Clinical trial NCT03249376
Conditions: Bipolar Depression
Sponsor: Intra-Cellular Therapies, Inc.
Start date: 2017-11-27; Completion date: 2019-03-01
Enrollment: 381 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study will evaluate the efficacy and safety of ITI-007 in a randomized, double-blind, parallel-group, placebo-controlled, multi-center study in patients diagnosed with Bipolar I or Bipolar II disorder having a major depressive episode.

Detailed description:

Arms: arm 1: Lumateperone 42 mg (ITI-007 60 mg tosylate) administered once daily every evening for 6 weeks arm 2: Placebo administered once daily every evening for 6 weeks
Interventions: intervention 1: Lumateperone intervention 2: Placebo
Intervention descriptions: intervention 1: Lumateperone 42 mg (ITI-007 60 mg tosylate) intervention 2: Placebo

Protocol documents:
Prot_000.pdf: 
NCT03249376 
 
 
Study ID: ITI-007-404 
 
 
Title: A Phase 3, Randomized, Double-blind, Placebo-Controlled, Multi-Center Study to Assess the 
Efficacy and Safety of Lumateperone Monotherapy in the Treatment of Patients With Major Depressive 
Episodes Associated With Bipolar I or II Disorder (Bipolar Depression) Conducted Globally 
 
 
 
 
 
Protocol Amendment Version 1.3 Date: November 5, 2018 


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Intra-Cellular Therapies, Inc. Confidential 
i  ITI-007-404 Protocol Amendment v 1.3 November 5, 2018 
 
 
 
 
A Phase 3, Randomized, Double-Blind, Placebo-
Controlled, Multi-Center Study to Assess the Efficacy 
and Safety of Lumateperone Monotherapy in the 
Treatment of Patients with Major Depressive Episodes 
Associated with Bipolar I or Bipolar II Disorder 
(Bipolar Depression) Conducted Globally 
ITI-007-404 
IND# 126,701 
EUDRA CT# 2017-002317-58 
Sponsor: Intra-Cellular Therapies, Inc. (ITI) 
Amendment Version 1.3 
November 5, 2018 
 
STATEMENT OF COMPLIANCE 
 
The study will be conducted in accordance with the International Conference on 
Harmonisation guidelines for Good Clinical Practice (ICH E6) and the Code of Federal 
Regulations on the Protection of Human Subjects (45 CFR Part 46).  
 
CONFIDENTIAL 
 
All financial and nonfinancial support for this study will be provided by Intra-Cellular 
Therapies, Inc. (ITI or ITCI).  The concepts and information contained in this document 
or generated during the study are considered proprietary and may not be disclosed in 
whole or in part without the expressed, written consent of ITI. 




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INVESTIGATOR SIGNATURE PAGE 
Study Title: A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multi-Center 
Study to Assess the Efficacy and Safety of Lumateperone Monotherapy in the 
Treatment of Patients with Major Depressive Episodes Associated with Bipolar I or 
Bipolar II Disorder (Bipolar Depression) Conducted Globally 
 
Protocol Number:  ITI-007-404 
The signature below constitutes the approval of this protocol and the attachments, and 
provides the necessary assurances that this trial will be conducted according to all 
stipulations of the protocol, 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 supply the investigational drug to any person not authorized to receive it.  
Confidentiality will be protected.  Patient identity will not be disclosed to third parties or 
appear in any study reports or publications. 
I will not disclose information regarding this clinical investigation or publish results of the 
investigation without prior authorization from ITI. 
Principal Investigator or Clinical Study Site Investigator: 
Signed: 
 
Date:  
 
Name:  
 
Title:  
 
 
 
 


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TABLE OF CONTENTS 
PAGE 
STATEMENT OF COMPLIANCE ................................................................................................. I 
INVESTIGATOR SIGNATURE PAGE ........................................................................................ III 
TABLE OF CONTENTS ............................................................................................................ IV 
LIST OF ABBREVIATIONS ..................................................................................................... VIII 
PROTOCOL SUMMARY ........................................................................................................... XI 
1 
KEY ROLES AND CONTACT INFORMATION ................................................................... 1 
2 
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ......... 2 
2.1 
Background Information .......................................................................................... 2 
2.2 
Rationale ................................................................................................................ 4 
2.3 
Potential Risks and Benefits ................................................................................... 5 
2.3.1 
Potential Risks ............................................................................................ 5 
2.3.2 
Potential Benefits ........................................................................................ 7 
3 
OBJECTIVES ..................................................................................................................... 8 
3.1 
Study Objectives ..................................................................................................... 8 
3.2 
Study Outcome Measures .................................................................................... 10 
3.2.1 
Primary ...................................................................................................... 10 
3.2.2 
Secondary ................................................................................................. 10 
4 
STUDY DESIGN .............................................................................................................. 11 
5 
STUDY ENROLLMENT AND WITHDRAWAL .................................................................. 12 
5.1 
Patient Inclusion Criteria ....................................................................................... 12 
5.2 
Patient Exclusion Criteria ...................................................................................... 13 
5.3 
Strategies for Recruitment and Retention ............................................................. 18 
5.4 
Treatment Assignment Procedures ....................................................................... 18 
5.4.1 
Randomization Procedures ....................................................................... 18 
5.4.2 
Masking Procedures .................................................................................. 19 
5.4.3 
Breaking the Blind ..................................................................................... 19 
5.5 
Patient Withdrawal ................................................................................................ 19 
5.5.1 
Reasons for Withdrawal ............................................................................ 20 
5.5.2 
Handling of Patient Withdrawals or Patient Discontinuation of Study 
Intervention ............................................................................................... 21 
5.6 
Premature Termination or Suspension of Study .................................................... 21 
6 
STUDY INTERVENTION .................................................................................................. 22 
6.1 
Study Product Description .................................................................................... 22 
6.1.1 
Acquisition ................................................................................................. 24 
6.1.2 
Formulation, Packaging, and Labeling....................................................... 24 
6.1.3 
Product Storage and Stability .................................................................... 24 
6.2 
Dosage, Preparation and Administration of Study Product .................................... 25 
6.3 
Modification of Study Product Administration for a Patient .................................... 25 
6.4 
Accountability Procedures for the Study Product .................................................. 26 
6.5 
Assessment of Patient Compliance with Study Product Administration ................. 26 
6.6 
Concomitant Medications/Treatments ................................................................... 26 


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7 
STUDY SCHEDULE ......................................................................................................... 28 
7.1 
Screening (Visit 1) ................................................................................................ 28 
7.2 
Enrollment/Baseline (Visit 2, Day 1) ...................................................................... 29 
7.3 
Visit 3, Day 8 ± 1 ................................................................................................... 29 
7.4 
Visit 4, Day 15 ± 1 ................................................................................................. 30 
7.5 
Visit 5, Day 22 ± 1 ................................................................................................. 30 
7.6 
Visit 6, Day 29 ± 1 ................................................................................................. 30 
7.7 
Visit 7, Day 36 ± 1 ................................................................................................. 31 
7.8 
Visit 8, Day 43 ± 1 ................................................................................................. 31 
7.9 
Follow-up (Visit 9, Day 57 ± 2) .............................................................................. 31 
7.10 
Early Discontinuation Visit (Visit 10, if needed) ..................................................... 32 
8 
STUDY PROCEDURES /EVALUATIONS ........................................................................ 33 
8.1 
Study Procedures/Evaluations .............................................................................. 33 
8.1.1 
Informed Consent ...................................................................................... 33 
8.1.2 
Medical History and Other Information ...................................................... 33 
8.1.3 
Modified Physical Examination .................................................................. 33 
8.1.4 
Electrocardiogram Assessments ............................................................... 34 
8.1.5 
Vital Sign Measurements........................................................................... 34 
8.1.6 
Mini International Neuropsychiatric Interview ............................................. 35 
8.1.7 
Columbia Suicide Severity Rating Scale .................................................... 35 
8.1.8 
Young Mania Rating Scale ........................................................................ 35 
8.1.9 
Clinical Global Impressions of Severity ...................................................... 36 
8.1.10 Eligibility Adjudication ................................................................................ 36 
8.2 
Efficacy Assessments and Procedures ................................................................. 36 
8.2.1 
MADRS ..................................................................................................... 36 
8.2.2 
Clinical Global Impression of Severity ....................................................... 37 
8.2.3 
Q-LES-Q-SF.............................................................................................. 37 
8.3 
Patient Placebo Questionnaire and Training: ........................................................ 37 
8.4 
Safety and Tolerability Assessments .................................................................... 37 
8.5 
Laboratory Procedures/Evaluations ...................................................................... 37 
8.5.1 
Clinical Laboratory Evaluations ................................................................. 37 
8.5.2 
Hepatitis Screening ................................................................................... 39 
8.5.3 
HIV Screening ........................................................................................... 39 
8.5.4 
Urine Drug and Alcohol Screening ............................................................ 39 
8.5.5 
Laboratory Assessments ........................................................................... 40 
8.5.6 
Urine and Serum Pregnancy Test ............................................................. 40 
8.5.7 
Frequency and Volume of Blood Collection ............................................... 40 
8.5.8 
Special Assays or Procedures ................................................................... 41 
8.6 
Pharmacokinetic Assessments ............................................................................. 41 
8.6.1 
Specimen Preparation, Handling, and Storage .......................................... 41 
8.6.2 
Specimen Shipment .................................................................................. 41 
9 
ASSESSMENT OF SAFETY ............................................................................................ 42 
9.1 
Specification of Safety Parameters ....................................................................... 42 
9.1.1 
C-SSRS .................................................................................................... 42 


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9.1.2 
YMRS........................................................................................................ 42 
9.1.3 
Abnormal Involuntary Movement Scale ..................................................... 42 
9.1.4 
Barnes Akathisia Rating Scale .................................................................. 42 
9.1.5 
Simpson-Angus Scale ............................................................................... 42 
9.1.6 
Vital Sign Measurements........................................................................... 43 
9.1.7 
ECG Assessments .................................................................................... 43 
9.1.8 
Physical and Neurological Examination ..................................................... 43 
9.1.9 
Unanticipated Problems ............................................................................ 43 
9.1.10 Adverse Events ......................................................................................... 45 
9.1.11 Serious Adverse Events ............................................................................ 46 
9.2 
Time Period and Frequency for Event Assessment and Follow-Up ....................... 47 
9.3 
Characteristics of an Adverse Event ..................................................................... 47 
9.3.1 
Relationship to Study Intervention ............................................................. 47 
9.3.2 
Expectedness of SAEs .............................................................................. 48 
9.3.3 
Severity of Event ....................................................................................... 49 
9.4 
Reporting Procedures ........................................................................................... 49 
9.4.1 
Unanticipated Problem Reporting to IRB/IEC ............................................ 50 
9.4.2 
Serious Adverse Event Reporting to the Sponsor ...................................... 50 
9.4.3 
Reporting of SAEs and AEs to FDA and Other Regulatory Authorities ...... 52 
9.4.4 
Reporting of Pregnancy ............................................................................. 52 
9.5 
Halting Rules ........................................................................................................ 52 
10 
STUDY OVERSIGHT ....................................................................................................... 53 
10.1 
External Data Monitoring Committee ......................................................... 53 
11 
CLINICAL SITE MONITORING ........................................................................................ 54 
12 
STATISTICAL CONSIDERATIONS .................................................................................. 55 
12.1 
Sample Size Considerations ................................................................................. 55 
12.2 
Planned Interim Analyses (if applicable) ............................................................... 55 
12.3 
Analysis Sets ........................................................................................................ 55 
12.4 
Statistical Analysis Methodology ........................................................................... 56 
12.4.1 Patient Disposition, Analysis of Demographics and Other Baseline 
Characteristics .......................................................................................... 57 
12.4.2 Prior and Concomitant Medications ........................................................... 58 
12.4.3 Study Medication Exposure and Treatment Compliance ........................... 58 
12.4.4 Analysis of Primary and Key Secondary Efficacy Endpoints ...................... 58 
12.4.5 Analysis of Other Secondary Efficacy Endpoints ....................................... 61 
12.4.6 Pharmacokinetic Analyses ........................................................................ 63 
13 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS .................. 64 
14 
QUALITY CONTROL AND QUALITY ASSURANCE ........................................................ 65 
15 
ETHICS/PROTECTION OF HUMAN SUBJECTS ............................................................. 66 
15.1 
Ethical Standard ................................................................................................... 66 
15.2 
Independent Ethics Committee or Institutional Review Board ............................... 66 
15.3 
Ethical Conduct of the Study ................................................................................. 66 
15.4 
Institutional Review Board .................................................................................... 66 
15.5 
Informed Consent Process ................................................................................... 67 


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15.6 
Patient Information and Consent ........................................................................... 67 
15.7 
Patient Confidentiality ........................................................................................... 68 
15.8 
Future Use of Stored Specimens and Other Identifiable Data ............................... 68 
16 
DATA HANDLING AND RECORD KEEPING ................................................................... 69 
16.1 
Data Management Responsibilities ....................................................................... 70 
16.2 
Data Capture Methods .......................................................................................... 70 
16.3 
Types of Data ....................................................................................................... 70 
16.4 
Schedule and Content of Reports ......................................................................... 70 
16.5 
Study Records Retention ...................................................................................... 70 
16.6 
Protocol Deviations ............................................................................................... 70 
17 
PUBLICATION/DATA SHARING POLICY ........................................................................ 72 
18 
LITERATURE REFERENCES .......................................................................................... 73 
SUPPLEMENTAL MATERIALS ................................................................................................ 75 
APPENDIX A: SCHEDULE OF EVENTS .................................................................................. 76 
 
 
 


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LIST OF ABBREVIATIONS 
5-HT2A 
5-Hydroxytryptomine 2A Receptor 
AE 
Adverse Event 
AIMS 
Abnormal Involuntary Movement Scale  
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of Covariance 
ARH 
Heterogeneous Autoregressive 
AST 
Aspartate Aminotransferase 
BARS 
Barnes Akathisia Rating Scale 
BLQ 
Below the limit of quantification 
BMI 
Body Mass Index 
CFR 
Code of Federal Regulations 
CGI-BP 
Clinical Global Impression Scale, Bipolar version 
CGI-BP-S 
Clinical Global Impression Scale, Bipolar version, Severity  
CI 
Confidence Interval 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CS 
Compound Symmetry 
CSH 
Heterogeneous Compound Symmetry 
C-SSRS 
Columbia Suicide Severity Rating Scale  
D2 
Dopamine 2 Receptor 
DSM-5 
Diagnostic and Statistical Manual, 5th Edition 
eCRF 
Electronic Case Report Form 
ECG 
Electrocardiogram 
ENR 
All Patients Enrolled 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HbA1C 
Glycated Hemoglobin A1C 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 


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IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ITI 
Intra-Cellular Therapies, Inc. 
ITT 
Intent to Treat 
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response System 
LDL 
Low-density Lipoprotein 
LOCF 
Last Observation Carried Over 
LSM 
Least-squares mean 
MADRS 
Montgomery-Åsberg Depression Rating Scale 
MDE 
Major Depressive Episode 
MedDRA 
Medical Dictionary for Regulatory Activities 
MINI 
Mini International Neuropsychiatric Interview (M.I.N.I.) 
MMRM 
Mixed Model for Repeated Measures 
NDA 
New Drug Application 
OHRP 
Office for Human Research Protections 
PET 
Positron Emission Tomography 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
PP 
Per Protocol  
QA 
Quality Assurance 
QC 
Quality Control 
Q-LES-Q-SF 
Quality of Life Enjoyment and Satisfaction Questionnaire – Short Form 
QTcB 
Corrected QT Interval Using the Bazett Formula 
QTcF 
Corrected QT Interval Using the Fridericia Formula 
RND 
All Patients Randomized 
SAE 
Serious Adverse Event 
SERT 
Serotonin Transporter 
SAP 
Statistical Analysis Plan 
SAS 
Simpson Angus Scale  
SOP 
Standard Operating Procedure 
TEAE 
Treatment emergent adverse event 
TOEP 
Toeplitz Structure 
TOEPH 
Heterogeneous Toeplitz Structure 
ULN 
Upper Limit of Normal 


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UP 
Unanticipated Problem 
US 
United States 
YMRS 
Young Mania Rating Scale  


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PROTOCOL SUMMARY 
 
Title: 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled, 
Multi-Center Study to Assess the Efficacy and Safety of 
Lumateperone Monotherapy in the Treatment of Patients with 
Major Depressive Episodes Associated with Bipolar I or Bipolar 
II Disorder (Bipolar Depression) Conducted Globally 
Précis: 
This is a Phase 3, randomized, double-blind, placebo-
controlled, multi-center study to evaluate the efficacy and 
safety of lumateperone monotherapy in the treatment of 
patients with major depressive episodes associated with 
Bipolar I or Bipolar II Disorder (Bipolar Depression). The 
study consists of the following periods: screening period, 
double-blind on-treatment period, and safety follow-up 
period.   
Screening Period (2 Weeks)  
Potential patients will be evaluated during a screening period 
lasting up to 2 weeks to ensure sufficient washout of restricted 
medications. Extension to the screening period may be 
approved by the Sponsor or representative in extenuating 
circumstances related to the patient or caregiver. 
 After obtaining written informed consent, diagnostic interviews 
and physical examinations will be conducted, vital signs and 
ECGs will be assessed, and blood samples for laboratory 
assessments will be collected.  Patients considered potentially 
eligible for participation will be required to discontinue their 
current antidepressant treatment and/or other psychotropic 
drugs. 
 
  
At baseline (Visit 2), patients who continue to meet all eligibility 
criteria will be randomly assigned in a 1:1 ratio to 1 of the 2 
treatment arms (60 mg ITI-007 or placebo) for a 6-week, 
double-blind treatment period. 
On-Treatment Period (6 Weeks)  
Patients will take their first dose of study medication the 
evening of their randomization visit.  A single dose will be 
taken each day in the evening for the duration of the on-


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treatment period.  Following randomization, patients will make 
clinic visits at Days 8, 15, 22, 29, 36 and 43. 
The on-study treatment period will be a total of 6 weeks. 
Safety Follow-up Period (2 Weeks) 
A return to the clinic for a safety follow-up visit will occur at 
Week 8, approximately 2 weeks following the last dose of 
study medication.  If possible, patients who withdraw 
prematurely will be seen for an early termination visit (within 1 
week of early termination) and will be asked to return to the 
clinic for a safety follow-up visit 2 weeks following their last 
dose of study medication. 
 
Objectives: 
Primary Objective: 
The primary objective of this study is to compare the efficacy of 
lumateperone administered orally once daily to that of placebo 
as measured by mean change from baseline to Day 43 in the 
total score on the Montgomery-Åsberg Depression Rating 
Scale (MADRS) in patients with Bipolar Depression.   
 
Secondary Objectives: 
 
Key Secondary Objective: 
The key secondary objective of this study is to compare the 
efficacy of lumateperone administered orally once daily to that 
of placebo as measured by mean change from baseline to Day 
43 in the total score on the Clinical Global Impression Scale, 
Bipolar version – Severity (CGI-BP-S) in patients with Bipolar 
Depression. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Safety Secondary Objectives: 
The safety secondary objectives of this study are to determine 
the safety and tolerability of lumateperone administered orally 
once daily for 6 weeks in patients with Bipolar Depression, 
compared to placebo.  Safety and tolerability will be assessed 
in relation to: 
• Incidence of adverse events (AEs); 
• Mean change from baseline in the Young Mania Rating 
Scale (YMRS); 
• Mean change from baseline in the Columbia Suicide 
Severity Rating Scale (C-SSRS); 
• Mean change from baseline in the Abnormal Involuntary 
Movement Scale (AIMS); 
• Mean change from baseline in the Barnes Akathisia 
Rating Scale (BARS); 
• Mean change from baseline in the Simpson Angus 
Scale (SAS); 
• Changes from baseline in clinical laboratory evaluations; 
• Changes from baseline in electrocardiograms (ECGs); 
• Changes from baseline in vital sign measurements; 


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• Physical and neurological examination findings. 
 
 
 
 
 
 
 
 
Population: 
Male and female patients between the ages of 18 and 75 
years, inclusive, with a diagnosis of Bipolar I or Bipolar II 
Disorder experiencing a major depressive episode may be 
eligible for participation in the study. (See Inclusion and 
Exclusion Criteria for details.) 
 
Patients will be enrolled in multiple countries globally. 
Phase: 
III 
Number of Sites: 
Approximately 70 sites   
Description of 
Intervention: 
Patients will be assigned to receive either lumateperone or 
placebo.  Doses in the clinical study refer to ITI-007 as the 
tosylate salt (lumateperone tosylate or ITI-007 tosylate).  ITI-007 
60 mg is equivalent to 42 mg active base (lumateperone). 
Patients will self-administer doses orally, once daily, at home, 
each evening, for the duration of the double-blind On-treatment 
Period.  Treatments will be provided in dose cards containing 
over-encapsulated tablets, and patients will be instructed to 
take 1 tablet per dose. 
Study Duration: 
Approximately 18 months from first patient screened or 17 
months from first patient randomized until data analysis is 
completed, assuming an approximate 13-month enrollment 
period depending on clinic and patient availability, plus two 
months to complete clinical conduct and an additional two 
months to complete data analysis. 
Patient 
Participation 
Duration: 
For each patient completing the study, the study will last a 
maximum of approximately 10-12 weeks (9 visits), including 
screening, the on-study treatment period, and the safety follow 
up. 


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Estimated Time to 
Complete 
Enrollment: 
Approximately 13 months is anticipated from first patient 
randomized to last patient randomized, depending on clinic 
and patient availability. 
 
 
Statistical 
Methods: 
A formal and detailed statistical analysis plan (SAP) will be 
finalized prior to unblinding the patients’ treatment 
assignments. 
Analysis of the Primary and Key Secondary Efficacy 
Endpoints 
The treatment effect on the primary efficacy endpoint will be 
evaluated using a mixed model repeated measures (MMRM) 
method.  The model will include the change from baseline at 
each pre-specified time point in the MADRS total score as the 
response variable, visit, treatment group, site (or pooled site), 
and the Bipolar Disorder stratification variable (Bipolar I and 
Bipolar II) as factors, the baseline MADRS total score as a 
covariate and interaction terms for treatment group-by-visit, 
and visit-by-baseline MADRS total score.
 
 
 
 
 
 
 
 
 
 
 
 
The Key Secondary Efficacy Endpoint will be analyzed using 
the MMRM method, similar to the one specified for the analysis 
of the primary efficacy endpoint, while substituting MADRS 
total score related variables in the MMRM with the 
corresponding CGI-BP-S related ones, such as baseline score 
and visit-by-baseline score interaction. 
 
 
 
 
 
 
 


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Safety Analyses 
All safety parameters will be summarized using the Safety 
Analysis Set.  Safety data such as reported and observed AEs, 
treatment emergent adverse events (TEAEs) and SAEs, 
clinical laboratory results, vital signs, physical and neurological 
examination findings, ECGs, and the different rating scales 
(YMRS, C SSRS, AIMS, BARS, and SAS) will be summarized 
by treatment group and visit.  When appropriate, out of range 
values will be flagged in data listings and tabulated.  Shift 
tables will be prepared for pre-specified safety measures, such 
as laboratory parameters, ECG and weight. 
 
 
 
 
 
 
 
 
Sample Size: 
Approximately 350 patients will be randomly assigned in a 1:1 
ratio to 1 of the 2 treatment groups (ITI-007 60 mg or placebo).  
A sample size of 350 randomized patients will provide 
approximately 326 evaluable patients assuming a 10% early 
discontinuation rate before the first post-dose assessment of 
the primary efficacy outcome measure (MADRS). 
Approximately 163 patients per treatment group will provide 


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85% power to detect a clinically relevant treatment difference 
from placebo of 3 points on the MADRS total score with a 
common standard deviation of 9.0 at an overall 2-sided 
significance level of 0.05. 


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Schematic of Study Design: 
 
Visit 1  
Screening 
 
 
 
 
 
 
 
 
 
 
Visit 2 
Study Day 1 
 
 
 
Visits 3-8 
Study Days 
8 - 43  
 
 
 
 
Visit 9 
Study Day 57 
 
Total N ~525:  Obtain informed consent. Screen potential patients by inclusion and 
exclusion criteria; obtain history, document per Schedule of Events. 
Perform baseline assessments per Schedule of Events. 
Dispense initial study treatment. 
Follow Up 
Perform safety measures per 
Schedule of Events. 
N ~ 350 Randomize 
Placebo 
N ~ 175 
ITI-007 60 
N ~ 175 
Double-Blind on-treatment period.  
Perform weekly assessments per Schedule of Events. 


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1 KEY ROLES AND CONTACT INFORMATION 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
Clinical Study Site 
Investigators: 
To be determined 
Institutions: 
To be determined   


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2 INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE  
2.1 
Background Information 
Bipolar Disorder is a serious psychiatric disorder associated with shifts in mood 
including manic or hypomanic episodes, depressed episodes, or mixed episodes.  
Bipolar I Disorder is defined by the presence of manic or mixed episodes, whereas 
Bipolar II Disorder is defined by hypomania, but both are often associated with major 
depressive episodes.  Bipolar Disorder affects approximately 5.7 million adult 
Americans, or about 2.6% of the U.S. population age 18 and older, every year 
according to the National Institute of Mental Health with similar prevalence worldwide.  
Depressive episodes associated with Bipolar Disorder tend to last longer, recur more 
often, and are associated with worse prognosis than manic/hypomanic episodes.  
Bipolar Depression, the predominant presentation of Bipolar Disorder, remains a 
significantly underserved medical need, with only a few regulatory-approved treatment 
options available. 
 
Intra-Cellular Therapies (ITI) is developing lumateperone (ITI-007), a new chemical 
entity, for the treatment of patients with schizophrenia, major depressive episodes 
(MDEs) associated with Bipolar I or Bipolar II Disorder (Bipolar Depression) and for the 
treatment of agitation associated with dementia, including Alzheimer’s disease.   
 
ITI-007 is a novel small molecule therapeutic agent designed specifically to combine 
serotonergic, dopaminergic and glutamatergic modulation in a dose-dependent manner. 
ITI-007 is a potent serotonin 5-HT2A receptor antagonist with mesolimbic/mesocortical 
selective modulation of phosphoprotein pathways downstream of dopamine receptors, 
serotonin reuptake inhibition, and indirect glutamatergic modulation (Snyder et al 2015).  
As a dopamine receptor protein phosphorylation modulator, ITI-007 has dual properties, 
acting as post-synaptic antagonist and as a pre-synaptic partial agonist at dopamine 2 
(D2) receptors in vivo, with mesolimbic/mesocortical selectivity.  ITI-007 also increases 
the phosphorylation of the NR2B, or GluN2B, subunit of N-methyl-D-aspartate channels 
in extrastriatal dopamine-rich brain regions (e.g., nucleus accumbens) and indirectly 
modulates glutamatergic (NDMA and AMPA) activity downstream from dopamine 1 
receptor activation. 
 
Evidence supports the use of D2 receptor antagonists in the treatment of Bipolar 
Disorder, including Bipolar Depression (Young et al 2013; Loebel et al 2014a, 2014b), 
as both monotherapy and adjunctive therapy to mood stabilizers.  The pharmacologic 
profile of ITI-007 includes both the post-synaptic D2 antagonism that appears efficacious 
in Bipolar Disorder and other pharmacological properties that may confer better safety 


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and tolerability than other D2 antagonists.  As a 5-HT2A receptor antagonist and 
serotonin reuptake inhibitor, ITI-007 is predicted to have antidepressant efficacy with 
fewer side effects than selective serotonin reuptake inhibitors (Meltzer et al 1989). ITI-
007’s indirect glutamatergic modulation in combination with serotonin reuptake inhibition 
predicts rapid-acting antidepressant response.  Importantly, ITI-007 lacks potent off-
target interactions that have been associated with side effects for other antipsychotics 
drugs approved for the treatment of Bipolar Depression.  For example, ITI-007 shows 
relatively weak affinity for 5-HT2C and no measurable affinity for H1 or muscarinic 
cholinergic receptors, which predict favorable body weight and metabolic profile 
responses to the extent that these receptors mediate such effects.  Additional details on 
the pharmacologic profile of ITI-007 can be found in the Investigator’s Brochure. 
 
Nonclinical data suggest that ITI-007 may have the potential to treat depression (Snyder 
et al 2015).  Antidepressant-like activity of ITI-007 was measured using the social defeat 
(resident-intruder) mouse model.  Mice exposed to repeated social defeat conditions 
display a reduced amount of time in contact with unfamiliar non-aggressive mice than 
normal controls.  Such defeat behavior is reversed by chronic (but not acute) treatment 
with clinically effective antidepressant drugs.  In this model, 1 m/kg ITI-007, 
administered once daily intraperitoneally for 28 days, reversed the defeat behavior, 
consistent with antidepressant efficacy.  Brain receptor target engagement was 
confirmed in healthy male volunteers in the ITI-007-003 positron emission tomography 
(PET) Phase 1 clinical trial (Davis et al 2015).  Positron emission tomography was used 
to determine dopamine D2 receptor, serotonin transporter (SERT), and serotonin 5-HT2A 
receptor occupancy in the brain at various times following single dose oral ITI-007 
administration. ITI-007 rapidly penetrated the brain, showed long-lasting and dose-
related occupancy, and was generally safe and well-tolerated.  Cortical 5-HT2A receptors 
were shown to be fully occupied at 10 mg ITI-007 (>85% occupancy).  A dose of 40 mg 
ITI-007 achieved up to 39% striatal D2 occupancy (average of 29%) and up to 31% 
striatal SERT occupancy (average of 22%). Together, these data confirm a central 
mechanism for ITI-007 at dopaminergic and serotonergic brain targets.  An additional 
PET study in patients with schizophrenia (ITI-007-008) demonstrated an average of 
approximately 40% striatal D2 receptor occupancy at 60 mg, at plasma steady state, 
lower than that observed with most antipsychotic drugs.  Relatively low striatal D2 
receptor occupancy likely contributes to a relatively low liability for extrapyramidal side 
effects and hyperprolactinemia compared to most antipsychotic drugs. 
 
Clinical data from three well-controlled studies in patient with schizophrenia (ITI-007-
005, ITI-007-301, and ITI-007-302) are consistent with respect to the pharmacological 
profile and prediction for antidepressant effects with favorable safety and tolerability.  In 
these three studies ITI-007 has been safely administered once daily for up to 42 days at 


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doses ranging from 20 mg to 140 mg.  Furthermore, the ITI-007 60 mg dose had a 
similar trajectory and magnitude of improvement in psychosis as demonstrated a 
reduction from baseline in the Positive and Negative Syndrome Scale (PANSS) Total 
Score in all three studies, which was statistically significant at Day 28 compared to 
placebo in two of these studies (ITI-007-005 and ITI-007-301).  In addition to improving 
psychotic symptoms, ITI-007 also improved symptoms of depression in patients with 
schizophrenia and comorbid depression at baseline. Safety data from these and other 
trials with ITI-007 have shown that ITI-007, which has been administered to more than 
1500 individuals, is well tolerated across a dose range from 1 mg to 140 mg and 
administered once daily for up to 42 days with a safety profile similar to placebo. These 
clinical data together with the nonclinical data and the pharmacological profile support 
the development of ITI-007 for the treatment of Bipolar Depression. Details on the 
profile of ITI-007 can be found in the ITI-007 Investigator’s Brochure.  
 
The purpose of this study is to evaluate the efficacy and safety of ITI-007 as a 
monotherapy for the treatment of Bipolar Depression. 
2.2 
Rationale 
The screening phase permits evaluation of diagnosis as well as the laboratory and ECG 
assessments and enables confirmation of eligibility for inclusion into the study.  The 
screening phase will be no longer than 14 days, unless confirmed by the Medical 
Monitor that a longer screening phase, not to exceed 28 days, is appropriate to ensure 
washout of excluded medication with long half-life (e.g., fluoxetine), under the 
supervision of the investigator before baseline.  Patients will be randomly assigned in a 
1:1 ratio to 1 of 2 treatment groups at the baseline visit and will receive treatment for up 
to 6 weeks.  In order to ensure patient safety, a mandatory 14-day follow-up visit will be 
performed after administration of the last dose of study medication.  Any ongoing AEs at 
the follow-up visit must be followed until resolution, until the AE stabilizes, until it is 
determined to be non-clinically significant, or until the patient is lost to follow-up. 
ITI-007 60 mg was selected to deliver full occupancy of the cortical 5-HT2A receptors 
(>85% occupancy) with modest striatal D2 receptor occupancy and SERT occupancy.  
Data from human PET brain receptor occupancy studies with ITI-007 indicates that a 
dose as low as 10 mg is associated with >85% occupancy of cortical 5-HT2A receptors, 
while the 60-mg dose demonstrates approximately 40% striatal D2 receptor occupancy. 
SERT occupancy has been demonstrated to be comparable to D2 receptor occupancy.  
Moreover, once daily oral administration ITI-007 60 mg has been shown to be well 
tolerated with no dose titration needed and with a safety profile similar to placebo with 
up to 6 weeks’ treatment duration in patients with schizophrenia. 


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Therefore, a fixed dose design will be employed in this study with once daily oral 
administration of ITI-007 60 mg (or placebo). 
The placebo control group is needed to establish the efficacy of a new compound. 
The treatment duration of 6 weeks has been chosen because this is considered an 
acceptable period to demonstrate efficacy in this patient population. 
The hypothesis is that ITI-007 60 mg will demonstrate efficacy for the treatment of 
Bipolar Depression with statistically significant superiority versus placebo on the primary 
outcome measure, mean change from baseline to Day 43 in the total score on the 
MADRS in patients with Bipolar Depression. 
 
2.3 
Potential Risks and Benefits 
2.3.1 
Potential Risks 
There are several potential risks associated with taking part in this research study. A 
patient’s Bipolar Depression may not improve and could even worsen by taking part in 
this study. Each of these risks are discussed below. Patients should ask their study 
doctor if they have any questions or concerns about these risks. 
During this study, patients will take either 60 mg ITI-007 or placebo. Neither the patient 
nor the study doctor will know which drug the patient is taking. 
ITI-007 is an experimental drug which is not approved by the FDA or any regulatory 
authority. In research studies already conducted with ITI-007, over 1500 people have 
received ITI-007. 
The most frequent side effect observed with ITI-007 60 mg and that has been reported 
at a rate twice that of placebo is: 
* Tiredness or sleepiness 
Additional side effects that have been observed with ITI-007 include: 
* Headache 
* Dizziness or lightheadedness  
* Low blood pressure or fast heartbeat when standing up suddenly 
* Tachycardia (fast heartbeat) without standing 
* Nausea and/or vomiting 


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* Abdominal pain/cramps 
* Feeling “drunk” 
* Diarrhea 
* Dry mouth 
* Weakness 
* Anxiety 
* Insomnia 
* Changes in levels of liver enzymes (which could indicate liver damage) 
* Hot and/or cold sensations 
* Stuffy nose 
* Sweating 
In test tube studies, ITI-007 showed potential to be toxic to genetic material (genes or 
DNA). When tested in two different animal studies, ITI-007 did not cause toxicity to 
genes. 
Only in dogs, long-term dosing of ITI-007 was associated with adverse findings that may 
not be relevant to humans given the striking differences in metabolism (the way the 
body breaks down the drug) between dogs and humans. Dogs are exposed to drug 
metabolites that are not detected in humans. Short-term exposure (6 weeks or less) of 
ITI-007 has been shown to be well-tolerated with a safety profile similar to placebo in 
over 1500 people.  There may be other side effects of ITI-007 that have not yet been 
observed or reported.  
ITI-007 is an experimental drug that is still being tested and may not be effective in the 
treatment of Bipolar Depression. The placebo is not an active drug. 
Throughout the study, patients will not be taking any other medication to treat Bipolar 
Depression. Therefore, it is possible that patients may experience an increase in Bipolar 
Depression symptoms. 
ECG:  Some areas where the electrodes (sticky patches) will be placed may need to be 
shaved.  The test is painless, but the electrodes may irritate skin. 
Blood Draw:  Drawing blood may cause discomfort, bruising and very rarely infection at 
the site where the skin is punctured by the needle. Patients may also experience 
dizziness, nausea or fainting during blood taking. Patients will have to fast for 10 hours 
(overnight) before blood draws. 
Harm to the Unborn Child:  Currently we are not fully aware of the effects of ITI-007 on 
unborn babies, or pregnant or breastfeeding women. In women who are pregnant, or 
may become pregnant, treatment with the ITI-007 may lead to new, previously 


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unknown, side effects and risks to the woman or her unborn baby. Because of this, 
women who can have children will be asked to take a pregnancy test, at the start of the 
study. Men and women taking study treatment must be using an effective form of birth 
control before starting the study treatment and while taking part in the study.  Any 
patient who is confirmed to be pregnant during the study will be immediately 
discontinued from study treatment. 
2.3.2 
Potential Benefits 
Patients will be monitored carefully for their mental health status and general health. 
Symptoms of Bipolar Disorder (Bipolar Depression) may improve during participation in 
this study, although half the people in the study will receive placebo and may not 
improve. However, the information obtained from this study may help to treat people 
with Bipolar Depression better in the future. 
 


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3 OBJECTIVES 
3.1 
Study Objectives 
3.1.1. Primary Objective: 
The primary objective of this study is to compare the efficacy of lumateperone 
administered orally once daily to that of placebo as measured by mean change from 
baseline to Day 43 in the total score on the Montgomery-Åsberg Depression Rating 
Scale (MADRS) in patients with Bipolar Depression. 
3.1.2. Secondary Objectives: 
3.1.2.1. 
Key Secondary Objective: 
The key secondary objective of this study is to compare the efficacy of lumateperone 
administered orally once daily to that of placebo as measured by mean change from 
baseline to Day 43 in the total score on the Clinical Global Impression Scale of Bipolar - 
Severity of Illness (CGI-BP-S) in patients with Bipolar Depression. 
 
 
 
 
 
 


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3.1.2.3. 
Safety Secondary Objectives: 
The safety secondary objectives of this study are to determine the safety and tolerability 
of lumateperone administered orally once daily for 6 weeks in patients with Bipolar 
Depression, compared to placebo.  Safety and tolerability will be assessed in relation to: 
• Incidence of adverse events (AEs); 
• Mean change from baseline in the Young Mania Rating Scale (YMRS); 
• Mean change from baseline in the Columbia Suicide Severity Rating Scale (C-
SSRS); 
• Mean change from baseline in the Abnormal Involuntary Movement Scale 
(AIMS); 
• Mean change from baseline in the Barnes Akathisia Rating Scale (BARS); 
• Mean change from baseline in the Simpson Angus Scale (SAS); 
• Changes from baseline in clinical laboratory evaluations; 


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• Changes from baseline in electrocardiograms (ECGs); 
• Changes from baseline in vital sign measurements; 
• Physical and neurological examination findings. 
3.2 
Study Outcome Measures 
3.2.1 
Primary 
The change from baseline to Day 43 in MADRS total score is the primary outcome 
measure for the study.  The MADRS is defined in Section 8.2.1 and will be assessed 
according to the Schedule of Events. 
3.2.2 
Secondary 
The key secondary outcome measure is change from baseline to Day 43 in CGI-BP-S 
total score.  CGI-BP-S is defined in section 8.1.9 and will be assessed according to the 
Schedule of Events. 
Other secondary efficacy outcome measures include change from baseline in the 
MADRS, CGI-BP-S, and the Q-LES-Q-SF.  These are described in Section 8 and will be 
assessed according to the Schedule of Events. 
The secondary safety outcome measures include AEs, YMRS, C-SSRS, AIMS, BARS, 
SAS, clinical laboratory evaluations, ECGs, vital signs, and physical exams and 
neurological findings.  These are described in Section 8 and will be conducted 
according to the Schedule of Events. 
 
 
 
 


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4 STUDY DESIGN 
This is a Phase 3, randomized, double-blind, placebo-controlled, multi-center study to 
evaluate the efficacy and safety of lumateperone monotherapy in the treatment of 
patients with major depressive episodes associated with Bipolar I or Bipolar II Disorder 
(Bipolar Depression). The study consists of the following periods: Screening Period, 
double-blind On-treatment Period, and Safety Follow-up Period. 
Screening Period (2 Weeks)  
Potential patients will be evaluated during a Screening Period lasting up to 2 weeks, to 
ensure sufficient washout of restricted medications.  Extension to the screening period 
may be approved by the Sponsor or representative in extenuating circumstances 
related to the patient or caregiver.  
After obtaining written informed consent, diagnostic interviews and physical 
examinations will be conducted, vital signs and ECGs will be assessed, and blood 
samples for laboratory assessments will be collected.  Patients considered potentially 
eligible for participation will be required to discontinue their current antidepressant 
treatment and/or other psychotropic drugs. 
At baseline (Visit 2), patients who continue to meet all eligibility criteria will be randomly 
assigned to 1 of the 2 treatment arms for a 6-week, double-blind treatment period.  
Patients will be randomly assigned to 1 of the following groups: 60 mg ITI-007 or 
matching placebo. 
Double-Blind On-Treatment Period (6 Weeks)  
Patients will take their first dose of study medication the evening of their baseline visit.  
A single dose will be taken each day in the evening, with or without food, for the 
duration of the 6-week On-treatment Period. 
Following randomization, patients will attend the clinic on Days 8, 15, 22, 29, 36 and 43. 
 
Safety Follow-up Period (2 Weeks) 
A return to the clinic for a safety follow-up visit will occur at Week 8, approximately 2 
weeks following the last dose of study medication.  If possible, patients who withdraw 
prematurely will be seen for an early termination visit (within 1 week of early 
termination) and will be asked to return to the clinic for a safety follow-up visit 2 weeks 
following withdrawal. 


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5 STUDY ENROLLMENT AND WITHDRAWAL 
 
5.1 
Patient Inclusion Criteria 
Each patient must meet all of the following criteria to be enrolled in this study: 
1. Is capable of understanding the written informed consent, provides signed and 
witnessed written informed consent, and agrees to comply with protocol 
requirements. 
2. Is between the ages of 18 and 75 years, inclusive, at the start of screening (both 
male and female patients are to be included). 
3. Meets the Diagnostic and Statistical Manual of Mental Disorder, 5th Edition 
(DSM-5) criteria for Bipolar I or Bipolar II Disorder as confirmed by the 
investigator or sponsor-approved expert site-based rater by a M.I.N.I. 
International Neuropsychiatric Interview and meeting all of the following 5 criteria: 
a. The start of the current MDE is at least 2 weeks but no more than 
6 months prior to the screening visit;  
b. Appropriate severity of illness, at least moderately ill, as measured by a 
rater-administered MADRS total score ≥20 and corresponding to a CGI-
BP-S score of ≥4 at the screening and baseline visits;  
c. Sufficient history and/or independent report (such as family member or 
outside practitioner) verifying that the current MDE is causing clinically 
significant distress or impairment in social, occupational, or other 
important areas of functioning;  
d. A lifetime history of at least 1 Bipolar manic episode or mixed episode 
(for Bipolar I) or hypomanic episode (for Bipolar II);  
e. A rater-administered YMRS total score of ≤12 at the screening and 
baseline visits.  
4. Has a body mass index (BMI) of 19 – 35 kg/m2, inclusive. 
5. Either must agree to use highly effective methods of birth control (defined as 
those, alone or in combination, that result in a failure rate less than 1 percent per 
year when used consistently and correctly) for at least 2 weeks prior to 
randomization (starting with signing informed consent) through to the end-of-
study follow-up visit or must be of non-childbearing potential (defined as either 
permanently sterilized or, if female, post-menopausal; the latter is defined as at 
least 1 year with no menses without an alternative medical explanation).  


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6. In the opinion of the investigator, the patient is willing and able to comply with 
study requirements, study visits, and to return to the clinic for follow-up 
evaluations as specified by the protocol.  
5.2 
Patient Exclusion Criteria 
Patients meeting any of the following criteria will be excluded from the study: 
1. The patient experiences a decrease in the rater-administered MADRS total score 
of ≥25% between screening and baseline visits.   
2. In the opinion of the investigator, the patient has a significant risk for suicidal 
behavior during the course of his or her participation in the study or  
a. At screening, the patient scores “yes” on Items 4 or 5 in the Suicidal 
Ideation section of the C-SSRS with reference to a 6-month period prior to 
screening; or  
b. At screening, the patient has had 1 or more suicidal attempts with 
reference to a 2-year period prior to screening; or  
c. At the baseline visit, the patient scores “yes” on Items 4 or 5 in the 
Suicidal Ideation section of the C-SSRS with reference to screening; or 
d. At screening or the baseline visit, scores ≥4 on Item 10 (suicidal thoughts) 
on the rater-administered MADRS; or 
e. Considered to be an imminent danger to himself, herself, or others. 
3. The patient is pregnant or breast-feeding; female patients of childbearing potential 
must have  negative urine and serum pregnancy tests at screening and a 
negative urine pregnancy test on Day 1 prior to study treatment administration. 
4. The patient has a history within 12 months of screening, based on previous 
psychiatric evaluation or a confirmed diagnosis upon screening based on the 
DSM-5, of a psychiatric diagnosis other than Bipolar Disorder, including: 
a. Schizophrenia or other psychotic disorder; 
b. Anxiety disorders such as panic disorder, general anxiety disorder, or 
post-traumatic stress disorder as a primary diagnosis (however, anxiety 
symptoms may be allowed, if secondary to Bipolar Disorder, provided 
these symptoms do not require current treatment); 
c. Feeding or eating disorder; 
d. Primary diagnosis of obsessive compulsive disorder; 
e. Personality disorder; 


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f. Moderate or severe substance use disorder (including for cannabis, 
excluding for nicotine); 
g. Any other psychiatric condition (other than Bipolar Disorder) that has been 
the main focus of treatment within 12 months of screening.  
5. Patients who have experienced hallucinations, delusions, or any other psychotic 
symptomatology in the current depressive episode may be allowed as long as 
these symptoms are not attributable to a primary DSM-5 diagnosis other than 
Bipolar Disorder as described in exclusion number 4. The presence of these 
symptoms should be reviewed with the Medical Monitor and the adjudication team 
on a case by case basis prior to inclusion.  Patients with YMRS of >12 will be 
reviewed on a case by case basis to rule out possible impending 
mania/hypomania.  
6. The patient has been hospitalized for mania associated with Bipolar I Disorder 
within 30 days of screening.   
Note: This criterion is included to ensure that any manic phase has completely 
resolved before enrollment in the study.   
7. The patient has received electroconvulsive therapy, vagal nerve stimulation, or 
repetitive trans-cranial magnetic stimulation within the last 5 years or received 
more than 1 course of electroconvulsive therapy during the patient’s lifetime.  
8. The patient is considered a rapid cycler, defined by the occurrence of at least 
6 major depressive, manic, hypomanic, or mixed episodes during the previous 
year.  These episodes must be demarcated either by a partial or full remission of 
at least 2 months' duration or by a switch to an episode of opposite polarity.  
(Each MDE must have lasted at least 2 weeks, each manic or mixed episode 
must have lasted at least 1 week, and each hypomanic episode must have lasted 
at least 4 days, as validated by a reliable informant).   
Note: This criterion is included to avoid spontaneous remission during 
participation in the study that might confound treatment results. 
9. The patient is considered treatment-resistant, defined as having a lifetime history 
of treatment resistance (no remission) to ≥2 treatments with medications 
approved by the regional regulatory authority for Bipolar Depression [which may 
include, for example, lurasidone, quetiapine or Symbyax (olanzapine/fluoxetine 
combination), depending on the region] at an adequate dose (per regulatory-
approved label) for an adequate duration (at least 6 weeks).  
10. The patient is currently receiving formal cognitive or behavioral therapy, 
systematic psychotherapy, or plans to initiate such therapy during the study. 


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11. The patient presents with a lifetime history of epilepsy, seizure or convulsion, or 
electroencephalogram with clinically significant abnormalities, delirium, dementia, 
amnestic, or other cognitive disorder or significant brain trauma.  
12. The patient has a positive test for drugs of abuse or alcohol at the screening visit, 
or presents evidence of either withdrawal from or acute intoxication with cocaine, 
opiates, amphetamines (including methamphetamine), alcohol, barbiturates, or 
hallucinogens or similar compounds.  The urine drug screen may be repeated 
once based on investigator judgment and reviewed for medical appropriateness 
by the Medical Monitor as part of the screening adjudication process. 
Note: Previous occasional use of alcohol or cannabis (but not synthetic 
marijuana/K2/Spice) or prescribed psychotropic (e.g., benzodiazepine, opiate) is 
allowed as long as the level of use does not meet DSM-5 criteria for any 
moderate or severe substance use disorder within the 12 months prior to 
screening and the use of alcohol or cannabis is not considered to be the 
precipitating factor of the current depressive episode, in the opinion of the 
investigator and any prescribed psychotropic is accompanied by evidence of 
prescription; patients are required to abstain from alcohol and drug use during the 
study. 
13. The patient has used 1 of the following agents under the specified conditions:  
a. Lifetime exposure to ITI-007 (i.e., participated in previous clinical study 
with ITI-007) or who has had exposure to any investigational product 
within 3 months of the baseline visit or participated in the past 4 years in 
>2 clinical studies of an investigational product with a central nervous 
system indication; 
b. Any strong or moderate cytochrome P450 3A4 inhibitor or inducer within 
7 days prior to the baseline visit;  
c. Use of any short-acting anxiolytic medications within 1 week of the 
baseline visit or of long-acting anxiolytics within 5 half-lives of the baseline 
visit;   
d. Drugs with known psychotropic properties or any non-psychotropic drugs 
with known or potentially significant central nervous system effects within 
the last 28 days or 5 half-lives before the baseline visit, whichever is less, 
as reviewed by the Medical Monitor, including, but not limited to:  


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i. sedative hypnotics (with the exception of zolpidem as needed, no 
more than 3 times per week, allowed during the screening period 
and the first 2 weeks of the treatment period); Note: If zolpidem is 
not available in specific regions, another sedative hypnotic may be 
approved by the Medical Monitor. 
ii. central opioid agonists/antagonists including tramadol;  
iii. anticonvulsants;  
iv. mood stabilizers, antipsychotics, antidepressants;  
v. methotrexate; 
vi. any known 5-HT2A receptor antagonist or inverse agonist including 
but not limited to mianserin, mirtazapine, nefazodone, 
cyproheptadine, pimavanserin, or fluvoxamine; 
vii. immunosuppressants; 
viii. dietary supplements, medical foods, or pharmaceuticals containing 
Omega-3 fatty acids, melatonin, St. John’s Wort, kava kava, 
Vitamin B12, folate (no L-methylfolate in current episode), or 
valerian root. Daily multivitamin use is not excluded. 
14. The patient has abnormal laboratory values or clinical findings at screening that 
are judged clinically significant and confirmed upon re-test (1 re-test prior to 
baseline visit is allowed and results must be available prior to the baseline visit 
and must have returned to within normal range), including, but not limited to:  
a. Aspartate aminotransferase (AST) >2.0 × the upper limit of normal (ULN) 
b. Alanine aminotransferase (ALT) >2.0 × the ULN 
c. Alkaline phosphatase >2.0 × the ULN 
d. Gamma-glutamyl transpeptidase >2.0 × the ULN  
e. Total bilirubin >1.5 × the ULN 
f. Serum creatinine >1.5 × the ULN 
g. Blood urea nitrogen >1.5 × the ULN 
h. Thyroid-stimulating hormone outside of the normal limits and clinically 
significant, as determined by the investigator.  Free thyroxine levels may 
be measured if thyroid-stimulating hormone level is high.  The patient will 
be excluded if the free thyroxine level is clinically significant. 


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i. 12-lead ECG (in a supine position after a rest of approximately 10 minutes 
at the screening visit) mean of triplicate corrected QT interval using the 
Fridericia formula (QTcF) >450 ms for males or females, corrected QT 
interval using the Bazett formula (QTcB) >450 ms for males or >470 ms for 
females, and/or heart rate ≤50 beats per minute, or evidence of clinically 
significant bundle-branch blocks. 
j. Any other clinically significant abnormal laboratory result at the time of the 
screening examination.  Note: medical conditions that are stable with 
medication (e.g., hypertension, high cholesterol, and hyperthyroidism) are 
allowed as long as the condition has been stable for at least 3 months 
prior to screening, the medications are documented and kept stable during 
the study, and the condition is not thought to affect safe participation in the 
study in the opinion of the investigator and confirmed by the Medical 
Monitor as part of the screening adjudication process. 
15. The patient has clinically significant cardiovascular (including but not limited to 
uncontrolled angina, or history of a myocardial infarction within 3 months prior to 
screening, or history of a clinically significant cardiac arrhythmia including 
antipsychotic drug-induced corrected QT interval prolongation), endocrine 
(including poorly controlled diabetes defined as glycated hemoglobin A1c 
[HbA1c] >53 mmol/mol [7.0%] at screening with no re-test allowed for HbA1c), 
hepatic, renal, pulmonary, gastrointestinal, neurological, malignancy (including 
any malignancy and/or chemotherapy within the 2 years prior to screening; 
malignancy more than 2 years prior to screening must have been local and 
without metastasis and/or recurrence, and if treated with chemotherapy, without 
nervous system complications; some malignancies, such as basal cell carcinoma, 
may not preclude participation and will be individually reviewed), 
pheochromocytoma, metabolic, psychiatric or other condition that might be 
detrimental to the patient if he or she participates in the study (in the opinion of 
the investigator).  
16. The patient has a history of human immunodeficiency virus (HIV) infection or has 
HIV antibodies in blood at screening. 
17. The patient has a history of hepatitis B or hepatitis C infection or shows evidence 
of active hepatitis B or hepatitis C infection at screening.  
18. The patient is unable to be safely discontinued from current antidepressant 
medication, mood stabilizers, anticholinergics, or other psychotropic medications 
(in the opinion of the investigator). 
19. The patient is judged by the investigator to be inappropriate for the study. 


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5.3 
Strategies for Recruitment and Retention 
Strategies for recruitment and retention will be determined by individual participating 
clinical study sites using Institutional Review Board (IRB) / Independent Ethics 
Committee (IEC) approved recruitment/retention materials consistent with ICH 
guidelines. Patients may be compensated for study participation as reviewed and 
approved by the IRB/IEC and consistent with customary regional practices and ICH 
guidelines. Patient compensation (if regionally allowed) will be described in the informed 
consent form. 
5.4 
Treatment Assignment Procedures 
At baseline (Visit 2), patients who continue to meet all eligibility criteria will be randomly 
assigned to 1 of the 2 treatment arms for a 6-week, double-blind on-treatment period.  
Patients will be randomly assigned on a 1:1 basis to 1 of the following groups: 60-mg 
ITI-007 or matching placebo.  The double-blind on-treatment period will be a total of 6 
weeks.   
5.4.1 
Randomization Procedures  
An interactive voice response system (IVRS)/interactive web response system (IWRS) 
(English only) will be used to administer the randomization schedule.  Unblinded 
biostatistics personnel not participating in the conduct of the study will generate a 
permuted block randomization schedule using SAS software Version 9.2 or later 
 
 for IVRS/IWRS, which will link sequential patient 
randomization numbers to treatment codes.  In the event that the blind needs to be 
broken because of a medical emergency, the investigator may unblind an individual 
patient’s treatment allocation (Section 5.4.3).  The randomization schedule will be 
stratified by Bipolar I or Bipolar II diagnoses at screening. 
Each patient will be assigned a randomization number, at the time of randomization, 
which will be separate from the patient identification number.  Once a randomization 
number has been allocated to a patient, it may not be assigned to another patient.   
The IVRS/IWRS will send visit notifications to the study site personnel, confirming the 
patient data that were entered.  The IVRS/IWRS notifications should be filed securely at 
the study site. 


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5.4.2   Masking Procedures  
The study will be performed in a double-blind manner.  All study treatment will be 
supplied in identical treatment cards and packaging, and will be similar in color, smell, 
taste, and appearance, thereby enabling double-blind conditions. 
5.4.3 Breaking the Blind 
A patient’s treatment assignment will not be broken until the end of the study unless 
medical treatment of the patient depends on knowing the study treatment the patient 
received.  In the event that the blind needs to be broken because of a medical 
emergency, the investigator may unblind an individual patient’s treatment allocation.  As 
soon as possible, the investigator should first contact the Medical Monitor to discuss the 
medical emergency and the reason for revealing the actual treatment received by that 
patient.  The treatment assignment will be unblinded through IVRS/IWRS.  Reasons for 
treatment unblinding must be clearly explained and justified in the eCRF.  The date on 
which the code was broken together with the identity of the person responsible must 
also be documented. 
Any patients whose treatments become unblinded will continue in the study as planned, 
but will be excluded from the per-protocol set (Section 12).   
The overall randomization code will be broken only for study reporting purposes.  This 
will occur once all final clinical data have been entered into the database and all data 
queries have been resolved.   
5.5 
Patient Withdrawal 
The planned overall duration of the study for each patient is up to 10-12 weeks (9 
visits): i.e. a screening phase of up to 2 weeks (to ensure sufficient washout of restricted 
medication), a double-blind on-treatment period of 6 weeks, and a follow-up phase of 2 
weeks.  The duration of the study is defined for each patient as the date signed written 
informed consent is obtained through the last follow-up visit on Day 57. Patients may 
withdraw voluntarily from the study or the investigator or sponsor may terminate a 
patient’s participation. 
Patients who have been randomly assigned to study drug and prematurely discontinue 
from the study will not be replaced.   
A patient who fails to satisfy inclusion and exhibits any of the exclusion criteria at 
screening may be rescreened with the permission of the Medical Monitor.  Any patient 
who is rescreened within 28 days of an initial screen may have some screening 
procedures waived by the Medical Monitor on a case by case basis; any patient who is 
rescreened more than 28 days following the previous screen (as defined by the date of 


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informed consent) will need to have all screening procedures repeated.  In all cases, a 
new informed consent must be obtained for a rescreen.  A patient may not be screened 
more than 2 times.  
5.5.1 
Reasons for Withdrawal 
Patients may withdraw from the study at any time and for any reason without prejudice 
to their future medical care by the investigator or at the study site.  Every effort should 
be made to keep patients in the study.  The reasons for patients not completing the 
study will be recorded.  A patient may be withdrawn from the study for any of the 
following reasons: 
1. Does not meet the protocol inclusion criteria or meets the protocol exclusion 
criteria. 
2. Noncompliance with the protocol. 
3. A serious or intolerable AE that, in the investigator’s opinion, requires withdrawal 
from the study.   
4. Laboratory safety assessments that reveal clinically significant hematological or 
biochemical changes from baseline values, or baseline laboratory safety 
assessments that are returned after randomization but reveal clinically significant 
hematological or biochemical changes from screening. 
5. Symptoms or an intercurrent illness not consistent with the protocol requirements 
or that justify withdrawal. 
6. Lost to follow-up. 
7. Other (e.g., pregnancy, development of contraindications of use of study drug). 
8. The investigator or sponsor decide to discontinue the patient’s participation in the 
study. 
9. The patient withdraws consent. If consent is withdrawn, the patient must be 
questioned by the investigator or study site staff whether the withdrawal is due to 
an AE, lack of efficacy, personal or family reasons, or whether the patient 
withdrew consent and refused all end-of-study procedures, including refusing to 
give a reason; these reasons must be documented in the case report form. 
The investigator will also withdraw a patient if ITI terminates the study.  Upon 
occurrence of a serious or intolerable AE, the investigator will confer with the sponsor or 
Medical Monitor as the sponsor’s designee.  If a patient is discontinued because of an 
AE, the event will be followed until it is resolved, stabilizes, is determined to be non-


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clinically significant, or the patient is lost to follow-up.  Any patient may withdraw his or 
her consent at any time. 
5.5.2 
Handling of Patient Withdrawals or Patient Discontinuation of Study 
Intervention 
Patients are free to withdraw from the study or study treatment at any time.  Patient 
participation in the study may be stopped at any time at the discretion of the investigator 
or at the request of the sponsor. 
Patients who discontinue study treatment or active participation in the study will no 
longer receive study treatment.  When a patient withdraws from the study, the reason(s) 
for withdrawal shall be recorded by the investigator on the relevant screen of the 
electronic case report form (eCRF).  Whenever possible, all patients who discontinue 
study treatment or withdraw from the study prematurely will undergo all end-of-study 
assessments.  Patients who fail to return for final assessments will be contacted by the 
study site (2 documented telephone calls followed by 1 registered letter or similar 
procedures depending on regional differences) in an attempt to have them comply with 
the protocol.   
It is vital to obtain follow-up data on any patient withdrawn as a result of an AE or 
serious AE (SAE).  In every case, efforts must be made to undertake protocol-specified, 
safety, follow-up procedures.  All data collected from all patients, including early 
withdrawals, will be used in the reporting and analysis of the study. 
5.6 
Premature Termination or Suspension of Study 
This study may be suspended or prematurely terminated by the sponsor.  Written 
notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to the investigator, and regulatory 
authorities.  If the study is prematurely terminated or suspended, the principal 
investigator will promptly inform the IRB/IEC and will provide the reason(s) for the 
termination or suspension.  
Circumstances that may warrant termination include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to patients. 
• Insufficient adherence to protocol requirements. 
• Data that are not sufficiently complete and/or evaluable.  
• Determination of futility. 


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6 STUDY INTERVENTION 
 
6.1 
Study Product Description 
ITI-007 will be supplied as 60-mg over-encapsulated tablets (capsules) (Table ).  The 
following drug supplies will be used in the study:  
Table 6-1 
Table for Dosing Schedule  
 
ITI-007 60 mg refers to the tosylate salt (ITI-007 tosylate or lumateperone tosylate) and 
is equivalent to 42 mg of the active base (lumateperone). 
 
 
Each ITI-007 dosing container will be labeled according to local laws and regulations.  
The composition of the over-encapsulated tablets is listed in Table 6-2. 
Study Treatment 
Dosing Schedule 
60-mg ITI-007 
1 over-encapsulated tablet of 60-mg ITI-007 
Daily Dose: 60-mg ITI-007 
Placebo 
1 over-encapsulated tablet of placebo 
Daily Dose: 0-mg ITI-007 


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6.1.1 
Acquisition 
Adequate supplies of ITI-007 and matched placebo will be provided to each study site. 
6.1.2 
Formulation, Packaging, and Labeling 
ITI-007 and matching placebo will be prepared according to current Good 
Manufacturing Practice standards in carded blister strips and shipped under ambient 
conditions.  Each treatment card will contain a sufficient quantity of capsules for 1 
patient for two weeks (14 doses, plus 2 extras), to be dispensed every other visit of the 
6-week treatment period.  Each ITI-007 dosing container will be labeled according to 
local laws and regulations.   
The dose card for each study treatment will contain two 1×8 strips of over-encapsulated 
tablets (final product in capsule form) as described in Table 6-.  
Table 6-3  
Bi-Weekly Treatment Cards 
Treatment 
Card Contents 
Placebo 
Two 1×8 strips of placebo over-
encapsulated tablets (8 over-
encapsulated tablets/strip)  
 
60-mg ITI-007 
Two 1×8 strips of 60-mg ITI-007 over-
encapsulated tablets (8 over-
encapsulated tablets/strip) 
 
Note: Each card will hold 16 over-encapsulated tablets in 2 strips of 8.   
 
6.1.3 
Product Storage and Stability 
Study treatment must be stored in a secure area (e.g., a locked cabinet) while in 
storage at the study site, protected from moisture, and kept at a room temperature 
between 15°C and 30°C (59°F-86°F).  Patients will be instructed to store the bi-weekly 
treatment card at room temperature at home, out of the reach of children.  Patients will 
be instructed to take 1 capsule per dose. Patients will be instructed to bring the bi-
weekly treatment card to the study site at the next visit to assess compliance. 
 


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6.2 
Dosage, Preparation and Administration of Study Product 
Patients will be assigned to receive either ITI-007 (60-mg dose) or placebo.  Study site 
personnel will receive a treatment card number from the IVRS/IWRS for each patient at 
every second clinic visit (e.g. at baseline and Study Days 15 and 29), to ensure that the 
correct investigational product is dispensed.  Patients will self-administer all doses 
orally, once daily, at home, in the evening for the duration of the on-treatment period.  
Treatment will be administered with or without food, between approximately 8:00 PM and 
10:30 PM, and at approximately the same time each day whenever possible.  
Treatments will be provided in dose cards containing 2 strips of over-encapsulated 
tablets.  Patients will be instructed to take 1 capsule per dose. Patients will be instructed 
to bring the bi-weekly treatment card to the study site at the next visit to assess 
compliance. 
6.3 
Modification of Study Product Administration for a Patient 
Patients who do not tolerate the study treatment should be withdrawn from the study 
treatment. There are no modifications of dosing allowed except withdrawal. See Section 
5.5 for details regarding patient withdrawal. 
An overdose is any dose of study treatment given to a patient or taken by a patient that 
exceeds the dose described in the protocol.  Any overdose, with or without associated 
AEs, must be promptly reported to the Medical Monitor.  Overdoses without signs or 
symptoms do not need to be recorded as AEs; in case of any AEs associated with the 
overdose, these should be reported on relevant AE/SAE sections in the eCRF. 
Previous clinical trials have evaluated ITI-007 in healthy volunteers with single doses up 
to and including 40 mg, multiple doses up to and including 20 mg administered once 
daily for 5 days, and multiple doses up to and including 30 mg administered once daily 
for 7 days in healthy geriatric volunteers.  Previous clinical trials have evaluated ITI-007 
in patients with schizophrenia with multiple doses up to and including 140 mg 
administered once daily for 5 days, multiple doses up to and including 120 mg 
administered once daily for 4 weeks, and multiple doses up to and including 60 mg 
administered once daily for 6 weeks.  In case of an overdose that exceeds the 
previously studied doses, the patient should be closely monitored (in a hospital setting 
as needed) with sufficient attention to the symptoms and the clinical course.  Supportive 
measures may include gastric lavage and respiratory and cardiovascular support as 
needed. 


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6.4 
Accountability Procedures for the Study Product 
The investigator will maintain accurate records of receipt of all test articles, including 
dates of receipt.  In addition, accurate records will be kept regarding when and how 
much test article is dispensed and used by each patient in the study.  Reasons for 
departure from the expected dispensing regimen must also be recorded.  At the 
completion of the study, to satisfy regulatory requirements regarding drug accountability, 
all study treatment will be reconciled and retained or destroyed according to applicable 
regulations. 
6.5 
Assessment of Patient Compliance with Study Product Administration 
Patient compliance will be assessed by capsule counts of unused study medication at 
each visit during the double-blind treatment phase.  Any irregularities in medication 
adherence should be discussed with the patient.  Any patient who misses 2 doses of 
study medication per week in any 2 weeks of the study treatment period or who misses 
3 or more doses of study medication in any single week should be considered for early 
discontinuation.  Any exceptions due to unusual circumstances should be discussed on 
a case-by-case basis with the Medical Monitor to determine whether a patient may 
continue despite apparent treatment compliance issues. 
Dispensing study treatment to be taken by patients in an outpatient study increases risk 
for medication errors.  All errors in medication dispensing or administration must be 
carefully documented.  These errors may include but are not limited to providing the 
wrong dose (not taking 1 capsule per dose or taking too many capsules per dose), 
losing medication, or administration at the wrong time of day.  Medication adherence will 
be emphasized at every visit.  Written instructions will be provided to the patients with 
the weekly medication card in order to minimize medication error.  Additional adherence 
procedures may be implemented. 
6.6 
Concomitant Medications/Treatments 
Patients are required not to use the following during the study: alcohol, cannabis, any 
known 5-HT2A receptor antagonist or inverse agonist, any strong or moderate 
cytochrome P450 3A4 inhibitor or inducer, any short-acting anxiolytic, or any drugs with 
known psychotropic properties or any non-psychotropic drugs with potential central 
nervous system effects.  The only exception is zolpidem, which may be taken no more 
than 3 times per week, allowed only during the screening period and taken within the 
first 2 weeks of the treatment period (Section 5.2, Exclusion 13).  Patients considered 
potentially eligible for participation will be required to discontinue their current 
antidepressant treatment and/or other psychotropic drugs for the duration of the study.  


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Discontinuation of long-acting prohibited medications that require more than a 2-week 
washout should be discussed on a case-by-case basis with the Medical Monitor for 
approval of a longer screening phase to ensure washout of excluded medication with 
longer half-life (e.g., fluoxetine) under the supervision of the investigator before 
baseline. 
 
Acetaminophen (Paracetamol) use is prohibited, but ibuprofen is allowed.  
 
Use of all concomitant medications will be recorded in the patient’s eCRF.  As a 
minimum requirement, the drug name and dates of administration are to be recorded.  
This will include all prescription drugs, herbal products, vitamins, minerals, and over-
the-counter medications.  Any changes in concomitant medications will also be 
recorded in the patient’s eCRF. 
 
Any concomitant medication deemed necessary for the welfare of the patient during the 
study may be given at the discretion of the investigator.  However, it is the responsibility 
of the investigator to ensure that details regarding the medication are recorded in full in 
the eCRF. 
 


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7 STUDY SCHEDULE 
Before participating in any study procedures, all potential study patients must sign an 
informed consent form (ICF).  Patients will have the opportunity to have any questions 
answered before signing the ICF.  The investigator must address all questions raised by 
the patient.  The investigator will also sign the ICF and a signed copy will be provided to 
the patient. 
The schedule of events for the study is presented in Appendix A.  Detailed instructions 
for the conduct of study assessments and procedures will be provided in the study 
reference manual. 
 
t 


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8 STUDY PROCEDURES /EVALUATIONS 
 
8.1 
Study Procedures/Evaluations 
After obtaining written informed consent, the following assessments are to be performed 
within 2 weeks prior to Day 1 (unless the Medical Monitor has approved an extended 
screening period to allow washout of prior long-acting psychotropic medication), 
according to the schedule of events in Appendix A; assessments can be conducted on 
different days within the screening period. 
8.1.1 Informed Consent 
Before any study-related activities the patient must sign and date an ICF approved by 
the responsible IRB/IEC.  The format and content of the ICF must have been agreed 
upon by the investigator, the appropriate IRB/IEC, and ITI.   
8.1.2 Medical History and Other Information 
Medical history information will be collected at screening and should include (but not be 
limited to) demographic information, current and past medical conditions, and current 
and past medications.  The medical history must be documented in the patient’s study 
chart prior to study treatment administration and also recorded in the appropriate eCRF.  
In addition to conventional medical history, information pertaining to the patient’s 
average alcohol and caffeine consumption and average tobacco and cannabis usage 
should be recorded in the eCRF.  Demographic information will also be collected.  
Patients will be checked for previous participation in an ITI-007 clinical study and for 
duplicate enrollment by study site staff using any methods available for identifying 
duplicate patients. 
8.1.3 Modified Physical Examination  
A modified physical examination, including neurological and excluding genital/rectal 
examinations, will be performed.  The examination should include evaluation of height 
(at screening only [m]); body weight (kg); waist circumference (cm); appearance and 
skin; head and neck; eyes, ears, nose, and throat; chest and lungs; heart; abdomen; 
and extremities.  Neurological findings will also be recorded. All physical examination 
findings must be documented in the patient’s study chart and also recorded in the 
eCRF.   


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8.1.4 Electrocardiogram Assessments 
Each ECG assessment at screening will comprise of triplicate 10-second epochs from 
12-lead ECGs recorded 5 minutes apart.  Subsequent ECGs will be single 10-second 
epochs from 12-lead ECGs. Electrocardiogram parameters to be measured include 
heart rate, QRS, PR, QT, QTcB, QTcF, and RR intervals.  
The ECG recordings will be made on ECG machines supplied by a central ECG 
laboratory.  Electrocardiogram data will be transferred to the central ECG laboratory on 
the same day as collected and interpretation will be provided to the study site within 
approximately 48 hours.  If any 12-lead ECG recording shows an arrhythmia other than 
a sinus arrhythmia, sinus tachycardia, or sinus bradycardia, an additional 12-lead ECG 
will be recorded to confirm the original tracing.  Any other clinically significant treatment-
emergent cardiac conduction abnormalities will be followed until no longer deemed 
necessary by the investigator. 
Central interpretations of ECG recordings obtained at screening will be the basis for 
determination that a patient is eligible for inclusion in the study.  Similarly, central 
interpretations of ECG recordings at baseline and other visits will be included in the final 
study data.  However, given that interpretations of recordings will not be available for up 
to 48 hours, investigators are to use machine generated parameters and clinical 
judgment to assess cardiac function for the purposes of immediate safety concerns.   
8.1.5 Vital Sign Measurements 
Vital signs include: respiratory rate, oral temperature, 60-second pulse readings, blood 
pressure, body weight and height (height only at V1, screening), waist circumference 
and BMI.  Vital signs are always taken after conducting the ECGs, as applicable, and 
prior to any other assessments, including needle sticks for laboratory or 
pharmacokinetic samples, scheduled for the same visit.  At V1, V2, V8, and V9 vital 
signs include 3-positional blood pressure readings (after at least 10 minutes in the 
supine position, after approximately 1 minute sitting, immediately upon standing, and 
after approximately 3 minutes standing). Pulse will be measured by counting pulse over 
60 seconds.  Height will be measured only at screening.  Body weight will be measured 
at all scheduled visits through Visit 9 (Day 57).  Each patient’s BMI will be calculated 
before Day 1 to ensure that the patient meets the BMI inclusion criterion.   
Vitals sign measurements should also be collected, if feasible, at the time of an AE such 
as vertigo, dizziness, fall, or any sign or symptom that might indicate a fall in blood 
pressure.   


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8.1.6 Mini International Neuropsychiatric Interview 
The major clinical criterion for inclusion in the study is that the patient be diagnosed with 
Bipolar I or Bipolar II Disorder, meeting the DSM-5 criteria.  The methodology for 
confirming this diagnosis is the M.I.N.I. International Neuropsychiatric Interview 7.0.2 
(8/8/16 version) by Dr. David V. Sheehan.  The M.I.N.I. is a well-validated clinical tool 
(Sheehan et al., 1998). It will be used in this study at screening only to confirm the 
diagnosis of Bipolar Depression in patients evaluated for inclusion in the study.  It will be 
completed by the investigator or an expert site-based rater approved by the sponsor.   
8.1.7 Columbia Suicide Severity Rating Scale 
The C-SSRS is a questionnaire developed and validated by Kelly Posner and 
colleagues (2011) for the assessment of suicidal ideation and behavior.  Several 
versions have been developed including the “baseline” and “screening” versions and a 
combined “baseline/screening” version of the scale which assesses suicidal ideation 
and behavior in a patient’s lifetime and during a predefined time period.  This version 
can assess a patient’s lifetime suicidality as well as eligibility based on 
inclusion/exclusion criteria.  A separate “Since Last Visit” version of the scale has been 
developed which is used to assess suicidality since the patient’s last visit.  This version 
is meant to assess patients who have completed at least 1 initial C-SSRS assessment, 
and should be used in every subsequent visit.  The “Since Last Visit” version of the C-
SSRS addresses any suicidal thoughts or behaviors the patient may have had since the 
last time the C-SSRS was administered.   
The C-SSRS will be administered by the investigator or an expert site-based rater, as 
indicated in the Schedule of Events (Appendix A).   
At screening, a patient will not be eligible if he or she reports suicidal ideation of type 4 
or 5 on the C-SSRS within 6 months prior to screening or any suicidal behavior in the 
last 2 years prior to screening, as indicated by any “yes” answers on the suicidal 
behavior section of the C-SSRS. 
8.1.8 Young Mania Rating Scale 
The YMRS is an 11-item, clinician-administered mania rating scale with established 
reliability, validity, and sensitivity that was designed to assess the severity of manic 
symptoms (Young et al 1978).  Four of the YMRS items are rated on a 0 to 8 scale, with 
the remaining 7 items rated on a 0 to 4 scale.  The total score is appropriate both for 
assessing baseline severity of manic symptoms and for assessing treatment-emergent 
manic symptoms in patients with Bipolar I or Bipolar II Disorder with Depression.  It will 


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be completed by the investigator or an expert site-based rater according to Appendix A 
(Schedule of Events). 
8.1.9 Clinical Global Impressions of Severity 
The Clinical Global Impressions Scale (CGI) has been modified specifically for use in 
assessing global illness severity and change in patients with Bipolar Disorder 
(Spearing et al 1997).  The CGI-BP-S is a standardized assessment tool that a clinician 
can use to rate the severity of illness, change over time, and efficacy of medication, 
taking into account the patient’s clinical condition and the severity of side effects.  The 
CGI-BP-S is used to document the clinician’s impression of the patient’s current illness 
state; it will be used in this study at screening (as a criterion for inclusion or exclusion) 
and throughout the study as a measure of efficacy.  Scores on the CGI-BP-S range from 
1 (not ill at all) to 7 (among the most extremely ill).  A CGI-BP-S assessment will be 
completed at screening by the investigator or another ITI-approved expert site-based 
rater according to Appendix A (Schedule of Events). 
  
 
 
 
 
   
8.2 Efficacy Assessments and Procedures 
8.2.1 MADRS 
The MADRS is a 10-item checklist designed to measure the overall severity of 
depressive symptoms (Montgomery and Åsberg, 1979).  Individual items are rated by 
the investigator (or another ITI-approved expert site-based rater) according to Appendix 
A (Schedule of Events) on a scale of 0 to 6 in which a score of 6 represents the most 
severe symptoms for each item assessed.  The total score ranges from 0 to 60. 
Remission of Depression based on the MADRS is generally defined as a patient with a 
MADRS total score of ≤12 at endpoint.  A “responder” on the MADRS is defined as a 
≥50% reduction from Baseline in total MADRS score at endpoint.   
The total score on the MADRS at screening is a major criterion for inclusion in the study, 
as well as the primary outcome measure for the study.    
 


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8.2.2 Clinical Global Impression of Severity  
The CGI-BP-S will be a clinical efficacy assessment by the investigator of each patient’s 
severity of illness, as described in Section 8.1.9. 
8.2.3 Q-LES-Q-SF  
The Q-LES-Q-SF is a patient self-reported questionnaire that assesses how satisfied a 
patient is, using a 5-point rating scale from very poor to very good, with 14 items 
(Endicott et al., 1993).  The items assessed include physical health, mood, work, 
household activities, social relationships, family relationships, leisure time activities, 
ability to function in daily life, sexual drive/interest/performance, economic status, 
living/housing situation, ability to get around physically without feeling dizzy or unsteady 
or falling, vision in terms of ability to do work or hobbies, and overall sense of well-being 
that are summed to provide a raw total score ranging from 14 to 70.  There are an 
additional 2 stand-alone items (1 for medication satisfaction and the other for overall life 
satisfaction).  The total raw score is converted to a percent score. The Q-LES-Q-SF will 
be administered according to Appendix A (Schedule of Events). 
8.3 Patient Placebo Questionnaire and Training: 
A brief placebo response questionnaire will be administered to assess the patient’s 
perception of likelihood their symptoms will improve as well as their perception at the 
end of the study whether they received placebo or active investigational drug.  A brief 
training module will be provided describing placebo response at baseline. 
8.4 Safety and Tolerability Assessments 
All patients who receive study treatment will be evaluated for safety.  Safety 
assessments will include incidence of AEs, suicidality assessment by the C-SSRS, 
mania assessment by the YMRS, movement disorder assessment by the AIMS, BARS 
and SAS, clinical laboratory evaluations, ECG evaluations, vital sign measurements, 
and physical examination and neurological findings according to Appendix A (Schedule 
of Events). 
8.5 
Laboratory Procedures/Evaluations 
8.5.1 
Clinical Laboratory Evaluations 
Blood and urine samples collected from patients will be forwarded to a central 
laboratory for analysis.  Further details regarding sample collections, processing and 
specific testing can be found in the study reference manual. 


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All samples for clinical laboratory analysis will be collected after an overnight fast 
(≥10 hours), after any scheduled ECG or vital signs have been recorded, and prior to 
dosing with study treatment.  Samples for clinical laboratory analysis will be used only 
for the evaluation of safety and tolerability.   
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECGs, vital sign measurements), including those that 
worsen from baseline, felt to be clinically significant, in the medical and scientific 
judgment of the investigator, are to be recorded as AEs or SAEs. 
However, any clinically significant safety assessments that are associated with the 
underlying disease, unless judged by the investigator to be more severe than expected 
for the patient’s condition, are not to be reported as AEs or SAEs. 
The following clinical analytes will be determined:  
Hematology: hematocrit; hemoglobin; HbA1c (only at screening V1 and end of study 
treatment V8); red blood cell count with indices (mean corpuscular volume, mean 
corpuscular hemoglobin, and mean corpuscular hemoglobin concentration); 
reticulocytes; white blood cell count and differential (neutrophils, lymphocytes, 
monocytes, eosinophils, and basophils) reported as percent (%) and absolute values; 
and platelets (platelet count, prothrombin time and partial thromboplastin time).  
Clinical chemistry: albumin; alkaline phosphatase; blood urea nitrogen; gamma-
glutamyl transferase; calcium; creatinine; glucose; insulin; cholesterol (high-density 
lipoprotein and low-density lipoprotein [LDL] [calculated] and homogenous LDL will be 
reported, and homogenous LDL will be reflexed if a patient’s triglycerides are >400); 
triglycerides; phosphate; potassium; prolactin; ALT; AST; lactate dehydrogenase; 
sodium; chloride; bilirubin (total, direct); total protein; uric acid; creatine phosphokinase; 
and thyroid panel (at screening only, thyroid-stimulating hormone will be assayed and if 
the result is abnormal, the free thyroxine and free triiodothyronine will be assayed).  
Urinalysis: macroscopic (pH, specific gravity, glucose, protein, ketones, nitrates, blood) 
and microscopic – report only if present (red blood cells/high-power field, white blood 
cells/high-power field, casts, epithelial cells, crystals, granulation). 
Serology: anti-HIV antibodies, hepatitis B surface antigen, and hepatitis C antibody 
(only during screening). 


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8.5.2 Hepatitis Screening 
Blood samples will be collected at screening from all patients in order to perform 
hepatitis B surface antigen and hepatitis C antibody (immunoglobulin G) testing.  Test 
results will be sent to the screening site and must be reviewed before the Day 1 visit.  
Any patient who tests positive for hepatitis B or C will be excluded from participating in 
the study.  Details regarding sample collection, processing, and shipping can be found 
in the study reference manual. 
8.5.3 HIV Screening 
Patients are required to provide blood samples for HIV virus types 1 and 2 testing.  Test 
results will be sent to the screening site and must be reviewed before the Day 1 visit.  
Any patient who tests positive for HIV will be excluded from participating in the study.  
Patients will be informed of positive HIV results and referred for follow-up testing and 
counseling, and health authorities will be notified of positive HIV results consistent with 
federal, state, and local laws.  Details regarding sample collection, processing, and 
shipping can be found in the study reference manual.  
8.5.4 Urine Drug and Alcohol Screening 
Qualitative urine drug (amphetamines, barbiturates, benzodiazepines, cannabinoids 
[THC], cocaine metabolites, methadone, opiates, phencyclidine, propoxyphene) and 
alcohol tests will be performed.  Any patient who tests positive for drugs of abuse or 
alcohol test at the screening visit, or presents evidence of either withdrawal from or 
acute intoxication with cocaine, opiates, amphetamines (including methamphetamine), 
alcohol, barbiturates, or hallucinogens or similar compounds will be excluded.  The 
urine drug screen may be repeated once based on investigator judgment and reviewed 
for medical appropriateness by the Medical Monitor as part of the screening 
adjudication process. 
Note: Previous occasional use of alcohol or cannabis (but not synthetic 
marijuana/K2/Spice) or prescribed psychotropic (e.g., benzodiazepine, opiate) is 
allowed as long as the level of use does not meet DSM-5 criteria for any moderate or 
severe substance use disorder within the 12 months prior to screening and the use of 
alcohol or cannabis is not considered to be the precipitating factor of the current 
depressive episode, in the opinion of the investigator and any prescribed psychotropic is 
accompanied by evidence of prescription; patients are required to abstain from alcohol 
and drug use during the study. 
Further information regarding sample collection, processing, and shipping can be found 
in the study reference manual. 




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. 
 
 


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9 ASSESSMENT OF SAFETY 
9.1 
Specification of Safety Parameters 
9.1.1 
C-SSRS 
The C-SSRS will be completed at screening, baseline, and at every subsequent 
scheduled clinic visit according to Appendix A (Schedule of Events).  Details of the C-
SSRS are presented in Section 8.1.7.   
9.1.2 
YMRS 
The YMRS will be completed at screening, baseline, and at every subsequent 
scheduled clinic visit according to Appendix A (Schedule of Events).  Details of the 
YMRS are presented in Section 8.1.8.   
9.1.3 
Abnormal Involuntary Movement Scale 
The AIMS (Guy 1976) measures facial and oral movements, extremity movements, and 
trunk movements.  Seven items are rated on a scale from none (0) to severe (4).  A 
score of “mild” (2) in 2 or more categories or a score of “moderate” or “severe” in any 1 
category results in a positive AIMS score (i.e., the scores are not averaged).  
Additionally, overall severity is scored on the basis of severity of abnormal movements 
and incapacitation due to abnormal movements.  The patient’s awareness of and 
distress caused by the abnormal movements are also noted.  The AIMS is to be 
completed at baseline and periodically throughout the study according to Appendix A 
(Schedule of Events).  
9.1.4 
Barnes Akathisia Rating Scale 
The BARS is a rating scale for drug-induced akathisia developed by Barnes (1989).  It 
includes the rating of observable restless movements, the subjective awareness of 
restlessness, and the distress associated with the akathisia.  There is also a global 
rating for severity.  The scale is completed by the investigator or an expert site-based 
rater after a standard examination.  Objective akathisia, subjective awareness and 
subjective distress are rated on a 4-point scale from 0 to 3, yielding a total score from 0 
to 9.  The Global Clinical Assessment of Akathisia is rated separately, on a 5-point scale 
from 0 to 4.  The BARS is to be completed at baseline and periodically throughout the 
study according to Appendix A (Schedule of Events).   
9.1.5 
Simpson-Angus Scale 
The SAS is a measure of extrapyramidal side effects (Simpson and Angus 1970).  Ten 
items including rating gait, arm dropping, shoulder shaking, elbow rigidity, wrist rigidity, 
leg pendulousness, head rotation, glabella tap, tremor, and salivation are rated on a 
scale from 0 (normal) to 4 (extreme in severity).  The SAS should be conducted by the 


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investigator or an expert site-based rater in a room where the patient can walk a 
sufficient distance to allow a natural pace (e.g., 15 paces).  Each side of the body 
should be examined.  The SAS is to be completed at baseline and periodically 
throughout the study according to Appendix A (Schedule of Events).   
9.1.6 
Vital Sign Measurements 
Vital signs will be measured at screening and at subsequent scheduled clinic visits 
according to Appendix A (Schedule of Events).  Details of the vital sign measurements 
are presented in Section 8.1.5. 
9.1.7 
ECG Assessments 
The ECG assessments will be performed at screening and periodically throughout the 
study, according to Appendix A (Schedule of Events).  Details of the ECG assessments 
are presented in Section 8.1.4.    
9.1.8 
Physical and Neurological Examination  
The physical and neurological examinations will be conducted at screening and 
periodically throughout the study, according to Appendix A (Schedule of Events).  
Details of the physical and neurological examinations are presented in Section 8.1.3.  
9.1.9 
Unanticipated Problems 
The investigator will review each SAE (Section 9.1.4) and evaluate the intensity and the 
causal relationship of the event to study treatment.  All SAEs will be recorded from 
signing of informed consent until follow-up.   
The investigator is responsible for providing notification to the sponsor or designee of 
any SAE, whether deemed related to study treatment or not, that a patient experiences 
during their participation in study within 24 hours of becoming aware of the event. 
As a minimum requirement, the initial notification should provide the following 
information: 
• Study number 
• Patient number 
• Gender 
• Date of birth 
• Name of investigator and full study site address 


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• Details of SAE 
• Criterion for classification as “serious” 
• Study treatment code, or name if unblinded, and treatment start date and stop 
date, if applicable 
• Date of SAE onset 
• Causality assessment (if sufficient information is available to make this 
classification) 
The sponsor will request clarification of omitted or discrepant information from the initial 
notification.  The investigator or an authorized delegate is responsible for transmitting 
(via fax or email) the requested information to the sponsor within 24 hours of the 
sponsor’s request. 
Initial reports of SAEs must be followed later with detailed descriptions, including clear 
photocopies of other documents as necessary (e.g., hospital reports, consultant reports, 
autopsy reports), with the study patient’s personal identifiers removed.  All relevant 
information obtained by the investigator through review of these documents will be 
recorded and transmitted to the sponsor within 24 hours of receipt of the information.  If 
a new SAE Report Form is transmitted, then the investigator must sign and date the 
form.  The sponsor may also request additional information on the SAE, which the 
investigator or an authorized delegate must transmit to the sponsor within 24 hours of 
the request. 
The SAE reporting contact information will be provided to all participating study sites by 
the contract research organization (CRO) before study initiation.   
The Office for Human Research Protections (OHRP) considers unanticipated problems 
involving risks to patients or others to include, in general, any incident, experience, or 
outcome that meets all of the following criteria: 
• unexpected in terms of nature, severity, or frequency given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB/IEC-approved research protocol and informed consent document; and (b) 
the characteristics of the patient population being studied; 
• related or possibly related to participation in the research (“possibly related” 
means there is a reasonable possibility that the incident, experience, or outcome 
may have been caused by the procedures involved in the research); and 


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• suggests that the research places patients or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized. 
9.1.10 Adverse Events 
The investigator is responsible for reporting all AEs that are observed or reported during 
the study, regardless of their relationship to study treatment or their clinical significance. 
9.1.10.1 
Definition of Adverse Event 
An AE is any untoward medical occurrence in a study patient administered a study 
treatment, whether or not considered drug related.  This can be any unfavorable and 
unintended sign (such as an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a study treatment, without any judgment of 
causality. 
The AE may be: 
• A new illness; 
• A worsening sign or symptom of the condition under treatment, or of a 
concomitant illness; 
• An effect of the study medication, including comparator; or 
• A combination of 2 or more of these factors. 
No causal relationship with the study medication or with the clinical study itself is implied 
by the use of the term AE. 
 
Surgical procedures themselves are not AEs; they are therapeutic measures for 
conditions that require surgery.  The condition for which the surgery is required may be 
an AE.  Planned surgical measures, if permitted by the clinical study protocol and the 
conditions leading to those measures are not AEs. 
 
All AEs fall into the categories of “nonserious” or “serious” (Section 9.1.4). 


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9.1.11 Serious Adverse Events 
9.1.11.1 
Definition of Serious Adverse Event 
An SAE is defined as any untoward medical occurrence that at any dose: 
• Results in death; 
• Is life threatening;  
• Requires hospitalization or prolongation in existing hospitalization; 
• Results in persistent or significant disability or incapacity; or 
• Is a congenital anomaly or birth defect. 
The term “life threatening” refers to an event in which the patient is at risk of death at 
the time of the event; it does not refer to an event, which hypothetically might have 
caused death if it were more severe. 
 
Medical and scientific judgment should be exercised in deciding whether an AE is 
serious.  Some important medical events that may not result in death, be life 
threatening, or require hospitalization may be considered SAEs when they may 
jeopardize the patient such that medical or surgical intervention is needed to prevent 1 
of the outcomes previously listed.  Examples of such medical events include intensive 
emergency treatment for an allergic reaction, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, and the development of drug dependency or drug 
abuse. 
 
Visits to urgent care or emergency room facilities may not warrant reporting as SAEs 
unless the patient is admitted to the hospital or the event meets other “serious” criteria. 
Events that are not clearly meeting “serious” criteria can be discussed on a case by 
case basis with the Medical Monitor to help the investigator determine whether the 
event meets “serious” criteria. 
 
If either the sponsor or principal investigator believes that any event is serious, the 
event must be considered and evaluated by the sponsor for possible expedited 
reporting. 
 
Clarification of the difference between "serious" and "severe": 
The term “severe” is often used to describe the intensity (severity) of a specific event 
(as in mild, moderate, or severe myocardial infarction); the event itself, however, may 
be of relatively minor medical significance (such as a severe headache).  This is not the 
same as “serious,” which is based on patient/event outcome or action criteria usually 


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associated with events that pose a threat to a patient’s life or functioning.  Seriousness 
(not severity) serves as a guide for defining regulatory reporting obligations. 
 
9.2 Time Period and Frequency for Event Assessment and Follow-Up 
For the purposes of this study, the period of observation extends from the time the 
patient gives his study-specific informed consent until the end of study procedures are 
completed. 
If the investigator detects an SAE in a study patient after the end of the period of 
observation and considers the event possibly related to prior study treatment, he or she 
should contact the sponsor to determine how the AE should be documented and 
reported. 
All AEs must be reported in detail on the appropriate page in the eCRF and followed to 
satisfactory resolution, until the investigator deems the event to be chronic or not 
clinically significant, or until the patient is considered to be stable. 
A follow-up telephone call will be performed for those patients with an ongoing AE which 
the investigator believes to be not related to study treatment administration.  A follow-up 
visit to the study site may occur for those patients with an ongoing AE which the 
investigator believes to be possibly related to study treatment administration. 
All AEs must be reported in detail on the appropriate page in the eCRF and followed 
until they are resolved or stable, or judged by the investigator to be not clinically 
significant. 
9.3 Characteristics of an Adverse Event 
9.3.1 
Relationship to Study Intervention 
By definition, any AE that starts before the first dose of study treatment administration is 
considered to be “unrelated.” 
The investigator will assess the causality/relationship between the study treatment and 
the AE according to Appendix A (Schedule of Events).  One of the following categories 
should be selected based on medical judgment, considering the following definitions 
and all contributing factors. 


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Table 9-1 
Causality Categories 
Category 
Definition 
Definitely related 
 
A clinical event, including laboratory test abnormality, occurs in a 
plausible time relationship to treatment administration, and which 
concurrent disease or other drugs or chemicals cannot explain. The 
response to withdrawal of the treatment (dechallenge1) should be 
clinically plausible.  The event must be definitive pharmacologically or 
phenomenologically, using a satisfactory rechallenge2 procedure if 
necessary. 
Probably related 
 
A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to administration of the treatment, unlikely to be 
attributed to concurrent disease or other drugs or chemicals, and which 
follows a clinically reasonable response on withdrawal (dechallenge).  
Rechallenge information is not required to fulfill this definition. 
Possibly related 
 
A clinical event, including laboratory test abnormality, with a reasonable 
possibility that the adverse event may have been caused by the 
treatment.  Information on treatment withdrawal may be lacking or 
unclear. 
Unlikely to be 
related 
 
A clinical event, including laboratory test abnormality, with a temporal 
relationship to treatment administration which makes a causal 
relationship improbable, and in which other drugs, chemicals or 
underlying disease provide plausible explanations. 
Unrelated 
 
A clinical event, including laboratory test abnormality, with little or no 
temporal relationship with treatment administration.  May have negative 
dechallenge and rechallenge information.  Typically, explained by 
extraneous factors (e.g., concomitant disease, environmental factors, or 
other drugs or chemicals). 
1 Dechallenge is when a drug suspected of causing an adverse event (AE) is discontinued.  If the 
symptoms of the AE disappear partially or completely, within a reasonable time from drug discontinuation, 
this is termed a positive dechallenge.  If the symptoms continue despite withdrawal of the drug, this is 
termed a negative dechallenge.  Note that there are exceptions when an AE does not disappear upon 
discontinuation of the drug, yet drug-relatedness clearly exists (e.g., bone marrow suppression, fixed drug 
eruptions, tardive dyskinesia). 
2 Rechallenge is when a drug suspected of causing an AE in a specific patient in the past is 
readministered to that patient.  If the AE recurs upon exposure, this is termed a positive rechallenge.  If 
the AE does not recur, this is termed a negative rechallenge. 
9.3.2 
Expectedness of SAEs 
The sponsor or designee will be responsible for determining whether an SAE is 
expected or unexpected.  An adverse event will be considered unexpected if the nature, 


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severity, or frequency of the event is not consistent with the risk information previously 
described for the intervention as documented in the Investigator’s Brochure.   
9.3.3 
Severity of Event 
The investigator will assess all AEs for intensity (severity) in accordance with the 
following standard ratings (Table 9-2): 
Table 9-2 
Intensity Categories 
Category 
Definition 
Mild 
Ordinarily transient symptoms, does not influence performance 
of patient’s daily activities.  Treatment is not ordinarily 
indicated. 
Moderate 
Marked symptoms, sufficient to make the patient 
uncomfortable.  Moderate influence on performance of 
patient’s daily activities. Treatment may be necessary. 
Severe 
Symptoms cause considerable discomfort. Substantial 
influence on patient’s daily activities.  May be unable to 
continue in the study and treatment may be necessary. 
Life 
threatening 
Extreme limitation in activity, significant assistance required; 
significant medical intervention/therapy required, 
hospitalization or hospice care probable. 
When changes in the intensity of an AE occur more frequently than once a day, the 
maximum intensity for the event should be noted for that day.  Any change in intensity 
of signs and symptoms over a number of days will be captured by recording a new AE, 
with the amended intensity grade and the date (and time, if known) of the change.  
9.4 
Reporting Procedures 
All AEs reported or observed during the study will be collected and recorded on the AE 
page of the eCRF for each patient from the date the ICF was signed until the end of 
their participation in the study, i.e., the patient has discontinued or completed the study. 
Adverse events may be volunteered spontaneously by the patient, or discovered by the 
study staff during physical examinations or by asking an open, non-leading question 
such as, “How have you been feeling since you were last asked?”  All AEs and any 
required remedial action will be recorded.  The nature of the AE, date (and time, if 
known) of the AE onset, date (and time, if known) of the AE outcome to date, severity, 
and action taken for the AE will be documented together with the investigator’s 
assessment of the seriousness of the AE and causal relationship to study treatment 
and/or study procedure.  


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All AEs should be recorded individually in the study patient’s own words (verbatim) 
unless, in the opinion of the investigator, the AEs constitute components of a recognized 
condition, disease or syndrome.  In the latter case, the condition, disease or syndrome 
should be named rather than each individual symptom.  The AEs will subsequently be 
coded using the latest version of Medical Dictionary for Regulatory Activities (MedDRA).  
9.4.1 
Unanticipated Problem Reporting to IRB/IEC 
Incidents or events that meet the OHRP criteria for unanticipated problems require the 
creation and completion of an unanticipated problem report form.  OHRP recommends 
that investigators include the following information when reporting an adverse event, or 
any other incident, experience, or outcome as an unanticipated problem to the IRB/IEC: 
• appropriate identifying information for the research protocol, such as the title, 
investigator’s name, and the IRB/IEC project number; 
• a detailed description of the adverse event, incident, experience, or outcome;  
• an explanation of the basis for determining that the adverse event, incident, 
experience, or outcome represents an unanticipated problem;  
• a description of any changes to the protocol or other corrective actions that have 
been taken or are proposed in response to the unanticipated problem. 
To satisfy the requirement for prompt reporting, unanticipated problems will be reported 
to the IRB/IEC according to institutional policy.  Unanticipated problems that are not 
adverse events will be reported to the sponsor within 2 weeks of the investigator 
becoming aware of the problem.  Unanticipated problems that are serious adverse 
events will be reported to the sponsor according to Section 9.4.2. 
Additional information will be provided in the study reference manual. 
 
9.4.2 
Serious Adverse Event Reporting to the Sponsor 
 
Any AE meeting the specified Serious Adverse Event criteria will be submitted on an 
SAE form to the sponsor’s centralized safety reporting system. This process applies to 
both initial and follow-up SAE reports. 
For any initial SAE, whether deemed related to the study treatment or not, the 
investigator will complete a Serious Adverse Event Form and submit via fax or email 
within 24 hours of becoming aware of the event. 


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As a minimum requirement, the initial notification should provide the following 
information: 
• Study number 
• Patient number 
• Gender 
• Date of birth 
• Name of investigator and full study site address 
• Details of SAE 
• Criterion for classification as “serious” 
• Study drug code, or name if unblinded, and treatment start date and stop date, if 
applicable 
• Date of SAE onset 
• Causality assessment (if sufficient information is available to make this classification) 
The sponsor will request clarification of omitted or discrepant information from the initial 
notification.  The investigator or an authorized delegate is responsible for providing the 
requested information to the sponsor within 24 hours of the sponsor’s request. 
Initial reports of SAEs must be followed later with detailed descriptions, including clear 
photocopies of other documents as necessary (e.g., hospital reports, consultant reports, 
autopsy reports), with the study patient’s personal identifiers removed.  All relevant 
information obtained by the investigator through review of these documents will be 
recorded and provided to the sponsor within 24 hours of receipt of the information.  If a 
new SAE Report Form is provided, then the investigator must sign and date the form.  
The sponsor may also request additional information on the SAE, which the investigator 
or an authorized delegate must provide to the sponsor within 24 hours of the request. 
The SAE reporting contact information will be provided to all participating study sites by 
the contract research organization (CRO) on behalf of the sponsor before study 
initiation.   
 


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9.4.3 
Reporting of SAEs and AEs to FDA and Other Regulatory Authorities 
The sponsor or designee will be responsible for complying with mandatory reporting of 
safety events to the Food and Drug Administration (FDA) and other regulatory 
authorities.  
9.4.4 
Reporting of Pregnancy 
Pregnancy is not regarded as an AE unless there is a suspicion that an investigational 
product may have interfered with the effectiveness of a contraceptive medication.  Any 
pregnancy that occurs in a patient or a partner of a patient during study participation 
must be reported using a clinical study pregnancy form.  To ensure patient safety, each 
pregnancy must be reported to the sponsor within 2 weeks of learning of its occurrence.  
The pregnancy must be followed up to determine outcome (including spontaneous 
miscarriage, elective termination, normal birth, or congenital abnormality) and status of 
mother and child. Pregnancy will result in immediate discontinuation from the study. .  
Pregnancy complications and elective terminations for medical reasons should not be 
reported as an AE or SAE.  Spontaneous miscarriages must be reported as an SAE. 
Any SAE occurring in association with a pregnancy, brought to the investigator’s 
attention after the patient has completed the study, and considered by the investigator 
as possibly related to the study treatment, must be promptly reported to ITI according to 
Section 9.4.2. 
9.5 
Halting Rules 
Individual patient participation in the study may be stopped at any time at the discretion 
of the investigator. Individual patient participation may also be stopped at any time at 
the request of the sponsor. Additionally, the sponsor may place a temporary or 
permanent suspension of enrollment at any site or for the entire study. Reasons for 
stopping or suspending patient participation and/or enrollment include, but are not 
limited to, violation of inclusion/exclusion criteria, major protocol deviation(s), or safety 
concern. 
Review of serious, unexpected, and related AEs by the IRB/IEC, the sponsor, or the 
FDA or relevant local regulatory authorities may also result in suspension of further trial 
interventions/administration of study product at a site. The FDA or other local regulatory 
authorities and study sponsor retain the authority to suspend additional enrollment and 
study interventions/administration of study product for a site or the entire study, as 
applicable. 
Although ITI has every intention of completing the study, ITI reserves the right to 
discontinue the study at any time for clinical or administrative reasons.  


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10 STUDY OVERSIGHT 
10.1 
External Data Monitoring Committee 
In addition to the investigator’s responsibility for oversight, study oversight will be under 
the direction of the sponsor and the Medical Monitor(s).  The Medical Monitor(s) will be 
available in real time to review and recommend appropriate action regarding adverse 
events and other safety issues. Blinded safety data across sites will be monitored 
throughout the study.  Blinded data regarding enrollment and retention, adverse events, 
outlier safety parameters (e.g. clinical laboratory results, ECG parameters) and other 
relevant parameters will be reviewed regularly. If necessary, additional steps may be 
taken to ensure data integrity and protocol compliance.  
 


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11 CLINICAL SITE MONITORING 
The clinical monitor, as a representative of the sponsor, has the obligation to closely 
follow the study.  In doing so, the monitor will visit the investigator and study site at 
periodic intervals, in addition to maintaining necessary telephone and letter contact with 
the investigator and study site.  The monitor will maintain current personal knowledge of 
the study through observation, review of study records and source documentation, and 
discussion of the conduct of the study with the investigator and personnel. 
All aspects of the study will be carefully monitored, by the sponsor or its designee, for 
compliance with applicable government regulation with respect to current GCP and 
current standard operating procedures. 
 


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12 STATISTICAL CONSIDERATIONS 
A formal and detailed statistical analysis plan (SAP) will be finalized prior to unblinding 
the patients’ treatment assignments and will provide further details regarding the 
definition of analysis endpoints and analysis methodology to address all study 
objectives.  Changes made to the data analysis methods as described in the protocol 
will be documented in the SAP and will not necessitate a protocol amendment.  All 
departures from the statistical analyses described in the approved protocol, whether 
made before or after unblinding, will be documented, and justified in the final clinical 
study report. 
A blinded data review will be conducted prior to unblinding the patients’ treatment 
assignments for assessing the accuracy and completeness of the study database and 
defining analysis sets, patient evaluability, and appropriateness of the planned statistical 
methods. 
12.1 
Sample Size Considerations 
Approximately 350 patients will be randomly assigned in a 1:1 ratio to 1 of the 2 
treatment arms (60 mg ITI-07 or placebo).  A sample size of 350 patients randomized, 
which will provide approximately 326 evaluable patients (approximately 163/treatment 
group) assuming a 10% early discontinuation rate before the first post-dose assessment 
in the primary efficacy outcome measure (MADRS), will provide 85% power to detect a 
clinically relevant treatment difference from placebo of 3 points on the MADRS total 
score with ITI-007, with a common standard deviation of 9.0at an overall 2-sided 
significance level of 0.05. 
12.2 
Planned Interim Analyses (if applicable) 
No interim analysis is currently planned. If an interim analysis is conducted, it will be 
described in the SAP which will be finalized before any unblinding of treatment groups 
occurs. 
12.3 
Analysis Sets 
The following analysis sets will be used in the statistical analyses. 
All Enrolled (ENR) Set:  The ENR Set will contain all patients who signed the informed 
consent or the study. 
All Patients Randomized (RND) Set:  The RND Set will contain all patients who signed 
the informed consent and were randomized to study medication.  Patients will be 
classified according to randomized treatment. 


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Intent-to-treat (ITT) Set:  The ITT Set will contain all randomized patients who received 
at least 1 dose of study drug and who had a valid (pre-dose) baseline assessment and 
at least 1 valid post-baseline assessment of MADRS.  Patients will be classified 
according to randomized treatment, regardless of the treatment received during the 
course of the study. 
Per-protocol (PP) Set:  The PP Set will contain all ITT patients who do not have any 
major protocol deviations.  The major protocol deviation criteria will be specified in the 
SAP and finalized as part of the blinded data review prior to the final database lock.  
Patients will be classified according to treatment actually received. 
Safety Analysis Set:  The Safety Analysis Set will contain all patients who received at 
least 1 dose of study drug.  Patients will be classified according to treatment actually 
received. 
Pharmacokinetic (PK) Set:  The PK Set will contain all patients who received at least 
one dose of study medication and had at least 1 PK sample collected and analyzed and 
for whom at least one valid assay result (according to laboratory guidelines) has been 
obtained.  Protocol deviations (e.g., dosing errors) and certain AEs (e.g., emesis) will be 
considered when assigning patients to the PK set.  Patients with partial data will be 
evaluated on a case-by-case basis to determine if sufficient data are available for 
meaningful analyses. 
Unless otherwise specified, the ITT and PP Sets will be used for analysis of efficacy 
endpoints and the Safety Analysis Set will be used for analysis of safety endpoints. 
12.4 
Statistical Analysis Methodology 
Categorical variables (e.g., AEs) will be summarized using the number and percentage 
of patients in specified categories.  Unless otherwise stated, the calculation of 
percentages will be based on the number of patients in the analysis set of interest.  
Continuous variables (e.g., MADRS score) will be summarized using descriptive 
statistics including number of patients, mean, standard deviation, median, minimum, 
and maximum. 
Source data for summary tables and statistical analyses will be presented as patient 
data listings. 
First treatment with study medication and baseline assessments are scheduled for Visit 
2 on Day 1.  For analysis purposes, baseline is defined as the last non-missing 
measurement before the first treatment with study medication.  Assessments on Day 1 
for which time are recorded will be considered baseline if the assessment time is before 
the time of the first treatment with study medication.  Assessments on Day 1 for which 


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the time is missing, and are, according to the study Schedule of Events, supposed to be 
collected prior to treatment (pre-dose), will be considered baseline. 
Safety, efficacy, and quality of life data will be listed for all treated patients and 
summarized by treatment group and time point (visit and relative study day), unless 
stated otherwise in the SAP.  All total and subscale scores will be derived from available 
individual items.  In case of missing items, the total and subscale scores will be 
considered missing.  Plasma concentrations below the limit of quantification (BLQ) will 
be flagged in the data listings and will be set to zero in the calculation of summary 
statistics of concentration values and derivations of PK parameters. 
Unless stated otherwise, statistical tests will be performed at a 2-sided significance level 
of 0.05, leading to 95% (2-sided) confidence intervals (CIs). 
All investigative sites with fewer than a prespecified number of patients who received 
ITI-007, as detailed in the SAP, will be pooled together and considered a single site for 
analysis as follows: the largest site with fewer than the prespecified number of ITI-007 
patients will be pooled with the smallest site with fewer than the prespecified number of 
ITI-007 patients within the same country or geographic region.  If this results in a pooled 
site still having fewer than the prespecified number of ITI-007 patients, this site will be 
pooled together with the next smallest investigative site within the same country or 
geographic region, if one exists; otherwise, no further pooling is needed.  If the primary 
efficacy analysis model presents convergence issues due to the too small number of 
patients per site, including pooled site, the same site pooling algorithm will be applied 
again, but this time pooling sites with a larger prespecified number of ITI-007 patients 
per site within each country or geographic region, as described in the SAP.  The pooled 
investigative sites, as determined based on the primary efficacy variable, will be used 
for any analysis model that includes site as a fixed effect. The actual investigative site 
numbers will be included in the listings. 
  All statistical analysis will be performed using SAS® software Version 9.4 or higher. 
Additional details regarding the statistical analysis methodology will be provided in the 
SAP. 
12.4.1 Patient Disposition, Analysis of Demographics and Other Baseline 
Characteristics 
Patient disposition will be summarized by treatment group, when applicable, and 
overall, including incidence of screening failure and incidence of treatment or study 
discontinuation and the corresponding reasons.  The number and percentage of 
randomized patients who discontinued due to an AE associated with worsening of 


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bipolar depression will be summarized.  Similarly, the number and percentage of 
randomized patients who discontinued due to an AE not associated with worsening of 
bipolar depression will also be presented.  Time to discontinuation due to all reasons, 
AEs (all, AEs associated with worsening of bipolar depression, and AEs not associated 
with bipolar depression), lack of efficacy, or due to any reason of special interest will be 
evaluated using the Kaplan-Meier method, where patients who complete the On-
treatment Period or who discontinue for a reason other than the one being evaluated, 
will be censored.  The Log-rank test will be used to compare the time to discontinuation 
between the treatment groups. 
Demographic and baseline characteristics, including Bipolar Disorder diagnosis and 
baseline efficacy parameters, will be listed and summarized by treatment group.  No 
inferential statistics will be presented. 
12.4.2 Prior and Concomitant Medications 
Prior, prior concomitant, concomitant, and post-treatment medications, defined by start 
and stop dates relative to study medication administration, will be summarized by 
preferred term and treatment group.  Patients with multiple occurrences of a medication 
in the same preferred term will only be counted once within the preferred term. 
During the study, a patient may be treated with zolpidem as described in Section 6.6.  
The number and percent of patients in the ITT Set receiving zolpidem and the total 
number of days on zolpidem will be summarized by treatment group for the Screening 
Period, for each week during the On-treatment Period and for post-treatment with ITI-
007. 
12.4.3 Study Medication Exposure and Treatment Compliance 
Exposure to study medication and treatment compliance will be presented using the ITT 
and Safety Analysis Sets.  Duration of exposure (days) and dosing compliance (%) will 
be calculated and summarized by treatment group.  Additionally, the number and 
percentage of patients exposed to study medication will be presented by study week, 
defined by the planned visits. 
12.4.4 Analysis of Primary and Key Secondary Efficacy Endpoints 
The study is designed to evaluate the efficacy profile of ITI-007 60 mg based on the 
following primary and key secondary efficacy endpoints: 
• Primary Endpoint – Change from baseline to Day 43 in the MADRS total score. 
• Key Secondary Endpoint – Change from baseline to Day 43 in the CGI-BP-S score. 


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Safety Analyses 
All safety parameters will be summarized using the safety analysis set. 
Safety data such as reported and observed AEs, treatment emergent AEs (TEAEs) and 
SAEs, clinical laboratory results, vital signs, physical examinations and neurological 
findings, ECGs, and the different rating scales (YMRS, C-SSRS, AIMS, BARS, and SAS) 
will be summarized by treatment group and visit.  When appropriate, out-of-range values 


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will be flagged in data listings and tabulated.  Shift tables will be prepared for pre-specified 
safety measures, such as laboratory parameters, ECG and weight.  Parameters collected 
in duplicate or triplicate will be analyzed as an average of the measures for the relevant 
time point, including baseline. 
Reported AE terms will be coded using the latest version of the Medical Dictionary for 
Regulatory Activities (MedDRA).  Treatment-emergent adverse events (TEAEs) will be 
defined as any AEs, regardless of the relationship to study drug, that occur or worsen in 
intensity after the first dose of study drug and on or before the date of last dose of study 
drug plus one day.  Treatment-related TEAEs will be defined as any TEAEs that are 
considered by the investigator to be either possibly, probably, or definitely related to study 
drug.  If relationship to study drug is missing, the TEAE will be considered as treatment-
related.  Severity of TEAEs will also be determined by the Investigator.  All TEAEs, 
treatment-related TEAEs, and serious TEAEs will be summarized by treatment group, 
primary system organ class categories, and preferred terms.  If a patient reports the same 
TEAE more than once within the same system organ class and preferred term, the event 
with the worst-case relationship to study drug will be used in the corresponding 
relationship summaries.  Similarly, if a patient reports a TEAE more than once within the 
same system organ class and preferred term, the event with the worst case severity will be 
used in the corresponding severity summaries. 
Patients who discontinue study or study drug due to AEs will be listed and summarized by 
system organ class and preferred term.  TEAEs will be categorized to monitor signals of 
potential abuse of ITI-007 and the number and percentage of patients with at least one 
abuse-related TEAE will be summarized by the pre-specified categories. 
Additional summaries of TEAEs will be presented as deemed necessary and will be 
specified in the SAP. 
Laboratory assessments, including hematology and chemistry, vital signs and ECGs, 
will be listed and summarized by treatment group and visit.  Summaries may include 
actual and change from baseline, incidence of abnormal values according to normal 
range criteria, shift from baseline to each visit according to markedly abnormal criteria, 
and listing of patients meeting certain abnormal criteria.  Pre -specified chemistry 
results, including but not limited to blood levels of fasting glucose, total cholesterol, 
triglycerides, and insulin will be evaluated for whether there is a difference between ITI-
007 and placebo.  Any comparison between the treatment groups will be considered 
exploratory. 


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The observed and change from baseline in the scores of the different rating scales 
(YMRS, C SSRS, AIMS, BARS, and SAS) will be summarized by treatment group and 
visit. 
Additional details for analyses on safety assessments will be provided in the SAP. 


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13 SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS 
Study staff will maintain appropriate medical and research records for this study, in 
compliance with ICH E6, Section 4.9 and regulatory and institutional requirements for 
the protection of confidentiality of patients.  Study staff will permit authorized 
representatives of the sponsor and regulatory agencies to examine (and when required 
by applicable law, to copy) research records for the purposes of quality assurance 
reviews, audits, and evaluation of the study safety, progress and data validity.   
 


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14 QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with Good Clinical Practice (GCP) and all applicable regulatory 
requirements, ITI or its designee may conduct a quality assurance audit of the study site 
records and regulatory agencies may conduct a regulatory inspection at any time during 
or after the study.  In the event of an audit or inspection, the investigator (and institution) 
must agree to grant the auditor(s) and inspector(s) direct access to all relevant 
documents and to allocate their time and the time of their staff to discuss any 
findings/relevant issues.  Responsibility for the accuracy, completeness, and reliability of 
the study data presented to the sponsor lies with the investigator generating the data. 


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15 ETHICS/PROTECTION OF HUMAN SUBJECTS 
15.1 
Ethical Standard 
15.2 
Independent Ethics Committee or Institutional Review Board 
Federal regulations and the International Conference on Harmonisation (ICH) guidelines 
require that approval be obtained from an Institutional Review Board (IRB) or 
Independent Ethics Committee (IEC) before participation of human patients in research 
studies.  Before study onset, the protocol, informed consent, advertisements to be used 
for the recruitment of study patients, and any other written information regarding this 
study to be provided to the patient or the patient’s legal guardian must be approved by 
the IRB/IEC.  Documentation of all IRB/IEC approvals and of the IRB/IEC compliance 
with ICH harmonised tripartite guideline E6(R1): GCP will be maintained by the study 
site and will be available for review by the sponsor or its designee. 
All IRB/IEC approvals should be signed by the IRB/IEC chairman or designee and must 
identify the IRB/IEC name and address; the clinical protocol by title, protocol number, or 
both; and the date approval or a favorable opinion was granted. 
The investigator is responsible for providing written summaries of the progress and 
status of the study at intervals not exceeding 1 year or otherwise specified by the 
IRB/IEC.  The investigator must promptly supply the sponsor or its designee, the 
IRB/IEC, and, where applicable, the institution, with written reports on any changes 
significantly affecting the conduct of the study or increasing the risk to patients. 
15.3 
Ethical Conduct of the Study 
The study will be performed in accordance with the ethical principles that have their 
origin in the Declaration of Helsinki, ICH GCP, and all applicable regulations. 
15.4 
Institutional Review Board 
The protocol, informed consent form(s), recruitment materials, and all patient materials 
will be submitted to the IRB/IEC and local regulatory authorities (where applicable) for 
review and approval.  Approval of both the protocol and the consent form must be 
obtained before any patient is enrolled.  Any amendment to the protocol will require 
review and approval by the IRB/IEC as well as local regulatory authorities, before the 
changes are implemented in the study.   


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15.5 
Informed Consent Process 
15.6 
Patient Information and Consent 
Informed consent is a process that is initiated prior to the individual agreeing to 
participate in the study and continues throughout study participation.  Extensive 
discussion of risks and possible benefits of study participation will be provided to 
patients and their families, if applicable.  A consent form describing in detail the study 
procedures and risks will be given to the patient.  Consent forms will be IRB/IEC-
approved, and the patient is required to read and review the document or have the 
document read to him or her.  The investigator or designee will explain the research 
study to the patient and answer any questions that may arise.  The patient will sign the 
informed consent document prior to any study-related assessments or procedures.  
Patients will be given the opportunity to discuss the study with their surrogates or think 
about it prior to agreeing to participate.  They may withdraw consent at any time 
throughout the course of the study.  A copy of the signed informed consent document 
will be given to patients for their records.  The rights and welfare of the patients will be 
protected by emphasizing to them that the quality of their clinical care will not be 
adversely affected if they decline to participate in this study. 
The consent process will be documented in the clinical or research record. 
A written informed consent in compliance with US Title 21 Code of Federal Regulations 
(CFR) Part 50 shall be obtained from each patient before entering the study or 
performing any unusual or nonroutine procedure that involves risk to the patient.  An 
informed consent template may be provided by the sponsor to clinical study sites.  If any 
institution-specific modifications to study-related procedures are proposed or made by 
the study site, the consent should be reviewed by the sponsor, its designee, or both 
before IRB/IEC submission.  Once reviewed, the consent will be submitted by the 
investigator to his or her IRB/IEC for review and approval before the start of the study.  
If the ICF is revised during the course of the study, all active participating patients must 
sign the revised form. 
Before recruitment and enrollment, each prospective patient or his or her legal guardian 
will be given a full explanation of the study and be allowed to read the approved ICF.  
Once the investigator is assured that the patient/legal guardian understands the 
implications of participating in the study, the patient/legal guardian will be asked to give 
consent to participate in the study by signing the ICF. 
The investigator shall retain the signed original ICF(s) and give a copy of the signed 
original form to the patient or legal guardian. 


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Neither the sponsor nor the CRO is financially responsible for further testing or 
treatment of any medical condition that may be detected during the screening process.  
In addition, in the absence of specific arrangements, neither the sponsor nor the CRO is 
financially responsible for further treatment of the patient’s disease. 
15.7 
Patient Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified 
in a manner designed to maintain patient confidentiality.  All records will be kept in a 
secure storage area with limited access.  Clinical information will not be released 
without the written permission of the patient (or the patient’s legal guardian), except as 
necessary for monitoring and auditing by the sponsor, its designee, the US FDA or other 
local regulatory authorities, or the IRB/IEC. 
The investigator and all employees and coworkers involved with this study may not 
disclose or use for any purpose other than performance of the study any data, record, or 
other unpublished, confidential information disclosed to those individuals for the 
purpose of the study.  Prior written agreement from the sponsor or its designee must be 
obtained for the disclosure of any said confidential information to other parties. 
15.8 
Future Use of Stored Specimens and Other Identifiable Data 
Residual blood samples collected for pharmacokinetic analysis may be maintained after 
the study is complete. Patients will provide informed consent form for the future use of 
his/her samples.  The sponsor or designee will maintain the samples up to 10 years 
following the completion of the study for pharmacokinetic analysis purposes only. 
Confidentiality will be protected for any future studies with the stored samples or data 
de-identified (identified by patient identification number only). Genetic testing will not be 
performed.   
 


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16 DATA HANDLING AND RECORD KEEPING 
Prior to beginning the study, the investigator will be asked to comply with ICH E6(R1) 
8.2 and Title 21 of the US Code of Federal Regulations (CFR) by providing the following 
essential documents, including but not limited to: 
• 
IRB/IEC approval 
• 
Original investigator-signed investigator agreement page of the protocol 
• 
Form FDA 1572, fully executed, and all updates on a new fully executed 
Form FDA 1572 
• 
Curriculum vitae for the investigator and each subinvestigator listed on 
Form FDA 1572 
• 
Financial disclosure information to allow the sponsor to submit complete 
and accurate certification or disclosure statements required under 21 CFR 
54.  In addition, the investigators must provide to the sponsor a commitment 
to promptly update this information if any relevant changes occur during the 
course of the investigation and for 1 year after study completion. 
• 
IRB/IEC-approved informed consent, samples of site advertisements for 
recruitment for this study, and any other written information regarding this 
study that is to be provided to the patient or legal guardian, and 
• 
Laboratory certifications and normal ranges for any local laboratories used 
by the study site, in accordance with 42 CFR 493 
 
As part of the responsibilities assumed by participating in the study, the investigator 
agrees to maintain adequate case histories for the patients treated as part of the 
research under this protocol.  The investigator agrees to maintain accurate eCRFs and 
source documentation as part of the case histories.  These source documents may 
include records of screening assessments such as the M.I.N.I., laboratory reports, and 
ECG strips.  
After database lock, each study site will receive a CD-ROM containing all of their study 
site-specific eCRF data as entered into the EDC, including full discrepancy and audit 
history.  Additionally, a CD-ROM copy of all of the study site’s data will be created and 
sent to the sponsor for storage.  The CRO will maintain a duplicate CD-ROM copy for 
their records.  In all cases, patient initials will not be collected or transmitted to the 
sponsor. 


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16.1 
Data Management Responsibilities 
Clinical data management will be performed in accordance with applicable ITI standards 
and data cleaning procedures to ensure the integrity of the data, e.g., removing errors 
and inconsistencies in the data.  Adverse events and concomitant medication terms will 
be coded using MedDRA, an internal validated medication dictionary. 
16.2 
Data Capture Methods 
Clinical study site personnel will enter patient data into electronic data capture (EDC).  
All eCRF fields are to be filled in.  If an item is not available or is not applicable, this fact 
should be indicated.  Blank fields should not be present unless otherwise directed.  The 
analysis data sets will be a combination of these data and data from other sources (e.g., 
laboratory data). 
16.3 
Types of Data 
Types of data that will be collected includes efficacy outcome assessments, safety 
outcome assessments, and pharmacokinetic assessments.  
16.4 
Schedule and Content of Reports 
The sponsor or designee will be responsible for clinical monitoring plans and reports, 
safety monitoring plans, data management plans, statistical analysis plans and the 
clinical study report. Masking procedures and breaking the blind are described in 
Sections 5.4.2 and 5.4.3, respectively.   
16.5 
Study Records Retention 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational product.  These 
documents should be retained for a longer period, however, if required by the applicable 
regulatory requirements or by an agreement with the sponsor.  It is the responsibility of 
the sponsor to inform the investigator/institution as to when these documents no longer 
need to be retained. 
16.6 
Protocol Deviations 
The investigator or designee must document and explain in the patient’s source 
documentation any deviation from the approved protocol.  The investigator may 
implement a deviation from, or a change of, the protocol to eliminate an immediate 
hazard to study patients without prior IRB/IEC approval.  As soon as possible after such 
an occurrence, the implemented deviation or change, the reasons for it, and any 
proposed protocol amendments should be submitted to the IRB/IEC for review and 
approval, to the sponsor for agreement, and to the regulatory authorities, if required. 


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A deviation from the protocol is an unintended or unanticipated departure from the 
procedures or processes approved by the sponsor and the IRB/IEC and agreed to by 
the investigator.  A significant deviation occurs when there is nonadherence to the 
protocol by the patient or investigator that results in a significant, additional risk to the 
patient.  Significant deviations can include nonadherence to inclusion or exclusion 
criteria, enrollment of the patient without prior sponsor approval, or nonadherence to 
FDA or local regulatory authority regulations or ICH GCP guidelines, and will lead to the 
patient being withdrawn from the study (Section 5.5). 
Protocol deviations will be documented by the clinical monitor throughout the course of 
monitoring visits.  Principal investigators will be notified in writing by the monitor of 
deviations.  The IRB/IEC should be notified of all protocol deviations in a timely manner. 
 
 


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18 LITERATURE REFERENCES 
Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiatry. 1989;154:672-6. 
Davis RE, Vanover KE, Zhou Y, et al. ITI-007 demonstrates brain occupancy at 
serotonin 5-HT2A and dopamine D2 receptors and serotonin transporters using positron 
emission tomography in healthy volunteers. Psychopharmacology (Berl). 
2015;232(15):2863-72. 
Endicott J, Nee J, Harrison W, Blumenthal R. Quality of Life Enjoyment and Satisfaction 
Questionnaire: A new measure. Psychopharmacology Bull. 1993;29:321-326. 
Guy W, editor. ECDEU Assessment Manual for Psychopharmacology. Rockville: U.S. 
Department of Health Education, and Welfare; 1976. 616 p. 
Loebel A, Cucchiaro J, Silva R, et al. Lurasidone monotherapy in the treatment of 
Bipolar I Depression: a randomized, double-blind, placebo-controlled study. Am J 
Psychiatry. 2014a;171(2):160-8. 
Loebel A, Cucchiaro J, Silva R, et al. Lurasidone as adjunctive therapy with lithium or 
valproate for the treatment of Bipolar I Depression: a randomized, double-blind, 
placebo-controlled study. Am J Psychiatry. 2014b;171(2):169-77.  
Montgomery SA and Åsberg M. A new depression scale designed to be sensitive to 
change. Br J Psychiatry 1979;134:382-389. 
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. 
Sheehan DV, Lecrubier Y, Harnett-Sheehan K, Amorim P, Janavs J, Weiller E, Hergueta 
T, Baker R, Dunbar G. The Mini International Neuropsychiatric Interview (M.I.N.I.): The 
Development and Validation of a Structured Diagnostic Psychiatric Interview. J Clin 
Psychiatry. 1998;59(suppl 20):22-33. 
Simpson GM. Angus JW. A rating scale for extrapyramidal side effects. Acta Psychiat 
Scand Suppl. 1970;212:11–9. 
Snyder GL, Vanover KE, Zhu H, et al. Functional profile of a novel modulator of 
serotonin, dopamine, and glutamate neurotransmission. Psychopharmacology (Berl). 
2015;232(3):605-21. 


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Spearing MK, Post RM, Leverich GS, et al. Modification of the Clinical Global 
Impressions (CGI) Scale for use in Bipolar illness (BP): the CGI-BP. Psychiatry Res. 
1997;73(3):159-71. 
Young RC, Biggs JT, Ziegler VE, et al. A rating scale for mania: reliability, validity and 
sensitivity. Br J Psychiatry. 1978;133:429–35. 
Young AH, Calabrese JR, Gustafsson U, et al. Quetiapine monotherapy in Bipolar II 
depression: combined data from four large, randomized studies. Int J Bipolar Disord. 
2013;1:10.   


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SAP_001.pdf: 
NCT03249376 
 
 
Study ID: ITI-007-404 
 
 
Title: A Phase 3, Randomized, Double-blind, Placebo-Controlled, Multi-Center Study to Assess the 
Efficacy and Safety of Lumateperone Monotherapy in the Treatment of Patients With Major Depressive 
Episodes Associated With Bipolar I or II Disorder (Bipolar Depression) Conducted Globally 
 
 
 
 
 
Statistical Analysis Plan Date: 12Jun2019 


 
 
 
 
 
 
Document: 
…\ITI\ITI-007\MYA11638\Biostatistics\Documentation\SAP\ITI-007-404 SAP Final V1.0 12JUN2019.docx 
Author: 
 
Version Number:1.0 
 
 
 
Version Date:  
12JUN2019 
The contents of this document are confidential and proprietary to Intra-Cellular Therapies, Inc. Unauthorized use, 
disclosure or reproduction is strictly prohibited. 
INTRA-CELLULAR THERAPIES INC. (ITCI)
STATISTICAL ANALYSIS PLAN: PROTOCOL ITI-007-404 
Page 1 of 53
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
ITI-007-404 
A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, MULTI-
CENTER STUDY TO ASSESS THE EFFICACY AND SAFETY OF LUMATEPERONE 
MONOTHERAPY IN THE TREATMENT OF SUBJECTS WITH MAJOR 
DEPRESSIVE EPISODES ASSOCIATED WITH BIPOLAR I OR BIPOLAR II 
DISORDER (BIPOLAR DEPRESSION) CONDUCTED GLOBALLY  
 
 
 
 
AUTHOR: 
 
 
VERSION NUMBER AND DATE: FINAL 1.0, 12JUN2019  
 
 
 
 






 
 
 
 
 
 
Document: 
…\ITI\ITI-007\MYA11638\Biostatistics\Documentation\SAP\ITI-007-404 SAP Final V1.0 12JUN2019.docx 
Author: 
 
Version Number:1.0 
 
 
 
Version Date:  
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TABLE OF CONTENTS 
1. LIST OF ABBREVIATIONS .............................................................................................................. 7 
2. INTRODUCTION ................................................................................................................................ 9 
3. STUDY OBJECTIVES ......................................................................................................................... 9 
3.1. 
Primary Objective ........................................................................................................................................9 
3.2. 
Secondary Objectives ..................................................................................................................................9 
3.2.1. 
Key Secondary Objective ............................................................................................................................9 
3.2.2. 
Other Efficacy Secondary Objectives ..........................................................................................................9 
3.2.3. 
 
 
 ....................................................................................................................10 
3.2.4. 
 
 .......................................................................................................................10 
4. STUDY DESIGN ............................................................................................................................... 11 
4.1. 
General Description ................................................................................................................................... 11 
4.2. 
 
 
 .............................................................................................................................. 11 
5. FINAL AND INTERIM ANALYSES .............................................................................................. 11 
5.1. 
Blinded Sample Size Re-estimation ............................................................................................................ 11 
5.2. 
Planned Interim Analysis ........................................................................................................................... 11 
5.3. 
Final Analysis ............................................................................................................................................. 12 
6. ANALYSIS SETS .............................................................................................................................. 12 
6.1. 
All Subjects Enrolled [ENR] Set .................................................................................................................. 12 
6.2. 
All Subjects Randomized [RND] Set ........................................................................................................... 12 
6.3. 
Intent-to-Treat [ITT] Set ............................................................................................................................. 12 
6.4. 
 
 
 
 ..................................................................................................................... 12 
6.5. 
 
 
 
 ................................................................................................................................. 12 
6.6. 
Safety Analysis [SAF] Set ........................................................................................................................... 13 
6.7. 
 
 
 .......................................................................................................................... 13 






 
 
 
 
 
 
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1. LIST OF ABBREVIATIONS 
AE
Adverse Event
AIMS 
Abnormal Involuntary Movement Scale 
ALT
Alanine aminotransferase
ANCOVA 
Analysis of Covariance 
AR(1)
Autoregressive(1)
ARH(1)
Heterogeneous autoregressive(1)
AST
Aspartate aminotransferase
BARS
Barnes Akathisia Rating Scale
BLQ 
Below limit of quantification 
BMI
Body mass index
C-SSRS 
Columbia – Suicide Severity Rating Scale 
CGI-BP-S
Clinical Global Impression Scale – Bipolar version, Severity
CI
Confidence interval
CPK 
Creatine phosphokinase  
CS
Compound symmetry
CSH 
Heterogeneous compound symmetry 
DNA
Deoxyribonucleic acid
ECG 
Electrocardiogram 
eCRF
Electronic Case Report Form
ENR
All Subjects Enrolled
FA0(q) 
No Diagonal Factor Analytic 
GGT
Gamma-glutamyl transferase
HbA1c 
Glycated Hemaglobin A1c 
HDL
High-density lipoprotein
HIV 
Human Immunodeficiency Virus 
HR
Heart rate
IEC
Independent Ethics Committee
IRB 
Institutional Review Board 
ITCI
Intra-Cellular Therapies, Inc. (Sponsor)
ITT 
Intent-to-treat 
LDL
Low-density lipoprotein
LOCF 
Last observation carried forward 
LOE
Lack of efficacy
LSM
Least-squares Mean
MADRS 
Montgomery-Åsberg Depression Rating Scale 
MAR
Missing at random
MCMC 
Monte Carlo Markov Chain 
MedDRA
Medical Dictionary for Regulatory Activities
MI 
Multiple imputation 
MMRM
Mixed-Effects Model for Repeated Measures
MNAR
Missing not at random
PK 
Pharmacokinetic(s) 
PP
Per protocol
PR 
PR interval of the electrocardiogram; time duration between the P and 


 
 
 
 
 
 
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R waves 
PT
Preferred Term
Q-LES-Q-
SF
Quality of Life Enjoyment and Satisfaction Questionnaire – Short 
Form
QRS
QRS interval of the electrocardiogram; duration of the QRS complex
QT 
QT interval of ECG, duration between the Q and T waves 
QTc
QT interval of ECG corrected for heart rate 
QTcB 
QT interval of ECG corrected for heart rate using Bazett’s formula  
QTcF
QT interval of ECG corrected for heart rate using Fridericia’s formula 
RNA 
Ribonucleic acid 
RND
All Subjects Randomized
RR 
Time duration between two consecutive R waves of the 
electrocardiogram
SAE
Serious Adverse Event
SAF 
Safety Analysis 
SAP
Statistical Analysis Plan
SAS 
Simpson-Angus Scale 
SAS®
Statistical Analysis Software
SENS 
Sensitivity 
SD
Standard deviation
SMQ
Standardized MedDRA Queries
SOC 
System Organ Class 
SUPPP
Supportive Per Protocol
TEAE 
Treatment-emergent adverse event 
TLFs
Tables, Listings and Figures
TOEP 
Toeplitz structure 
TOEPH
Heterogeneous Toeplitz structure
ULQ
Upper limit of quantification
WBC 
White blood cells 
WHO
World Health Organisation
YMRS 
Young Mania Rating Scale 
 
 
 


 
 
 
 
 
 
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2. INTRODUCTION 
This document describes the rules and conventions to be used in the presentation and 
analysis of efficacy, safety, and pharmacokinetic (PK) data for Protocol ITI-007-404. It 
describes the data to be summarized and analyzed, including specifics of the statistical 
analyses to be performed. 
This statistical analysis plan (SAP) is based on Protocol Version 1.3, dated November 5, 2018.  
3. STUDY OBJECTIVES  
3.1. PRIMARY OBJECTIVE 
The primary objective of this study is to compare the efficacy of lumateperone administered 
orally once daily to that of placebo as measured by mean change from baseline to Day 43 in 
the total score on the Montgomery-Åsberg Depression Rating Scale (MADRS) in subjects with 
Bipolar Depression. 
3.2. SECONDARY OBJECTIVES 
3.2.1. 
KEY SECONDARY OBJECTIVE 
The key secondary objective of this study is to compare the efficacy of lumateperone 
administered orally once daily to that of placebo as measured by mean change from baseline 
to Day 43 in the total score on the Clinical Global Impression Scale, Bipolar version – Severity 
(CGI-BP-S) in subjects with Bipolar Depression. 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
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3.2.3. 
SAFETY SECONDARY OBJECTIVES 
The safety secondary objectives of this study are to determine the safety and tolerability of 
lumateperone, administered orally once daily for 6 weeks in subjects with Bipolar Depression, 
compared to placebo. Safety and tolerability will be assessed in relation to: 
o Incidence of adverse events (AEs);  
o Mean change from baseline in the Young Mania Rating Scale (YMRS); 
o Mean change from baseline in the Columbia Suicide Severity Rating Scale (C-
SSRS); 
o Mean change from baseline in the Abnormal Involuntary Movement Scale 
(AIMS); 
o Mean change from baseline in the Barnes Akathisia Rating Scale (BARS); 
o Mean change from baseline in the Simpson Angus Scale (SAS); 
o Changes from baseline in clinical laboratory evaluations; 
o Changes from baseline in electrocardiograms (ECGs); 
o Changes from baseline in vital sign measurements;  
o Physical and neurological examination findings. 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
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4. STUDY DESIGN 
4.1. GENERAL DESCRIPTION 
Study participation will last approximately 10 weeks (up to 9 visits) and will include the 
following three periods: a Screening Period, lasting up to 2 weeks, unless the Sponsor or 
representative, in extenuating circumstances related to the subject or the caregiver, where 
applicable, authorizes a longer period; a 6-week double-blind On-Treatment Period of daily 
administration of the study medication; and a Safety Follow-up Period of approximately 2 
weeks after the last dose of study medication for subjects who completed the planned 6 weeks 
of treatment. The timing of assessments during each study period are described in the 
Schedule of Events (Appendix A of the protocol and Appendix 1).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
5. FINAL AND INTERIM ANALYSES 
5.1. BLINDED SAMPLE SIZE RE-ESTIMATION 
An unplanned blinded sample size re-estimation was conducted based on a blinded data 
review of the efficacy data during the study. The estimated pooled standard deviation (SD) 
was 8.82, which was larger than what was assumed at study planning. The sample size was 
therefore increased to a total of 350 randomized subjects, based on an assumed SD of 9.0, to 
ensure 90% statistical power. 
5.2. PLANNED INTERIM ANALYSIS 
None planned. 


 
 
 
 
 
 
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5.3. FINAL ANALYSIS 
The final analyses detailed in this SAP will be performed by IQVIA Biostatistics following Intra-
Cellular Therapies, Inc (ITCI) authorization of the SAP, ITCI authorization of Analysis Sets, 
final Database Lock and Unblinding of Treatment. 
6. ANALYSIS SETS 
Analysis of efficacy and safety endpoints will be performed based on the analysis sets defined 
in this section and as specified for each endpoint throughout this SAP. 
 
 
 
 
 
 
 
 
 
 
  
 
, the inclusion/exclusion of 
subjects from each analysis set will be determined prior to the final analysis (and approved by 
ITCI) based on blinded data review.  
6.1. ALL SUBJECTS ENROLLED [ENR] SET  
The All Subjects Enrolled (ENR) Set will contain all subjects who signed the informed consent 
for this study. 
6.2. ALL SUBJECTS RANDOMIZED [RND] SET 
The All Subjects Randomized (RND) Set will contain all subjects who signed the informed 
consent and were randomized to study medication.  Subjects will be classified according to 
randomized treatment for analyses and displays based on the RND Set. 
6.3. INTENT-TO-TREAT [ITT] SET 
The Intent-To-Treat (ITT) Set will contain all randomized subjects who received at least one 
dose of the study medication and who had a valid baseline (pre-dose) measurement and at 
least one valid post baseline measurement of MADRS total score. All analyses using the ITT 
Set will classify subjects according to the randomized treatment, regardless of the treatment 
received during the course of the study.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 






 
 
 
 
 
 
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blood pressure), the average of the last non-missing pre-treatment measurements will be 
considered as baseline. 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
Unless otherwise specified, the following calculations will be used for change from baseline 
and percent change from baseline: 
Change from baseline visit will be calculated as: 
 
Value at Visit X  – Baseline Value 
Percent change from baseline will be calculated as: 
 
୚ୟ୪୳ୣ ୟ୲ ୚୧ୱ୧୲  ଡ଼ ି୆ୟୱୣ୪୧୬ୣ ୚ୟ୪୳ୣ
୆ୟୱୣ୪୧୬ୣ ୚ୟ୪୳ୣ
 ×  100 
All investigative sites with fewer than 4 ITT subjects will be pooled as follows: The largest site 
with fewer than 4 ITT subjects will be pooled with the smallest site with fewer than 4 ITT 
subjects . If this results in a pooled site still having fewer than 4 ITT subjects, this site will be 
pooled together with the next smallest investigative site, if one exists; otherwise, no further 
pooling is needed. Sites with the same number of ITT subjects will be ordered in ascending 
order of their numerical site identification number. This will serve as a tie-breaker rule in case 
multiple sites have the same number of ITT subjects. If the primary efficacy analysis model, 
described in section 15.1.3 presents convergence issues due to the too small number of 
subjects per site, the same site pooling algorithm will be applied again, but this time pooling 
sites with fewer than 8 ITT subjects. Should the primary efficacy analysis model still present 
convergence issues, after testing the sequence of correlation structures listed in section 
15.1.3, then including the site effect in the model will be reconsidered and may be dropped. 
These pooled investigative sites, as determined based on the primary efficacy response 
variable, will be used for any analysis that has investigative site as a fixed effect in the model. 
The actual investigative site numbers will be included in the by-subject listings. 
The default significance level for statistical tests will be 5%; confidence intervals (CIs) will be 
95% and all tests will be two-sided, unless otherwise specified in the description of the 
analyses. All analyses will be conducted using SAS® version 9.4 or higher. 
7.1. MISSING DATA 
The total and subscale scores of any assessment with more than one item, such as MADRS, 
CGI-BP-S, YMARS, CSSR-S, Q-LES-Q-SF, AIMS, BARS and SAS, will be derived from the 
individual items. Any individual missing item in any scale will not be imputed. If one or more 
items are missing at a visit, then the associated total score or subscale score will be set to 
missing.  
The main objective of the analyses in this study is to evaluate treatment effect of 60 mg 
ITI-007 compared to placebo if the treatment is administered for the planned treatment 
duration. In order to evaluate this estimand in the presence of subjects that may discontinue 
treatment prematurely, the primary efficacy analysis will be performed based on the 
assumption of data being missing at random (MAR). This implies that subjects discontinuing 
from treatment early are considered to have unobserved values similar to the observed ones 


 
 
 
 
 
 
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in their respective treatment group for subjects who have similar history, i.e., the distribution of 
the unobserved future values for subjects who had discontinued treatment is the same as the 
distribution of the observed values for those subjects who completed treatment, conditional on 
the available data prior to discontinuation. 
The Mixed-Effects Model for Repeated Measures (MMRM) method will be used for the 
analysis of the primary and key secondary efficacy endpoints. The MMRM approach does not 
impute missing data but is based on all subjects included in the analysis set using all available 
longitudinal data (either complete or partial). This approach is based on the MAR assumption 
as described above. 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 




 
 
 
 
 
 
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≤ Day 15, > Day 15 - ≤ Day 22, > Day 22 - ≤ Day 29, > Day 29 - ≤ Day 36, > Day 36 - ≤ Day 
43) for all subjects in the SAF Set. The reasons for study discontinuation and treatment 
discontinuation are listed in Table B. 
A subject is defined to have completed treatment if the subject completed the 6-week On-
Treatment period as recorded on the End of Treatment CRF page. 
A subject is defined to have completed the study if the subject has completed the 6-week On-
Treatment Period and the end of study follow-up assessments as recorded on the End of 
Study CRF page. 
Table B: 
Reasons for Study Withdrawal and Study Medication Discontinuation 
Terminology  
Case Report Form Terminology 
Study 
Study 
Medication 
Screen failure 
X 
 
   Adverse event 
     Adverse event associated with worsening of bipolar 
depression* 
     Adverse event not associated with worsening of bipolar 
depression* 
X 
 
X 
 
X 
X 
 
X 
 
X 
Death 
X 
X 
Lack of efficacy 
X 
X 
Lost to Follow-up 
X 
 
Protocol violation  
X 
X 
Physician decision 
X 
X 
Study terminated by sponsor 
X 
X 
Subject withdrew consent: 
Personal or family reasons; 
Refused to provide a reason or refused all end-of-study 
procedures; 
Self-reported adverse event; 
Self-reported lack of efficacy 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
Other 
X 
X 
* Adverse event associated with worsening of bipolar depression will be identified by a Medical Monitor 
review prior to database lock.  
 
The number and percentage of randomized subjects who discontinued due to an adverse 
event associated with worsening of bipolar depression will be summarized. The number and 
percentage of randomized subjects discontinued due to an adverse event not associated with 
worsening of bipolar depression will also be presented.  






 
 
 
 
 
 
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Bipolar Disorder Diagnosis 
o Bipolar disorder diagnosis (Bipolar I or II); 
o Age at first diagnosis of Bipolar Disorder (years);  
o Duration of current major depressive episode (weeks); 
o Number of lifetime depressive episodes; 
o Hospitalization for emotional or psychiatric problems; 
o Number of hospitalizations in lifetime; 
o Hospitalization in the past year; 
Baseline Efficacy 
o Baseline efficacy parameters, including MADRS total score, MADRS item 4 
score, CGI-BP-S subscale scores, CGI-BP-S total score and Q-LES-Q-SF score 
Bipolar Disorder Baseline Safety  
o Baseline safety parameters, including total scores for the following: SAS, AIMS, 
BARS, YMRS, and CSSR-S 
12. MEDICAL HISTORY 
Medical history information will be presented for the SAF Set and will be coded using a current 
version of the Medical Dictionary for Regulatory Activities (MedDRA). 
Medical History conditions are defined as those current and past conditions at Screening. 
The number and percentage of subjects with at least one pre-existing condition as well as the 
number of subjects having pre-existing conditions will be summarized by system organ class 
(SOC), preferred term (PT), treatment group and overall. For each subject, multiple reports of 
pre-existing conditions that map to a common PT and SOC will be condensed into a single 
medical history for incidence counts. 
13. PRIOR AND CONCOMITANT MEDICATIONS 
Medications will be presented for the SAF Set and coded to preferred names using the WHO 
Drug Dictionary. 
Medications will be classified as prior, prior concomitant, concomitant, or post-treatment based 
on start and end dates. See APPENDIX 2 for handling of partial dates for medications. In the 
case where it is not possible to classify a medication due to missing dates the medication will 
be classified by the worst case, i.e. concomitant. 
A medication is considered to have started prior to the first dose of study medication if 
indicated to have started prior to the first dose of study medication on the eCRF. If the 
medication started prior to the first dose of study medication, it is considered to have ended 
prior to the first dose of study medication if indicated to have ended prior to the first dose of 
study medication on the eCRF. 


 
 
 
 
 
 
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A medication is considered to have started after the last dose of study medication if indicated 
as such on the eCRF, assuming it started after completion of all study procedures and 
assessment related to the last dose of study medication. 
o ‘Prior’ medications are medications which started and stopped prior to date of 
first dose of study medication. 
o ‘Prior concomitant’ medications are medications which started prior to and 
stopped after the date of first dose of study medication.  
o ‘Concomitant’ medications are medications which:  
• 
started after the date of first dose of study medication and started prior 
to the date of last dose of study medication,  
• 
AND stopped after the date of first dose of study medication or were 
ongoing at the completion of Day 43 post-dose assessments on Day 43 
(or last treatment day for subjects who discontinue treatment), or were 
ongoing after the last dose of study medication (if planned assessments 
are not performed).  
o ‘Post-treatment’ medications are medications which started after completion of 
Day 43 post-dose assessments (or after last treatment day for subjects who 
discontinue treatment).  
Prior, prior concomitant, concomitant, and post-treatment medication use will be summarized 
by PT using frequencies and percentages by treatment group. Medications will be sorted 
alphabetically by PT in summaries. Subjects with multiple occurrences of a medication in the 
same PT will only be counted once within the PT for each summary.  
During the study, a subject may be treated with zolpidem, benzodiazepines, zopiclone, 
eszopiclone or zalaplon if taken no more than 3 times per week and only during the Screening 
Period or first 2 weeks of the On-Treatment Period. The number and percent of subjects in the 
ITT Set receiving zolpidem, benzodiazepines, zopiclone, eszopiclone or zalaplon and the total 
number of days on zolpidem, benzodiazepines, zopiclone, eszopiclone or zalaplon will be 
summarized by treatment group for the Screening Period, for each week during the On-
treatment period (Days 1-8, Days 9-15, Days 16-22, Days 23-29, Days 30-36 and Days 37-
43), and for post treatment. 
Other medications will be summarized by treatment group and study period if deemed 
necessary. 
14. STUDY MEDICATION EXPOSURE AND TREATMENT COMPLIANCE 
Exposure to study medication and treatment compliance will be presented for the ITT and SAF 
Sets.  
The date of first and last study medication administration will be taken from the eCRF’s 
‘Dosing’  and ‘End of Treatment’ forms, respectively. If a discontinued subject is missing the 
end of treatment date from the ‘End of Treatment’ form, the last known dispense date will be 
used as the date of last study medication administration.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
  


 
 
 
 
 
 
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Duration of exposure will be summarized by treatment group as a continuous variable, using 
mean, SD, median, minimum and maximum. In addition, the number and percentage of 
subjects within each planned Study Week (1-8 days, 9-15 days, 16-22 days, 23-29 days, 30-
36 days, 37-43 days, and > 43 days) will be presented.    
Compliance with study medication will be derived from the drug return CRF page. For each 
subject, overall compliance with study medication (%) will be calculated as 100 x (Number of 
compliant days) / (Number of days in the On-Treatment Period), where a compliant day is 
defined as any day during the On-Treatment Period on which the subject took 1 capsule, and 
‘Number of days in the On-Treatment Period’ is equivalent to ‘Duration of Exposure’ as defined 
above. The number and percentage of compliant and non compliant subjects will be 
presented. Non-compliant subjects are defined as those subjects with a compliance less than 
80% or greater than 120%. 
15. 
 EFFICACY OUTCOMES 
15.1. 
PRIMARY EFFICACY 
15.1.1. 
PRIMARY EFFICACY VARIABLE AND DERIVATION 
The primary efficacy variable is change from baseline to Day 43 in the MADRS total score.  
The MADRS is a 10-item checklist designed to measure the overall severity of depressive 
symptoms. The MADRS individual items are rated by a qualified site rater at each site on a 
scale of 0 to 6 in which a score of 6 represents the most severe symptoms for each item 
assessed. The MADRS total score is the sum of all 10 items and ranges from 0 to 60. If one or 
more items are missing at a visit, the total score will also be set to missing for that visit. 
15.1.2. 
MISSING DATA METHODS FOR PRIMARY EFFICACY ENDPOINT 
The primary analysis method for evaluating the primary efficacy endpoint is the likelihood-
based MMRM method described in detail in Section 15.1.3. The use of MMRM inherently 
implies that the treatment effect on the change from baseline in the MADRS total score will be 
similar for the subjects who withdraw and for those who complete the treatment in their 
respective treatment groups, conditional on the outcomes observed prior to withdrawal (MAR 
assumption), as described in section 7.1. Sensitivity analysis of the primary efficacy endpoint 
will be performed to evaluate the robustness of the MMRM method under different 
assumptions on the mechanism of missng data, as detailed in Section 15.1.4.   
If a patient has the score of one or more items missing at a visit, the total score for that patient 
will be set to missing for that visit. 
15.1.3. 
PRIMARY ANALYSIS OF PRIMARY EFFICACY VARIABLE 
The treatment effect on the primary efficacy endpoint will be estimated using an MMRM 
method. The model will include the change from baseline at each pre-specified time point as 
the response variable, study visit, Bipolar Disorder stratification variable at screening (Bipolar I 


 
 
 
 
 
 
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or Bipolar II), treatment (60 mg ITI-007 or placebo) and site (or pooled site) as factors, 
baseline MADRS total score as covariate and interaction terms for baseline MADRS total 
score-by-study visit and treatment-by-study visit. The subject term will be included in the 
model as a random effect while all other terms will be considered fixed effects. An 
unstructured covariance matrix will be used to model the correlation among repeated 
measurements within subject. 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The Kenward-Rogers method will be used to estimate the denominator degrees of freedom. 
The treatment and treatment-by-study visit interaction terms allow for comparisons of the 
treatment groups at the time point of interest (Days 8, 15, 22, 29, 36 and 43). Treatment 
differences will be evaluated via contrasts for the study visit-by-treatment factor.  
The change from baseline to Day 43 will be used for the primary efficacy analysis, and will be 
performed for the ITT Set 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Summary statistics for change from baseline in MADRS total score will be presented by 
treatment group and study visit (Day), as well as least-squares mean (LSM) estimates, 
standard errorsand the corresponding 95% CI for LSMs.Contrast estimates (LSM differences) 
for between-group comparison, the corresponding standard errors, 95% CIs, effect sizes, and 
p-values will also be presented for each study visit (Day). Effect size will be calculated for the 
ITI-007 60 mg treatment group as: 
 
୐ୗ ୑ୣୟ୬ ୈ୧୤୤ୣ୰ୣ୬ୡୣ
୔୭୭୪ୣୢ ୣୱ୲୧୫ୟ୲ୣ ୭୤ ୵୧୲୦୧୬ ୱ୳ୠ୨ୣୡ୲ ୣ୰୰୭୰ ୱ୲ୟ୬ୢୟ୰ୢ ୢୣ୴୧ୟ୲୧୭୬  .  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
15.2. 
KEY SECONDARY EFFICACY ENDPOINT 
The key secondary efficacy endpoint is the change from baseline to Day 43 in the Clinical 
Global Impression scale, Bipolar Version, for Severity (CGI-BP-S).  
The CGI-BP-S is a single value assessment of illness severity in mania, depression and 
overall bipolar illness and ranges from 1=‘Normal, not at all ill’ to 7=‘Very severely ill’ It is used 
in this study at screening (as a criterion for inclusion or exclusion), at baseline, and throughout 
the study, at Days 8, 15, 22, 29, 36, and 43. A higher score is associated with greater illness 
severity. The CGI-BP-S has 3 subscales, one each for mania, depression and overall bipolar 
illness. These 3 subscales are included in the calculation of the CGI-BP-S total score which 
will be recorded on the Clinical Global Impressions – Bipolar (CGI-S-BP) CRF page. 














 
 
 
 
 
 
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(MedDRA) central coding dictionary currently in effect at the time of analysis or database lock. 
Treatment emergent adverse events (TEAEs) are defined as AEs that started or worsened in 
severity on or after the first dose of study medication and on or before the date last dose of 
study medication plus one day.  
All AEs with an onset date after the last dose of study medication plus one day will be listed in 
the AE data listing and labelled as ‘Follow-up Adverse Event’.  
See APPENDIX 2 for handling of partial or completely missing dates for AEs. In the case 
where it is not possible to define an AE as treatment emergent or not due to missing dates, the 
AE will be classified as the worst case, i.e. treatment emergent.  
An overall summary of number of subjects within each of the categories described in the sub-
sections 16.1.1 and 16.1.2 below will be provided as specified in the TLF shells.  
Listings will include all AEs, TEAEs and Non-TEAEs. A seperate listing for TEAEs leading to 
study discontinuation will be presented. 
16.1.1. 
AES AND TEAES  
Incidence of TEAEs will be presented by System Organ Class (SOC) and Preferred Term (PT) 
and also broken down further by maximum severity and relationship to study medication.  
The number and percentage of subjects with at least one TEAE and total number of subjects 
experiencing TEAEs will be summarized by PT, SOC and treatment group. A summary of 
TEAEs will be provided with only PTs and a separate summary for only SOCs. Additional 
summaries of TEAEs and TEAEs related to study medications (‘possibly related’, ‘probably 
related’, or ‘definitely related’) will be provided for PTs occurring in at least 5% of subjects in 
any treatment group (60 mg ITI-007 or placebo). Within each subject, multiple reports of 
events that mapped to a common MedDRA PT and SOC will be condensed into a single AE 
for incidence counts. Summaries will present SOCs in alphabetical order and PTs by 
descending (total) frequency within SOCs, by treatment group. 
TEAEs will also be categorized according to the onset date of the TEAEs. The total number of 
subjects having events for each PT and SOC will be summarized by first onset categories, 
based on planned study visits (Day 1 - ≤ Day 8, > Day 8 - ≤ Day 15, > Day 15 - ≤ Day 22, > 
Day 22 - ≤ Day 29, > Day 29 - ≤ Day 43). 
The relative risk of at least one TEAE and for each PT and SOC will also be presented along 
with 95% CIs and p-values obtained by the Chi-square test for association.  
AE severity is classified as “mild”, “moderate”, “severe”, “life-threatening” by the investigator. 
AEs and TEAEs with a missing severity will be classified as “not specified”. If a subject reports 
a TEAE more than once within the same PT and SOC, the event with the worst case severity 
will be used in the corresponding severity summaries. 
Relationship to study medication, as indicated by the Investigator, is classified as ”unrelated”, 
“unlikely to be related”, “possibly related”, “probably related”, “definitely related” (increasing 
severity of relationship). A “related” TEAE is defined as a TEAE ”possibly related”, ”probably 
related” or “definitely related” to study medication. TEAEs with a missing relationship to study 
medication will be regarded as “related”. If a subject reports the same AE more than once 
within the same PT and SOC, the AE with the worst case relationship to study medication will 


 
 
 
 
 
 
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be used in the corresponding relationship summaries. A summary of related TEAEs by SOC 
and PT will be presented. 
AEs leading to study discontinuation will be identified by using the Completion/Withdrawal 
from Study page of the eCRFs, where ‘Primary Reason’ indicates “AE”. TEAE leading to 
disontinuation of study medication will be identified by using the End-of-Treatment page of the 
eCRFs, where ‘Primary Reason’ indicates “AE”.  
For AEs leading to early study withdrawal or discontinuation of study medication, summaries 
of incidence rates (frequencies and percentages) by SOC and PT will be prepared. 
16.1.2. 
SERIOUS ADVERSE EVENTS AND DEATH 
Serious adverse events are those events recorded as “Serious” on the Adverse Events page 
of the eCRF. SAEs will be listed and summarized by SOC and PT. 
AEs leading to death are those events which are recorded as “Fatal” on the Adverse Events 
page of the (e)CRF. Deaths may also be recorded on the End of Treatment page and the 
Completion/Withdrawal from Study page of eCRF. A listing all deaths will be prepared based 
on these sources. A listing of all TEAEs leading to death will also be prepared. 
16.1.3. 
EXTRAPYRAMIDAL TEAES 
Extrapyramidal TEAEs will be defined by the Standard MedDRA Query (SMQ) labeled as 
Extrapyramidal Syndrome.  The number and percentage of subjects with at least one TEAE 
PT mapped to an extrapyramidal term contained in the SMQ will be presented.  In addition, the 
extrapyramidal terms will be summarized.  Separate tables will be presented for the narrow 
and broad interpretation of the SMQ. 
16.1.4. 
ABUSE-RELATED TEAES 
TEAEs will be categorized as defined in the table below to monitor signals of potential abuse 
of ITI-007. The number and percentage of subjects with at least one abuse-related TEAE will 
be summarized by category and the applicable PTs below. 
Table D: 
Abuse-Related PTs 
Category 
Applicable Preferred Terms 
Euphoria 
Euphoric mood; Elevated mood; Feeling abnormal; Feeling 
drunk; Feeling of relaxation; Dizziness; Thinking abnormal; 
Hallucination; Inappropriate affect 
Impaired attention, 
cognition, and mood 
Somnolence; Sedation; Mood disorders and disturbances 
Dissociative/psychotic 
Psychosis; Aggression; Confusion and disorientation 
Other related terms  
Drug tolerance; Habituation; Drug withdrawal syndrome; 


 
 
 
 
 
 
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Substance-related disorders 
16.2. 
LABORATORY EVALUATIONS 
Results from the central laboratory will be included in the reporting of this study for 
hematology, clinical chemistry, urinalysis and screening serology. A list of laboratory 
assessments to be included in the outputs is included in the protocol, Section 8.5. Summary 
statistics will be presented in standard international (SI) and US conventional units. 
Quantitative laboratory measurements reported as “< X”, i.e. below the lower limit of 
quantitation (BLQ), or “> X”, i.e. above the upper limit of quantitation (ULQ), will be converted 
to X for the purpose of quantitative summaries, but will be presented as recorded, i.e. as “< X” 
or “> X” in the listings.  
Blood samples for laboratory evaluations will be collected after an overnight fast (≥10 hours) 
during screening and on Days 8, 22, 43 and Day 57 safety follow-up or during the 
discontinuation visit. All non fasting results for glucose, insulin and triglycerides will be 
excluded from descriptive statistics but will appear in the data listings. 
The following summaries will be provided for laboratory data: 
o Actual and change from baseline by visit, and for last on-treatment assessment 
where applicable (for quantitative measurements) 
o Incidence of abnormal values according to normal range criteria 
o Shift from baseline according to normal range criteria (for quantitative 
measurements and categorical measurements) 
o Shift from baseline according to markedly abnormal criteria defined in Section 
16.2.1 (for quantitative measurements and categorical measurements) 
o Listing of subjects meeting markedly abnormal criteria. 
o Incidence of liver function related values meeting pre-defined criteria, as defined 
in Section 16.2.2, during the treatment period and the entire study 
16.2.1. 
LABORATORY REFERENCE RANGES AND MARKEDLY ABNORMAL CRITERIA 
Quantitative laboratory measurements will be compared with the relevant laboratory reference 
ranges in SI units and US Conventional units and categorized as: 
o Low: Below the lower limit of the laboratory reference range.  
o Normal: Within the laboratory reference range (upper and lower limit included). 
o High: Above the upper limit of the laboratory reference range.  
In addition to the high and low quantitative laboratory assignments (as identified by means of 
the laboratory reference ranges), markedly abnormal quantitative safety (and other) laboratory 
assessments will also be identified in accordance with the predefined markedly abnormal 
criteria as presented in Table E: 








 
 
 
 
 
 
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o Shift from baseline to each visit according to markedly abnormal criteria (for 
quantitative measurements and categorical measurements) 
o Incidence of markedly abnormal results defined in Section 16.3.1 
o Listing of subjects meeting markedly abnormal criteria 
16.3.1. 
ECG MARKEDLY ABNORMAL CRITERIA 
Markedly abnormal quantitative ECG measurements will be identified in accordance with the 
following predefined markedly abnormal criteria: 
o Absolute values for QT, QTcB and QTcF intervals will be classified as: 
o > 450 msec 
o > 480 msec 
o > 500 msec 
o Change from Baseline for QT, QTcB and QTcF intervals will be classified as: 
o > 30 msec increase from baseline 
o > 60 msec increase from baseline 
16.4. 
VITAL SIGNS 
The following vital signs measurements will be reported for this study: 
o Systolic blood pressure (mmHg) 
o Diastolic blood pressure (mmHg) 
o Pulse rate (bpm) 
o Respiratory rate (breaths/min) 
 
o Oral temperature (⁰C) 
o Height (cm) at screening 
o Weight (kg) 
o BMI (kg/m2) [ calculated as weight (kg) / height (m)2] 
Vital signs, including systolic blood pressure, diastolic blood pressure, pulse rate, respiratory 
rate, oral temperature and body weight, are recorded at screening, baseline and Days 8, 15, 
22, 29, 36, 43 and 57At screening, baseline and days 43 and 57 vital signs include the 3-
positional blood pressure and pulse rate will be measured after 10 minutes in the supine 
position, 1-minute sitting, immediately after standing, and 3 minutes after standing at 
screening, baseline, day 43 and day 57. These 3-positional results will be averaged at each 
visit and used for the summary and analyses. Pulse will be measured by counting pulse over 
60 seconds. Height will be measured only at screening.  
BMI measurements classify a subject’s weight status as underweight, normal, overweight, or 
obese using Table G:. Shifts from Baseline to Day 43 will be produced by treatment group for 
the SAF Set to show the percentage of subjects who fall into each BMI category combination. 






 
 
 
 
 
 
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depression. It will be completed by the investigator or an expert site-based rater.  
The observed and change from baseline in YMRS total score will be summarized by treatment 
and visit. 
16.6.2. 
BARNES AKATHISIA RATING SCALE (BARS) 
The BARS is a rating scale, measuring the observable, restless movements that characterize 
akathisia. It consists of 4 items: objective restlessness, awareness of restlessness, distress 
related to restlessness and global clinical assessment of akathisia. Each item is on a 4-point 
scale (0 to 3), except for the global clinical assessment which is on a 6-point scale (0 to 5), 
both using low values to represent absence of akathisia and high representing severe 
akathisia. The BARS total score is the sum of items 1 through 3 and ranges from 0 to 9. 
Higher values of the BARS total score indicate akathisia is higher in severity. If one or more 
items at a visit are missing the total will not be calculated. 
The observed and change from baseline in BARS total scores to Day 43 will be summarized 
by treatment. 
16.6.3. 
ABNORMAL INVOLUNTARY MOVEMENT SCALE (AIMS) 
The AIMS is a clinician rated assessment of abnormal movements. It contains items related to: 
facial and oral movements; extremity movements; trunk movements; global judgments and 
dental status. Seven items of the AIMS range from 0= “None” to 4= “Severe”. A score of “mild” 
(2) in two or more categories or a score of “moderate” or “severe” in any one category results 
in a positive AIMS score (i.e. the scores are not averaged). The global severity score is the 
response to “Severity of abnormal movements” found within the global judgments section. 
Additionally, overall severity is scored on the basis of severity of abnormal movements and 
incapacitation due to abnormal movements.  
The (non-global) AIMS total score is the sum of items 1 through 7. The possible range for the 
AIMS total score is 0 to 28. Higher values of the total AIMS score indicate increased severity in 
abnormal movement. If one or more of the AIMS total score items are missing at a visit, the 
score will be set to missing. 
The observed and change from baseline in AIMS total scores to Day 43 will be summarized by 
treatment. 
16.6.4. 
SIMPSON-ANGUS RATING SCALE (SAS) 
The SAS is a measure of extrapyramidal side effects consisting of 10 items: gait, arm 
dropping, shoulder shaking, elbow rigidity, wrist rigidity, head rotation, glabella tap, tremor,  
salivation and akathisia. Items are rated on a scale from 0 (normal) to 4 (extreme in severity).  
The SAS total score is defined as the sum of all 10 items and ranges between 0 and 40. Lower 
values of the SAS total score indicate milder symptoms. If one or more items are missing at a 
visit the SAS total score will be set to missing. 
The observed and change from baseline in SAS total scores to Day 43 will be summarized by 
treatment. 


 
 
 
 
 
 
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16.6.5. 
COLUMBIA SUICIDE SEVERITY RATING SCALE (C-SSRS) 
The C-SSRS is an instrument designed to systematically assess and track suicidal behavior 
and suicidal ideation throughout the study. The C-SSRS includes the following four sections: 
Suicidal Ideation, Ideation Intensity, Suicidal Behavior and Actual Suicide Attempts. The 
strength of this suicide classification system is in its ability to accurately and comprehensively 
assess suicidality, while limiting the over-identification of suicidal behavior. The C-SSRS will 
be administered by a trained rater at the site. 
Suicidal Ideation is assessed by 5 questions, the responses to which equate to a 6-point scale 
from 0=”No ideation present” to 5=”Active ideation with plan and intent”.  A score of 4 or 5 on 
this scale indicates serious suicidal ideation. Any score greater than 0 will be counted as 
having suicidal ideation.  
The Ideation Intensity total score is the sum of five items from the Ideation Intensity scale: 
frequency, duration, controllability, deterrents, and reasons for ideation. If a subject did not 
endorse any suicidal ideation, a score of 0 for the intensity total score will be given. The 
possible range for the Intensity total score is 0 to 25. 
The number and percentage of subjects with each type of suicidal ideation or any suicidal 
ideation during each study period will be summarized. The most severe ideation, the ideation 
intensity items (frequency, duration, controllability, deterrents, and reasons for ideation), and 
the ideation intensity total score will also be summarized descriptively. 
Suicidal Behavior is collected as actual attempt, non-suicidal self-injurious behaviour, 
interrupted attempt, aborted attempt, preparatory acts or behavior, suicidal behavior, and 
suicide. The number and percentage of subjects with each type of suicidal attempt (actual 
attempts, interrupted attempts, aborted attempts, and preparatory acts or behavior) will be 
summarized for each scheduled visit and overall by study period. The number and percentage 
of subjects with any suicidal behavior and those completing suicide will also be summarized 
for each scheduled visit and overall by study period.  
The number and percentage of subjects with suicidality as measured by the C-SSRS will be 
summarized, where suicidality is defined as having at least one occurrence of suicidal ideation 
or at least one occurrence of suicidal behavior. The suicidality indicator will be set to 1 if the 
subject exhibits suicidality for each visit, 0 if the subject does not exhibit suicidality, and 
missing otherwise. This data will be summarized at each scheduled visit and overall by study 
period (treatment and post-treatment).  
Data collected on actual suicide attempts (lethality of actual attempts and potential lethality of 
attempts) will be presented in a data listing.  
An overall summary of C-SSRS data (post-baseline data across all scheduled visits) will 
include the frequency and percentage of the following: 
o At least one suicidal ideation post-baseline 
o Emergence of suicidal ideation (no suicidal ideation at baseline, and any type of 
suicidal ideation post-baseline) 
o Emergence of serious suicidal ideation (no suicidal ideation at baseline, and any 
serious suicidal ideation [ideation score of 4 or 5] post-baseline) 
o Most severe type of ideation post-baseline 


 
 
 
 
 
 
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o Worsening of suicidal ideation (most severe suicidal ideation post-Baseline was 
more severe than it was at baseline) 
o At least one suicidal behavior post-baseline 
o Emergence of suicidal behavior (no suicidal behavior at baseline, and any type 
of suicidal behavior post-baseline) 
o At least one actual attempt post-baseline 
o At least one interrupted attempt post-baseline 
o At least one aborted attempt post-baseline 
o At least one preparatory acts or behaviors post-baseline 
o At least one instance of suicidality [any ideation or behavior] post-baseline 
o Emergence of suicidality (no suicidality at baseline, and any suicidality post-
baseline) 
o Any completed suicides post-baseline 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
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18. REFERENCES 
Koch, G. and Wienner, L.E. Commentary for the Missing Data Working Group’s Perspective 
for Regulatory Clinical Trials, Estimands, and Sensitivity analyses. Statist. Med. 2016, 35 
2887–2893.  
LaVange LM and Permutt T (2015). A regulatory perspective on missing data in the aftermath 
of the NRC report. Statist. Med.35(17):2853-64. 
Little, R., Yau, L. (1996). Intention-to-treat analysis for longitudinal studies with drop-outs. 
Biometrics. 52, 1324-1333. 
National Research Council. The Prevention and Treatment of Missing Data in Clinical Trials. 
National Academies Press: Washington, D.C., 2010. 
Permutt, T. (2016a) A taxonomy of estimands for regulatory clinical trials with discontinuation. 
Statistics in Medicine. 2016; 35(17): 2865-2875. 
Permutt T for the Missing Data Working Group (2016b). Sensitivity analysis for missing data in 
regulatory submissions. Statist. Med. 35(17):2876–2879. 
O’Kelly, M., Ratitch, B. (editors). Clinical Trials with Missing Data: A Guide for Practitioners. 
Wiley, 2014. 
Ratitch, B., O’Kelly, M., Tosiello, R. (2013). Missing data in clinical trials: From clinical 
assumptions to statistical analysis using pattern mixture models. Pharmaceutical Statistics. 12, 
337-347. 
Shih WJ (2016). Comments on the three papers by the FDA/CDER research team on the 
regulatory perspective of the missing data problem. Statist. Med. 35:2880–2886.


 
 
 
 
 
 
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