law. 
Once signed, the original informed consent form, subject authorization form (if applicable), and 
subject information sheet (if applicable) will be stored in the investigator’s site file. The 
investigator must document the date the subject signs the informed consent in the subject’s 
medical record. Copies of the signed informed consent form, the signed subject authorization 
form (if applicable), and subject information sheet (if applicable) shall be given to the subject. 
All revised informed consent forms must be reviewed and signed by relevant subjects or the 
relevant subject’s legally acceptable representative in the same manner as the original informed 
consent. The date the revised consent was obtained should be recorded in the subject’s medical 
record, and the subject should receive a copy of the revised informed consent form. 
Subjects who consented and provided a pharmacogenomic sample for DNA and RNA analysis 
can withdraw their consent and request disposal of a stored sample at any time prior to analysis. 
Notify sponsor of consent withdrawal. 


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15.3 
Subject Confidentiality 
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or 
date of birth, and subject initials may be used to verify the subject and accuracy of the subject’s 
unique identification number. 
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the 
sponsor requires the investigator to permit its monitor or designee’s monitor, representatives 
from any regulatory authority (e.g., FDA, Medicines and Healthcare products Regulatory 
Agency, Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and 
the appropriate IRBs and IECs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a subject’s study 
participation, and autopsy reports. Access to a subject’s original medical records requires the 
specific authorization of the subject as part of the informed consent process (see Section 15.2). 
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (i.e., subject name, address, and other identifier 
fields not collected on the subject’s eCRF). 
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy 
15.4.1 Publication and Disclosure 
The investigator is obliged to provide the sponsor with complete test results and all data derived 
by the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor. 
The sponsor may publish any data and information from the study (including data and 
information generated by the investigator) without the consent of the investigator. Manuscript 
authorship for any peer-reviewed publication will appropriately reflect contributions to the 
production and review of the document. All publications and presentations must be prepared in 
accordance with this section and the Clinical Study Site Agreement. In the event of any 
discrepancy between the protocol and the Clinical Study Site Agreement, the Clinical Study Site 
Agreement will prevail. 
15.4.2 Clinical Trial Registration  
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations, and guidance, Cerevance will, at a minimum register 
interventional clinical trials it sponsors on ClinicalTrials.gov or other publicly accessible 
websites before start of study. Cerevance contact information, along with investigator’s city, 
state (for American investigators), country, and recruiting status will be registered and available 


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for public viewing. For some registries, Cerevance will assist callers in locating trial sites closest 
to their homes by providing the investigator name, address, and phone number to the callers 
requesting trial information. Once subjects receive investigator contact information, they may 
call the site requesting enrollment into the trial. The investigative sites are encouraged to handle 
the trial inquiries according to their established subject Screening process. If the caller asks 
additional questions beyond the topic of trial enrollment, they should be referred to the sponsor. 
Any investigator who objects to Cerevance providing this information to callers must provide 
Cerevance with a written notice requesting that their information not be listed on the registry site. 
15.4.3 Clinical Trial Results Disclosure  
Cerevance may post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites, as required by applicable laws and/or regulations. 
15.5 
Insurance and Compensation for Injury 
Each subject in the study must be insured in accordance with the regulations applicable to the 
site where the subject is participating. If a local underwriter is required, then the sponsor or 
sponsor’s designee will obtain clinical study insurance against the risk of injury to clinical study 
subjects. Refer to the Clinical Study Site Agreement regarding the sponsor’s policy on subject 
compensation and treatment for injury. If the investigator has questions regarding this policy, he 
or she should contact the sponsor or sponsor’s designee. 


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16.0 
REFERENCES 
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2. Green MF. Cognitive impairment and functional outcome in schizophrenia and bipolar 
disorder. J Clin Psychiatry 2006;67 Suppl 9:3-8; discussion 36-42. 
3. Harvey PD, Velligan DI, Bellack AS. Performance-based measures of functional skills: 
usefulness in clinical treatment studies. Schizophr Bull 2007;33(5):1138-48. 
4. Heinrichs RW. The primacy of cognition in schizophrenia. Am Psychol 2005;60(3):229-42. 
5. McNally JM, McCarley RW, Brown RE. Impaired GABAergic neurotransmission in 
schizophrenia underlies impairments in cortical gamma band oscillations. Curr Psychiatry 
Rep 2013;15(3):346. 
6. Cardin JA, Carlen M, Meletis K, Knoblich U, Zhang F, Deisseroth K, et al. Driving fast-
spiking cells induces gamma rhythm and controls sensory responses. Nature 
2009;459(7247):663-7. 
7. Whittington MA, Traub RD, Faulkner HJ, Stanford IM, Jefferys JG. Recurrent excitatory 
postsynaptic potentials induced by synchronized fast cortical oscillations. Proc Natl Acad Sci 
U S A 1997;94(22):12198-203. 
8. Rotaru DC, Lewis DA, Gonzalez-Burgos G. The role of glutamatergic inputs onto 
parvalbumin-positive interneurons: relevance for schizophrenia. Rev Neurosci 
2012;23(1):97-109. 
9. Gonzalez-Burgos G, Lewis DA. NMDA receptor hypofunction, parvalbumin-positive 
neurons, and cortical gamma oscillations in schizophrenia. Schizophr Bull 2012;38(5):950-7. 
10. Curley AA, Lewis DA. Cortical basket cell dysfunction in schizophrenia. J Physiol 
2012;590(Pt 4):715-24. 
11. Tian G, Kong Q, Lai L, Ray-Chaudhury A, Lin CG. Increased expression of cholesterol 24S-
hydroxylase results in disruption of glial glutamate transporter EAAT2 association with lipid 
rafts: a potential role in Alzheimer's disease. J Neurochem 2010;113(4):978-89. 
12. Kawaguchi Y, Shindou T. Noradrenergic excitation and inhibition of GABAergic cell types 
in rat frontal cortex. J Neurosci 1998;18(17):6963-76. 
13. Kawaguchi Y. Selective cholinergic modulation of cortical GABAergic cell subtypes. J 
Neurophysiol 1997;78(3):1743-7. 
14. Lee S, Hjerling-Leffler J, Zagha E, Fishell G, Rudy B. The largest group of superficial 
neocortical GABAergic interneurons expresses ionotropic serotonin receptors. J Neurosci 
2010;30(50):16796-808. 
15. Koike K, Hashimoto K, Takai N, Shimizu E, Komatsu N, Watanabe H, et al. Tropisetron 
improves deficits in auditory P50 suppression in schizophrenia. Schizophr Res 
2005;76(1):67-72. 
16. Lummis SC. 5-HT3 receptors. J Biol Chem 2012;287(48):40239-45. 


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17. Adler LE, Cawthra EM, Donovan KA, Harris JG, Nagamoto HT, Olincy A, et al. Improved 
p50 auditory gating with ondansetron in medicated schizophrenia patients. Am J Psychiatry 
2005;162(2):386-8. 
18. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders 
(DSM-5). 5th ed. Arlington, VA: American Psychiatric Association; 2013. 
19. Smucny J, Wylie K, Rojas D, Stevens K, Olincy A, Kronberg E, et al. Evidence for gamma 
and beta sensory gating deficits as translational endophenotypes for schizophrenia. 
Psychiatry Res 2013;214(2):169-74. 
20. Kay SR. Positive-negative symptom assessment in schizophrenia: psychometric issues and 
scale comparison. Psychiatr Q 1990;61(3):163-78. 
21. Mundt JC, Greist JH, Jefferson JW, Federico M, Mann JJ, Posner K. Prediction of suicidal 
behavior in clinical research by lifetime suicidal ideation and behavior ascertained by the 
electronic Columbia-Suicide Severity Rating Scale. J Clin Psychiatry 2013;74(9):887-93. 
22. Javitt D. Neurophysiological models for new treatment development in schizophrenia: early 
sensory approaches. The New York Academy of Sciences. 2015;1344: 92-104.  
23. Lee M, Sehatpour P, Hoptman MJ, Lakatos P, Dias EC, Kantrowitz JT, Martinez AM, Javitt 
DC. Neural mechanisms of mismatch negativity dysfunction in schizophrenia. Mol 
Psychiatry. 2017;22(11):1585-1593. doi: 10.1038/mp.2017.3. 
24. Javitt D and Sweet R. Auditory dysfunction in schizophrenia: integrating clinical and basic 
features. Nat Rev Neurosci. 2015; 16(9): 535–550. doi:10.1038/nrn4002. 
25. Eisensamer B, Uhr M, Meyr S, Gimpl G, Deiml T, Rammes G, Lambert JJ, Zieglgänsberger 
W, Holsboer F, Rupprecht R. Antidepressants and antipsychotic drugs colocalize with 5-HT3 
receptors in raft-like domains. J Neurosci. 2005 Nov  2;25(44):10198-206. PubMed PMID: 
16267227. 
26. Eisensamer B, Rammes G, Gimpl G, Shapa M, Ferrari U, Hapfelmeier G, Bondy B, Parsons 
C, Gilling K, Zieglgänsberger W, Holsboer F, Rupprecht R. Antidepressants are functional 
antagonists at the serotonin type 3 (5-HT3) receptor. Mol Psychiatry. 2003 Nov;8(12):994-
1007. PubMed PMID: 14647397. 
27. Rammes G, Eisensamer B, Ferrari U, Shapa M, Gimpl G, Gilling K, Parsons C, Riering K, 
Hapfelmeier G, Bondy B, Zieglgänsberger W, Holsboer F, Rupprecht R. Antipsychotic drugs 
antagonize human serotonin type 3 receptor currents in a noncompetitive manner. Mol 
Psychiatry. 2004 Sep;9(9):846-58, 818. PubMed PMID: 15024394. 
28. Hartman LI, Heinrichs RW, Mashhadi F. The continuing story of schizophrenia and 
schizoaffective disorder: One condition or two? Schizophr Res Cogn. 2019. 16:36-42. 
29. Avissar M, Xie S, Vail B, Lopez-Calderon J, Wang Y, Javitt DC. Meta-analysis of mismatch 
negativity to simple versus complex deviants in schizophrenia. Schizophr Res. 2018. 191:25-
34. 
 
 


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Appendix A Schedule of Study Procedures 
 
 
 
CVN058 and Placebo 
Treatment Periods 1, 2, and 3 
(a) 
End of 
Treatment 
 
Follow-up  
Study Day: 
Visit 1: 
Screening 
 
Day 1 
pre-dose 
Day 1 
post-dose 
Period 3, 
End Day 1  
Early 
Termination 
(c)  
Day 7-10 
After End of 
Treatment 
(b) 
Informed consent 
X 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Reproductive Status 
X 
 
 
 
 
 
Social History 
X 
 
 
 
 
 
Medication history 
X 
 
 
 
 
 
Physical examination  
X 
X 
 
X 
X 
 
Vital signs (d) 
X 
X 
X 
 
X 
 
Weight, height, and BMI 
(e) 
X 
 
 
X 
X 
 
Concomitant medications 
(f) 
X 
X 
X 
 
X 
X 
Medical history (g) 
X 
 
 
 
 
 
Clinical laboratory tests 
(h) 
X 
 
 
X 
X 
 
Hepatitis panel 
X 
 
 
 
 
 
Audiometric Screening 
and Tone Matching test 
(i) 
X 
 
 
 
 
 
FSH (j) 
X 
 
 
 
 
 
Pregnancy test (hCG), 
serum except as noted 
X 
X (urine) 
 
 
X 
 
Urine drug and saliva 
alcohol screen 
X 
 
 
 
 
 
ECG (k) 
X 
 
 
 
 
 
EEG battery (l) 
 
 
X 
 
 
 
MMN (m) 
 
 
X 
 
 
 
DNA sample collection 
(n) 
 
X 
 
 
 
 
RNA sample collection 
(o) 
 
X 
X 
 
 
 
PK blood collection (p) 
 
X 
X 
 
X 
 
Study drug dosing (q) 
 
 
X 
 
 
 
PTE assessment (r) 
X 
X 
 
 
 
 
AE assessment (s) 
 
 
X 
 
X 
X 
C-SSRS (t) 
X 
 
X 
 
X 
 
PANSS (u) 
X 
 
X 
 
X 
 
Footnotes are on last table page. 


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(a) Minimum 7-day and maximum 10-day washout period is required in between Treatment Periods 1, 2 and 3.  
(b) The Follow-up Visit will occur by telephone 7-10 days after End of Treatment unless abnormal, clinically significant findings 
were observed upon discharge. In these cases, subjects must then be brought back to the clinic for re-evaluation per investigator’s 
discretion. 
(c) Conduct procedures for subjects discontinued early per Protocol Section 7.6. The PK sample should be collected at the Early 
Termination Visit, if within 1 hour of a scheduled PK time point. 
(d) Vital signs (oral temperature, respiration, pulse, and blood pressure) will be obtained at Screening, and in Periods 1, 2, and 3 
(pre dose [within 30 minutes prior to dosing], and at 1 and 5 hours post dose), and at Early Termination (if applicable), and if 
clinically indicated according to Investigator discretion at the Follow-up visit. Vital signs will be collected with a window of ±15 
minutes. 
(e) Height and BMI will be collected at Screening only. 
(f) Record all patient medications from Screening and throughout the study. 
(g) All new medical history arising after signing ICF should be recorded as PTE or AE.  
(h) Clinical laboratory tests (hematology, serum chemistry, urinalysis, and coagulation) will be collected at Screening and prior to 
check-out at End of Treatment or Early Termination, and at the Investigator discretion if a Follow-up Visit is indicated.  
(i) Audiometric Screening assessment conducted according to local practice.  
(j) A FSH level will be obtained on post-menopausal women (defined as continuous amenorrhea of at least 2 years and not 
surgically sterile). 
(k) ECGs will be collected with a window of ±2 minutes. 
(l) For the EEG battery, testing will be done at Day 1 starting approximately 1.5 hours post dose for each period and will last 
approximately 3 hours. NOTE: Subjects should refrain from drinking coffee and smoking approximately 1 hour prior to the EEG 
assessment until discharge from clinic at the end of the afternoon.  
(m) MMN will be the first EEG assessment conducted in the battery. EEG (MMN) assessment will be collected with a window of 
±60 minutes. 
(n) One blood sample (6 mL) will be collected for pharmacogenomic analysis prior to study drug administration on Day 1 of 
Period 1 only. If isolation of DNA from the first sample was not successful or possible, a second aliquot of blood may 
be taken, if feasible. 
(o) Two 2.5 mL whole blood samples will be collected for each Period (Periods 1, 2, and 3) on Day 1 at pre-dose, and 5 hours 
post- dose.  
(p) Blood samples (6 mL) for PK analyses will be collected at pre -dose (within 15 minutes prior to dosing), and 1 and 5 hours 
post dose. PK collection for pre-dose will be (within 15 minutes prior to dosing), ±15 minutes at the 1 hour post-dose time point, 
and ±30 minutes at the 5 hour post-dose time point. 
(q) Dosing will only occur on Day 1 of each period, and signals the start of the post-dose Day 1 visit assessments. 
(r) PTEs will be collected from signing of informed consent up until dosing on Day 1; PTEs will be captured on the AE CRF 
page. 
(s) Any adverse event with onset or exacerbation after dosing on Day 1 of Period 1 will be captured as an AE or SAE. 
(t) The Screening/Baseline C-SSRS will be administered at Screening and the Since Last Visit C-SSRS will be administered after 
EEG/ERP collection on each dosing day, and End of Treatment or Early Termination (if applicable). 
(u) The Screening/Baseline PANSS will be collected at Screening, approximately 5 hours after each dose (post EEG) and at Early 
Termination (if applicable). PANSS will be collected with a window of ±45 minutes. 
 


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Appendix B Responsibilities of the Investigator 
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on investigators by the FDA are 
summarized in the “Statement of Investigator” (Form 1572) which must be completed and 
signed before the investigator may participate in this study. 
The investigator agrees to assume the following responsibilities by signing a Form 1572.  
1. Conduct the study in accordance with the protocol. 
2. Personally conduct or supervise the staff who will assist in the protocol. 
3. Ensure that study related procedures; including study specific (non-routine/non- standard 
panel) Screening assessments are NOT performed on potential subjects prior to the receipt of 
written approval from relevant governing bodies/authorities. 
4. Ensure that all colleagues and employees assisting in the conduct of the study are informed 
of these obligations. 
5. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform 
to 21 CFR Part 56 ICH, and local regulatory requirements. 
6. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and 
approval of the protocol. Promptly report to the IRB/IEC all changes in research activity and 
all anticipated risks to subjects. Make at least yearly reports on the progress of the study to 
the IRB/IEC, and issue a final report within 3 months of study completion. 
7. Ensure that requirements for informed consent, as outlined in 21 CRF Part 50 ICH and local 
regulations, are met. 
8. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each informed consent form should contain a subject 
authorization section that describes the uses and disclosures of a subject’s personal 
information (including personal health information) that will take place in connection with 
the study. If an informed consent form does not include such a subject authorization, then the 
investigator must obtain a separate subject authorization form from each subject or the 
subject’s legally acceptable representative. 
9. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc., and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents. 
10. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents. 
11. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor. 


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12. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours. 
 

SAP_001.pdf: 
Cerevance Alpha, Inc. 
CVN058 Oral Solution 
Clinical Study Report: CVN058-103 
IND 121,520 
CONFIDENTIAL 
16.1.9 
Documentation of Statistical Methods 
Statistical Analysis Plan, Version 4.0, Date: 07 May 2020 


Cerevance Alpha 
Study Number CVN058-103-001 
Statistical Analysis Plan – Final v4.0 
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Study Number CVN058-103 
A Placebo-Controlled Study to Evaluate the Effect of a Single Dose of CVN058 
on Mismatch Negativity in Subjects with Stable Schizophrenia  
Document type: 
Statistical Analysis Plan  
Document status: 
Final v 4.0 
Release date: 
07-MAY-2020
Protocol: 
CVN058-103  
Protocol Version dated September 24th, 2019; Amendment No. 4 
Prepared by: 
Clinilabs, Inc. 
                                                          NCT Number: NCT03669250
This NCT number has been applied to the document for purposes of posting on Clinicaltrials.gov


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This study will be conducted in compliance with the Protocol, Good Clinical Practice and all other 
applicable regulatory requirements, including the archiving of essential documents. 
 
Document History 
 
Version 
Number 
Author 
Date  
Change 
V1 
 
23Jul2019 
 
V2 
 
07Aug2019 
Additions to TOC; revisions to Interim 
Analyses testing based on data 
availability 
V3 
 
24SEP2019 
Unblinding of interim analysis.  
V4 
 
07May2020 
Revisions to TOC to add Exploratory 
Parameter analyses; Revisions to dose 
levels per IA results. 
PPD
PPD
PPD
PPD




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Table of Contents 
1. 
Glossary and Abbreviations ............................................................................................. 6 
2. 
Introduction .................................................................................................................... 8 
2.1. 
Background ....................................................................................................................... 8 
2.2. 
Clinical ............................................................................................................................... 9 
2.3. 
Study Rationale ............................................................................................................... 10 
3. 
Study Objectives and Endpoints ..................................................................................... 11 
3.1. 
Objectives ....................................................................................................................... 11 
3.1.1. Primary Objective ............................................................................................................ 11 
3.1.2. Secondary Objective ........................................................................................................ 11 
3.1.3. Exploratory Objectives .................................................................................................... 11 
3.2. 
Endpoints ........................................................................................................................ 12 
3.2.1. Primary Endpoint (PDC Population) ................................................................................. 12 
3.2.2. Secondary Endpoints (SAF Population) ............................................................................ 12 
3.2.3. Exploratory Endpoints (PDC Population) .......................................................................... 12 
4. 
Study Design .................................................................................................................. 13 
4.1. 
Overall Study Design ....................................................................................................... 13 
4.2. 
Subjects ........................................................................................................................... 13 
4.3. 
Study Design Summary .................................................................................................... 13 
5. 
Determination of Sample Size ........................................................................................ 14 
6. 
Analysis Populations ...................................................................................................... 14 
7. 
Statistical Analysis ......................................................................................................... 15 
7.1. 
General Considerations ................................................................................................... 15 
7.1.1. Overall ............................................................................................................................ 15 
7.1.2. Safety Analysis ................................................................................................................ 16 
7.1.3. Pharmacokinetic Analysis ................................................................................................ 16 
7.1.4. Pharmacodynamic Analysis ............................................................................................. 16 
7.1.4.1 
Primary Analysis ........................................................................................................................ 17 
7.1.4.2 
Exploratory Analyses ................................................................................................................. 17 
7.1.5 Adjustments for Covariates ............................................................................................. 18 
7.1.6 Testing ............................................................................................................................ 18 
7.1.7 Baseline Values ............................................................................................................... 18 
7.1.8 Handling of Missing Data ................................................................................................. 19 
8. 
Sample-size Re-assessment and Futility Analysis ........................................................... 19 
8.1. 
Sample-size Re-assessment ............................................................................................. 19 
8.2. 
Interim Futility Analysis ................................................................................................... 20 
9. 
Background Characteristics ............................................................................................ 21 
9.1. 
Subject Disposition .......................................................................................................... 21 


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9.2. 
Protocol Deviations ......................................................................................................... 21 
9.3. 
Demographic and Baseline Characteristics ....................................................................... 21 
9.4. 
Prior and Concomitant Medications ................................................................................ 21 
9.5. 
Medical History ............................................................................................................... 22 
10. Adjustments for Covariates ........................................................................................... 23 
11. Safety Analysis .............................................................................................................. 23 
11.1. 
Pre-treatment Events and Adverse Events ....................................................................... 23 
11.2. 
Laboratory Data .............................................................................................................. 24 
11.3. 
Vital Signs and Body Measurements ................................................................................ 24 
11.4. 
ECG Assessment .............................................................................................................. 25 
11.5. 
Additional Assessment Items ........................................................................................... 25 
12. Planned Tables, Listings and Figures .............................................................................. 28 
12.1. 
Planned Tables ................................................................................................................ 28 
12.2. 
Planned Listings ............................................................................................................... 30 
12.3. 
Planned Figures ............................................................................................................... 31 
 
 
 


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1. Glossary and Abbreviations 
Abbreviation 
Definition 
5-HT 
5-hydroxytryptamine (serotonin) 
AE 
adverse event 
ALT 
alanine aminotransferase 
ATC 
Anatomical/Therapeutic/Chemical Class 
AST 
aspartate aminotransferase 
BMI 
Body Mass Index 
AUC 
area under the plasma concentration-time curve 
AUCt  
area under the plasma concentration-time curve from 0 to time of last 
quantifiable concentration  
CIAS 
cognitive impairment associated with schizophrenia 
Cmax 
maximum observed plasma concentration 
CNS 
central nervous system 
CSF 
cerebrospinal fluid 
C-SSRS  
Columbia-Suicide Severity Rating Scale 
ECG 
Electrocardiogram 
EEG 
Electroencephalography 
Fz 
frontal electrodes 
FzCz 
frontocentral electrodes 
GABA 
γ-aminobutyric acid 
GGT 
γ-glutamyl transferase 
ICH 
International Conference on Harmonisation 
INR 
international normalized ratio 
LFT 
liver function test 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMN 
mismatch negativity 
msec 
Milliseconds 
NFSI 
non-fasting spiking interneurons 
PANSS 
Positive and Negative Syndrome Scale 
PD 
pharmacodynamic(s) 


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Abbreviation 
Definition 
PK 
pharmacokinetic(s) 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
PTE 
pretreatment event 
Pz 
parietal electrodes 
P50 Ratio 
ratio of amplitude of the auditory evoked potential P50 from the second 
stimulus (S2) compared to the first stimulus (S1) 
QTcB 
QT interval with Bazett correction method 
QTcF 
QT interval with Fridericia correction method 
SAE 
serious adverse event 
SAF 
safety population 
SAP  
statistical analysis plan 
t1/2z 
terminal elimination half-life 
CVN058 
also known as ENV8058 and TAK-058 
TEAE 
treatment-emergent adverse event 
tmax 
time to reach Cmax 
Vz/F 
apparent volume of distribution during the terminal phase 
WHODRUG  
World Health Organization Drug Dictionary 
 
 
 


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2. Introduction 
2.1. 
Background 
Schizophrenia is a complex psychiatric disorder comprising several clinical features. While the 
most well-known schizophrenia symptom domains are the so-called positive symptoms, e.g., 
hallucinations, delusions, disorganization of thought, bizarre behavior, and incongruity of affect, 
schizophrenics also commonly experience so-called negative symptoms, e.g., avolition (loss of 
motivation), blunt affect, alogia (reduced speech), and anhedonia (reduced ability to experience 
pleasure), mood disorders, and cognitive impairment. Cognitive impairment associated with 
schizophrenia (CIAS) is observed in most cases, usually precedes psychosis, and can involve 
deficits in a broad range of cognitive domains. Cognitive impairment is considered a core feature 
of schizophrenia and represents an area of significant unmet medical need.  
Cognitive deficits in schizophrenia include problems in speed of processing, attention/vigilance, 
working memory, verbal learning, visual learning, reasoning and problem solving, and social 
cognition [1]. These cognitive deficits are believed to underlie much of the significant functional 
impairments observed in schizophrenia, such as impairment in independent living skills, social 
functions, vocational functioning, and self-care [2]. Thus, the core nature of CIAS and the 
associations that have been demonstrated with functional disability suggest that improving 
cognitive impairment may lead to improved functional outcomes [3]. The cognitive impairments 
manifest as deficits not only in high-level processes, such as working memory or executive 
processing, but also as deficits in neurophysiological responses to simple auditory and visual 
stimuli [4].  
Mismatch negativity (MMN) is an established biomarker of cerebral cortical function [5]. This 
signal is obtained as an evoked potential during an auditory oddball task in which a subject is 
repeatedly exposed to auditory tones and a small proportion of those tones (the “deviant” 
stimuli) differ from the others (the “standard” stimuli) in their pitch frequency or duration. 
Typically, the tones are presented and the evoked potentials are recorded while subjects are 
engaged on a different task, such as reading. Normally, the occurrence of a deviant stimulus 
increases the amplitude of the negative component in the evoked potential occurring at around 
200 msec. MMN is the difference in amplitude between deviant and standard stimuli responses 
and is considered to represent an aspect of pre-attentive novelty detection. MMN is consistently 
reduced in schizophrenia patients relative to healthy individuals, a finding extensively replicated 


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and with a large effect size (Cohen’s d = 1), and this reduction (impairment) in MMN is associated 
with poor psychosocial functioning. Thus, MMN is potentially a useful biomarker in studies 
seeking to establish whether candidate therapeutic compounds may have a beneficial effect on 
CIAS.  
2.2. 
Clinical 
Two human clinical studies of CVN058 have been completed (ENV8058_101 and TAK-058- 1002).   
CVN058 is orally absorbed and readily passes the blood brain barrier, allowing it to occupy 
cortical 5-HT3 receptors. In study ENV8058_101, CVN058 was well tolerated up to a dose of 150 
mg administered orally as a single dose in aqueous solution. There were no deaths or other 
serious adverse events (SAEs) reported in this study and no subject discontinued study due to a 
treatment-emergent adverse event (TEAE). There were no clinically significant laboratory 
abnormalities, electrocardiogram (ECG) changes or changes in vital signs in the completed single 
dose study.  
The mean Cmax and area under the plasma concentration–time curve (AUC) values of CVN058 
increased less than proportionally with increasing CVN058 dose across the dose range of 5 to 150 
mg, but mean Cmax and AUC values increased in an approximately dose proportional manner 
across the 5 to 45 mg dose range. The rate of appearance of CVN058 in plasma was rapid with 
median time to Cmax (tmax) values of 1 to 1.25 hours across the dose range of 5 to 150 mg. The 
mean terminal elimination half-life (t1/2z) values of CVN058 ranged from approximately 2.8 to 
10.5 hours across the cohorts; the lower doses (5 to 30 mg) had lower mean t1/2z values 
compared to the higher doses (45 to 150 mg). There were no trends with mean apparent 
clearance values of CVN058 with increasing dose from 5 to 45 mg, but faster apparent clearance 
was observed at the 75 and 150 mg doses, possibly due to decreased bioavailability (BA) at higher 
doses. The mean apparent volume of distribution (Vz/F) increased as dose increased. Excretion 
of unchanged CVN058 in the urine was ≤2.3% of the administered CVN058 dose over the dose 
range evaluated.  
In the multiple-rising dose study (TAK-058-1002), CVN058 was well-tolerated at daily doses of 25, 
75, and 150 mg for 7 days, and at a single 300 mg dose, in aqueous solution. There were no 
deaths or other SAEs reported in this study and no subject discontinued study due to a TEAE. 
There were no clinically significant laboratory abnormalities, ECG changes or changes in vital 
signs in the completed single dose study. Following single or multiple doses, the mean Cmax and 


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AUC values of CVN058 increased less than proportionally with increasing CVN058 dose across the 
dose range of 25 to 300 mg. No accumulation was observed following daily administration. 
CVN058 concentrations in cerebrospinal fluid (CSF) were assessed after daily doses of CVN058 75 
mg for 5 days. The CSF concentrations averaged 17.5 ng/mL, or approximately 1% of the 
concentration in plasma.  
The statistical methods to be implemented during the analyses of data collected within the scope 
of the present study, CVN058-103, will be outlined in this document.  The purpose of this plan is 
to provide specific guidelines from which the statistical analysis will proceed.  Any deviations 
from this plan will be documented in the clinical study report. 
2.3. 
Study Rationale 
This study will explore central target engagement and proof of mechanism by measuring auditory 
evoked potential MMN as a pharmacodynamic (PD) marker of CNS response to the selective 5-
HT3 receptor antagonist CVN058. It has been reported that subjects with schizophrenia 
commonly demonstrate a deficit in neural processing that is manifested as a reduction in MMN 
and impairment of auditory sensory gating (P50) [8]. Other 5-HT3 receptor antagonists have been 
reported to improve impairments in auditory evoked potentials in schizophrenic subjects. In a 
study with ondansetron, a widely-prescribed 5-HT3 receptor antagonist, using P50 auditory 
gating as the auditory evoked potential measure, subjects were given a single dose of 
ondansetron (16 mg) or placebo in a double-blind, placebo-controlled, randomized and balanced 
crossover design [9]. Serial measurements of the P50 evoked potential were done at Baseline 
and 1, 2, and 3 hours after receipt of placebo or ondansetron. The results of the study indicated 
that ondansetron significantly enhanced P50 auditory gating in subjects with schizophrenia. 
Tropisetron, a 5-HT3 antagonist that also has α7 nicotinic cholinergic agonist activity, has similarly 
been shown to improve P50 auditory gating in subjects with schizophrenia [10].  
While the P50 signal is likely a reflection of brainstem and thalamic network activity and is 
sensitive to antipsychotic treatment, MMN is thought to reflect excitation-inhibition balance in 
cortical circuits and is not sensitive to antipsychotic treatment [8]. Therefore, to evaluate the 
potential for CVN058 to improve cognitive function in schizophrenics, MMN will be used as a PD 
marker. The study will be performed as a 3-way crossover to assess the effect on MMN of CVN058 
at two dose levels relative to placebo, with each subject serving as his or her own control to 
reduce variability. P50 auditory gating will also be measured, as an exploratory endpoint, along 
with other potentially informative electrophysiological and psychometric parameters.  


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Medications that might inhibit or mask the effects of CVN058 will not be permitted as 
concomitant medications. These include serotonin reuptake inhibitors which increase synaptic 
serotonin levels, as well as drugs that bind to 5-HT3 at clinically relevant concentrations or are 
reported to inhibit signaling through 5-HT3 non-competitively, including some antipsychotic 
drugs [11], [12], [13]. Permissible antipsychotic medications are risperidone (Risperdal), 
haloperidol (Haldol), quetiapine (Seroquel), aripiprazole (Abilify) and paliperidone (Invega).  
3. Study Objectives and Endpoints 
3.1. 
Objectives 
3.1.1. Primary Objective 
• 
To determine whether improvement in MMN is demonstrated after administration of 
CVN058 compared to placebo in subjects with schizophrenia.  
3.1.2. Secondary Objective 
• 
To assess the safety and tolerability of single doses of CVN058 in subjects with 
schizophrenia.  
3.1.3. Exploratory Objectives 
• 
To determine whether improvement in P50 auditory gating, gamma power, and P300 
is demonstrated after administration of CVN058 compared to placebo in subjects with 
schizophrenia. 
• 
• 
To explore the exposure-response relationship for CVN058 in subjects with 
schizophrenia. 


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3.2. 
Endpoints 
3.2.1. Primary Endpoint (PDC Population) 
• 
Mean amplitude of duration MMN at 5 electrodes surrounding frontal (Fz) electrodes 
following administration of CVN058 compared to placebo. 
3.2.2. Secondary Endpoints (SAF Population) 
• 
Percentage of subjects who experience at least one (1) TEAE 
• 
Percentage of subjects who experience at least one (1) clinically significant abnormal 
laboratory test result 
3.2.3. Exploratory Endpoints (PDC Population) 
• 
Pre-stimulus gamma amplitude following administration of CVN058 compared to 
placebo  
• 
P300 amplitude and latency at average of 5 centroparietal electrodes around parietal 
electrodes (Pz) following administration of CVN058 compared to placebo  
• 
MMN amplitude to additional deviants (frequency, intensity, location, frequency-
modulation) and latency to all deviants following administration of CVN058 compared 
to placebo 


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4. Study Design 
4.1. 
Overall Study Design 
This is a phase 1, double-blind, placebo-controlled, 3 period cross-over study to evaluate CVN058 
target engagement by measuring auditory evoked potential MMN downstream to 5-HT3 as a 
pharmacodynamic (PD) marker.  
4.2. 
Subjects 
The study population will include male and female subjects with schizophrenia, age 18 to 50 years 
old, inclusive, and who satisfy all entry criteria. 
4.3. 
Study Design Summary 
In the initial study design, subjects were randomized to 1 of 6 treatment sequences to receive 1 
of 3 dose regimens in each period. Each dose regimen consisted of a single oral administration of 
CVN058 (15 mg or 150 mg initially) or a matching placebo; study drug to be administered with 
water in the morning. The sequence will determine the order in which a subject will receive each 
of the 3 regimens. Discontinued subjects may be replaced so that 20 completed subjects are 
available for analysis.  
After the Interim Analysis, the 15 mg dose in each treatment sequence was replaced with a 75 
mg dose under Protocol Amendment 4, applicable to all subjects randomized. 
 
Each treatment period is less than 1 day in duration, with a minimum of 7-day washout, maximum 
10-day washout between doses. A follow-up telephone call will occur approximately 7-10 days 
following the last dose received. Subjects may be inpatients or outpatients at the discretion of 
the Investigator.  
At each testing session, subjects will undergo post dose EEG testing including: MMN, P50, qEEG, 
gamma power, and P300. Testing sessions will begin approximately 1.5 hours post-dose. Prior to 
dose and at various time points post-dose, blood samples will be collected for the assessment of 
plasma concentrations of CVN058 and biomarkers.  
Study procedures will be conducted at approximately the same times across Treatment Periods 
to minimize diurnal effects on outcomes. The effect of CVN058 on MMN as well as on exploratory 
measures (e.g., P50 auditory gating, gamma power, and P300) will be compared to placebo.  


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5. Determination of Sample Size 
Enrollment of at least 20 subjects with schizophrenia (including schizoaffective disorder) is 
estimated to provide >80% power to detect a median effect size of Cohen’s d=0.5. Discontinued 
or withdrawn subjects and subjects for whom MMN is not available for all three study periods 
may be replaced. The sample size chosen of at least 20 completed subjects is considered to be 
sufficient to explore the changes in MMN between CVN058 and placebo as well as safety and 
tolerability of CVN058 in this population.  There will be approximately three (3) study sites in the 
United States.  The sample size is subject to re-estimation based on preliminary data. 
The sample size re-estimation will occur after twelve (12) subjects have completed all study visits.  
Full details are discussed in Section 8.   
6. Analysis Populations 
Three subject populations will be defined for this study. 
• 
Safety Set population (SAF): The Safety Set population will consist of all subjects who are 
randomized and receive study drug. Subjects in this analysis set will be used for 
demographic, baseline characteristics and safety summaries. 
• 
Pharmacokinetic population (PK):  The PK population will consist of all subjects who 
receive study drug and have at least one (1) measurable plasma concentration of CVN058.  
• 
Pharmacodynamic population (PD): The PD population will consist of all subjects who 
receive study drug and have measurements in both the placebo-dosed period and at least 
one (1) CVN058-dosed period for at least one (1) EEG/evoked response endpoint.    
• 
Pharmacodynamic completers population (PDC): The PDC population will consist of all 
subjects who receive study drug and have values in the placebo-dosed period and both 
CVN058-dosed periods for at least one (1) EEG/evoked response endpoint. 
If any subjects are found to be noncompliant in dosing schedule or with incomplete data, a 
decision will be made on a case-by-case basis as to their inclusion in the PK and PD endpoint 
analyses, but data for all subjects will be presented in the subject listings. 


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7. Statistical Analysis 
7.1. 
General Considerations 
7.1.1. Overall 
The statistical analyses will be reported using summary tables, figures and listings (TFLs).  
Numbering for TFLs will be based on the recommended numbering convention provided by the 
International Council for Harmonisation (ICH). All summary tables will be presented by treatment 
group. Listing of Screen Failures will also be presented based on Eligibility Criteria 
(Inclusion/Exclusion) not met. Select baseline tables may also include a total column summary. 
Tables and listings will be presented in RTF format.  
Continuous (quantitative) variable summaries will include the number of subjects (n) with non-
missing values, mean, standard deviation (SD), median, minimum, maximum and quartiles. 
Categorical (qualitative) variables will be summarized by frequencies and percentages of subjects 
in corresponding categories. The denominator for the percentage calculation will be based upon 
the total number of subjects in the study population for the treatment or sequence group with 
non-missing data for the variable of interest. 
The minimum and maximum will be reported with the same degree of precision (i.e., the same 
number of decimal places) as the observed data. Measures of location (mean and median) will 
be reported to one degree of precision more than the observed data and measures of spread 
(standard deviation) will be reported to two degrees of precision more than the observed data. 
Percentages will be presented to one decimal place unless otherwise specified. Assessments 
done on unscheduled visits will not be summarized but will be listed.  
P-values ≥0.001 will be reported to four decimal places; P-values less than 0.001 will be reported 
as “<0.001”. 
For analysis purposes, repeat laboratory rest results will not be used unless the original 
laboratory value is missing or indicated as invalid, in which case the first non-missing repeat 
laboratory value will be used for data analysis. 
All collected data will be presented in listings and will be sorted by subject.  CDISC-compliant 
datasets (STDM and ADAM) will also be provided to the sponsor. 


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7.1.2. Safety Analysis  
The Safety Set population will be used for all summaries of Adverse Events (AEs), Pre-Treatment 
Adverse Events (PTEs), TEAEs, laboratory tests, and vital signs. All safety data will be summarized 
by treatment.  
AEs will be presented in listings. TEAEs will be classified according to system organ class and 
preferred term and will be tabulated with a breakdown by treatment and by event severity. 
Similar TEAE tabulations will be performed on those events assessed by the investigator as 
related to study drug.  
Individual results of vital signs will be listed and observed values and changes from Baseline in 
vital signs will be summarized by treatment.  
Physical exam findings, suicidality assessments (C-SSRS), PANSS scores, Diagnostic Screening 
results and pregnancy test results will be presented in subject-level listings. 
7.1.3. Pharmacokinetic Analysis 
Blood samples will be collected for the determination of plasma concentration of CVN058, and 
its metabolite if appropriate, at the following time-points:  Pre-dose (within 15 minutes prior to 
dosing), and a one (1) hour (pre-EEG) and five (5) hours (post-EEG) post-dose.  The plasma 
concentration data (parameters Cmax, tmax and AUC (0 to 5 hrs.) will be summarized over each 
scheduled sampling interval using descriptive statistics (arithmetic mean, SD, median, minimum 
and maximum). Individual plasma concentration data versus time will be presented in a data 
listing.  
Descriptive statistics will be used to summarize the plasma PK parameters for CVN058, and its 
metabolite if appropriate. In addition, geometric mean and percent coefficient of variation will 
be computed for Cmax and AUCt.  
7.1.4. Pharmacodynamic Analysis 
In general, observed values for the PD parameters (MMN and exploratory PD parameters [P50, 
qEEG and P300]) in each treatment period will be summarized by treatment and compared to 
time-matched placebo assessments using summary statistics. Summaries presented will include 
difference values (CVN058 – placebo).   


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7.1.4.1 Primary Analysis  
The Primary Endpoint analysis will be performed on the PD population and will consist of a 
comparison of the post dose PD parameter Mean Amplitude of Duration MMN versus the 
parameter at time-matched placebo period timepoints using Generalized Linear Models with 
factors for sequence, subject nested within sequence, period, site and treatment. Two-sided 80% 
confidence intervals will be constructed for the least squares mean differences between CVN058 
and placebo in PD parameters at the post-dose time point for each treatment period.  
To maintain overall control of alpha (Type I error rate), the Primary Analysis will employ 
sequential testing, beginning with the higher dose (e.g., CVN058 150 mg) vs. Placebo using alpha 
= 0.10 and one-sided significance testing.  If significant results are obtained from that first 
comparison, sequential significance testing of the next lower dose or doses (e.g., CVN058 75 mg) 
vs. Placebo will then be performed.   If the first comparison yields a non-significant result, testing 
of the latter vs. Placebo will be performed to generate a nominal p-value, but that result will not 
be formally statistically significant regardless of the p-value. 
Effect size will be calculated and summarized for comparisons of CVN058 to Placebo using 
Cohen’s d which expresses the difference between the means of two groups as a function of their 
pooled standard deviation.  
Exposure-response relationships for CVN058 will be explored graphically. 
7.1.4.2 Exploratory Analyses  
Exploratory endpoint analyses will consist of a comparison of each exploratory post-dose PD 
parameter versus the same parameter at time-matched placebo period timepoints using 
Generalized Linear Models and including factors for sequence, subject nested within sequence, 
period, site and treatment. Two-sided 80% confidence intervals will be constructed for the least 
squares mean differences between CVN058 and placebo in changes of PD parameters at the post-
dose time point.  
There will be no adjustment to maintain overall control of alpha (Type I error rate) for exploratory 
endpoints. 


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Effect sizes will be calculated and summarized for comparisons of CVN058 to placebo using 
Cohen’s d which expresses the difference between the means of two groups as a function of their 
pooled standard deviation.  
Exposure-response relationships for CVN058 will be explored graphically. 
7.1.5 
Adjustments for Covariates 
Randomization for this study will be stratified by the study site in which subjects are enrolled.  
The model for the primary analysis will include this stratification variable as a main effect.  This 
stratification variable may also be included as a factor for select secondary variables. Baseline 
values will also be used as a covariate when baseline is available for the endpoint.  
7.1.6 
Testing 
Unless noted otherwise, all statistical tests will be one-sided with a significance level of α = 0.10.  
Tests will be declared statistically significant if the calculated p-value is < 0.10.  
The analyses described in this plan are considered a priori, in that they have been defined prior 
to database lock.  Any additional analysis performed after database lock will be considered post-
hoc and exploratory.  Post-hoc analyses will be labeled as such on the output and identified in 
the CSR. 
All analyses and tabulations will be performed using SAS version 9.4. Upon completion, all SAS 
programs will be validated by an independent programmer.  The validation process will be used 
to confirm that statistically valid methods have been implemented and that all data 
manipulations and calculations are accurate.  Checks will be made to ensure accuracy, 
consistency with this plan, consistency with tables, and consistency between tables and 
corresponding data listings. 
7.1.7 
Baseline Values 
Unless otherwise noted, baseline is defined as the Period 1 – Day 1 (pre-dose) value recorded 
prior to the first study treatment.  However, the baseline value for clinical laboratory assessments 
is defined as Visit 1 - Screening Day-28 for Hematology, Serum Chemistry, Urinalysis and 
Coagulation.  If a baseline value is missing, the last non-missing value prior to the first study 


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treatment will be used.  When applicable, unscheduled visits will be used in the determination 
of baseline values. 
7.1.8 
Handling of Missing Data 
In general, with the exception of the primary and secondary variables, missing values are not 
considered for percentage calculations, unless stated otherwise.  In these cases, footnotes will 
specify the percentage denominator definition.  
8. Sample-size Re-assessment and Futility Analysis 
8.1. 
Sample-size Re-assessment  
Sample size re-estimation may occur when MMN data from all 3 periods are available for 12 
patients, or when 20 patients have been dosed and are expected to complete the study, 
whichever is sooner. To ensure adequate study power, sample size may be increased up to a total 
of 40 patients.  
The original study SAP describes procedures for a blinded interim analysis and sample size re-
assessment. Upon review of the outputs from the blinded interim analysis (which included data 
only from the first 12 subjects, who had already completed the study), the Sponsor determined 
that an unblinded analysis of those interim data is necessary to properly inform decisions about 
study continuation and dose selection. Unblinding of the interim analysis data was thus 
introduced in Protocol Amendment 4, and the SAP has been modified accordingly.  
The unblinded sample size re-estimation procedure will be performed utilizing the following 
steps: 
1) Based on treatment allocations, only subjects with evaluable MMN data from all three 
study periods will be included in the sample size re-estimation. 
2) Sample size re-estimation calculation will be based on the specifications of 
approximately 80% power and alpha=0.10 utilizing SAS Proc GLMPOWER for Analysis of 
Variance and the unblinded group values by treatment assignment (placebo, CVN058 15 
mg, CVN058 150 mg) and standard deviation values from the twelve (12) study subjects.    
 


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8.2. 
Interim Futility Analysis 
As noted above, the original SAP describes procedures for a blinded interim analysis, while 
unblinding of the interim analysis was introduced in Protocol Amendment 4.  This version (3.0) 
of the SAP has been modified accordingly to incorporate changes that correspond to the updates 
in Protocol Amendment 4. 
An unblinded interim analysis for futility will be performed when twelve (12) subjects have 
completed all study visits.  An analysis structured identically to the Primary Analysis, unblinded 
to treatment, will be performed using data only from the first 12 subjects, who have already 
completed the study. This analysis will utilize the O’Brien-Fleming group-sequential stopping 
boundary to control alpha (α).  SAS Proc SEQTEST will be employed to perform the conditional 
power analysis for one interim analysis.  Study stoppage for futility may occur if conditional 
power for both active treatment arms is very low.   
However, multiple stopping rules may be implemented if preliminary results indicate that the 
study may yield beneficial results based on other outcome variables.  Additional outcome 
variables to assess in determining study stoppage include, but are not limited to:   
• 
Early phase (120 msec - 200 msec) MMN 
• 
Late phase (200 msec - 260 msec) MMN 
• 
Cohen’s d for MMN 
• 
Differences in the secondary endpoints when comparing treatment assignments, utilizing 
appropriate testing (test selection dependent upon frequency counts) for comparisons of 
proportions. 
Additionally, prior to study stoppage, an assessment will be performed to calculate the 
conditional power values associated with protocol-permissible increases in the sample size (i.e., 
up to N=40), based on the observed unblinded data at the time of the interim analysis.   


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9. Background Characteristics 
9.1. 
Subject Disposition 
Study completion and reasons for discontinuation for all randomized subjects in the study will be 
summarized for each treatment group.  Discontinuations by reason will be tabulated for each 
treatment group.  All randomized subjects and study completion status will be presented in a 
listing. 
9.2. 
Protocol Deviations 
All major protocol deviations will be listed.  
9.3. 
Demographic and Baseline Characteristics 
Continuous demographic variables (e.g., age, height, weight) will be summarized by descriptive 
statistics for each treatment group.  Qualitative demographic characteristics (e.g., gender, race, 
ethnicity) will be summarized by counts and percentages for each treatment group.  
Demographics will also be presented in a subject listing. 
9.4. 
Prior and Concomitant Medications 
Per protocol, medications that might inhibit or mask the effects of CVN058 are not permitted as 
concomitant medications. These include serotonin reuptake inhibitors which increase synaptic 
serotonin levels, as well as drugs that bind to 5-HT3 receptors at clinically relevant concentrations 
or are reported to inhibit signaling through 5-HT3 non-competitively, including some 
antipsychotic drugs [14], [15], [16]. Permissible antipsychotic medications are risperidone 
(Risperdal), haloperidol (Haldol), quetiapine (Seroquel), aripiprazole (Abilify) and paliperidone 
(Invega). 
All medications taken during the course of the study with a start date or an end date on or after 
the date of the first study treatment or marked as ongoing will be considered concomitant. 
Medications stopped prior to the date of the first study treatment will be considered prior 
medications.  
If start and/or end dates for medications are missing, the dates will be imputed as described 
below.   


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Imputing partial or missing start dates: 
• 
If the year is unknown, the start date will not be imputed.  The data will remain missing. 
• 
If the month is unknown, and the year is the same as the first treatment date of the study, 
and the corresponding stop date is not prior to the first treatment date of the study, then 
impute the month and day of the date to be equal to the first dose month and day.  
Otherwise, impute the month as January. 
• 
If the day is unknown and the month and year are the same as the first treatment date of 
the study, and the corresponding stop date is not prior to the first treatment date of the 
study, then impute the day to be equal to the day of the first treatment.  Otherwise, 
impute the day as ‘01’. 
Imputing partial or missing end dates: 
• 
If the year is unknown, the end date will not be imputed.  The data will remain missing. 
• 
If the month is unknown, impute the month as December. 
• 
If the day is unknown, impute the day to be the last day of the month. 
If 
an 
imputed 
stop 
date 
is 
greater 
than 
the 
last 
medication 
date 
or 
study 
completion/discontinuation date, then the imputed stop date will be set equal to the maximum 
of these two dates (last medication date or completion/discontinuation date). 
The number and percentage of subjects using each concomitant medication will be summarized 
for each dose group according to the World Health Organization Drug Dictionary (WHODRUG) 
(Version 01 March 2018) Anatomic Therapeutic Class (ATC) Level II preferred term. Subjects with 
multiple use of a concomitant medication during a treatment period will be counted only once 
for a given drug class or Preferred Term (PT) for the treatment period. Medication summaries 
will be based on the Safety Population (SAF) and presented in summary tables and a subject 
listing. 
9.5. 
Medical History 
Medical history (prior and ongoing medical illness) will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA, Version 21.0) coding dictionary.  Medical history to be obtained 
will include determining whether the subject has any significant conditions or diseases relevant 
to the disease under study that stopped at or prior to signing of informed consent. Ongoing 


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conditions are considered concurrent medical conditions.  Medication history information to be 
obtained includes any medication relevant to eligibility criteria stopped at or within 45 days prior 
to signing of informed consent. 
Prior and ongoing medical conditions will be summarized by presenting for each group the 
number and percentage of subjects having any condition. Prior and ongoing conditions will be 
presented in separate Medical History tables. 
Subject data listing of all medical history will also be presented. 
10. Adjustments for Covariates 
Randomization for this study will be stratified by the study site in which subjects are enrolled.  
The model for the primary analysis will include this stratification variable as a main effect.  This 
stratification variable may also be included as a factor for select secondary variables. Baseline 
values will also be used as a covariate when baseline is available for the endpoint.  
11. Safety Analysis 
All safety analysis will be based on the SAF population.  Analysis using the SAF population will be 
based on the actual treatment received. 
11.1. 
Pre-treatment Events and Adverse Events 
All Pre-treatment Events (PTEs) will be presented in a subject-level listing. 
Adverse events and medical conditions will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) (Version 21.0). Treatment-emergent adverse events (TEAEs) will be defined 
as any event with onset during or after the first dose of study treatment (active or placebo).   
Treatment-emergent adverse events will be summarized for each treatment group by presenting 
the number and percentage of subjects having any treatment-emergent AE, having an AE in each 
body system, and having each individual AE. (Note: In any given category [e.g., body system] a 
subject will only be counted once.) 
Serious TEAEs, TEAEs by severity and TEAEs by relationship to study drug will also be summarized 
by treatment group.   


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All AEs will be presented in a subject-level listing.   
11.2. 
Laboratory Data 
The summary statistics of raw data (hematology, chemistry, coagulation and applicable 
urinalysis) and change from baseline values (means, medians, standard deviations, min, and max) 
will be presented.  For urinalysis parameters that are categorical, the number and percentage of 
subjects falling under each category of the test will be presented.  Clinical laboratory tests to be 
performed are: 
Category 
Parameters 
Hematology 
RBC, WBC with differential (percentage and absolute), 
Hemoglobin, Hematocrit, Platelets, Prothrombin Time (PT), 
International Normalized Ratio (INR), Partial Thromboplastin 
Time (PTT) 
Serum Chemistry 
ALT, Albumin, Alkaline phosphatase, AST, Total bilirubin, 
Direct bilirubin, Total protein, Creatinine, Blood urea nitrogen, 
Creatine kinase, GGT, Potassium, Sodium, Glucose, Chloride, 
Bicarbonate, Calcium  
Urinalysis 
pH, Specific gravity, Protein, Glucose, Blood, Nitrite 
 
Microscopic Analysis (only if positive dipstick results):  
.  RBC/high power field 
.  WBC/high power field 
.  Epithelial cells, casts etc. 
11.3. 
Vital Signs and Body Measurements 
Data from vital signs and body measurements (see below) will be listed. Observed values and 
change from baseline will be summarized by treatment group.  Variables to be summarized are: 
Variable 
Heart Rate 
Diastolic Blood Pressure 


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Systolic Blood Pressure 
Respiratory Rate 
Temperature 
Weight 
   
11.4. 
ECG Assessment 
Data from ECG measurements (heart rate, PR interval, RR interval, QRS interval, QT interval, QTcF 
and QTcB intervals) will be presented in subject-level listings. 
11.5. 
Additional Assessment Items 
Physical Examination, Urine Pregnancy, C-SSRS, PANSS and qEEG results will be presented in 
subject-level listings. 
 
 
 
 


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REFERENCES  
 
1. 
Green MF. Cognitive impairment and functional outcome in schizophrenia and bipolar 
disorder. J Clin Psychiatry 2006;67 Suppl 9:3-8; discussion 36-42.   
2. 
Harvey PD, Velligan DI, Bellack AS. Performance-based measures of functional skills: 
usefulness in clinical treatment studies. Schizophr Bull 2007;33(5):1138-48.   
3. Heinrichs RW. The primacy of cognition in schizophrenia. Am Psychol 2005;60(3):229-42.  
4. 
Javitt DC. Neurophysiological models for new treatment development in schizophrenia: 
early sensory approaches. The New York Academy of Sciences. 2015;1344: 92-104. 
5. 
Lee S, Hjerling-Leffler J, Zagha E, Fishell G, Rudy B. The largest group of superficial 
neocortical GABAergic interneurons expresses ionotropic serotonin receptors. J Neurosci 
2010;30(50):16796-808. 
6. 
Lummis SC. 5-HT3 receptors. J Biol Chem 2012;287(48):40239-45.   
7. 
Javitt D and Sweet R. Auditory dysfunction in schizophrenia: integrating clinical and basic 
features. Nat Rev Neurosci. 2015; 16(9): 535–550. doi:10.1038/nrn4002.   
8. 
Adler LE, Cawthra EM, Donovan KA, Harris JG, Nagamoto HT, Olincy A, et al. Improved p50 
auditory gating with ondansetron in medicated schizophrenia patients. Am J Psychiatry 
2005;162(2):386-8.   
9. 
Koike K, Hashimoto K, Takai N, Shimizu E, Komatsu N, Watanabe H, et al. Tropisetron 
improves deficits in auditory P50 suppression in schizophrenia. Schizophr Res 
2005;76(1):67-72.   
10. Eisensamer B, Uhr M, Meyr S, Gimpl G, Deiml T, Rammes G, Lambert JJ, Zieglgänsberger W, 
Holsboer F, Rupprecht R. Antidepressants and antipsychotic drugs colocalize with 5-HT3 
receptors in raft-like domains. J Neurosci. 2005 Nov 2;25(44):10198-206. PubMed PMID: 
16267227.   
11. Eisensamer B, Rammes G, Gimpl G, Shapa M, Ferrari U, Hapfelmeier G, Bondy B, Parsons C, 
Gilling K, Zieglgänsberger W, Holsboer F, Rupprecht R. Antidepressants are functional 
antagonists at the serotonin type 3 (5-HT3) receptor. Mol Psychiatry. 2003 Nov;8(12):994- 
1007. PubMed PMID: 14647397.   
12. Rammes G, Eisensamer B, Ferrari U, Shapa M, Gimpl G, Gilling K, Parsons C, Riering K, 
Hapfelmeier G, Bondy B, Zieglgänsberger W, Holsboer F, Rupprecht R. Antipsychotic drugs 


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antagonize human serotonin type 3 receptor currents in a noncompetitive manner. Mol 
Psychiatry. 2004 Sep;9(9):846-58, 818. PubMed PMID: 15024394. 
13. O’Brien, P, Fleming, T. A multiple testing procedure for clinical trials.  Biometrics, 1979 Sep; 
35(3):549-56.  PubMed PMID:  497341.   
14. Eisensamer B, Uhr M, Meyr S, Gimpl G, Deiml T, Rammes G, Lambert JJ, Zieglgänsberger W, 
Holsboer F, Rupprecht R. Antidepressants and antipsychotic drugs colocalize with 5-HT3 
receptors in raft-like domains. J Neurosci. 2005 Nov 2;25(44):10198-206. PubMed PMID: 
16267227.   
15. Eisensamer B, Rammes G, Gimpl G, Shapa M, Ferrari U, Hapfelmeier G, Bondy B, Parsons C, 
Gilling K, Zieglgänsberger W, Holsboer F, Rupprecht R. Antidepressants are functional 
antagonists at the serotonin type 3 (5-HT3) receptor. Mol Psychiatry. 2003 Nov;8(12):994- 
1007. PubMed PMID: 14647397. 
16. Rammes G, Eisensamer B, Ferrari U, Shapa M, Gimpl G, Gilling K, Parsons C, Riering K, 
Hapfelmeier G, Bondy B, Zieglgänsberger W, Holsboer F, Rupprecht R. Antipsychotic drugs 
antagonize human serotonin type 3 receptor currents in a noncompetitive manner. Mol 
Psychiatry. 2004 Sep;9(9):846-58, 818. PubMed PMID: 15024394. 
 
 
 


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12. Planned Tables, Listings and Figures 
12.1. 
Planned Tables 
Table Number 
Table Title 
14.1.1.1 
Subject Disposition by Treatment Sequence and Overall (All Subjects) 
14.1.1.2 
Subject Disposition by Dose Level and Overall (All Subjects) 
14.1.2.1 
Demographics and Baseline Characteristics by Treatment Sequence and Overall (All 
Subjects) 
14.1.2.2 
Demographics and Baseline Characteristics by Dose Level and Overall (All Subjects) 
14.1.3.1 
Medical History by Dose Level and Overall (All Subjects):  Reported at Baseline 
14.1.3.2 
Medical History by Dose Level and Overall (All Subjects):  Ongoing 
14.2.1.1 
Primary Analysis:  MMN Improvement (CVN058 vs. Placebo), Summary Statistics and 
Modeling Summary of Amplitude of Duration MMN (PD) by Dose Level  
14.2.2.1 
Secondary Analysis:  Summary of Subject Adverse Events (SAF) by Most Recently 
Administered Dose Level and Overall 
14.2.2.2 
Treatment-Emergent Adverse Events by SOC and PT (SAF) by Most Recently 
Administered Dose Level and Overall 
14.2.2.3 
Serious Treatment-Emergent Adverse Events by SOC and PT (SAF) by Most Recently 
Administered Dose Level and Overall 
14.2.2.4 
Treatment-Emergent Adverse Events by Severity, SOC and PT (SAF) by Most Recently 
Administered Dose Level and Overall 
14.2.2.5 
Treatment-Emergent Adverse Events by Relationship to Study Drug (SAF) by Most 
Recently Administered Dose Level and Overall 
14.2.3.1 
Secondary Analysis:  Summary of Clinically Significant Abnormal Laboratory Test Results 
(SAF) by Most Recently Administered Dose Level and Overall 
14.2.3.2 
Summary of Hematology Laboratory Data (SAF) Overall 
14.2.3.3 
Summary of Chemistry Laboratory Data (SAF) Overall 
14.2.3.4 
Summary of Urinalysis Laboratory Data (Continuous Variables) (SAF) Overall 
14.2.3.5 
Summary of Urinalysis Laboratory Data (Categorical Variables) (SAF) Overall 
14.2.4 
Summary of Vital Signs and Body Measurements (SAF) by Most Recently Administered 
Dose Level and Overall 
14.2.5.1 
Pharmacokinetic Analysis:  Summary at Scheduled Sampling Intervals (PK) by Dose Level 
14.2.5.2 
Pharmacokinetic Analysis:  Summary of PK Parameters (PK) by Dose Level 
14.2.5.3.1 
Pharmacodynamic Analysis:  Summary of P50 Ratio (S2/S1) (PD) by Dose Level 
14.2.5.3.2 
Pharmacodynamic Analysis:  Summary of P50 Differences (S2-S1) (PD) by Dose Level 
14.2.5.3.3 
Pharmacodynamic Analysis:  Summary of Pre-stimulus Gamma Amplitude (PD) by Dose 
Level 
14.2.5.3.4 
Pharmacodynamic Analysis:  Summary of P300 Amplitude (PD) by Dose Level 
14.2.5.3.5 
Pharmacodynamic Analysis:  Summary of P300 Latency (PD) by Dose Level 
14.2.5.3.6 
Pharmacodynamic Analysis:  Summary of Amplitude of Frequency MMN (PD) by Dose 
Level 


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Table Number 
Table Title 
14.2.5.3.7 
Pharmacodynamic Analysis:  Summary of Amplitude of Intensity MMN (PD) by Dose 
Level 
14.2.5.3.8 
Pharmacodynamic Analysis:  Summary of Amplitude of Location MMN (PD) by Dose 
Level 
14.2.5.3.9 
Pharmacodynamic Analysis:  Summary of Amplitude of Frequency-Modulation MMN 
(PD) by Dose Level 
14.2.5.3.10 
Pharmacodynamic Analysis:  Summary of Latency to Peak Amplitude of Frequency 
MMN (PD) by Dose Level 
14.2.5.3.11 
Pharmacodynamic Analysis:  Summary of Latency to Peak Amplitude of Intensity MMN 
(PD) by Dose Level 
14.2.5.3.12 
Pharmacodynamic Analysis:  Summary of Latency to Peak Amplitude of Location MMN 
(PD) by Dose Level 
14.2.5.3.13 
Pharmacodynamic Analysis:  Summary of Latency to Peak Amplitude of Frequency-
Modulation MMN (PD) by Dose Level 
14.2.5.4.1 
Pharmacodynamic Analysis:  ANCOVA Modeling (PD) of P50 Ratio (S2/S1) 
14.2.5.4.2 
Pharmacodynamic Analysis:  ANCOVA Modeling (PD) of P50 Differences (S2-S1) 
14.2.5.4.3 
Pharmacodynamic Analysis:  ANCOVA Modeling (PD) of Pre-stimulus Gamma Amplitude 
14.2.5.4.4 
Pharmacodynamic Analysis:  ANCOVA Modeling (PD) of P300 Amplitude 
14.2.5.4.5 
Pharmacodynamic Analysis:  ANCOVA Modeling (PD) of P300 Latency 
14.2.5.4.6 
Pharmacodynamic Analysis:  ANCOVA Modeling (PD) of Amplitude of Frequency MMN 
14.2.5.4.7 
Pharmacodynamic Analysis:  ANCOVA Modeling (PD) of Amplitude of Intensity MMN 
14.2.5.4.8 
Pharmacodynamic Analysis:  ANCOVA Modeling (PD) of Amplitude of Location MMN 
14.2.5.4.9 
Pharmacodynamic Analysis:  ANCOVA Modeling (PD) of Frequency-Modulation MMN 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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12.2. 
Planned Listings 
Listing 
Number 
Listing Title 
16.2.1.1 
Subject Disposition 
16.2.1.2 
Subject Screen Failures 
16.2.2 
Protocol Deviations 
16.2.3 
Demographics 
16.2.4.1 
Medical History 
16.2.4.2 
Prior and Concomitant Medications 
16.2.5.1 
Primary Endpoints:  MMN  
16.2.5.2 
Exploratory Endpoints:  P50, qEEG and P300 
16.2.5.3 
Audiometric Screening and Tone Matching Test 
16.2.6.1 
Pre-treatment Events 
16.2.6.2 
Adverse Events 
16.2.6.3 
Serious Adverse Events 
16.2.7.1 
Hematology Laboratory Parameters 
16.2.7.2 
Chemistry Laboratory Parameters 
16.2.7.3 
Urinalysis Laboratory Parameters 
16.2.7.4 
Urine Pregnancy Test 
16.2.8.1 
Physical Exam 
16.2.8.2 
Vital Signs 
16.2.8.3 
ECG 
16.2.9.1 
C-SSRS 
16.2.9.2 
PANSS 
16.2.10 
Pharmacokinetics 
16.2.11 
Eligibility Criteria 
16.2.12 
Study Drug Administration 


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12.3. 
Planned Figures 
Figure Number 
Figure Title 
16.3.1.1 
Box-plot:  Amplitude of Duration MMN (CVN058 versus Placebo) 
16.3.1.2 
Box-plot:  Change (CVN058 - Placebo) in Amplitude of Duration MMN 
16.3.2.1 
Box-plot:  P50 Ratio (S2/S1) (CVN058 versus Placebo)  
16.3.2.2 
Box-plot:  P50 Difference (S2-S1) (CVN058 versus Placebo) 
16.3.3 
Box-plot:  Pre-stimulus Gamma Amplitude (CVN058 versus Placebo) 
16.3.4.1 
Box-plot:  P300 Amplitude (CVN058 versus Placebo) 
16.3.4.2 
Box-plot:  P300 Latency (CVN058 versus Placebo)  
16.3.5.1.1 
Box-plot:  Amplitude of Frequency MMN (CVN058 versus Placebo) 
16.3.5.1.2 
Box-plot:  Amplitude of Intensity MMN (CVN058 versus Placebo) 
16.3.5.1.3 
Box-plot:  Amplitude of Location MMN (CVN058 versus Placebo) 
16.3.5.1.4 
Box-plot:  Amplitude of Frequency-Modulation MMN (CVN058 versus Placebo)  
16.3.5.2.1 
Box-plot:  Latency to Peak Amplitude of Frequency MMN (CVN058 versus Placebo)  
16.3.5.2.2 
Box-plot:  Latency to Peak Amplitude of Intensity MMN (CVN058 versus Placebo) 
16.3.5.2.3 
Box-plot:  Latency to Peak Amplitude of Location MMN  
16.3.5.2.4 
Box-plot:  Latency to Peak Amplitude of Frequency-Modulation MMN  
16.3.6.1 
Pharmacokinetic Relationships:  Scatterplot of Individual CVN058 Concentration Values 
Versus Time by Dose with Calculations of Summary Statistics 
16.3.6.4.1.1 
Pharmacokinetic Relationships:  Scatterplot of Change from Placebo in Amplitude of 
Duration MMN versus CVN058 Concentration at 1-Hour Timepoint 
16.3.6.4.1.2 
Pharmacokinetic Relationships:  Scatterplot of Change from Placebo in Amplitude of 
Duration MMN versus CVN058 Concentration at 5-Hour Timepoint 
16.3.6.4.2.1 
Pharmacokinetic Relationships:  Scatterplot of Change from Placebo in P50 Ratio (S2/S1) 
versus CVN058 Concentration at 1-Hour Timepoint 
16.3.6.4.2.2 
Pharmacokinetic Relationships:  Scatterplot of Change from Placebo in P50 Ratio (S2/S1) 
versus CVN058 Concentration at 5-Hour Timepoint 
16.3.6.4.3.1 
Pharmacokinetic Relationships:  Scatterplot of Change from Placebo in P50 Difference 
(S2-S1) versus CVN058 Concentration at 1-Hour Timepoint 
16.3.6.4.3.2 
Pharmacokinetic Relationships:  Scatterplot of Change from Placebo in P50 Difference 
(S2-S1) versus CVN058 Concentration at 5-Hour Timepoint 
16.3.6.4.4.1 
Pharmacokinetic Relationships:  Scatterplot of Change from Placebo in Pre-Stimulus 
Gamma Amplitude versus CVN058 Concentration at 1-Hour Timepoint 
16.3.6.4.4.2 
Pharmacokinetic Relationships:  Scatterplot of Change from Placebo in Pre-Stimulus 
Gamma Amplitude versus CVN058 Concentration at 5-Hour Timepoint 
16.3.6.4.5.1 
Pharmacokinetic Relationships:  Scatterplot of Change from Placebo in P300 Amplitude 
versus CVN058 Concentration at 1-Hour Timepoint 
16.3.6.4.5.2 
Pharmacokinetic Relationships:  Scatterplot of Change from Placebo in P300 Amplitude 
versus CVN058 Concentration at 5-Hour Timepoint