A Randomized, Double-Blind, Placebo-Controlled, Multiple Ascending Dose Study to Evaluate the Safety, Tolerability and Pharmacokinetics of ITI-333 in Healthy Subjects
Phase: PHASE1
Conditions: Healthy Volunteers
Sponsor: Intra-Cellular Therapies, Inc.

NCT05732194 
Study ID: ITI-333-002 
Title: A Randomized, Double-Blind, Placebo-Controlled, Multiple Ascending 
Dose Study to Evaluate the Safety, Tolerability and Pharmacokinetics of ITI-
333 in Healthy Subjects 
Protocol Amendment Version 1.0 Date: November 06, 2023 

 
 
 
 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT 1: SUMMARY OF CHANGES ..................................................... 3 
TABLE OF CONTENTS ................................................................................................................ 4 
LIST OF TABLES .......................................................................................................................... 8 
LIST OF ABBREVIATIONS ......................................................................................................... 9 
1. 
PROTOCOL SYNOPSIS AND SCHEDULE OF EVALUATIONS ................................ 11 
2. 
ETHICAL CONSIDERATIONS ....................................................................................... 19 
2.1 
Institutional Review Board............................................................................................. 19 
2.2 
Ethical Conduct of the Study ......................................................................................... 19 
2.3 
Subject Information and Informed Consent ................................................................... 19 
3. 
STUDY ADMINISTRATIVE STRUCTURE ................................................................... 20 
4. 
INTRODUCTION ............................................................................................................. 21 
5. 
STUDY OBJECTIVES ...................................................................................................... 23 
6. 
INVESTIGATIONAL PLAN ............................................................................................ 24 
6.1 
Overall Study Design and Plan ...................................................................................... 24 
6.2 
Scientific Rationale for Study Design ............................................................................ 25 
6.2.1 
Study Design............................................................................................................... 25 
 
 
6.3 
Study Population ............................................................................................................ 26 
6.3.1 
Inclusion Criteria ........................................................................................................ 26 
6.3.2 
Exclusion Criteria ....................................................................................................... 27 
6.4 
Discontinuation of Subjects from Therapy or Assessment ............................................ 29 
6.4.1 
Subject Replacement Procedures................................................................................ 30 
6.5 
Changes in the Conduct of the Study ............................................................................. 30 
7. 
STUDY DRUGS ................................................................................................................ 31 
7.1 
Study Drugs Administered ............................................................................................. 31 
7.1.1 
ITI-333 ........................................................................................................................ 31 
7.1.2 
Placebo........................................................................................................................ 32 
7.2 
Preparation, Handling, Storage, and Accountability of Study Drug .............................. 32 
 
 
7.2.2 
Handling and Storage ................................................................................................. 32 

 
 
 
 
7.2.3 
Study Drug Accountability ......................................................................................... 32 
7.3 
Method of Assigning Subjects to Treatment Groups ..................................................... 32 
7.4 
Blinding and Unblinding Procedures ............................................................................. 33 
7.5 
Monitoring Treatment Compliance ................................................................................ 34 
7.6 
Prior and Concomitant Medications ............................................................................... 34 
7.6.1 
Prior medications ........................................................................................................ 34 
7.6.2 
Concomitant Medications ........................................................................................... 34 
7.7 
General Considerations and Restrictions ....................................................................... 35 
7.7.1 
Meals and Dietary Restrictions................................................................................... 35 
7.7.2 
Caffeine, Alcohol, Nicotine, and Activity Restrictions .............................................. 35 
8. 
ASSESSMENTS ................................................................................................................ 36 
8.1 
Safety .............................................................................................................................. 36 
8.1.1 
Adverse Events ........................................................................................................... 36 
8.1.2 
Pregnancy ................................................................................................................... 40 
8.1.3 
Potential Hy’s Law Cases ........................................................................................... 41 
 
 
8.1.5 
Opioid-specific Safety Considerations ....................................................................... 45 
8.1.6 
Clinical Laboratory Determinations ........................................................................... 46 
8.1.7 
Electrocardiograms ..................................................................................................... 47 
8.1.8 
Vital Signs .................................................................................................................. 48 
 
 
8.2 
Pharmacokinetic Assessments ........................................................................................ 50 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
9. 
STATISTICAL METHODS .............................................................................................. 65 
9.1 
General Considerations .................................................................................................. 65 
9.2 
Determination of Sample Size ........................................................................................ 65 
9.3 
Analysis Populations ...................................................................................................... 65 
9.4 
Statistical Analyses ........................................................................................................ 65 
9.4.1 
Subject Disposition ..................................................................................................... 65 
9.4.2 
Demographic and Other Baseline Characteristics ...................................................... 66 
9.4.3 
Prior and Concomitant Medication............................................................................. 66 
9.4.4 
Extent of Exposure and Treatment Compliance ......................................................... 66 
9.4.5 
Safety Analyses .......................................................................................................... 67 
9.4.6 
Analyses of Pharmacokinetic Endpoints .................................................................... 68 
 
 
 
 
9.5 
Interim Analysis ............................................................................................................. 70 
9.6 
Data Monitoring Committee (DMC) .............................................................................. 71 
9.7 
Protocol Deviations ........................................................................................................ 71 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL MONITORING ............. 72 
10.1 
Study Termination .......................................................................................................... 72 
10.2 
Investigator Obligations ................................................................................................. 72 
10.2.1 Documentation............................................................................................................ 72 
10.2.2 Performance ................................................................................................................ 72 
10.2.3 Use of Investigational Materials ................................................................................. 72 
10.2.4 Case Report Forms ..................................................................................................... 73 
10.2.5 Retention and Review of Records .............................................................................. 73 
10.2.6 Subject Confidentiality ............................................................................................... 73 
10.3 
Data Quality Assurance .................................................................................................. 73 
10.3.1 Data Monitoring ......................................................................................................... 73 
10.3.2 Data Recording and Documentation........................................................................... 74 
 
 

 
 
 
 
11. 
REFERENCES .................................................................................................................. 76 
12. 
APPENDICES ................................................................................................................... 77 
12.1 
Appendix I. Elements Of Informed Consent .................................................................. 77 
13. 
INVESTIGATOR SIGNATURE PAGE ........................................................................... 79 

 
 
 
 
LIST OF TABLES 
 
Table 8-1: Medically Significant Adverse Events ........................................................................ 43 

 
 
 
 
FDA 
Food and Drug Administration 
FR 
Federal Register 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency 
 
 
ICF 
informed consent form 
ICH 
International Council on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use  
IRB 
Institutional Review Board 
IUD 
intrauterine device 
 
 
 
 
MedDRA 
Medical Dictionary for Regulatory Activities 
msec 
millisecond(s) 
 
 
 
 
PK 
pharmacokinetic 
 
 
 
  
QTcF 
QT interval corrected for heart rate using the Fridericia formula  
SAD 
single ascending dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SOC 
system organ class 
SpO2 
Oxygen saturation 
 
 
TEAE 
treatment-emergent adverse event 
 
 
Tmax 
time to reach maximum observed plasma drug concentration  
UDS 
urine drug screen 
ULN 
upper limit of normal 
 
 
 
 

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2. 
ETHICAL CONSIDERATIONS 
2.1 
Institutional Review Board  
Approval by the Institutional Review Board (IRB) before the start of the study will be the 
responsibility of the Investigator. A copy of the approval letter will be supplied to Intra-Cellular 
Therapies, Inc. (the Sponsor) or its designee along with a roster of IRB members. During the study, 
the Investigator will provide timely and accurate reports to the IRB on the progress of the study, 
at intervals not exceeding 1 year (or as appropriate) and will notify the IRB of serious adverse 
events (SAEs) or other significant safety findings. The study protocol, informed consent form 
(ICF), information sheet, advertisements, and amendments (if any) will be approved by the IRB at 
the study center in conformance with applicable regulations. 
2.2 
Ethical Conduct of the Study 
This clinical study will be conducted in accordance with the ethical principles that have their 
origins in the Declaration of Helsinki. This clinical study will comply with the ICH Guidance on 
General Considerations for Clinical Trials (ICH-E8; 62 FR 66113, 17 Dec 1997) and GCP 
(ICH-E6; 62 FR 25692, March 2018), as well as CFR Part 312 and applicable local regulations. 
2.3 
Subject Information and Informed Consent 
A written informed consent in compliance with US Title 21 Code of Federal Regulations (CFR) 
Part 50 shall be obtained from each subject before entering the study or performing any study-
specific procedure that involves risk to the subject. If the ICF is revised during the study, all active 
participating subjects must sign the revised form. The informed consent statement shall contain all 
the elements of informed consent listed in Appendix I of this protocol. 
Before any screening procedures, each prospective subject will be given a full explanation of the 
study and be allowed to read the approved ICF. After receiving an explanation of study procedures, 
subjects will have the opportunity to have any questions answered before signing the ICF. The 
Investigator must address all questions raised by the subject. Each subject will read, assent to an 
understanding of, and sign the ICF. Each subject will be made aware that he/she may withdraw 
from the study at any time. 
The Investigator or designee will also sign the ICF and provide copies of the ICF and the HIPAA 
(Health Insurance Portability and Accountability Act) authorization or other locally applicable 
form to the subject. The Investigator shall retain the signed original ICF and the HIPAA or other 
locally applicable form. 

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3. 
STUDY ADMINISTRATIVE STRUCTURE 
Contact information for vendors responsible for study conduct and a list of Sponsor contacts will 
be provided to the study center. 

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7. Willing to be confined to the clinical research unit for the duration of the inpatient period 
of the study, and, in the opinion of the Investigator, willing and able to comply with all 
Investigator and staff instructions. 
6.3.2 Exclusion Criteria 
Subjects who meet any of the following criteria will not be eligible to participate in the study: 
1. Clinically significant abnormality within 2 years of Screening that in the Investigator’s 
opinion may place the subject at risk or interfere with study outcome variables; this 
includes, but is not limited to, history of or current cardiac, hepatic, renal, neurologic, 
gastrointestinal, pulmonary, endocrinologic, hematologic, or immunologic disease or 
history of malignancy;  
2. Any clinical condition or procedure (eg, gastric bypass or cholecystectomy) that may 
affect the absorption, distribution, biotransformation, or excretion of ITI-333. Subjects 
with a history of appendectomy are eligible for study participation; 
3. Current or recent (within 3 months prior to Screening) unstable angina; a history of 
myocardial infarction within 3 months prior to Screening; or a history of a clinically 
significant cardiac arrhythmia; 
4. History of psychiatric condition that in the Investigator’s opinion may be detrimental to 
participation in the study; 
5. Any history of Substance Use Disorder as defined by the Diagnostic and Statistical 
Manual of Mental Disorders, Fifth Edition, Text Revision (American Psychiatric 
Association, 2022); 
6. Any suicidal ideation including but not limited to wishes to be dead or any thought of 
killing self within 6 months of Screening, any suicide attempt within 2 years prior to 
Screening based on the Columbia-Suicide Severity Rating Scale (C-SSRS), and/or any 
current concerns for subject’s safety as assessed by the Investigator;  
7. Previously participated in an investigational study of ITI-333; 
8. Likely allergy or sensitivity to ITI-333 or its excipients based on known allergies or 
hypersensitivities to drugs with shared pharmacology which may be suggestive of an 
increased potential for an adverse reaction to ITI-333; 
 
 
11. Clinically significant abnormal findings in vital sign assessments, including oxygen 
saturation (SpO2) < 96% and respiratory rate < 12 breaths per minute, supine systolic 
blood pressure > 140 mm Hg or < 90 mm Hg, or supine diastolic blood pressure 
> 90 mm Hg or < 50 mm Hg, or supine pulse rate > 100 bpm or < 45 bpm at Screening or 
Day -1. One repeat of vital signs assessment may be performed to confirm out of range 
values; 

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28. Has participated in strenuous activity within 48 hours prior to dosing with study drug on 
Day 1; 
29. Directly or indirectly involved in the conduct and administration of this study as an 
investigator, sub-investigator, study coordinator or other study staff member, or an 
employee of the Sponsor or a first-degree family member, significant other or relative 
residing with one of the above persons involved directly or indirectly in the study;  
30. Planning or scheduled for any surgical procedure or dental care during the duration of the 
study; 
31. Females who are currently breastfeeding; 
32. Any subject judged by the Investigator to be inappropriate for the study. 
6.4 
Discontinuation of Subjects from Therapy or Assessment 
A premature discontinuation will occur when a subject who receives at least one dose of study 
drug ceases participation in the study, regardless of circumstances, before the completion of all 
study visits and procedures. Subjects can be prematurely discontinued from the study for the 
following reasons: 
 Death 
 AE 
 Lost to follow-up  
 Pregnancy 
 Physician decision 
 Protocol violation 
 Study terminated by Sponsor 
 Withdrawal by subject  
 Other 
NOTE: If a subject discontinues due to withdrawal of consent and a concurrent AE was reported, 
the study center should query and confirm the primary reason for discontinuation and record the 
primary reason for discontinuation on the electronic case report form (eCRF). 
All subjects who received study drug and prematurely discontinue from the study regardless of 
cause should undergo final assessments at the Early Termination (ET) Visit at the time of 
discontinuation. In addition, subjects should return to the study center for the SFU Visit 10 days 
(± 1 day) after the last dose of study drug. 
Subjects who are lost to follow-up and do not return to the study center for final assessments must 
be requested in writing to return to the study center for a final assessment. A copy of the letter, 
together with the source documentation, will be kept in the Investigator’s files.  

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Protocol ITI-333-002 
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The reason for premature discontinuation from the study will be recorded on the Study 
Termination Page of the eCRF. Study center staff may be contacted by the Sponsor after each 
premature discontinuation to ensure that proper characterization of the reason for discontinuation 
is captured. 
6.4.1 Subject Replacement Procedures 
Subjects who prematurely discontinue from the study for any reason may be replaced at the 
discretion of the Sponsor. Replacement subjects will be assigned a new study identification 
number not previously assigned. 
6.5 
Changes in the Conduct of the Study 
Any amendment to this protocol will be provided by the Sponsor in writing to the Investigator. No 
protocol amendment may be implemented before it has been approved by the IRB and the signature 
page, signed by the Investigator, has been received by the Sponsor. If the protocol is amended to 
eliminate or reduce the risk to subjects, the amendment may be implemented before IRB review 
and approval. However, the IRB must be informed in writing of such an amendment, and approval 
must be obtained within reasonable time limits. 

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Protocol ITI-333-002 
Multiple Ascending Dose Study 
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7.7 
General Considerations and Restrictions 
7.7.1 Meals and Dietary Restrictions 
Consumption of any food or beverage containing grapefruit, pomelo, poppy seeds, or Seville 
oranges is not allowed from within 48 hours prior to dosing with study drug on Day 1 through 
completion of the last PK sample collection. 
No water is to be ingested for 1 hour before and 1 hour after each dose administration; during the 
rest of the study, water will be available ad libitum. 
Subjects will be fasted for at least 10 hours prior to each administration of study drug and prior to 
tests for chemistry. Subjects will continue to fast for at least 4 hours after dosing on Days 1 and 
14; and for at least 2 hours postdose on Days 2-13.   
All meals provided while in the study center will be standardized, low-fat meals (< 20 g) and 
should not contain any foods or beverages that are restricted. All study procedures and meals 
should be scheduled at approximately the same time throughout the study, as appropriate. A copy 
of the menu with nutritional content of each component of each meal and snack will be made 
available to the Sponsor before the start of the study. 
7.7.2 Caffeine, Alcohol, Nicotine, and Activity Restrictions 
To be eligible in the study, subjects must have a negative alcohol test at Screening and Day -1. 
Subjects must abstain from consuming alcohol within 48 hours prior to dosing with study drug on 
Day 1 and through completion of the last PK sample collection.  
Consumption of caffeine- and xanthine-containing products is not allowed within 24 hours prior 
to dosing with study drug on Day 1 and through completion of the last PK sample collection. 
Subjects must not have used nicotine or nicotine containing products within the 6 months prior to 
Screening. Subjects must agree to abstain from nicotine and nicotine containing products from 
Screening through completion of all study procedures at the SFU Visit. 
Subjects must refrain from strenuous activity from 48 hours prior to dosing with study drug on 
Day 1 through to completion of all study procedures at the SFU Visit. 

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Preplanned hospitalizations (eg, elective procedures for pre-existing conditions that did not 
worsen, such as cosmetic surgery and hysterectomy) are excluded from SAE reporting.  
8.1.1.3 Classification of Adverse Events and Serious Adverse Events 
8.1.1.3.1 
Severity 
The Investigator will provide an assessment of the severity of each AE by recording a severity 
rating on the appropriate AE reporting page of the subject’s eCRF. Severity, which is a description 
of the intensity of manifestation of the AE, is distinct from seriousness, which implies a subject 
outcome or AE-required treatment measure associated with a threat to life or functionality (Section 
8.1.1.2). Severity will be assessed according to the following scale: 
Mild: 
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities 
of daily living. 
Moderate: 
A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research 
subject. 
Severe: 
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention. 
8.1.1.3.2 
Causality Assessment 
For each occurrence of an AE or SAE, the Investigator must provide an assessment of causal 
relationship to study drug 
. The causality assessment must be 
recorded on the appropriate AE reporting page of the subject’s eCRF. Causal relationship must be 
assessed by answering the following question: 
Is there a reasonable possibility the study drug caused the event? 
Yes : 
There is evidence to suggest a causal relationship between the study drug and 
adverse event, ie:  
 There is a reasonable temporal relationship between the study drug and the event, and  
 The event is unlikely to be attributed to underlying/concurrent disease, other drugs or other 
factors, and/or 
 Positive de-challenge and/or re-challenge exist 
OR 

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9.4.2 Demographic and Other Baseline Characteristics 
Demographic parameters (eg, age, race, ethnicity, sex, weight, height, BMI) and other baseline 
characteristics will be summarized by cohort and treatment, ITI-333 combined across all cohorts, 
placebo combined across all cohorts, and total across all cohorts for the Safety Population. 
Descriptive statistics (n, mean, median, SD, minimum, and maximum) will be presented for 
continuous variables. Frequency distributions (counts and percentages) will be presented for 
categorical variables. 
Medical and surgical history and physical findings will be summarized by system organ class and 
preferred term and by cohort and treatment, ITI-333 combined across all cohorts, and placebo 
combined across all cohorts for the Safety Population. 
9.4.3 Prior and Concomitant Medication 
A prior medication will be defined as any other medication which started and stopped before the 
first dose of study drug. A prior concomitant medication will be defined as any other medications 
which started before and stopped after the first dose of study drug. A concomitant medication will 
be defined as any other medication which started after the first dose of study drug but before the 
end of the treatment period. 
Prior, prior concomitant, and concomitant medication use will be coded using the latest version of 
the World Health Organization Drug Dictionary and listed by therapeutic class for the Safety 
Population. 
9.4.4 Extent of Exposure and Treatment Compliance 
9.4.4.1 Extent of Exposure 
Each subject will receive an oral dose of ITI-333 once daily for 14 days. Exposure to study drug 
will be summarized for treatment duration, calculated as the number of days from the date of the 
first dose of study drug taken to the date of the last dose taken, inclusive. Descriptive statistics (n, 
mean, median, SD, minimum, and maximum) for exposure to study drug will be presented by 
cohort and treatment, ITI-333 combined across all cohorts, and placebo combined across all 
cohorts for the Safety Population.   
9.4.4.2 Treatment Compliance 
Treatment compliance is defined as the total number of study doses actually taken by a subject 
during the study divided by the number of study doses that were expected to be taken during the 
study multiplied by 100. The total number of study doses actually taken during the study will be 
calculated from the study treatment record in which only entire doses administered will be counted. 
Descriptive statistics for treatment compliance will be presented by cohort and treatment, ITI-333 
combined across all cohorts, and placebo combined across all cohorts for the Safety Population. 

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9.6 
Data Monitoring Committee (DMC) 
An independent DMC will be formed. Details on the composition of the DMC will be provided in 
the DMC charter which will be finalized prior to randomization of any subject. 
The DMC will be provided with unblinded clinical safety data and PK data in order to fully evaluate 
the safety, tolerability, and PK of ITI-333 at each cohort. The DMC will provide recommendations 
on the conduct of the trial, specifically dose escalation. DMC will also review available data when 
any stopping criteria are met within a cohort. Details related to the DMC and the review of the 
data will be provided in the DMC charter. 
9.7 
Protocol Deviations 
A deviation from the protocol is an unanticipated departure from the procedures or processes. A 
major protocol deviation occurs when there is nonadherence to the protocol by the subject or 
Investigator that results in a significant, additional risk to the subject, or may have an effect on the 
integrity of the study data. Major protocol deviations can include, for example, nonadherence to 
inclusion or exclusion criteria or nonadherence to ICH GCP guidelines and may lead to the subject 
being withdrawn from the study. 
The Investigator or designee must document and explain in the subject’s source documentation 
any deviation from the approved protocol. Protocol deviations will be documented by the clinical 
monitor throughout the course of monitoring visits. Investigators will be notified in writing by the 
clinical monitor of protocol deviations. The IRB should be notified of all major protocol deviations 
in a timely manner in accordance with IRB reporting guidelines. 
A listing of major protocol deviations will be provided for the Safety Population. 

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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL MONITORING 
10.1 
Study Termination 
The Sponsor reserves the right to terminate the study in its entirety or at a specific study center 
before study completion.  
10.2 
Investigator Obligations 
10.2.1 Documentation 
The Investigator must provide the following to the Sponsor, before the start of the study: 
 A completed and signed Form FDA 1572. If, during the study, any changes are made that 
are not reflected on Form FDA 1572, a new Form FDA 1572 must be completed and 
returned to the Sponsor for submission to the FDA 
 A fully executed contract 
 The curricula vitae for the Investigator and all sub-Investigators listed on Form FDA 1572, 
including a copy of each physician’s license 
 Financial disclosure agreement completed and signed by the Investigator and all sub-
Investigators listed on Form FDA 1572 
 A copy of the original IRB approval for conducting the study. If the study is ongoing, 
renewals must be submitted at yearly intervals. All subsequent modifications must be 
submitted and approved by the IRB 
 A copy of the IRB-approved ICF 
 A copy of the applicable local privacy forms 
 A list of the IRB members 
 A copy of the laboratory certifications and reference ranges 
 The Investigator’s Statement page in this protocol signed and dated by the Investigator 
10.2.2 Performance 
The Investigator must demonstrate reasonable efforts to recruit qualified subjects for the study. 
10.2.3 Use of Investigational Materials 
Study drug must be stored in a secured place and must be locked. A representative from the 
Sponsor will inventory the study drug at the study center. The Investigator must maintain adequate 
records documenting the receipt and disposition of all study supplies. The Sponsor may supply 
forms on which to record the date the study drug was received and a dispensing record in which 
to record each subject’s use. All unused study drug will either be destroyed at the study center 
upon approval by the Sponsor or returned to the Sponsor-designated central depot, as instructed 
by the Sponsor. 

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10.2.4 Case Report Forms 
All subject data relating to the study, except for data electronically transmitted (eg, central 
laboratory results), will be recorded on eCRFs to be provided by the Sponsor through the EDC 
system. The Investigator is responsible for verifying that all data entries in the eCRFs are accurate 
and correct by electronically signing the completed eCRFs submitted to the Sponsor. The 
Investigator must maintain and retain accurate documentation that supports the information 
entered into the EDC system for source document verification and possible regulatory inspection. 
10.2.5 Retention and Review of Records 
Records and documents pertaining to the conduct of this study, including eCRFs, source 
documents (eg, medical records, laboratory reports), consent forms, regulatory documents, and 
medication inventory records must be retained by the Investigator for a period of at least 15 years 
after study completion unless local regulations or institutional policies require a longer retention 
period or otherwise notified in writing by the Sponsor. 
No study records shall be destroyed without notifying the Sponsor and providing the Sponsor the 
opportunity to arrange long-term storage for such study records or authorizing in writing the 
destruction of records after the required retention period. 
The Investigator must permit access to any documentation relating to the study upon request of 
the Sponsor or applicable regulatory authorities. If the Investigator for the study retires, relocates, 
or for other reasons withdraws from the responsibility of keeping the study records, custody must 
be transferred to a suitable alternate custodian employee of the institution or to a suitably qualified 
and responsible third party. The Sponsor must be notified in writing of the name and address of 
the new custodian in advance of the transfer. 
10.2.6 Subject Confidentiality 
All subject records will be identified by subject identification number only. Subjects’ names are 
not to be transmitted to the Sponsor.  
10.3 
Data Quality Assurance 
10.3.1 Data Monitoring 
Before any subject enters the study, a representative of the Sponsor will meet with the Investigator 
and the study center staff to review the procedures to be followed during the study. Electronic data 
capture (EDC) functionality training is provided via computer-based training to train Investigators 
and authorized designees on recording the data in the eCRFs using the EDC system.  
The Investigator will maintain complete source documents (eg, signed ICFs, written or electronic 
medical records, pharmacy records). Source documents provide evidence for the existence of study 
subjects and substantiate the integrity of the data collected in the eCRF. The Investigator will make 
available to the study monitor or designee source documents (written notes and electronic medical 
records, if used), signed ICFs, and all other study-related documents. 

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Study monitor or designee, appointed by the Sponsor, will perform ongoing source document 
verification to confirm that data entered into the eCRF are accurate, complete, and verifiable from 
source documents; that the safety and rights of subjects are protected; and that the study is 
conducted in accordance with the currently approved protocol and any other study agreements, 
ICH GCP, and all applicable regulatory requirements. After the first subject is enrolled, the study 
monitor or designee, will periodically monitor the progress of the study by conducting on-site or 
remote visits. In addition to on-site source document verification, study monitors will review study 
progress remotely, possibly warranting more frequent communication and/or study center visits. 
Details of monitoring activities are provided in the Monitoring Plan. 
10.3.2 Data Recording and Documentation 
Data collection will involve the use of the EDC system, to which only authorized personnel will 
have access. Subject data are to be entered into the EDC system by the Investigator or designee 
using their assigned EDC user account. The Investigator or designee will record all subjects’ study 
data in the eCRF, unless the data are transmitted to the Sponsor electronically (eg, laboratory data). 
Data entered in the eCRF must be consistent with the source documents or the discrepancies must 
be explained. The Investigator is responsible for verifying that all data entries are accurate and 
correct. The Investigator may need to request previous or external medical records to support study 
data. 
The Sponsor is responsible for the data management of this study, including quality checking of 
the data. After data entry into the EDC system by the Investigator or designee, a combination of 
manual and programmatic edit checks will be used to review the data for completeness, logic, and 
adherence to study protocol. As a result of these edit checks, data monitoring, and reviews, queries 
may be electronically issued to the study center and should be answered electronically via the EDC 
system. Each query will carry identifying information (assigned username, date, and time) to assist 
the Sponsor and the Investigator on the origin of the data clarification request and the response 
provided by the Investigator. All data changes made to the subject’s data via a data query will be 
approved by the Investigator prior to final database lock. 
The Investigator or designee will be responsible for approving all changes performed on the data 
and endorsing the subject data within the EDC system. This approval method will include applying 
an electronic signature linked to a uniquely assigned username and password that together will 
represent a traditional handwritten signature used in the past. After all data have been reviewed 
and all issues have been resolved, the database will be locked. 
All data collected in the context of this study will be stored and evaluated per regulatory 
requirements and applicable guidance for electronic records. Also, data will be stored and 
evaluated in such a way as to guarantee subject confidentiality in accordance with the legal 
stipulations applying to confidentiality of data. Study records (eg, copies of eCRFs, laboratory 
reports, and regulatory documents) will be retained at the study center, along with adequate source 
documentation, according to FDA and ICH requirements. All study records must be available for 
inspection by the Sponsor, its authorized representatives, the FDA, or other health authorities. 

Intra-Cellular Therapies, Inc. 
Protocol ITI-333-002 
Multiple Ascending Dose Study 
Protocol Amendment 1 
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06 Nov 2023 
 
 
 
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11. 
REFERENCES 
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 
5th Ed., Text Revision. American Psychiatric Association; 2022. 
Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0 Published: November 
27, 2017. https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5 
_Quick_Reference_8.5x11.pdf. Accessed on December 7, 2022. 
Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: initial 
validity and internal consistency findings from three multisite studies with adolescents and 
adults. Am J Psychiatry. 2011;168(12):1266-77. 

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Protocol ITI-333-002 
Multiple Ascending Dose Study 
Protocol Amendment 1 
Confidential 
06 Nov 2023 
 
 
 
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12. 
APPENDICES 
12.1 
Appendix I. Elements Of Informed Consent 
Procedures will comply with 21 CFR, Parts 50 (Subpart D) and 312. Signed informed consent will 
be obtained from each subject participating in a clinical research study. The consent must include 
the following items: 
 A statement that the study involves research and an explanation of the purposes of the 
research; a description of the procedures to be followed and the identification of any 
procedures that are experimental; and the expected duration of the subject’s participation 
 A description of any reasonably foreseeable risks or discomforts to the subject 
 A description of any benefits to the subject or to others that may reasonably be expected 
from the research. If the subject is to be paid for participating in the study, the consent 
form must state the amount that he/she will receive and the schedule of payment (to ensure 
neither coercion nor undue influence). 
 A disclosure of appropriate alternative procedures or courses of treatment, if any, that 
might be advantageous to the subject 
 A statement describing the extent, if any, to which confidentiality of records identifying 
the subject will be maintained and noting the possibility that the FDA, the Sponsor, the 
IRB, or an authorized contract research organization may inspect the records 
 For research involving more than minimal risk, an explanation of whether any medical 
treatment is available if injury occurs and, if so, what it consists of or where further 
information may be obtained 
 An explanation of whom to contact, including the relevant telephone number, for answers 
to pertinent questions about the research and the research subject’s rights and whom to 
contact in the event of a research-related injury to the subject. (Note: In some cases, it may 
be necessary to identify a person other than the Investigator as the contact. The guidance 
of the IRB may be required.) 
 A statement that participation is voluntary, that refusal to participate will involve no 
penalty or loss of benefits to which the subject is otherwise entitled, and that the subject 
may discontinue participation at any time without penalty or loss of benefits to which the 
subject is otherwise entitled 
 A statement that the particular treatment or procedures may involve risks to the subject 
(or to the embryo or fetus if the subject may become pregnant) that are at present 
unforeseeable 
 The expected circumstances for which the subject’s participation may be terminated by 
the Investigator without regard to subject consent 
 Any additional costs to the subject that may result from participation in the research 
 The consequences of a subject’s decision to withdraw from the research and procedures 
for an orderly termination of the subject’s participation 

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Multiple Ascending Dose Study 
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06 Nov 2023 
 
 
 
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 A statement that significant new findings developed during the course of the research that 
may relate to the subject’s willingness to continue participation will be provided to the 
subject. 
 The approximate number of subjects involved in the study 
 A statement of permission providing subject’s consent to participate (eg, “I agree to 
participate. . .”)  
 A place for the subject’s signature and date of signing of the ICF  
 A statement indicating that information about this study may be entered, if required, into 
a databank that is publicly accessible at www.ClinicalTrials.gov. 
 A copy of the signed consent form must be given to the subject. 
 
 
 

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Protocol ITI-333-002 
Multiple Ascending Dose Study 
Protocol Amendment 1 
Confidential 
06 Nov 2023 
 
 
 
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13. 
INVESTIGATOR SIGNATURE PAGE 
I agree to conduct the study in accordance with Protocol Amendment 1 for Study ITI-333-002 
(dated 06 Nov 2023) and with all applicable government regulations and GCP guidance, including 
all statements regarding confidentiality, and according to local legal and regulatory requirements 
and applicable US federal and/or local regulations and ICH guidelines. 
I will not disclose information regarding this clinical investigation or publish results of the 
investigation without prior authorization from Intra-Cellular Therapies, Inc. 
 
 
_____________________________________ 
______________________________ 
Principal Investigator Signature 
Date 
 
_____________________________________ 
 
 
Principal Investigator Name (printed)