A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multi-Center Study With an Open-Label Extension to Assess the Efficacy and Safety of ITI-007 Monotherapy in the Treatment of Patients With Major Depressive Episodes Associated With Bipolar I or Bipolar II Disorder (Bipolar Depression)
Phase: PHASE3
Conditions: Bipolar Depression
Sponsor: Intra-Cellular Therapies, Inc.

NCT02600494 
 
 
 
 
Study ID: ITI-007-401 
 
 
 
Title: A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multi-Center 
           Study with an Open-Label Extension to Assess the Efficacy and Safety of 
           ITI-007 Monotherapy in the Treatment of Patients with Major Depressive 
           Episodes Associated with Bipolar I or Bipolar II Disorder (Bipolar 
           Depression) 
 
 
 
Protocol Version 1.4 Date: 09 March 2018 

Intra-Cellular Therapies, Inc. 
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ITI-007 
Protocol: ITI-007-401 
 
  9 March 2018 
 
CLINICAL STUDY PROTOCOL 
ITI-007-401 
 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multi-Center 
Study with an Open-Label Extension to Assess the Efficacy and Safety of 
ITI-007 Monotherapy in the Treatment of Patients with Major Depressive 
Episodes Associated with Bipolar I or Bipolar II Disorder (Bipolar 
Depression) 
 
Confidential 
 

Intra-Cellular Therapies, Inc. 
Confidential 
ITI-007 
Protocol: ITI-007-401 
 
  9 March 2018 
Version of Protocol:  
Version 1.4 
Date of Protocol:  
9 March 2018 
 
CONFIDENTIAL  
All financial and nonfinancial support for this study will be provided by Intra-Cellular 
Therapies, Inc. (ITI).  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.   
The study will be conducted according to the International Council for Harmonisation 
harmonised tripartite guideline E6(R1): Good Clinical Practice. 
 

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Declaration of Investigator 
I have read and understood all sections of the protocol entitled “A Phase 3, randomized, 
double-blind, placebo-controlled, multi-center study with an open-label extension to assess 
the efficacy and safety of ITI-007 monotherapy in the treatment of patients with major 
depressive episodes associated with bipolar I or bipolar II disorder (bipolar depression)” and 
the accompanying investigator’s brochure issued 18-May-2017. 
I agree to supervise all aspects of the protocol and to conduct the clinical investigation in 
accordance with the Amended Protocol Version 1.4 dated 9 March 2018, the International 
Council for Harmonisation harmonised tripartite guideline E6(R1): Good Clinical Practice 
and all applicable government regulations.  I will not make changes to the protocol before 
consulting with ITI or implement protocol changes without independent ethics committee 
approval except to eliminate an immediate risk to patients.  I agree to administer study 
treatment only to patients under my personal supervision or the supervision of a 
subinvestigator. 
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. 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
Printed Name of Principal Investigator 
 
 
 
 

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Table of Contents 
Table of Contents .......................................................................................................................5 
List of Tables ..............................................................................................................................9 
Protocol Synopsis.....................................................................................................................10 
List of Abbreviations................................................................................................................40 
1 
Introduction ......................................................................................................................42 
2 
Study Objectives...............................................................................................................45 
2.1 
Primary Objectives..................................................................................................45 
2.1.1 
Part A Primary Objectives........................................................................45 
2.1.2 
Part B Primary Objective .........................................................................45 
2.2 
Secondary Objectives..............................................................................................46 
2.2.1 
Part A Secondary Objectives - Efficacy ...................................................46 
2.2.2 
Part A Secondary Objectives - Safety ......................................................47 
 
 
2.2.4 
Part B Secondary Objectives – Effectiveness ..........................................48 
2.3 
Exploratory Objectives (Part A)..............................................................................48 
3 
Investigational Plan ..........................................................................................................49 
3.1 
Study Design ...........................................................................................................49 
3.1.1 
Part A Study Periods (up to 10 Weeks, Including Screening/Baseline) ...49 
3.1.2 
Part B Study Periods (up to Approximately 6 months [175 days]) .........50 
3.1.3 
Rationale of Study Design .......................................................................50 
4 
Patient Selection and Withdrawal Criteria .......................................................................52 
4.1 
Selection of Study Population .................................................................................52 
4.1.1 
Part A Inclusion Criteria ..........................................................................52 
4.1.2 
Part A Exclusion Criteria .........................................................................53 
4.1.3 
Part B Inclusion Criteria ..........................................................................59 
4.1.4 
Part B Exclusion Criteria .........................................................................59 
4.2 
Withdrawal of Patients from the Study ...................................................................65 
4.2.1 
Reasons for Withdrawal/Discontinuation ................................................65 
4.2.2 
Handling of Withdrawals .........................................................................66 
4.2.3 
Replacements ...........................................................................................67 

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5 
Study Treatments ..............................................................................................................68 
5.1 
Method of Assigning Patients to Treatment Groups ...............................................68 
5.2 
Treatments Administered ........................................................................................68 
5.3 
Identity of Investigational Product..........................................................................69 
5.3.1 
Investigational Product for Part A ...........................................................69 
5.3.2 
Investigational Product for Part B ...........................................................71 
5.4 
Management of Clinical Supplies ...........................................................................72 
5.4.1 
Study Drug Packaging and Storage .........................................................72 
5.4.2 
Test Article Accountability ......................................................................74 
5.5 
Overdose Management ...........................................................................................74 
5.5.1 
Treatment of Overdose ............................................................................74 
5.5.2 
Medication Errors ....................................................................................75 
5.5.3 
Treatment of Medication Errors ...............................................................75 
5.6 
Blinding...................................................................................................................75 
5.6.1 
Breaking the Blind ...................................................................................75 
5.7 
Treatment Compliance ............................................................................................76 
5.8 
Prior and Concomitant Therapy ..............................................................................76 
6 
Study Assessments and Procedures ..................................................................................79 
6.1 
Screening Assessments and Procedures ..................................................................85 
6.1.1 
Informed Consent ....................................................................................85 
6.1.2 
Medical History and Other Information ..................................................85 
6.1.3 
Modified Physical Examination...............................................................86 
6.1.4 
Electrocardiogram Assessments ..............................................................86 
6.1.5 
Vital Sign Measurements .........................................................................87 
6.1.6 
Hepatitis Screening ..................................................................................87 
6.1.7 
HIV Screening .........................................................................................88 
6.1.8 
Urine Drug and Alcohol Screening ..........................................................88 
6.1.9 
Laboratory Assessments ..........................................................................88 
6.1.10 
Urine Pregnancy Test ...............................................................................88 
6.1.11 
Structured Clinical Interview ...................................................................89 
6.1.12 
Bipolarity Index (BPI) .............................................................................89 
6.1.13 
Columbia Suicide Severity Rating Scale .................................................90 
6.1.14 
Young Mania Rating Scale ......................................................................90 

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6.1.15 
Clinical Global Impressions of Severity ..................................................91 
6.1.16 
Eligibility Adjudication (Part A only) ......................................................92 
6.2 
Efficacy Assessments and Procedures ....................................................................92 
6.2.1 
MADRS ...................................................................................................92 
6.2.2 
Clinical Global Impression of Severity ...................................................93 
6.2.3 
SDS (Part A Only)....................................................................................93 
6.2.4 
Q-LES-Q-SF ............................................................................................94 
6.2.5 
WHO-5 Well-Being Index (Part A Only) .................................................94 
6.2.6 
NEO-FFI (Part A Only)............................................................................94 
6.3 
Safety and Tolerability Assessments .......................................................................95 
6.3.1 
Adverse Events ........................................................................................95 
6.3.2 
Safety Assessments ................................................................................103 
6.4 
Safety Monitoring Committee ..............................................................................105 
6.5 
Laboratory Analyses .............................................................................................105 
 
 
6.7 
Sample Collections ...............................................................................................107 
 
 
 
 
6.7.3 
Frequency and Volume of Blood Collection ..........................................107 
6.8 
Pregnancy ..............................................................................................................109 
7 
Statistical and Analytical Plan ........................................................................................ 110 
7.1 
Analysis Endpoints ............................................................................................... 110 
7.1.1 
Primary Efficacy Endpoints (Part A) ..................................................... 110 
7.1.2 
Secondary Efficacy Endpoints (Part A) ................................................. 110 
7.1.3 
Secondary Effectiveness Endpoints (Part B) ......................................... 112 
 
 
7.1.5 
Safety Endpoints (Parts A and B) .......................................................... 113 
7.2 
Sample Size Calculations ...................................................................................... 113 
7.3 
Analysis Sets ......................................................................................................... 114 
7.4 
Description of Subgroups to be Analyzed ............................................................ 115 
7.5 
Statistical Analysis Methodology ......................................................................... 116 
7.5.1 
Patient Disposition, Analysis of Demographics and Other Baseline 
Characteristics ........................................................................................ 116 

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7.5.2 
Prior and Concomitant Medications ...................................................... 117 
7.5.3 
Study Medication Exposure and Treatment Compliance ...................... 117 
7.5.4 
Analysis of Part A Primary Endpoint - Efficacy  ................................... 118 
7.5.5 
Analysis of Part A Secondary Endpoint - Efficacy  ...............................121 
7.5.6 
Analyses of Part A Exploratory Endpoints- Efficacy  ...........................121 
7.5.7 
Analyses of Part B Secondary Endpoints - Effectiveness .....................121 
7.5.8 
Safety Analyses (Parts A and B) ............................................................122 
7.5.9 
Pharmacokinetic Analyses (Part A) .......................................................123 
7.5.10 
Interim Analysis .....................................................................................123 
7.6 
Data Quality Assurance.........................................................................................124 
7.6.1 
Data Management ..................................................................................124 
8 
Ethics ..............................................................................................................................126 
8.1 
Independent Ethics Committee or Institutional Review Board ............................126 
8.2 
Ethical Conduct of the Study ................................................................................126 
8.3 
Patient Information and Consent ..........................................................................126 
9 
Investigator’s Obligations ..............................................................................................128 
9.1 
Confidentiality ......................................................................................................128 
9.2 
Financial Disclosure and Obligations ...................................................................128 
9.3 
Investigator Documentation ..................................................................................129 
9.4 
Study Conduct .......................................................................................................129 
9.5 
Adherence to Protocol...........................................................................................130 
9.6 
Adverse Events and Study Report Requirements .................................................130 
9.7 
Investigator’s Final Report ...................................................................................130 
9.8 
Records Retention .................................................................................................130 
9.9 
Publications ...........................................................................................................130 
10 Study Management .........................................................................................................132 
10.1 Monitoring ............................................................................................................132 
10.1.1 
External Data Monitoring Committee ...................................................132 
10.1.2 
Monitoring of the Study .........................................................................132 
10.1.3 
Inspection of Records ............................................................................132 
10.2 Management of Protocol Amendments and Deviations........................................133 
10.2.1 
Modification of the Protocol ..................................................................133 

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10.2.2 
Protocol Deviations................................................................................133 
10.3 Study Termination .................................................................................................134 
10.4 Final Report ..........................................................................................................134 
11 Reference List.................................................................................................................135 
 
List of Tables 
Table 5–1 
Table for Dosing Schedule .............................................................................. 69 
Table 5–2 
Dosage Composition for Part A ...................................................................... 70 
Table 5–3  
Part A Weekly Treatment Cards ...................................................................... 73 
Table 5-4 
Part B Treatment Cards for 4 Weeks of Treatment ......................................... 74 
Table 6–1 
Part A Schedule of Events ............................................................................... 80 
Table 6-2 
Part B – Schedule of Events............................................................................ 82 
Table 6–3 
Causality Categories ....................................................................................... 98 
Table 6-4 
Intensity Categories ........................................................................................ 99 
Table 6–5 
Number and Volume of Blood Samples for Part A ....................................... 108 
Table 6-6 
Number and Volume of Blood Samples for Part B ....................................... 108 
 

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Protocol Synopsis 
Protocol Number: 
ITI-007-401 
Title: 
A Phase 3, randomized, double-blind, placebo-controlled, multi-
center study with an open-label extension to assess the efficacy 
and safety of ITI-007 monotherapy in the treatment of patients 
with major depressive episodes associated with bipolar I or 
bipolar II disorder (bipolar depression) 
Sponsor: 
Intra-Cellular Therapies, Inc. (ITI) 
Study Phase: 
Phase 3 
Study Sites: 
Approximately 60 study sites in 1 country (United States) 
Indication: 
Major depressive episodes associated with bipolar I or bipolar II 
disorder (bipolar depression) 
Rationale: 
As a dopamine receptor protein phosphorylation modulator, 
ITI-007 has dual properties, acting as a post-synaptic antagonist 
and as a pre-synaptic partial agonist at dopamine 2 (D2) 
receptors in vivo, with mesolimbic/mesocortical selectivity.  
ITI-007 also indirectly modulates glutamatergic activity by 
increasing the phosphorylation of the NR2B, or GluN2B, 
subunit of N-methyl-D-aspartate channels in extrastriatal 
dopamine-rich brain regions (e.g., nucleus accumbens), likely 
downstream from dopamine 1 receptor activation.  ITI-007 has 
been tested in a number of animal models that suggests efficacy 
for the treatment of bipolar depression. 
Evidence supports the use of D2 receptor antagonists in the 
treatment of bipolar disorder, including bipolar depression, 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 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.  
Importantly, ITI-007 lacks potent off-target interactions that 
have been associated with side effects for other antipsychotic 
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 

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profile responses to the extent that these receptors mediate such 
effects.   
Nonclinical data suggest that ITI-007 may have the potential to 
treat depression.  Antidepressant-like activity of ITI-007 was 
measured using the social defeat (resident-intruder) mouse 
model.  In this model, 1 mg/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 
Phase 1 clinical trial.  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 
serotonin transporter occupancy (average of 22%).  Together, 
these data confirm a central mechanism for ITI-007 at 
dopaminergic and serotonergic brain targets.  Projecting 
occupancy to higher doses based on plasma levels, it was 
estimated that a dose of 60-mg ITI-007 should achieve 
approximately 50% striatal D2 receptor occupancy and similar or 
slightly less serotonin transporter occupancy.   
Clinical data from the ITI-007-005 Phase 2 trial in patients with 
schizophrenia are consistent with the pharmacological profile 
and prediction for antidepressant effects with favorable safety 
and tolerability.  Data supporting an improvement in symptoms 
of depression emerged from a prespecified subgroup analysis of 
patients with both schizophrenia and comorbid depression in this 
trial.  In addition to meeting the primary efficacy endpoint for 
improving psychosis in the intent-to-treat population, data in the 
subgroup of patients with comorbid depression at baseline 
showed statistically significant reduction in symptoms of 
depression and in psychosis at the 60-mg ITI-007 dose level.  
Safety data from this and other trials with ITI-007 have shown 
that ITI-007, administered to more than 1600 patients, is 
generally well tolerated across a dose range from 1 mg to 
140 mg and administered once daily for up to 42 days (6 weeks).  
Additionally, ITI-007 is being evaluated in an open-label safety 
switching study (ITI-007-303) in patients with schizophrenia for 
up to 1-year treatment duration; initial data with exposures more 
than 3 months treatment duration indicate that ITI-007 is 
generally safe and well-tolerated.  These clinical data together 

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with the nonclinical data and the pharmacological profile 
support the development of ITI-007 for the treatment of bipolar 
depression.   
Objectives Part A 
(Double-blind, placebo-
controlled phase): 
Primary Objective 
The primary objective of Part A of this study is to compare the 
efficacy of 2 doses of ITI-007 administered orally once daily to 
that of placebo in mean change from baseline in the total score 
on the rater-administered Montgomery-Åsberg Depression 
Rating Scale (MADRS) in patients with bipolar depression at 
Week 6.   
 
Secondary Objectives 
Key Secondary Objective 
The key secondary objective of Part A of this study is to 
compare the efficacy of 2 doses of ITI-007 administered orally 
once daily to that of placebo in time to first response, defined as 
the number of days from first dose of study drug to the earliest 
date the patient experiences a sustained ≥50% reduction from 
baseline in the rater-administered MADRS total score. 
Other Efficacy Secondary Objectives of Part A of this study 
are to compare the efficacy of 2 doses of ITI-007 administered 
orally once daily to that of placebo in relation to: 
• MADRS: 
o Time course of improvement, as measured by mean 
change from baseline in the MADRS total score at 
each assessment time point; 
o Time course of improvement, as measured by the 
proportion of treatment responders where response is 
defined as a ≥50% decrease in the MADRS total 
score from baseline at each assessment time point, 
including at Week 6; 
o Time course of improvement, as measured by the 
proportion of remitters where remission is defined as 
a MADRS total score ≤12 at each assessment time 
point, including at Week 6;  
o The improvement in sleep, as measured by Item 4 
(reduced sleep) on the MADRS in patients with at 
least mild sleep disturbance at baseline, defined by a 
score of ≥2 on Item 4; 
o Change from baseline in MADRS individual item 
scores at Weeks 1, 2, 3, 4, 5, and 6; 

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• Clinical Global Impression Scale, Bipolar version (CGI-BP): 
o Time course of improvement, measured by mean 
change from baseline in the CGI-BP – Severity 
(CGI-BP-S) score at each assessment time point, 
including at Week 6; 
• Mean change from baseline in the Sheehan Disability Scale 
(SDS) total score; 
• Mean change from baseline in the Quality of Life Enjoyment 
and Satisfaction Questionnaire – Short Form (Q-LES-Q-SF);  
• Mean change from baseline in the WHO-5 Well-being Index; 
• Mean change from baseline in the Neuroticism, 
Extraversion, and Openness to Experience-Five Factor 
Inventory (NEO-FFI). 
Safety Secondary Objectives of Part A of this study are to 
determine the safety and tolerability of 2 doses of ITI-007 via 
changes in the following: 
• Incidence of adverse events (AEs) 
• Young Mania Rating Scale (YMRS) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
• Abnormal Involuntary Movement Scale (AIMS) 
• Barnes Akathisia Rating Scale (BARS) 
• Simpson Angus Scale (SAS) 
• Clinical laboratory evaluations 
• Electrocardiograms (ECGs) 
• Vital sign measurements 
• Physical examination and neurological findings 
 
  
 
 
 
 
 
Exploratory Objectives 
The exploratory objective of Part A of this study are to:  
• Assess protein biomarkers in blood samples, including but 
not limited to p11 protein; 

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Objectives Part B 
(Open-label extension 
phase) 
Primary Objective 
The primary objective of Part B of this study is to determine the 
safety and tolerability of ITI-007 60 mg administered orally 
once daily for up to approximately 6 months (175 days) in 
patients with bipolar disorder.  Safety and tolerability will be 
assessed in relation to: 
• Incidence of AEs 
• Mean change from baseline in the YMRS 
• Mean change from baseline in MADRS 
• Mean change from baseline in the C-SSRS 
• Mean change from baseline in the AIMS 
• Mean change from baseline in the BARS 
• Mean change from baseline in the SAS 
• Changes from baseline in clinical laboratory evaluations 
• Changes from baseline in ECGs 
• Changes from baseline in vital sign measurements 
• Physical examination and neurological findings 
 
Secondary Effectiveness Objectives 
Secondary effectiveness objectives of Part B of this study are to 
determine whether 60 mg ITI-007, administered once daily for 
up to approximately 6 months to patients with bipolar disorder 
who have responded to treatment with ITI-007, improves and/or 
maintains symptoms, function and quality of life as measured by 
change from baseline on the following measures: 
• MADRS total score; 
• CGI-BP-S; 
• Q-LES-Q-SF 

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Patient Population: 
Inclusion Criteria (Part A) 
1. Is capable of understanding the written informed consent, 
provides signed and witnessed written informed consent, 
and agrees to comply with protocol requirements.  
2. The patient 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 Structured 
Clinical Interview for DSM-5 Disorders – Clinical Trials 
Version (SCID-5-CT) 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 major depressive 
episode 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. The presence of 
psychotic symptoms may result in an increased 
YMRS without evidence of mania/hypomania. 
Therefore, a patient with a YMRS > 12 AND 
psychotic symptoms may be included pending 
adjudication review by Medical Monitor for 
diagnostic certainty of the depressive episode.  
4. Has a body mass index (BMI) of 18-35 kg/m2, inclusive. 

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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). 
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. 
 
Exclusion Criteria (Part A) 
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. 

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3. The patient is pregnant or breast-feeding; female patients 
of childbearing potential must have a negative urine 
pregnancy test at screening and 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 as assessed 
by the SCID-5-CT, 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; 
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 #4.  The presence of these symptoms should be 
reviewed with the medical monitor and adjudication team 
prior to inclusion.  The presence of psychotic symptoms 
may result in an increase in YMRS to > 12 in the absence 
of impending mania/hypomania, therefore these patients 
will be reviewed on a case by case basis to rule out 
possible impending mania/hypomania. 

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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 FDA-approved 
medications for Bipolar depression (lurasidone, 
quetiapine or Symbyax) at an adequate dose (per FDA-
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. 
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.  

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12. The patient has a positive test for drugs of abuse or 
alcohol test at the screening or baseline visits, 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 cannabis 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 as verified 
by DupCheck) 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 long-acting anxiolytics within 5 half-
lives of the baseline visit.   

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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:  
i. sedative hypnotics (with the exception of 
zolpidem and zolpidem CR as noted in the 
concomitant medication section, allowed 
during the screening period and the first 2 
weeks of the treatment period);  
ii. central opioid agonists/antagonists 
including tramadol (Ultram);  
iii. anticonvulsants;  
iv. mood stabilizers, antipsychotics, 
antidepressants; EXCEPTION:  long 
acting injectable antipsychotics must be 
washed out 1.5 cycles or 28 days, 
whichever is LONGER, before baseline 
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, or medical foods 
must be approved by the Medical 
Monitor.  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:  

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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. 
i. 12-lead ECG (in a supine position at rest at the 
screening or baseline visit) corrected QT interval 
using the Fridericia formula (QTcF) >450 ms, 
and/or heart rate ≤50 beats per minute, or 
evidence of clinically significant bundle-branch 
blocks. The ECG may be repeated one time at the 
investigator’s discretion to ensure the 
reproducibility of results. 
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 

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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. At Screening, the patient has a history of Hepatitis B or 
Hepatitis C infection (or demonstrated Hepatitis B surface 
antigen or Hepatitis C antibodies), AND evidence of 
active disease defined as elevated ALT, AST or bilirubin 
levels as specified in Exclusion 14. 
18. The patient is an employee of the investigator or study 
center, or immediate family (i.e., spouse, parent, child, or 
sibling, whether biological or legally adopted) of such 
employees, the investigator, ITI, or contract research 
organizations conducting the study.  
19. 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). 
20. The patient is judged by the investigator to be 
inappropriate for the study. 

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Inclusion Criteria (Part B) 
Each patient continuing into Part B of the study must meet all of 
the following criteria: 
1. Patient must have safely (in the opinion of the 
investigator and confirmed by the Medical Monitor) 
completed Part A and in the opinion of the investigator is 
willing and able to comply with study requirements as 
specified by the protocol.  
1. [Note: patients who had experienced significant AEs 
which were thought to be possibly related to blinded 
study medication, should not be enrolled into the open-
label extension]; 
2. Patients must be capable of understanding the written 
informed consent, providing signed and witnessed 
written informed consent, and agreeing to comply with 
protocol requirements for Part B of the study; a separate 
written informed consent must be provided for 
continuation into the open-label extension after treatment 
in Part A has been completed. 
3. Patients must agree to use highly effective methods of 
birth control (as defined in Part A Inclusion #5) for at 
least 2 weeks prior to randomization (starting with 
informed consent) through to the end of study visit, or, 
patients must be of non-childbearing potential (as 
defined in Part A Inclusion #5). 
 
Exclusion Criteria (Part B) Re-Screening 
Since all prior participants in Part A were required to satisfy 
exclusion criteria for participation in that part of the study, the 
investigator should assess where there has been any change of 
status.  In the event of a recently emerged new medical 
condition, this should be evaluated carefully and discussed with 
the Medical Monitor before including the patient in Part B.   
Patients who safely completed Part A of the study prior to the 
open-label extension becoming available, will undergo screening 
procedures and must be eligible according to the abbreviated 
Part A exclusion criteria as described below. Any references to 
adjudication in Part B will be limited to review by the Medical 
Monitor.  

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Please note these Part B Exclusion Criteria are numbered to 
coincide with the Part A Exclusion Criteria for consistency of 
reference. 
Patients meeting any of the following criteria will be excluded 
from the study: 
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 Visit 10 Screening, the patient scores “yes” on 
Items 4 or 5 in the Suicidal Ideation section of the 
C-SSRS with reference to the last visit; or  
b. At Visit 10 Screening, the patient has had 1 or 
more suicidal attempts with reference to a 2-year 
period prior to screening; or  
c. At the Visit 11 Baseline Visit, the patient scores 
“yes” on Items 4 or 5 in the Suicidal Ideation 
section of the C-SSRS with reference to the last 
visit; or 
d. At Visit 10 Screening or the Visit 11 Baseline 
Visit, scores ≥4 on Item 10 (suicidal thoughts) on 
the self-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 a negative urine 
pregnancy test at Visit 10 Screening and on Visit 11 
Baseline Visit prior to study treatment administration. 
4. The patient is assessed by the investigator as not having 
had a change in primary diagnosis at Visit 10 Screening, 
as compared to Visit 1 Screening. 
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.  

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9. The patient is considered treatment-resistant, defined as 
having a lifetime history of treatment resistance (no 
remission) to ≥2 treatments with FDA-approved 
medications for Bipolar depression (lurasidone, 
quetiapine or Symbyax) at an adequate dose (per FDA-
approved label) for an adequate duration (at least 6 
weeks).  
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 test at the Visit 10 Screening or Visit 11 Baseline 
visits, 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 cannabis use during 
the study. 
13. The patient has used 1 of the following agents under the 
specified conditions:  
b. Any strong or moderate cytochrome P450 3A4 
inhibitor or inducer within 7 days prior to the Visit 
11 Baseline Visit.  

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c. Use of any long-acting anxiolytics within 5 half-
lives of the Visit 11 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 Visit 11 
Baseline Visit, whichever is less, as reviewed by 
the medical monitor including, but not limited to:  
i. sedative hypnotics (with the 
exception of zolpidem and 
zolpidem CR as noted in the 
concomitant medication section)  
ii. central opioid agonists/antagonists 
including tramadol (Ultram);  
iii. anticonvulsants;  
iv. mood stabilizers, antipsychotics, 
antidepressants; EXCEPTION:  
long acting injectable 
antipsychotics must be washed out 
1.5 cycles or 28 days, whichever is 
LONGER, before baseline 
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, or medical 
foods must be approved by the 
Medical Monitor.  Daily 
multivitamin use is not excluded. 

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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 Visit 11 
Baseline visit is allowed and results must be available 
prior to the Visit 11 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. 
i) 12-lead ECG (in a supine position at rest at the 
Visit 10 Screening or Visit 11 Baseline visit) 
corrected QT interval using the Fridericia formula 
(QTcF) >450 ms, and/or heart rate ≤50 beats per 
minute, or evidence of clinically significant 
bundle-branch blocks. The ECG may be repeated 
one time at the investigator’s discretion to ensure 
the reproducibility of results. 

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j) Any other clinically significant abnormal 
laboratory result at the time of the Visit 10 
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 Visit 10 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 Visit 10 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 Visit 10 
Screening; malignancy more than 2 years prior to Visit 
10 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. 

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17. The patient has a history of hepatitis B or hepatitis C 
infection (or demonstrated Hepatitis B surface antigen or 
Hepatitis C antibodies), AND evidence of active disease 
defined as elevated ALT, AST or bilirubin levels as 
specified in Exclusion 14.  
18. The patient is an employee of the investigator or study 
center, or immediate family (i.e., spouse, parent, child, or 
sibling, whether biological or legally adopted) of such 
employees, the investigator, ITI, or contract research 
organizations conducting the study.  
19. 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). 
20. The patient is judged by the investigator to be 
inappropriate for the study. 
Exclusion Criteria (Part B) Direct Rollover 
Patients directly enrolling into the open-label extension upon 
completing Part A, presenting at the Day 43 visit with any of the 
following characteristics, will be excluded from the study:  
1. Is, in the opinion of the investigator, unable to comply 
with study procedures; 
2. Has a significant risk for suicidal behavior during the 
course of their participation in the study or is considered 
to be an imminent danger to themselves or others, in the 
opinion of the investigator, and/or as assessed by the C-
SSRS; or > 4 on item 10 of the subject-rated MADRS 
3. Clinically significant (in the investigator’s judgement) 
abnormal laboratory results at the time of the last study 
evaluation.  
Note: medical conditions are allowed as long as the 
condition has been stable during Part A, 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; 
4. The patient is pregnant or breast-feeding; female patients 
of childbearing potential must have a negative pregnancy 
test at rescreening (if applicable) and upon entry to Part 
B of the study prior to treatment administration;  

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5. Has a positive qualitative urine drug or alcohol test 
(which may be confirmed with additional testing) at the 
last evaluation, or evidence of either withdrawal from, or 
acute intoxication with cocaine, opiates, amphetamines 
(including methamphetamine), alcohol, barbiturates, or 
hallucinogens or similar compounds;  
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 cannabis use during the study.; 
6. Is judged by the investigator to be inappropriate for the 
study.   
Study Design: 
This study will be conducted in 2 parts, Part A and Part B.  
Part A is a randomized, double-blind, placebo-controlled, two-
stage adaptive design with a single interim analysis (IA) and a 
final analysis.  In Part B, patients who safely completed 
participation in Part A may be enrolled in an open-label 
extension. 
Part A Study Periods (up to 10 Weeks, Including 
Screening/Baseline) 
Part A of the study consists of the following periods: screening 
period, on-treatment period, and safety follow-up period.  
Patients who roll directly over into Part B will not have a unique 
safety follow-up visit after the 6-week treatment. 
Screening Period (2 Weeks)  
Potential patients will be evaluated during a screening period 
lasting up to 2 weeks, unless confirmed by the medical monitor 
that a longer screening phase, lasting no longer than 28 days, is 
appropriate to ensure washout of excluded medications with 
long half-lives (e.g., fluoxetine), under the supervision of the 
investigator before baseline.   
After obtaining written informed consent, diagnostic interviews 
and physical examinations will be conducted, vital signs and 

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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. 
Adjudication of patient eligibility will be determined by remote, 
independent expert raters and medical monitor(s).  
At baseline (Visit 2), patients who continue to meet all eligibility 
criteria will be randomly assigned to 1 of the 3 treatment arms 
for a 6-week, double-blind treatment period.  Patients will be 
randomly assigned to 1 of the following groups: 40-mg ITI-007, 
60-mg ITI-007, or matching placebo.   
On-Treatment Period (6 Weeks)  
Patients will take their first dose of study medication the evening 
of their baseline randomization visit.  A single dose will be taken 
each day in the evening for the duration of the on-treatment 
period.  
Following randomization, patients will attend the clinic at 
Weeks 1, 2, 3, 4, 5, and 6. 
The on-study treatment period will be a total of 6 weeks.   
Safety Follow-up Period (2 Weeks) 
For those patients not continuing on to Part B, 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 discontinue treatment 
prematurely will be seen for an early termination visit (within 1 
week of last dose, when possible) and will be asked to return to 
the clinic for a safety follow-up visit 2 weeks following 
withdrawal.   

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Part B Study Periods (Up to Approximately 6 Months 
[175 Days]) 
Part B of the study will be an open-label extension.  Patients 
enrolling directly into the open-label extension will have their 
baseline visit on Visit 8 (Study Day 43 of Part A).  Patients who 
safely complete Part A of the study prior to the open-label 
extension becoming available will undergo screening procedures 
for determination of their eligibility for Part B.  Subsequent 
post-dose clinical evaluations will occur on Study Days 8, 15, 
and 25, then every 25  3 days (Study Days 50, 75, 100, 125, 
150, and 175) of Part B.  Evaluations on Days 75, 125, and 150 
will be conducted by telephone.  A safety follow-up visit will be 
completed at approximately Day 189. Patients must undergo 
these scheduled clinical evaluations in order to continue to 
receive study drug.  Unscheduled clinical evaluations may occur 
at any time if deemed appropriate by the investigator, to 
discontinue patient participation, and/or for safety follow up.  
Patients will return for a final safety follow-up visit 
approximately 2 weeks after their last dose of study drug. 
Concomitant Medications 
The use of concomitant medications has some restrictions in 
both Part A and Part B of the protocol.  Details of these 
restrictions are listed in Section 5.8 of the protocol. 
Estimated Study 
Duration: 
In Part A, the study will last a maximum of approximately 10-12 
weeks (9 visits).   
In Part B, the duration of individual patient participation in the 
study will be determined based on clinical grounds, but may 
continue for up to approximately 6 months (175 days) plus the 
safety follow-up visit (6.5 months).  After the final treatment 
visit, patients will return to prior therapy or standard of care 
therapy as determined by the investigator. 

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Analysis Sets: 
The following analysis sets will be used for the analyses: The 
All Patients Enrolled (ENR) Set will contain all patients who 
signed informed consent for the study.  
The All Patients Randomized (RND) Set will contain all patients 
who signed the informed consent and were randomized to study 
drug. 
Primary, secondary, and exploratory efficacy analyses of Part A 
data will be performed using the Intent-to-Treat (ITT) Set, which 
will contain all randomly assigned patients who received at least 
one dose of study drug and who had a valid baseline (pre-dose) 
measurement and at least one valid post-baseline measurement 
of MADRS. 
For Part A, the Per-protocol (PP) Set will contain all ITT 
patients who did not have any major protocol deviations.  
Patients will be classified according to the randomized 
treatment.  For part B, the PP Set will contain all patients in the 
Safety Analysis Set who did not have any major protocol 
deviations.   
The Safety Analysis Set will contain all patients who received at 
least 1 dose of study drug.  In Part A, patients will be classified 
according to the treatment received.    
 
 
 
 
 
 
 
 
 
   
The following analysis sets will be used for the analyses of Part 
B data: ENR, Safety Analysis, and Part B PP Sets.  The 
classification of patients according to study drug does not apply 
to Part B. 
Efficacy Assessments: 
For Part A, the efficacy assessments will include: the MADRS, 
the CGI-BP-S, the SDS, the Q-LES-Q-SF, the WHO-5 
Well-being Index and the NEO-FFI. 
For Part B, effectiveness assessments will include: MADRS. 
CGI-BP-S, and Q-LES-Q. 

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Safety Assessments: 
Safety assessments for both study parts will include incidence of 
AEs; suicidality assessment by the C-SSRS; mania assessment 
by the YMRS; movement disorder assessment by the AIMS, the 
BARS, and the SAS; clinical laboratory evaluations; ECG 
evaluations; vital sign measurements; physical examination; and 
neurological findings.   
Study Drug, Dosage, 
and Route of 
Administration: 
In Part A, patients will be assigned to receive either ITI-007 
(40- or 60-mg doses) or placebo.  Patients will self-administer 
all doses orally, once daily, at home, each evening, for the 
duration of the on-treatment period.  Treatments will be provided 
in dose cards containing 2 strips of over-encapsulated tablets, 
and patients will be instructed to take 2 capsules (1 capsule from 
each strip) per dose. 
In Part B, all patients will receive ITI-007 60 mg.  Patients will 
self-administer all doses orally, once daily, at home, each 
evening for up to 6 months.  Treatment will be provided in dose 
cards containing 28 tablets and patients will be instructed to take 
1 tablet per dose.  A one-time dose reduction to 40 mg will be 
allowed if the 60 mg dose is not tolerated.  If the patient does not 
tolerate the 40 mg dose, the patient should be withdrawn from 
the study. 

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Sample Size: 
In Part A, approximately 549 patients will be randomly assigned 
in a 1:1:1 ratio to 1 of the 3 treatment arms, which will provide 
approximately 471 evaluable patients, assuming an approximate 
14% early discontinuation rate before a post-dose assessment in 
the primary efficacy endpoint.   
In Part B, up to approximately 549 patients will be enrolled.  
The sample size is not based on statistical considerations, rather 
on the number of patients who may be eligible based on 
participation in Part A of the study.  It is estimated that the 
majority of patients will continue treatment for the full 
6 months.   
Statistical Methods: 
Patient Disposition, Demographics, and Other Baseline Data 
Patient disposition will be summarized for each Part by 
treatment group, when applicable, and overall, including 
incidence of screening, screening failure and incidence of 
treatment or study discontinuation and the corresponding 
reasons for discontinuation.  Time to treatment discontinuation 
due to all reasons, adverse events, lack of efficacy, or due to any 
other reason of special interest will be evaluated separately 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 each 
treatment group and the placebo group (Part A).   
Demographic and baseline characteristics, including bipolar 
disorder diagnosis and bipolar disorder baseline efficacy 
measures, will be summarized for each Part and by treatment 
group for Part A only.   No inferential statistics will be presented.  
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 for each Part and by treatment group for Part A only.  
Additionally, for Part A, the number and percent of patients in 
the ITT Set receiving concomitant medications of special 
interest, such as zolpidem, and the total number of days on each 
medication will be summarized by treatment group for the 
Screening Period, for each week during the On-Treatment Period 
and for post treatment.  Other medications will be summarized 
by treatment group and study period if deemed necessary. 

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Study Medication Exposure and Treatment Compliance  
Exposure to study medication and treatment compliance will be 
presented for each Part using the Safety Analysis Set and 
additionally, for Part A, using the ITT Set.  Duration of exposure 
(days) and dosing compliance (%) will be calculated and 
summarized for each Part and by treatment group for Part A 
only.  In addition, the number and percentage of patients 
exposed to study medication will be presented.   
Efficacy Analysis – Part A 
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 rater-administered MADRS total score as the 
response variable and visit, treatment, site, and the stratification 
variable, bipolar disorder at screening (I or II), as factors, the 
baseline MADRS total score as a covariate, and interaction 
terms for treatment-by-visit, visit-by-baseline MADRS total 
score, and treatment-by-site.  Estimates for change from baseline 
in MADRS total score, standard errors and 95% confidence 
intervals (CIs) will be presented by treatment group and time 
point.  The least-squares mean difference between ITI-007 
groups and placebo along with the corresponding 95% 
confidence intervals (CIs), effect sizes, and p-values will be 
presented for each visit. 
The key secondary efficacy endpoint, time to first response, 
defined as ≥50% reduction from baseline in rater-administered 
MADRS total score and maintaining it through the end of the 6-
week treatment, will be analyzed using time-to-event methods.  
Time to the first response for treatment responders will be 
analyzed using the Cox’s Proportional Hazards model with 
terms for treatment, site, baseline MADRS total score, the 
bipolar disorder stratification variable and treatment-by-site 
interaction. Patients who do not experience at least 50% 
reduction from baseline in the rater-administered MADRS total 
score, or do not maintain it through the end of the 6-week 
treatment, and patients who discontinue treatment, will be 
considered non-responders and will be censored. 
Time to first response will be compared between treatment 
groups using the Kaplan-Meier product limit method. 

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The primary and key secondary efficacy endpoints will be 
evaluated using a gatekeeping procedure to adjust for 
multiplicity while controlling the overall Type I error rate in the 
strong sense at a two-sided alpha=0.05.  The primary endpoint 
will serve as a gatekeeper for the key secondary endpoint in the 
sense that a key secondary endpoint will be tested only if at least 
one primary test is significant, as described in Section 7.5.4 of 
the protocol and detailed in the Statistical Analysis Plan (SAP). 
 
 
 
 
 
Binary secondary endpoints (proportion of treatment responders, 
proportion of remitters) will be analyzed using a logistic 
regression model with terms for treatment and the bipolar 
disorder at screening (I or II) stratification variable.  An estimate 
and 95% CI for the odds ratio between each dose of ITI-007 and 
placebo will be presented for each of the proportions evaluated. 
The CGI-BP-S, improvement in sleep, SDS, Q-LES-Q-SF, 
WHO-5 and NEO-FFI scores and the changes from baseline will 
be summarized by treatment and visit. 
The analyses of secondary efficacy endpoints, other than the key 
secondary one, will not be adjusted for multiple comparisons. 
Analysis of Secondary Effectiveness Endpoints – Part B 
Analyses of effectiveness endpoints in Part B will be performed 
on the Safety Analysis Set and will primarily consist of change 
from baseline descriptive summaries of MADRS, CGI-BP-S, 
and Q-LES-Q-SF. 
Safety Analyses – Parts A and B 
All safety parameters will be summarized using the Safety 
Analysis Set.   
Medical history, prior medications, concomitant medications, 
and compliance/exposure will be summarized using descriptive 
statistics.  Safety data such as reported and observed AEs, 
treatment emergent AEs (TEAEs) and serious AEs (SAEs), 
clinical laboratory results, vital signs, physical examinations and 
neurological findings, ECGs, and the different rating scales will 
be summarized by visit (Part A and Part B) and treatment group 

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(Part A).  Parameters planned to be collected more than once at 
pre-specified time points will be analyzed as an average of the 
measures for the relevant time point, including screening or 
baseline. 
Reported AE terms will be coded using the latest version of the 
Medical Dictionary for Regulatory Activities (MeDRA).  TEAEs 
and SAEs will be listed and summarized by system organ class 
(SOC), preferred term (PT), relationship to study drug, intensity 
(Part A and Part B) and by treatment group (Part A).   
Patients who discontinued study or study drug due to an AE will 
be listed and summarized by SOC and PT (Parts A and B) and 
by treatment group (Part A).  
Laboratory assessments, including hematology and chemistry, 
vital signs, and ECGs, will be listed and summarized by visit 
and time point (Parts A and B) and by treatment group (Part A).  
Summaries will include actual and change values, incidence of 
abnormal values according to normal range criteria, shifts from 
baseline to each visit and time point according to markedly 
abnormal criteria, and listings of patients meeting markedly 
abnormal criteria.  
The observed and change in YMRS, AIMS, BARS, SAS, and C-
SSRS scores will be summarized by visit (Parts A and B) and by 
treatment group (Part A). 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
Subgroup Analyses – Parts A and B 

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Subgroup analyses of efficacy and safety variables may be 
conducted as deemed necessary and will be detailed in the 
Statistical Analysis Plan (SAP). 
Interim Analysis – Part A 
One Interim Analysis (IA) is planned during Part A of the study, 
after 375 patients have completed the 6-week treatment period 
or confirmed to have discontinued treatment or study prior to 
first post-baseline assessment of MADRS.  The IA will be 
conducted such that the ongoing study integrity is maintained, 
and the interim data will be reviewed by an independent external 
unblinded Data Monitoring Committee (DMC). 
The IA will be used to review interim safety and efficacy data 
and reassess the assumptions of variability and effect size.  It 
may be used for a decision to terminate the study due to superior 
efficacy or to adjust the sample size.   
Date of Protocol: 
9 March 2018 
 

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List of Abbreviations 
Abbreviation 
Definition 
AE 
adverse event 
AIMS 
Abnormal Involuntary Movement Scale 
ALT 
alanine aminotransferase 
AMPA 
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
BARS 
Barnes Akathisia Rating Scale 
BLQ 
below the limit of quantification 
BMI 
body mass index 
BPI 
Bipolarity 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 
CRO 
contract research organization 
C-SSRS 
Columbia Suicide Severity Rating Scale 
C-VISATM 
Clinical Validation Inventory for Study Admission (Bracket) 
D2 
dopamine 2 receptor 
DMC 
Data Monitoring Committee 
DSM-5 
Diagnostic and Statistical Manual, 5th Edition 
ECG 
electrocardiogram 
eCRF 
electronic case report form  
EDC 
electronic data capture 
FDA 
Food and Drug Administration 
FWER 
familywise error rate 
GCP 
Good Clinical Practice 
HbA1c 
glycated hemoglobin A1c 
HIV 
human immunodeficiency virus 
IA 
interim analysis 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 

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Abbreviation 
Definition 
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 forward 
MADRS 
Montgomery-Åsberg Depression Rating Scale  
MDE 
major depressive episode 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed model repeated measures  
NEO-FFI 
Neuroticism, Extraversion, and Openness to Experience-Five Factor 
Inventory 
NMDA 
N-methyl-D-aspartate 
PET 
positron emission tomography 
PK 
pharmacokinetic 
PP 
per-protocol 
Q-LES-Q-SF 
Quality of Life Enjoyment and Satisfaction Questionnaire – Short Form 
QTcF 
corrected QT interval using the Fridericia formula 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
Simpson Angus Scale 
SCID-5-CT 
Structured Clinical Interview for DSM-5 Disorders – Clinical Trials 
Version 
SDS 
Sheehan Disability Scale 
SERT 
serotonin transporter 
TEAE 
treatment-emergent adverse event  
ULN 
upper limit of normal 
YMRS 
Young Mania Rating Scale 

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1 Introduction 
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.  
Depressive episodes associated with bipolar disorder tend to last longer, recur more often, 
and are associated with a worse prognosis than manic/hypomanic episodes.  Bipolar 
depression, the predominant presentation of bipolar disorder, remains a significantly 
underserved medical need, with only a few Food and Drug Administration (FDA)-approved 
treatment options available. 
Intra-Cellular Therapies (ITI) is developing ITI-007, a new chemical entity, for the treatment 
of patients with major depressive episodes (MDEs) associated with bipolar I or bipolar II 
disorder (bipolar depression).  ITI-007 is currently in Phase 3 clinical development in the 
United States for the treatment of schizophrenia. 
ITI-007 is a novel small molecule therapeutic agent designed specifically to combine, in a 
dose-dependent manner, potent serotonin 5-HT2A receptor antagonism with both 
mesolimbic/mesocortical selective modulation of phosphoprotein pathways downstream of 
dopamine receptors and serotonin reuptake inhibition (Snyder, 2015).  As a dopamine 
receptor protein phosphorylation modulator, ITI-007 has dual properties, acting as a 
post-synaptic antagonist and as a pre-synaptic partial agonist at dopamine 2 (D2) receptors in 
vivo, with mesolimbic/mesocortical selectivity.  ITI-007 also indirectly enhances 
glutamatergic activity by increasing the phosphorylation of the NR2B, or GluN2B, subunit of 
N-methyl-D-aspartate channels in extrastriatal dopamine-rich brain regions (e.g., nucleus 
accumbens), via N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-
isoxazolepropionic acid (AMPA) currents downstream from dopamine 1 receptor activation.  
ITI-007 has been tested in a number of animal models that suggests efficacy for the treatment 
of bipolar depression. 
Evidence supports the use of D2 receptor antagonists in the treatment of bipolar disorder, 
including bipolar depression (Young, 2013; Loebel, 2014a; Loebel, 2014b), as both 
monotherapy and adjunctive therapy to mood stabilizers.  The pharmacologic profile of 

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ITI-007 includes both the post-synaptic D2 antagonism that appears efficacious in bipolar 
disorder and other pharmacological properties that may confer better safety 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.  Importantly, ITI-007 lacks potent off-target interactions that 
have been associated with side effects for other antipsychotic 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 of the pharmacologic profile of ITI-007 can be found 
in the most recent version of the investigator’s brochure.  
Nonclinical data suggest that ITI-007 may have the potential to treat depression 
(Snyder, 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 mg/kg ITI-007, administered once daily 
intraperitoneally for 28 days, reversed the defeat behavior, consistent with antidepressant 
efficacy.  5-HT2A receptor antagonism in vivo combined with antidepressant and 
antipsychotic efficacy in animal models predicts efficacy in bipolar depression.  Moreover, 
indirect glutamatergic enhancement via both NMDA and AMPA currents following D1 
receptor activation predicts a rapid-acting antidepressant response. 
Brain receptor target engagement was confirmed in healthy male volunteers in the 
ITI-007-003 positron emission tomography (PET) Phase 1 clinical trial (Davis, 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.  
Projecting occupancy to higher doses based on plasma levels, it was estimated that a dose of 

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60-mg ITI-007 should achieve approximately 50% striatal D2 receptor occupancy and similar 
or slightly less SERT occupancy.   
Clinical data from the ITI-007-005 Phase 2 trial in patients with schizophrenia are consistent 
with the pharmacological profile and prediction for antidepressant effects with favorable 
safety and tolerability.  Data supporting an improvement in symptoms of depression emerged 
from a prespecified subgroup analysis of patients with both schizophrenia and comorbid 
depression in this trial.  In addition to meeting the primary efficacy endpoint for improving 
psychosis in the intent-to-treat population, data in the subgroup of patients with comorbid 
depression at baseline showed statistically significant reduction in symptoms of depression 
and in psychosis at the 60-mg ITI-007 dose level.  Safety data from this and other trials with 
ITI-007 have shown that ITI-007, administered to more than 1600 patients, is generally well 
tolerated across a dose range from 1 mg to 140 mg and administered once daily for up to 6 
weeks.  Additionally, ITI-007 is being evaluated in an open-label safety switching study (ITI-
007-303) in patients with schizophrenia for up to a 1-year treatment duration; initial data with 
exposures more than 3 months treatment duration indicate that ITI-007 is generally safe and 
well-tolerated.  These clinical data together with the nonclinical data and the pharmacological 
profile support the development of ITI-007 for the treatment of bipolar depression.   

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2 Study Objectives 
2.1 Primary Objectives 
2.1.1 Part A Primary Objectives 
The primary objective of Part A of this study is to compare the efficacy of 2 doses of ITI-007 
administered orally once daily to that of placebo in mean change from baseline in the total 
score on the rater-administered Montgomery-Åsberg Depression Rating Scale (MADRS) in 
patients with bipolar depression at Week 6.   
2.1.2 Part B Primary Objective 
The primary objective of Part B of this study is to determine the safety and tolerability of 
ITI-007 60 mg administered orally once daily for 6 months in patients with bipolar disorder.  
Safety and tolerability will be assessed in relation to: 
• Incidence of AEs 
• Mean change from baseline in the YMRS 
• Mean change from baseline in MADRS 
• Mean change from baseline in the C-SSRS 
• Mean change from baseline in the AIMS 
• Mean change from baseline in the BARS 
• Mean change from baseline in the SAS 
• Changes from baseline in clinical laboratory evaluations 
• Changes from baseline in ECGs 
• Changes from baseline in vital sign measurements 
• Physical examination and neurological findings 

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2.2 Secondary Objectives  
2.2.1 Part A Secondary Objectives - Efficacy 
2.2.1.1 Key Secondary Objectives - Efficacy (Part A) 
The key secondary objective of Part A of this study is to compare the efficacy of 2 doses of 
ITI-007 administered orally once daily to that of placebo in time to first response, defined as 
the number of days from first dose of study drug to the earliest date the patient experiences a 
sustained ≥50% reduction from baseline in the rater-administered MADRS total score. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 

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2.2.2 Part A Secondary Objectives - Safety 
The safety objectives of Part A of this study are to determine the safety and tolerability of 
2 doses of ITI-007 via change in the following safety endpoints: 
• Incidence of adverse events (AEs) 
• Young Mania Rating Scale (YMRS) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
• Abnormal Involuntary Movement Scale (AIMS) 
• Barnes Akathisia Rating Scale (BARS) 
• Simpson Angus Scale (SAS) 
• Clinical laboratory evaluations 
• Electrocardiograms (ECGs) 
• Vital sign measurements 
• Physical examination and neurological findings. 
 
  
  

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 Part B Secondary Objectives – Effectiveness 
Secondary effectiveness objectives of Part B of this study are to determine whether 60 mg 
ITI-007, administered once daily for up to approximately 6 months to patients with bipolar 
disorder who have responded to treatment with ITI-007, improves and/or maintains 
symptoms, function, and quality of life as measured by change from baseline on the 
following measures: 
• MADRS total score 
• CGI-BP-S 
• Q-LES-Q-SF. 
 
  
 
 
 
 
 
 
 
 
 

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3 Investigational Plan 
3.1 Study Design 
This study will be conducted in 2 parts:  Part A and Part B.  Part A is a randomized, 
double-blind, placebo-controlled, two-stage adaptive design study comparing the efficacy 
and safety of ITI-007 versus placebo administered orally once daily in patients with bipolar 
depression.  For Part A, there will be a single interim analysis (IA) and a final analysis.  In 
Part B, patients who safely completed participation in Part A may be enrolled in an open-
label extension. 
3.1.1 Part A Study Periods (up to 10 Weeks, Including Screening/Baseline) 
Part A of the study consists of the following periods: screening period, on-treatment period, 
and safety follow-up period.  Patients who rollover directly into Part B will not have a unique 
safety follow-up visit after the 6-week treatment. 
Screening Period (2 Weeks) 
Potential patients will be evaluated during a screening period lasting up to 2 weeks, unless 
confirmed by the medical monitor that a longer screening phase, lasting no longer than 
28 days, is appropriate to ensure washout of excluded medications with long half-lives (e.g., 
fluoxetine), under the supervision of the investigator before baseline.   
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 3 treatment arms for a 6-week, double-blind treatment period.  Patients 
will be randomly assigned to 1 of the following groups: 40-mg ITI-007, 60-mg ITI-007, or 
matching placebo.   

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On-Treatment Period (6 Weeks) 
Patients will take their first dose of study medication the evening of their baseline 
randomization visit.  A single dose will be taken each day in the evening for the duration of 
the on-treatment period.  
Following randomization, patients will attend the clinic at Weeks 1, 2, 3, 4, 5, and 6. 
The on-study treatment period will be a total of 6 weeks.   
Safety Follow-up Period (2 Weeks) 
For those patients not continuing on to Part B, 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 discontinue treatment prematurely will be seen for an 
early termination visit (within 1 week of the last dose of study drug when possible) and will 
be asked to return to the clinic for a safety follow-up visit 2 weeks following withdrawal.   
3.1.2 Part B Study Periods (up to Approximately 6 months [175 days]) 
Part B of the study will be an open-label extension.  Patients enrolling directly into the 
open-label extension will have their baseline visit at Visit 8 (Study Day 43) of Part A.  
Patients who safely completed Part A of the study prior to open-label extension becoming 
available, will undergo screening procedures for determination of their eligibility for Part B.  
Subsequent post-dose clinical evaluations will occur on Study Days 8, 15, and 25, then every 
25 ± 3 days (Study Days 50, 75, 100, 125, 150, and 175) of Part B.  Evaluations on Days 75, 
125, and 150 will be conducted by telephone.  Patients must undergo these scheduled clinical 
evaluations in order to continue to receive study treatment.  Unscheduled clinical evaluations 
may occur at any time if deemed appropriate by the investigator, to discontinue patient 
participation, and/or for safety follow-up.  Patients will return for a final safety follow-up 
visit approximately 2 weeks after their last dose of study treatment. 
3.1.3 Rationale of Study Design  
In Part A, the screening phase permits evaluation of 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 

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long half-life (e.g., fluoxetine), under the supervision of the investigator before baseline.  
Patients will be randomly assigned to 1 of 3 treatment groups (1:1:1) 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. 
In Part B, patients who safely completed participation in Part A may enroll in an open-label 
extension.  Patients enrolling into the open-label extension upon completing treatment in 
Part A will have their Part B baseline visit on Visit 8 (Study Day 43) of Part A.  Patients who 
safely (in the opinion of the investigator and confirmed by the Medical Monitor) completed 
Part A of the study prior to the open-label extension becoming available, will undergo re-
screening procedures for determination of their eligibility for Part B. 
For Part A, 2 ITI-007 doses were selected to deliver full occupancy of the cortical 5-HT2A 
receptors (>85% occupancy) at both doses.  Data from a human PET brain receptor 
occupancy study in healthy male volunteers indicates that 40-mg ITI-007 is associated with 
up to 39% striatal D2 receptor occupancy (average of 29%) and up to 31% striatal SERT 
occupancy (average of 22%) while the 60-mg dose is projected to achieve up to 50% striatal 
D2 receptor occupancy and similar or slightly less SERT occupancy.  These doses have been 
shown to be generally safe and well tolerated and enable an exploration of the dose required 
to achieve efficacy in this patient population.  
The doses to be administered in Part A of the present study, 40- and 60-mg ITI-007, were 
shown to be generally well tolerated in prior studies with no evidence of a need for drug 
titration.  Therefore, a fixed-dose design will be employed in this study.  
In Part A, the placebo control group is needed to establish the efficacy of a new compound. 
For Part A, the treatment duration of 6 weeks has been chosen because this is considered an 
acceptable period to demonstrate efficacy in this patient population. 
Part B of the study is to determine the safety and effectiveness of ITI-007 (60 mg) 
administered daily for up to approximately 6 months (175 days) in patients with bipolar 
depression who safely completed Part A of the study. 

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4 Patient Selection and Withdrawal Criteria 
4.1 Selection of Study Population 
Approximately 549 patients (183 patients/arm in Part A) will be enrolled at approximately 
60 study sites in the United States.  In Part A, patients will be randomly assigned to study 
treatment only if they meet all of the inclusion criteria and none of the exclusion criteria.  In 
Part B, up to 549 patients who safely completed Part A may receive ITI-007 60 mg. 
Deviations from the inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability, or patient 
safety.  Therefore, adherence to the criteria, as specified in the protocol, is essential. 
In Part A, appropriateness of patient eligibility will be assessed by expert site-based raters 
and investigators and confirmed by remote, independent expert raters and/or medical 
monitor(s) by a systematic adjudication process in concert with the sponsor.  In Part B, 
appropriateness of patient eligibility will be assessed by the investigator.  In the event of a 
recently emerged new medical condition, this should be evaluated carefully and discussed 
with the Medical Monitor prior to participation in Part B of the study.  Once a final decision 
is made, no waivers for exceptions will be provided. 
4.1.1 Part A 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 Structured Clinical Interview for DSM-
5 Disorders – Clinical Trials Version (SCID-5-CT) and meeting all of the following 
5 criteria: 

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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.  The presence of psychotic symptoms may result in an increased 
YMRS without evidence of mania/hypomania. Therefore, a patient with a 
YMRS >12 AND psychotic symptoms may be included pending 
adjudication review for diagnostic certainty of the depressive episode.  
4. Has a body mass index (BMI) of 18 – 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).  
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. 
4.1.2 Part A 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.  

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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 a negative urine pregnancy test at screening and 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 as assessed 
by the SCID-5-CT, 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; 
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;  

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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 #4.  The presence of these symptoms should be 
reviewed with the medical monitor and adjudication team prior to inclusion.  The 
presence of psychotic symptoms may result in an increase in YMRS to > 12 in the 
absence of impending mania/hypomania, therefore these patients 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 FDA-approved medications 
for Bipolar depression (lurasidone, quetiapine or Symbyax) at an adequate dose (per 
FDA-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 test at the screening or 
baseline visits, 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 cannabis 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 as verified by DupCheck) 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 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 and zolpidem CR as 
noted in the concomitant medication section, allowed during the 
screening period and the first 2 weeks of the treatment period);  
ii. central opioid agonists/antagonists including tramadol (Ultram);  
iii. anticonvulsants;  
iv. mood stabilizers, antipsychotics, antidepressants; EXCEPTION:  long 
acting injectable antipsychotics must be washed out 1.5 cycles or 28 
days, whichever is LONGER, before baseline 
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, or medical foods must be approved by the 
Medical Monitor.  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 

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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. 
i. 12-lead ECG (in a supine position at rest at the screening or baseline visit) 
corrected QT interval using the Fridericia formula (QTcF) >450 ms, and/or 
heart rate ≤50 beats per minute, or evidence of clinically significant 
bundle-branch blocks. The ECG may be repeated one time at the investigator’s 
discretion to ensure the reproducibility of results. 
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. 

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17. At Screening, the patient has a history of Hepatitis B or Hepatitis C infection (or 
demonstrates Hepatitis B surface antigens or Hepatitis C antibodies), AND evidence 
of active disease defined as elevated ALT, AST or bilirubin levels as specified in 
Exclusion 14. 
18. The patient is an employee of the investigator or study center, or immediate family 
(i.e., spouse, parent, child, or sibling, whether biological or legally adopted) of such 
employees, the investigator, ITI, or contract research organizations conducting the 
study.  
19. 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). 
20. The patient is judged by the investigator to be inappropriate for the study. 
4.1.3 Part B Inclusion Criteria 
Each patient continuing into Part B of the study must meet all of the following criteria: 
1. Patients must have safely (in the opinion of the investigator, and confirmed by the 
Medical Monitor) completed Part A.  
[Note: patients who had experienced significant AEs which were thought to be 
possibly related to blinded study medication, should not be enrolled into the open-
label extension]; 
2.   Patients must be capable of understanding the written informed consent, providing 
signed and witnessed written informed consent, and agreeing to comply with protocol 
requirements for Part B of the study; a separate written informed consent must be 
provided for continuation into the open-label extension after treatment in Part A has 
been completed. 
3. Patients must agree to use highly effective methods of birth control (as defined in Part 
A Inclusion #5) for at least 2 weeks prior to randomization (starting with informed 
consent) through to the end of study visit, or, patients must be of non-childbearing 
potential (as defined in Part A Inclusion #5). 
 
4.1.4 Part B Exclusion Criteria 
Exclusion Criteria (Part B) Re-Screening 

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Since all prior participants in Part A were required to satisfy exclusion criteria for 
participation in that part of the study, the investigator should assess where there has been any 
change of status.  In the event of a recently emerged new medical condition, this should be 
evaluated carefully and discussed with the Medical Monitor before including the patient in 
Part B.   
Patients who safely completed Part A of the study prior to the open-label extension becoming 
available, will undergo screening procedures and must be eligible according to the 
abbreviated Part A exclusion criteria as described below. Any references to adjudication in 
Part B refer to a review by the Medical Monitor.  
Please note these Part B Exclusion Criteria are numbered to coincide with the Part A 
Exclusion Criteria for consistency of reference. 
Patients meeting any of the following criteria will be excluded from the study: 
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 Visit 10 screening, the patient scores “yes” on Items 4 or 5 in the Suicidal 
Ideation section of the C-SSRS with reference to the last visit; or  
b. At Visit 10 screening, the patient has had 1 or more suicidal attempts with 
reference to a 2-year period prior to screening; or  
c. At the Visit 11 Baseline Visit, the patient scores “yes” on Items 4 or 5 in the 
Suicidal Ideation section of the C-SSRS with reference to the last visit; or 
d. At Visit 10 Screening or the Visit 11 Baseline Visit, scores ≥4 on Item 10 
(suicidal thoughts) on the self-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 a negative urine pregnancy test at Visit 10 Screening and on Visit 11 
Baseline Visit prior to study treatment administration. 
4. The patient is assessed by the investigator as not having had a change in primary 
diagnosis at Visit 10 Screening, as compared to Visit 1 Screening. 

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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.  
9. The patient is considered treatment-resistant, defined as having a lifetime history of 
treatment resistance (no remission) to ≥2 treatments with FDA-approved medications 
for Bipolar depression (lurasidone, quetiapine or Symbyax) at an adequate dose (per 
FDA-approved label) for an adequate duration (at least 6 weeks).  
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 test at the Visit 10 
Screening or Visit 11 Baseline visits, 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 cannabis use during the study. 
13. The patient has used 1 of the following agents under the specified conditions:  
b. Any strong or moderate cytochrome P450 3A4 inhibitor or inducer within 
7 days prior to the Visit 11 Baseline Visit.  
c. Use of any long-acting anxiolytics within 5 half-lives of the Visit 11 Baseline 
Visit.   

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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 Visit 11 Baseline Visit, whichever is less, as 
reviewed by the medical monitor including, but not limited to:  
i. sedative hypnotics (with the exception of zolpidem and 
zolpidem CR as noted in the concomitant medication section)  
ii. central opioid agonists/antagonists including tramadol (Ultram);  
iii. anticonvulsants;  
iv. mood stabilizers, antipsychotics, antidepressants; EXCEPTION:  
long acting injectable antipsychotics must be washed out 1.5 
cycles or 28 days, whichever is LONGER, before baseline 
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, or medical foods must be approved by the 
Medical Monitor.  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 Visit 11 
Baseline visit is allowed and results must be available prior to the Visit 11 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 

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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. 
i) 12-lead ECG (in a supine position at rest at the Visit 10 Screening or Visit 11 
Baseline visit) corrected QT interval using the Fridericia formula (QTcF) 
>450 ms, and/or heart rate ≤50 beats per minute, or evidence of clinically 
significant bundle-branch blocks. The ECG may be repeated one time at the 
investigator’s discretion to ensure the reproducibility of results. 
j) Any other clinically significant abnormal laboratory result at the time of the 
Visit 10 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 
Visit 10 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 
Visit 10 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 Visit 10 Screening; 
malignancy more than 2 years prior to Visit 10 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. 

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17. The patient has a history of hepatitis B or hepatitis C infection (or demonstrated 
Hepatitis B surface antigen or Hepatitis C antibodies),  AND evidence of active 
disease defined as elevated ALT, AST or bilirubin levels as specified in Exclusion 14.  
18. The patient is an employee of the investigator or study center, or immediate family 
(i.e., spouse, parent, child, or sibling, whether biological or legally adopted) of such 
employees, the investigator, ITI, or contract research organizations conducting the 
study.  
19. 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). 
20. The patient is judged by the investigator to be inappropriate for the study. 
Exclusion Criteria (Part B) Direct Rollover 
Patients directly enrolling into the open-label extension upon completing Part A, presenting 
at the Day 43 visit with any of the following characteristics, will be excluded from the study:  
1. Is, in the opinion of the investigator, unable to comply with study procedures; 
2. Has a significant risk for suicidal behavior during the course of their participation in 
the study or is considered to be an imminent danger to themselves or others, in the 
opinion of the investigator, and/or as assessed by the C-SSRS; or > 4 on item 10 of 
the subject-rated MADRS 
3. Clinically significant (in the investigator’s judgement) abnormal laboratory results at 
the time of the last study evaluation.  
[Note: medical conditions are allowed as long as the condition has been stable during 
Part A, 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]; 
4. The patient is pregnant or breast-feeding; female patients of childbearing potential 
must have a negative pregnancy test at rescreening (if applicable) and upon entry to 
Part B of the study prior to treatment administration;  
5. Has a positive qualitative urine drug or alcohol test (which may be confirmed with 
additional testing) at the last evaluation, or evidence of either withdrawal from, or 
acute intoxication with cocaine, opiates, amphetamines (including 
methamphetamine), alcohol, barbiturates, or hallucinogens or similar compounds;  

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[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 cannabis use during the study.]; 
6. Is judged by the investigator to be inappropriate for the study.   
 
4.2 Withdrawal of Patients from the Study 
For Part A, the planned overall duration of the study for each patient is up to 10-12 weeks (9 
visits): a screening phase of up to 2 weeks (exceptions may be given to allow for washout of 
previous medication with a long half-life, as reviewed and approved by the medical monitor, 
but not to exceed 28 days), a treatment phase 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 provided through the last follow-up visit on Day 56 for patients who participate in 
Part A only. 
In Part B, the planned overall duration of the study for each patient is up to approximately 
6 months.  For patients who completed Part A prior to the open-label extension becoming 
available, a screening phase would be up to 14 days, a treatment phase of up to 175 days 
 3 days, and a safety follow-up visit after return to standard of care.  The duration of the 
study is defined for each patient as the date signed written informed consent is provided 
through the last visit on Day 189  3 days. 
4.2.1 Reasons for Withdrawal/Discontinuation 
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. 

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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 in Part A or enrolling into the open-label 
extension in Part B, 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-clinically significant, or the 
patient is lost to follow-up.  Any patient may withdraw his or her consent at any time. 
4.2.2 Handling of Withdrawals 
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 drug.  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 

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(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) 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. 
4.2.3 Replacements 
In Part A, 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 criteria or exhibits any of the exclusion criteria at 
screening may be rescreened with the permission of the medical monitor.  In Part A and if 
applicable in Part B, 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 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.   

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5 Study Treatments 
5.1 Method of Assigning Patients to Treatment Groups 
In Part A, patients who continue to meet all eligibility criteria at baseline (Visit 2) will be 
randomly assigned to 1 of the 3 treatment arms for a 6-week, double-blind treatment period.  
Patients will be randomly assigned to 1 of the following groups: 40-mg ITI-007, 60-mg ITI-
007, or matching placebo.  The on-study treatment period will be a total of 6 weeks.   
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 (SAS Institute Inc, 
Cary, North Carolina) 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 5.6.1).  The randomization schedule will be stratified by Bipolar I or Bipolar II 
diagnoses at screening. 
Each patient will be assigned a randomization number, 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 center personnel, confirming the 
patient data that were entered.  The IVRS/IWRS notifications should be filed securely at the 
study site.   
In Part B, enrollment will occur on Day 43, Visit 8 which is Day 1 of Part B.  If a patient is 
required to undergo screening (Visit 10), upon determination of his/her eligibility for Part B, 
the enrollment will occur on Visit 11 as indicated in the Schedule of Events.  Patients will be 
issued treatment cards of ITI-007 (60 mg).  ITI-007 will be administered orally once daily as 
tablet for up to approximately 6 months (175 days). 
5.2 Treatments Administered 
In Part A, patients will be assigned to receive either ITI-007 (40- or 60-mg doses) or placebo.  
Study center personnel will receive a treatment card number from the IVRS/IWRS for each 
patient at each clinic visit, to ensure that the correct investigational product is dispensed.  

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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 between 8:00 PM and 
10:30 PM, at approximately the same time each day whenever possible.  Treatments will be 
provided in dose cards containing 2 strips of over-encapsulated tablets (Section 5.4.1).  
Patients will be instructed to take 2 capsules (1 capsule from each strip) per dose.   
In Part B, all patients will receive ITI-007 (60 mg).  Patients will self-administer all doses 
orally, once daily, at home, in the evening for up to approximately 6 months (175 days) at 
approximately the same time each day whenever possible.  Patients will be instructed to take 
1 tablet per dose. (Section 5.3.2).  
In Part B, a one-time dose reduction will be allowed for patients who (in the opinion of the 
investigator and as confirmed by the Medical Monitor) are not tolerating the 60 mg dosage.  
If the patient is not able to tolerate the 40 mg dose, they must be withdrawn from the study 
and undergo evaluations required in the early termination visit. 
5.3 Identity of Investigational Product 
5.3.1 Investigational Product for Part A 
ITI-007 will be supplied as 20- and 60-mg over-encapsulated tablets (capsules) (Table 5–1).  
The following drug supplies will be used in the study:  
Table 5–1 
Table for Dosing Schedule  
 
  
Study Drug 
Dosing Schedule 
40-mg ITI-007 
2 over-encapsulated tablets of 20-mg ITI-007 
Daily Dose: 40-mg ITI-007 
60-mg ITI-007 
2 over-encapsulated tablets: 1 over-encapsulated tablet of 
60-mg ITI-007 and 1 over-encapsulated tablet of placebo  
Daily Dose: 60-mg ITI-007 
Placebo 
2 over-encapsulated tablets of placebo 
Daily Dose: 0-mg ITI-007 

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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 5–2. 
Table 5–2 
Dosage Composition for Part A 
Ingredient 
Quantity/Tablet (mg) 
 
20-mg coated tablet 
60-mg coated tablet Placebo coated 
tablet 
ITI-007 
20  
60.0 
Not Applicable 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
   

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Over-encapsulated placebo tablets are identical in appearance to ITI-007 and have the same 
excipient ingredients as ITI-007 but do not have the active compound. 
5.3.2 Investigational Product for Part B 
ITI-007 will be supplied as 60-mg tablets for once-daily oral administration during Part B. 
The composition of the tablets is listed in Table 5-3 Dosage Composition for Part B. 
ITI-007 will be supplied as 20 and 60 mg tablets.  For dose reduction, two 20 mg tablets will 
be used for the 40mg dose. 

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5.4 Management of Clinical Supplies 
5.4.1 Study Drug Packaging and Storage 
In Part A, ITI-007 and matching placebo will be prepared according to current Good 
Manufacturing Practice standards in carded blister strips and shipped under ambient 
conditions by Catalent, on behalf of ITI.  Each treatment card will contain a sufficient 
quantity for 1 patient for each week (7 doses, plus 1 extra) of the 6-week treatment period, to 
be distributed at weekly visits.  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 5–3.  

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Table 5–3  
Part A 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 
One 1×8 strip of 60-mg ITI-007 over-
encapsulated tablets (8 over-encapsulated 
tablets/strip);  
One 1x8 strip of placebo over-encapsulated 
tablets (8 over-encapsulated tablets /strip) 
 
40-mg ITI-007 
Two 1×8 strips of 20-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.   
 
Study drug 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 weekly treatment card at room 
temperature at home, out of the reach of children.  Patients will be instructed to take 
2 capsules, 1 capsule from each strip per dose for Part A. 
In Part B, ITI-007 will be provided to the study site by Catalent on behalf of ITI.  Each 
treatment card will provide sufficient quantity for 1 patient for 4 weeks (28 doses).  At the 
Part B, enrollment visit (Visit 8 of Part A), the patient will receive treatment cards containing 
sufficient quantities for 4 weeks.  Each ITI-007 dosing container will be labeled according to 
local laws and regulations.   
The treatment card for each study treatment is presented in Table 5-5.  

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Table 5-4 
Part B Treatment Cards for 4 Weeks of Treatment 
Treatment  
Card Contents 
60 mg ITI-007 
Two 2 × 7 strips of 60 mg ITI-007 tablets (14 tablets/strip) 
Note: Each treatment card will hold 28 tablets each. 
 
Treatment  
Card Contents 
40 mg ITI-007 (two 
20 mg tablets 
Four 2 × 7 strips of 20 mg ITI-007 tablets (14 tablets/strip) 
Note: Each treatment card will hold 56 tablets each. 
 
Study drug must be stored in a secured locked area while in storage at the study site, 
protected from moisture, and kept at room temperature between 15 and 30°C (59 - 86 °F).  
Patients will be instructed to store the treatment card at room temperature, out of the reach of 
children.  Patients will be instructed to take 1 tablet 60 mg each day per dose for Part B 
unless their dosage is reduced to two 20 mg tablets daily for a dose of 40 mg. 
5.4.2 Test Article Accountability 
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 drug will be 
reconciled and retained or destroyed according to applicable regulations. 
5.5 Overdose Management 
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. 
5.5.1 Treatment of Overdose 
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 

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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 schizophrenic 
patients 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 with sufficient attention to the symptoms and the clinical course.  Supportive 
measures may include gastric lavage and respiratory and cardiovascular support as needed.  
5.5.2 Medication Errors 
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 (in 
Part A, not taking 2 capsules per dose or taking too many capsules per dose; in Part B, taking 
more than 1 tablet 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.   
5.5.3 Treatment of Medication Errors 
The treatment of medication errors should be discussed with the medical monitor on a 
case-by-case basis.  In the case of overdose, see Section 5.5.1. 
5.6 Blinding 
Part A of the study will be performed in a double-blind manner.  All study drug will be 
supplied in identical treatment cards and packaging, and will be similar in color, smell, taste, 
and appearance, thereby enabling double-blind conditions. 
Part B will be conducted as an open-label trial and no blinding procedures are required. 
5.6.1 Breaking the Blind 
In Part A, 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 

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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 be discontinued from the study.   
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.   
5.7 Treatment Compliance 
Patient compliance will be assessed by capsule counts of unused study medication at each 
visit during the double-blind treatment phase for Part A and unused study drug at each visit 
during Part B (Table 6–1 and Table 6-2).   
In Part A, 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. 
In Part B, for patients missing more than approximately 20% of their doses, the investigator 
will be responsible to determine if patient’s missed doses should result in patient termination 
from the study.  These cases should be discussed with the medical monitor. 
5.8 Prior and Concomitant Therapy  
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.  In Part A drugs with known psychotropic properties or any non-
psychotropic drugs with potential central nervous system effects are prohibited, with the 
exceptions of zolpidem and with the following restrictions:  

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PART A Restrictions: 
Concomitant 
Medication 
Dose 
Indication 
Study period 
allowance 
Assessment 
restrictions 
Zolpidem 
Up to 
10mg/day 
(bedtime) 
insomnia 
During screening and 
first two weeks of the 
treatment period 
Prohibited at least 8 
hours prior to any 
psychiatric 
assessments 
Zolpidem CR  
Up to 
12.5mg/day 
(bedtime) 
insomnia 
 
In Part B, drugs with known psychotropic properties or any non-psychotropic drugs with 
potential central nervous system effects are prohibited, with the exception of zolpidem and 
lorazepam with the restrictions provided in the table below. The table below is a guideline 
for use of these medications; any use outside of these guidelines must be approved by the 
Medical Monitor:  
PART B Restrictions: 
Concomitant 
Medication 
Dose 
Indication 
Study period 
allowance 
Assessment 
restrictions 
Zolpidem 
Up to 10mg/day 
(bedtime) 
insomnia 
All of Part B 
Prohibited at least 8 
hours prior to any 
psychiatric assessments 
Zolpidem CR 
Up to 12.5 
mg/day (bedtime) 
insomnia 
Lorazepam 
Up to 6 mg in any 
given week  
Agitation, 
anxiety or 
insomnia 
 
(Section 4.1.2, 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.  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 

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medication with longer half-life (e.g., fluoxetine) under the supervision of the investigator 
before baseline. 
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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6 Study Assessments and Procedures 
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.  Separate written informed consent must be provided for each part of the study. 
 
 
   

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6.1 Screening Assessments and Procedures 
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 schedules of events in Table 6–1 and Table 6-2 for Parts A and B, respectively; 
assessments can be conducted on different days within the screening period. 
6.1.1 Informed Consent 
For both study parts, before any study-related activities the patient must sign and date an ICF 
approved by the responsible institutional review board (IRB).  The format and content of the 
ICF must have been agreed upon by the investigator, the appropriate IRB, and ITI.   
For Part A only, A separate ICF will be provided for the collection of samples to be used in 
the determination of genetic biomarkers.  Patients may withhold consent to provide such 
samples and still participate in the study without prejudice. 
6.1.2 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 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 the DupCheck.org website and other methods 
for identifying duplicate patients. 

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6.1.3 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.  All 
physical examination findings must be documented in the patient’s study chart and also 
recorded in the eCRF.   
6.1.4 Electrocardiogram Assessments 
In Part A, each ECG assessment will be comprised of a10-second epoch from a 12-lead ECG.   
Electrocardiogram parameters to be measured include heart rate, QRS, PR, QT, 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.   
In Part B, a standard single 12-lead ECG will be performed at the visits indicated in 
Table 6-2.  Electrocardiograms will be performed after patients have been supine for at least 

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10 minutes.  Electrocardiogram parameters to be measured include heart rate, QRS, PR, QT, 
QTcF, and RR intervals. 
The ECG results will be centrally read and evaluated by the investigator for clinical 
significance.  The investigator will assess whether any findings should be considered as AEs, 
and, if so, will be recorded as such.  
6.1.5 Vital Sign Measurements 
In Part A, vital sign assessments will include supine blood pressure and pulse rate, respiratory 
rate, and oral temperature.  Blood pressure and pulse rate will be measured after 10 minutes 
in the supine position.  Height will be measured only at screening.  Body weight and waist 
circumference 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.   
In Part B, vital sign assessments will be performed at the visits indicated in Table 6-2, and 
will include blood pressure and pulse rate, respiratory rate, and oral temperature.  The blood 
pressure and pulse rate will be measured after 10 minutes in the supine position.  Height will 
be measured only at screening.  Body weight will be measured at all scheduled visits. 
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.   
6.1.6 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, AND shows evidence of active disease will be excluded from 
participating in the study.  Details regarding sample collection, processing, and shipping can 
be found in the study reference manual. 

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6.1.7 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.  
6.1.8 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 any drug or alcohol at screening will be 
excluded from participating in the study except as noted in Exclusion #12.  Further 
information regarding sample collection, processing, and shipping can be found in the study 
reference manual. 
6.1.9 Laboratory Assessments 
Laboratory assessments performed at screening are described in Section 6.5. 
6.1.10 Urine Pregnancy Test 
Female patients who are of childbearing potential will undergo urine pregnancy tests at the 
study clinic using a urine dipstick.  If the pregnancy test at screening or Day 1 is positive, the 
patient will not be eligible to participate in the study.  If a urine pregnancy test performed 
after initiation of study treatment is positive, it should be confirmed by a serum pregnancy 
test.  Further details regarding sample collection and processing can be found in the study 
reference manual. 

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6.1.11 Structured Clinical 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 SCID-5-CT, which is a semi-structured interview for making 
the major DSM-5 diagnoses (First, 2014).  It will be used in this study at screening in Part A 
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.   
6.1.12 Bipolarity Index (BPI) 
The Bipolarity Index was designed to provide a measure of quantitative measure of 
diagnostic confidence by mapping the known information about an individual patient on five 
dimensions of illness (signs and symptoms, age of onset, course of illness, response to 
treatment and family history) onto a scoring hierarchy based on the presence of elements 
considered most characteristics of bipolar disorder.  The information necessary to score the 
Bipolarity Index can be extracted from clinical interviews, either administered by clinicians 
or as a self-report questionnaire.  The BPI will be completed by a qualified site-based rater at 
the screening visit in Part A only.   The patient’s responses to the BPI and the Bipolarity 
Index score generated by the BPI may be reviewed by an independent expert as a component 
of the systematic patient adjudication process in Part A.   
The Bipolarity Index was developed by a group of Bipolar Disorder experts including Gary 
Sachs (Sachs, 2004).  The scoring system is divided into five dimensions including episode 
characteristics, age of onset (1st affective episode), course of illness/associated features, 
response to treatment, and family history.  Each dimension is given a score of 0-20 based on 
its correlation with BD characteristics, and the scores are added to derive the Bipolarity index 
score.  The maximum score is 100.  The score represents how close the patient is to having 
bipolar disorder.  The Bipolarity Index has been used to evaluate diagnostic confidence for 
patients entering global clinical trials. 

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6.1.13 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/participant may have had since the last time the C-SSRS was administered.   
In Part A, the C-SSRS will be administered by the investigator or an expert site-based rater, 
as indicated in the Schedules of Events (Table 6–1 and Table 6-2 for Parts A and B, 
respectively).  In Part B, on Days 75, 125, and 150, the C-SSRS will be administered via 
telephone by a qualified site-based rater. Concerns for participant safety after phone 
interviews should be addressed immediately by the investigator. 
At screening a potential study participant 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.  
[Note: For Part B, all C-SSRS assessments used should be the “Since Last Visit” version, 
since the patient has had an initial assessment at the Part A Screening Visit.] 
6.1.14 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, 1978).  Four of the YMRS items are rated on a 0 to 8 scale, with the 

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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.  In Part A, it will be 
completed by the investigator or an expert site-based rater.   
At each visit with a YMRS assessment, the rater-administered YMRS interview will be audio 
recorded; at each visit after the screening visit, a computer-administered YMRS interview 
will also be completed by patients.   The computer-administered interview will involve a 
series of probe and follow up questions with multiple-choice response options.  At all visits 
(except screening) the rater-administered YMRS will be conducted before the computer-
administered YMRS. 
In Part B, YMRS administration will be done by each patient who will complete an 
interactive, computer-administrated YMRS interview on the dedicated study device. 
6.1.15 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, 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 (Section 6.2.2).  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 in 
Part A by the investigator or another ITI-approved expert site-based rater.   
In Part B, the CGI-BP-S will be administered after review of the patient-completed 
computerized MADRS and YMRS assessments. 

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6.2 Efficacy Assessments and Procedures 
6.2.1 MADRS 
The MADRS is a 10-item checklist designed to measure the overall severity of depressive 
symptoms.  Individual items are rated by the investigator (or another ITI-approved expert 
site-based rater) 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.    
In Part A, at each visit with a MADRS assessment, the rater-administered MADRS interview 
will be audio recorded; at each visit after the screening visit, a computer-administered 
MADRS interview will also be completed by patients.   The computer-administered 
interview will involve a series of probe and follow up questions with multiple-choice 
response options.  At all visits (except screening) the rater-administered MADRS will be 
conducted before the computer-administered MADRS. 

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In Part B, MADRS administration will be done by each patient, who will complete an 
interactive, computer-administered MADRS interview on the dedicated study device. 
6.2.2 Clinical Global Impression of Severity  
The CGI-BP-S (Section 6.1.15) will be a clinical efficacy assessment by the investigator of 
each patient’s severity of illness.  The CGI-BP-S score at Part A screening will be considered 
in the adjudication process for enrollment (Section 6.1.16).  The Clinical Global Impression 
Scale is a widely accepted measure of illness severity in a variety of psychiatric disorders.  
These items have been extensively used in psychopharmacologic trials since their 
introduction into the Early Clinical Drug Evaluation Unit Assessment Manual for 
Psychopharmacologic Trials published by the US National Institute of Mental Health.  The 
Clinical Global Impression Scale is rated by the clinician based on all information available 
at the time of rating.  The bipolar version has been validated for use as a global clinical 
assessment of symptoms specific to bipolar disorder. 
The severity of illness is rated on a 1 to 7 scale.  The clinician indicates his or her assessment 
of the patient's severity of illness relative to the clinician’s experience with the population 
experiencing bipolar depression. 
6.2.3 SDS (Part A Only) 
The SDS is a validated patient self-reported measure of psychosocial disability.  It is widely 
used in many chronic mental illnesses because of its generic design.  The SDS consists of 
3 subscales for the items "Work/School," "Social Life," and "Family Life/Home 
Responsibilities."  Each subscale consists of a visual analog scale on which the patient scores 
each item from 0 ("not at all") to 10 ("extremely") in response to each question of how much 
each subscale aspect is impaired.  Changes in the score for each item are evaluated to assess 
the change in severity of each domain.  The scores may also be summed across the 
3 subscales to assess overall change in disability. 

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6.2.4 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.  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. 
6.2.5 WHO-5 Well-Being Index (Part A Only) 
The WHO-5 is a patient-reported outcome measure developed by the World Health 
Organization.  This self-reported questionnaire consists of 5 questions regarding subjective 
quality of life based on positive mood, vitality, and general interest, each rated on a 6-point 
Likert scale from 0 (at no time) to 5 (all the time).  The sum of scores represents the raw 
scores with 0 representing the worst possible quality of life and 25 representing the best 
possible quality of life.  A score below 13 represents poor well-being.  To calculate the 
percentage score, the raw score is multiplied by 4, with 100% representing the best possible 
quality of life.  A 10% difference over time indicates a meaningful change.  The WHO-5 has 
been found to have adequate validity as an outcome measure in clinical trials (Topp, 2015).   
6.2.6 NEO-FFI (Part A Only) 
The NEO-FFI is a 60-item self-report scale (Costa, 1992).  Each item is ranted on a 5-point 
scale.  Twelve items assess each of five dimensions of personality: neuroticism (N), 
extraversion (E), conscientiousness (C), openness (O), and agreeableness (A).  

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6.3 Safety and Tolerability Assessments 
All patients who receive study drug 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.   
6.3.1 Adverse Events 
The investigator is responsible for reporting all AEs that are observed or reported during the 
study, regardless of their relationship to study drug or their clinical significance. 
6.3.1.1 Definition of Adverse Event 
An AE is any untoward medical occurrence in a study patient administered a study drug, 
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 drug, 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. 

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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 (Sections 6.3.1.2 and 6.3.1.3). 
6.3.1.2 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. 
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. 

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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 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. 
6.3.1.3 Nonserious Adverse Event 
A nonserious AE is any AE not meeting the SAE criteria.  
6.3.1.4 Definition of Relationship to Study Drug 
By definition, any AE that starts before the first dose of study drug administration is 
considered to be “unrelated.” 
The investigator will assess the causality/relationship between the study drug and the AE 
(Table 6–3).  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 6–3 
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 
time sequence to administration of the treatment, but which could also 
be explained by concurrent disease or other drugs or chemicals.  
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). 

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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. 
 
6.3.1.5 Definition of Intensity 
The principal investigator will assess all AEs for intensity (severity) in accordance with the 
following standard ratings (Table 6-4): 
Table 6-4 
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.  

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6.3.1.6 Period of Observation for Adverse Events 
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. 
Serious AEs occurring after completion or discontinuation of the study should be reported if 
they occur within 30 days after the last dose of study treatment.  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. 
6.3.1.7 Documenting, Reporting, and Eliciting Adverse Events  
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 drug and/or study procedure.  
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).  

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6.3.1.8 Notification About Serious or Unexpected Adverse Events 
The investigator will review each SAE (Section 6.3.1.2) and evaluate the intensity and the 
causal relationship of the event to study drug.  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 drug 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 
• 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) 

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The sponsor will request clarification of omitted or discrepant information from the initial 
notification.  The investigator or an authorized delegate is responsible for faxing 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 faxed to the sponsor within 24 hours of receipt of the information.  If a new SAE Report 
Form is faxed, 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 fax 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.   
6.3.1.9 Exceptions 
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.  As 
discussed in Section 6.3.1.2, medical and scientific judgment should be exercised in deciding 
whether an AE is serious.  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. 
6.3.1.10 Follow-Up of Adverse Events 
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 drug administration.  A follow-up visit to 

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the study site may occur for those patients with an ongoing AE which the investigator 
believes to be possibly related to study drug 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. 
6.3.2 Safety Assessments 
Safety assessments scheduled through the course of the study (Table 6–1 and Table 6-2 for 
Parts A and B, respectively) will include suicidality assessment by the C-SSRS, mania 
assessment by the YMRS, movement disorder assessment by the AIMS, BARS and SAS, 
vital sign measurements, ECG evaluations, and physical and neurological examination.  
6.3.2.1 C-SSRS 
The C-SSRS will be completed at screening, baseline, and at every subsequent scheduled 
clinic visit (Table 6–1 and Table 6-2 for Parts A and B, respectively).  Details of the C-SSRS 
are presented in Section 6.1.13.   
6.3.2.2 YMRS 
The YMRS will be completed at screening, baseline, and at every subsequent scheduled 
clinic visit (Table 6–1 and Table 6-2 for Parts A and B, respectively).  Details of the YMRS 
are presented in Section 6.1.14.   
6.3.2.3 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 

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throughout the study as specified in the schedule of events (Table 6–1 and Table 6-2 for 
Parts A and B, respectively).  
6.3.2.4 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 as specified in the schedule of 
events (Table 6–1 and Table 6-2 for Parts A and B, respectively).   
6.3.2.5 Simpson-Angus Scale 
The SAS is a measure of extrapyramidal side effects (Simpson, 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 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 as specified in the schedule of events 
(Table 6–1 and Table 6-2 for Parts A and B, respectively).   
6.3.2.6 Vital Sign Measurements 
Vital signs will be measured at screening and at every subsequent scheduled clinic visit 
(Table 6–1 and Table 6-2 for Parts A and B, respectively).  Details of the vital sign 
measurements are presented in Section 6.1.5.  

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6.3.2.7 ECG Assessments 
The ECG assessments will be performed at screening and periodically throughout the study, 
as scheduled (Table 6–1 and Table 6-2 for Parts A and B, respectively).  Details of the ECG 
assessments are presented in Section 6.1.4.    
6.3.2.8 Physical and Neurological Examination  
The physical and neurological examinations will be conducted at screening and periodically 
throughout the study, as scheduled (Table 6–1 and Table 6-2 for Parts A and B, respectively).  
Details of the physical and neurological examinations are presented in Section 6.1.3.   
6.4 Safety Monitoring Committee 
No safety monitoring committee will be used for the study.   
6.5 Laboratory Analyses 
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. 
All samples for clinical laboratory analysis will be collected after an overnight fast 
(≥10 hours), for all visits subsequent to screening, prior to dosing with study drug.  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. 

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The following clinical analytes will be determined:  
Hematology: hematocrit; hemoglobin; HbA1c; 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, 
international normalization ratio).  
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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6.7 Sample Collections 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
6.7.3 Frequency and Volume of Blood Collection 
Blood samples will be collected for laboratory assessments, hepatitis and HIV screening, 
determination of plasma concentrations of ITI-007 and metabolites, and also for the 
assessment of protein and genetic biomarkers.  The sampling times for all blood sample 

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collections are given in Table 6–1 and Table 6-2 for Parts A and B, respectively (Schedules of 
Events).  
The estimates of blood sample volume and sample numbers are presented in Table 6–5.   
Table 6–5 
Number and Volume of Blood Samples for Part A 
Number of Blood Samples 
Study Day/Visit 
PK  
 
Protein 
Biomarker 
Genetic 
Biomarker 
Laboratory 
Assessment 
Hepatitis 
Screening 
HIV 
Screening 
Screening 
 
 
 
X 
X 
X 
Day 1 
 
X 
X 
X 
 
 
Day 8 
X 
X 
 
X 
 
 
Day 22 
X 
X 
 
X 
 
 
Day 43 
X 
X 
 
X 
 
 
Day 57 
 
 
 
X 
 
 
Total number of 
samples  
4 samples 
4 samples  
1 sample  
6 samples 
1 sample  
1 sample  
Total maximum 
volume1 
40 mL 
40 mL 
10 mL 
60 mL 
10 mL 
10 mL 
Total blood volume per patient: up to 170 mL 
1 Each sample will have a volume of up to 10 mL.  
Note: Additional blood samples may be collected for repeat safety follow up. 
 
Table 6-6 
Number and Volume of Blood Samples for Part B 
Study Day 
Laboratory 
Assessment 
Hepatitis 
Screening 
HIV 
Screening 
Screening 
X 
X 
X 
Days 25, 75, 125, 175, 189 
X 
 
 
Days 75, 175, 189 
 
 
 
Total number of samples  
6 samples 
1 sample 
1 sample 
Total maximum volume1 
60 mL 
10 mL 
10 mL 
1 Each sample will have a volume of up to 10 mL.  
Note: Additional blood samples may be collected for repeat safety follow up. 
 

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6.8 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 during study participation must be reported using a clinical study pregnancy form.  
The patient must stop study drug immediately after pregnancy is discovered and have an 
Early Termination visit as soon as possible.  Additionally, each pregnancy must be reported to 
ITI 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, even if the patient was discontinued 
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. 

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7 Statistical and Analytical Plan 
A formal and detailed statistical analysis plan (SAP) for Part A will be finalized prior to the 
planned IA, and will provide further details regarding the definition of analysis endpoints, 
analysis methodology, and the IA to address all study objectives.  Similarly, a SAP for Part B 
will be finalized prior to database lock.  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 database lock, will be documented, and justified in the final 
clinical study report.   
Blinded (Part A) and unblinded (Part B) data review will be conducted prior to unblinding 
the patients’ treatment assignments (Part A) or finalizing the outputs (Part B) for assessing 
the accuracy and completeness of the study database and defining analysis datasets.  An 
unblinded review of Part A interim data will be conducted by an independent external 
unblinded Data Monitoring Committee (DMC) in accordance with the IA plan.   
7.1 Analysis Endpoints 
7.1.1 Primary Efficacy Endpoints (Part A) 
The primary efficacy endpoint of Part A is the change from baseline in the rater-administered 
MADRS total score at Week 6.   
7.1.2 Secondary Efficacy Endpoints (Part A) 
7.1.2.1 Key Secondary Efficacy Endpoint (Part A) 
The key secondary objective of Part A of this study is to compare the efficacy of 2 doses of 
ITI-007 administered orally once daily to that of placebo in time to first response, defined as 
the number of days from first dose of study drug to the earliest date the patient experiences a 
sustained ≥50% reduction from baseline in the rater-administered MADRS total score. 
 

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7.1.2.2 Other Secondary Efficacy Endpoints (Part A) 
• MADRS: 
o Time course of improvement, as measured by mean change from baseline in 
the MADRS total score at each assessment time point; 
o The proportion of treatment responders, where response is defined as a ≥50% 
decrease in the MADRS total score from baseline at Weeks 1, 2, 3, 4, 5, and 6.  
Patients who discontinue treatment early will be imputed as non-responders in 
the responder analysis.   
o The proportion of remitters, where remission is defined as a MADRS total 
score ≤12 at Weeks 1, 2, 3, 4, 5, and 6.  Patients who discontinue treatment 
early will be imputed as non-remitters in the remitter analysis.   
o Change from baseline in MADRS Item 4 “reduced sleep” score for patients 
with baseline MADRS Item 4 score ≥4 (patients with mild sleep disturbance) 
at Weeks 1, 2, 3, 4, 5, and 6. 
o Change from baseline in MADRS individual item scores at Weeks 1, 2, 3, 4, 
5, and 6. 
• CGI-BP: 
o Change from baseline in the CGI-BP-S score at Weeks 1, 2, 3, 4, 5, and 6; 
• SDS:  
o Change from baseline in the score for each item and total score at Weeks 3 
and 6; 
• Q-LES-Q-SF:  
o Change from baseline in the percent score at Weeks 3 and 6. 

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• WHO-5 Well-Being Index 
o Change from baseline in the percent score at Weeks 3 and 6. 
• NEO-FFI 
o Change from baseline in the percent score at Week 6. 
 
 
 
  
 
  
7.1.3 Secondary Effectiveness Endpoints (Part B) 
Secondary effectiveness objectives of Part B of this study are to determine whether 60 mg 
ITI-007, administered once daily for up to approximately 6 months to patients with bipolar 
disorder who have responded to treatment with ITI-007, improves and/or maintains 
symptoms, function, and quality of life as measured by change from baseline on the 
following measures: 
• MADRS total score; 
• CGI-BP-S; 
• Q-LES-Q-SF 
 
 
 
 
 
   

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7.1.5 Safety Endpoints (Parts A and B) 
• AEs;  
• YMRS total score; 
• MADRS score (safety endpoint for Part B only); 
• C-SSRS scores; 
• AIMS scores; 
• BARS scores; 
• SAS score; 
• Physical examination and neurological findings; 
• Vital signs (blood pressure, heart rate), weight, and height (height, only at screening); 
• ECGs; 
• Clinical laboratory evaluations. 
7.2 Sample Size Calculations 
In Part A, approximately 549 patients will be randomly assigned in a 1:1:1 ratio to 1 of the 3 
treatment arms, which will provide approximately 471 evaluable patients, assuming an 
approximate 14% early discontinuation rate before a post-dose assessment in the primary 
efficacy endpoint (MADRS).  A sample size of 471 patients (157/arm) will provide at least 
90% power to detect a clinically relevant treatment difference from placebo of 3 points on the 
MADRS total score within each ITI-007 dose level, with a common standard deviation of 7.5 

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at an overall 2-sided significance level of 0.05.  It was not possible to apply the proposed 
Hommel procedure for multiplicity adjustments (for comparing 2 doses of ITI-007 to 
placebo) to the sample size calculation; therefore, the sample size calculation used a more 
conservative Bonferroni adjustment.  The study therefore has at least 90% power to detect the 
previously mentioned clinically relevant treatment difference within each ITI-007 dose.  The 
sample size calculation was performed using PASS software version 12. 
In Part B, up to approximately 549 patients will be enrolled.  The sample size is not based on 
statistical considerations, rather on the number of patients who may be eligible based on 
participation in Part A of the study.  It is estimated that the majority of patients will continue 
treatment for the full 6 months.   
7.3 Analysis Sets 
The following analysis sets will be used in the statistical analyses. 
All Patients Enrolled (ENR) Set: The ENR Set will contain all patients who signed informed 
consent for the study.  
All Patients Randomized (RND) Set: The RND Set will contain all patients who signed the 
informed consent and were randomized to study drug. 
Intent-to-treat (ITT) Set:  The ITT Set will contain all randomly assigned patients who 
received at least 1 dose of study drug and who have a valid (pre-dose) baseline measurement 
and at least 1 valid post-baseline measurement of MADRS.  Primary, secondary, and 
exploratory efficacy analyses of Part A data will be performed using the ITT Set.  All 
analyses using the ITT will group patients according to randomized treatment, regardless of 
the treatment received during the course of the study.   
Per-protocol (PP) Set:  For Part A, the PP Set will contain all ITT patients who did not have 
any major protocol deviations.  For Part B, the PP Set will contain all patients in the Safety 
Analysis Set who did not have any major protocol deviations.  The major protocol deviation 
criteria will be finalized prior to any analysis.  For Part A, all analyses using the PP Set will 

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group patients according to the treatment actually received.  The classification of patients 
according to study drug does not apply to Part B. 
Safety Analysis Set:  The Safety Analysis Set will contain all patients who took at least 
1 dose of study drug.  All analyses using the Safety Set will group patients according to 
treatment actually received.  In case of incorrect dosing, the treatment most often received 
will be taken as the actual treatment.   
 
 
 
 
 
 
The following analysis sets will be used for the analyses of Part B data: ENR Set, Safety 
Analysis Set, and PP Sets.  The classification of patients according to study drug does not 
apply to Part B.   
Unless otherwise specified, the ITT and PP Sets will be used for analysis of efficacy 
endpoints in Part A and the Safety Set will be used for analysis of safety endpoints in Part A 
and safety and effectiveness endpoints in Part B. 
7.4 Description of Subgroups to be Analyzed 
Subgroup analyses of efficacy and safety variables may be conducted as deemed appropriate.  
For subgroup analyses using either MMRM or ANCOVA with LOCF, the corresponding 
subgroup terms will be added to the model: subgroup, subgroup-by-treatment, subgroup-by-
visit, and subgroup-by-treatment-by-visit interactions.  Subgroup analyses will be detailed in 
the SAP. 

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7.5 Statistical Analysis Methodology 
Categorical variables (e.g., race and gender) will be summarized using the number and 
percentage of patients in specified categories will be presented.  Unless otherwise specified, 
descriptive statistics of continuous variables (e.g., age, height, weight) will consist of the 
number of patients (n), mean, standard deviation, median, minimum, and maximum.  Source 
data for summary tables and statistical analyses will be presented as patient data listings.   
Unless stated otherwise, statistical tests will be 2-sided and use a 5% significance level, 
leading to 95% (2-sided) confidence intervals (CIs).  All statistical analyses will be 
performed using SAS software Version 9.2 or higher.  Adjustments for multiplicity due to the 
comparison of 2 doses of ITI-007 versus placebo for primary efficacy variables will be made 
using the Hommel procedure.  No adjustment for multiplicity will be made for secondary 
efficacy (Part A) or safety variables (Part A), or any analysis of Part B data, unless otherwise 
stated in the SAP. 
All investigative sites with fewer than 5 patients per treatment group with non-missing values 
of the response variable will be pooled together and considered a single site for analysis.  If 
this results in a site still having fewer than 5 patients per treatment group, this site will be 
pooled together with the next smallest investigative site, if one exists; otherwise, no further 
pooling is needed.  These pooled investigative sites 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 listings. 
Additional details regarding the statistical analysis methodology will be provided in the SAP. 
7.5.1 
Patient Disposition, Analysis of Demographics and Other Baseline 
Characteristics 
Patient disposition will be summarized for each Part by treatment group, when applicable, 
and overall, including incidence of screen failure, and treatment or study discontinuation and 
the corresponding reasons.  The number and percentage of randomized patients who 
discontinued due to an adverse event associated with worsening of bipolar depression will be 

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summarized.  Similarly, the number and percentage of randomized patients who discontinued 
due to an adverse event not associated with worsening of bipolar depression will also be 
presented.  Time to treatment discontinuation due to all reasons, adverse events, lack of 
efficacy, or due to any other reason of special interest will be evaluated separately 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 each treatment group and 
the placebo group (Part A).   
Demographic and baseline characteristics, including bipolar disorder diagnosis and bipolar 
disorder baseline efficacy measures, will be summarized for each part by treatment group for 
Part A only using descriptive statistics.  No inferential statistics will be presented.  
7.5.2 
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 
for each Part and by treatment group for Part A only, using the Safety Analysis Set.  Patients 
with multiple occurrences of a medication in the same preferred term and study period will 
only be counted once within the preferred term and study period. 
During the study, a patient may be treated with zolpidem as described in Section 5.8.  For 
Part A, 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.  Other 
medications will be summarized for Part A by treatment group and study period or overall for 
Part B if deemed necessary.  
7.5.3 
Study Medication Exposure and Treatment Compliance 
Exposure to study medication and treatment compliance will be presented for each Part using 
the Safety Analysis Set and, additionally for Part A, using the ITT Set.  Duration of exposure 
(days) and dosing compliance (%) will be calculated and summarized for each Part and by 

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treatment group for Part A only.  In addition, the number and percentage of patients exposed 
to study medication will be presented.  
7.5.4 Analysis of Part A Primary and Key Secondary Efficacy Endpoints 
Part A of the study is designed to evaluate the efficacy of two doses of ITI-007, 60 mg and 40 
mg, based on the primary and key secondary endpoints.  The primary efficacy endpoint, 
mean change from baseline to Week 6 in the rater-administered MADRS total score, 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 rater-administered 
MADRS total score as the response variable and visit, treatment, site, and the bipolar 
disorder at screening (I or II) stratification variable as factors, the baseline MADRS total 
score as a covariate, and interaction terms for treatment-by-visit, visit-by-baseline MADRS 
total score, and treatment-by-site.  An unstructured covariance matrix will be used to model 
the correlation among repeated measurements within patient.  If convergence cannot be 
attained with the unstructured correlation matrix, alternative structures will be evaluated in 
the order specified in the SAP.  Model parameters will be estimated using restricted 
maximum likelihood.  The Kenward-Roger approximation will be used to estimate the 
denominator degrees of freedom. 
  Estimates for change from baseline in MADRS total score, standard errors and 95% 
confidence intervals (CIs) will be presented by treatment group and time point.  The least-
squares mean difference between treatment groups will be presented along with the 
corresponding 95% CIs, effect sizes, and p-values will be presented for each visit.   
Sensitivity analyses will be conducted to assess the impact of missing data and the robustness 
of the MMRM results for the primary efficacy analysis, such as a pattern-mixture model 
using a placebo-based multiple imputation method and delta-adjusted tipping point analysis, 
and will be detailed in the SAP.   
As a supportive analysis of the primary efficacy variable, the change from baseline in 
MADRS total score will be evaluated using analysis of covariance (ANCOVA) with last 
observation carried forward (LOCF), defined as the last post-baseline measurement collected 

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within the study On-Treatment Period.  Analysis of the LOCF Week 6 endpoint will provide 
an estimate of efficacy attributable to ITI-007 compared to placebo at the end of period of 
adherence to treatment without taking into account the ability of patients to adhere to 
treatment for the full planned period of 6 weeks.  Least square means for each treatment, the 
least squares mean difference between treatment groups, the associated standard errors and 
two-sided 95% CIs for the differences between the treatment groups, and p-values for 
between-treatment tests of differences will be presented.  This analysis will be conducted for 
the ITT set and PP set. 
The key secondary efficacy endpoint, time to first response, defined as ≥50% reduction from 
baseline in rater-administered MADRS total score and maintaining it through the end of the 
6-week treatment, will be analyzed using time-to-event methods.  Time to the first response 
will be analyzed using the Cox’s Proportional Hazards model with terms for treatment, site, 
baseline MADRS total score, the bipolar disorder stratification variable and treatment-by-site 
interaction. Patients who do not experience at least 50% reduction from baseline in the rater-
administered MADRS total score, or do not maintain it through the end of the 6-week 
treatment, and patients who discontinue treatment, will be considered non-responders and 
will be censored. 
Time to first response will be compared between treatment groups using the Kaplan-Meier 
product limit method. 
Evaluating the efficacy of two doses of ITI-007 vs. placebo based on the primary and key 
secondary efficacy endpoints requires multiple comparisons defined by four hypotheses 
which are grouped into two families corresponding to the two endpoints: 
• Family 1 – Primary Efficacy Endpoint: 
• Let P1 represents the hypothesis associated with the primary efficacy endpoint for 60 
mg ITI-007 vs. Placebo; 
• Let P2 represents the hypothesis associated with the primary efficacy endpoint for 40 
mg ITI-007 vs. Placebo; 
• Family 2 – Key Secondary Efficacy Endpoint: 

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7.5.7 Analyses of Part B Secondary Endpoints - Effectiveness 
Secondary effectiveness objectives of Part B of this study are to determine whether 60 mg 
ITI-007, administered once daily for up to approximately 6 months to patients with bipolar 
disorder and who have responded to treatment with ITI-007, improves and/or maintains 
symptoms, function, and quality of life as measured by change from baseline on the 
following measures: 
• MADRS total score; 
• CGI BP-S; 
• Q-LES-Q-SF 

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Unless otherwise stated, analyses of Part B effectiveness endpoints will primarily consist of 
change from baseline summaries for the single treatment group of ITI-007 60 mg and will be 
conducted on the Safety Set.  
7.5.8 Safety Analyses (Parts A and B) 
All safety parameters will be summarized using the Safety Analysis Set.     
Medical history, prior medications, concomitant medications, and compliance/exposure will 
be summarized by treatment group using descriptive statistics.  Safety data such as reported 
and observed AEs, TEAEs, 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 visit (Part A and Part B) and 
treatment group (Part A).  Parameters planned to be collected more than once at pre-specified 
timepoints will be analyzed as an average of the measures for the relevant time point, 
including screening and baseline.   
Observed and reported AE terms will be coded using the latest version of MedDRA.  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 within 14 days after the last dose of study 
drug. Study-drug-related TEAEs will be defined as any AEs 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.  TEAEs, and 
SAEs will be listed summarized by SOC, PT, relationship to study drug, intensity (Part A and 
Part B) and treatment group (Part A).  Patients who discontinue study or study drug due to an 
AE will be listed and summarized by SOC and PT (Parts A and B) and by treatment group 
(Part A). 
Laboratory assessments, including hematology and chemistry, vital signs, and ECGs, will be 
listed and summarized by visit and time point (Parts A and B and by treatment group 
(Part A).  Summaries will include actual and change from baseline values, incidence of 
abnormal values according to normal range criteria, shifts from baseline to each visit and 

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time point according to markedly abnormal criteria, and listings of patients meeting markedly 
abnormal criteria. 
The observed and change from baseline in YMRS, AIMS, BARS, SAS and C-SSRS scores 
will be summarized by visits (Part A and B) and by treatment group (Part A). 
Additional details for analyses on safety parameters will be provided in the statistical 
analysis plan. 
 
 
 
 
 
 
 
 
 
   
7.5.10 Interim Analysis 
One IA is planned during Part A of the study, after 375 patients have completed the 6-week 
treatment period or confirmed to have discontinued treatment or study.  The IA will be 
conducted such that the ongoing study integrity is maintained, and the interim data will be 
reviewed by an independent external unblinded DMC. 
The IA will be used to review interim safety and efficacy data and reassess the assumptions 
on variability and effect size.  It may be used for a decision to terminate the study due to 
superior efficacy or to adjust the sample size.  Additional details regarding the statistical 
analysis methodology will be provided in the SAP. 

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7.6 Data 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. 
7.6.1 Data Management 
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 SCID-5-CT (Table 6–1), laboratory reports, and ECG strips.  
Investigative 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). 
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. 
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 

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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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8 Ethics 
8.1 Independent Ethics Committee or Institutional Review Board 
Federal regulations and the International Council for Harmonisation (ICH) guidelines require 
that approval be obtained from an IRB 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.  
Documentation of all IRB approvals and of the IRB 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 approvals should be signed by the IRB chairman or designee and must identify the 
IRB 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.  The 
investigator must promptly supply the sponsor or its designee, the IRB, and, where 
applicable, the institution, with written reports on any changes significantly affecting the 
conduct of the study or increasing the risk to patients. 
8.2 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. 
8.3 Patient Information and Consent 
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 investigative sites.  If any institution-specific 

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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 submission.  Once 
reviewed, the consent will be submitted by the investigator to his or her IRB 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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9 Investigator’s Obligations 
The following administrative items are meant to guide the investigator in the conduct of the 
study but may change based on industry and government standard operating procedures, 
working practice documents, or guidelines.  Changes will be reported to the IRB and will not 
result in protocol amendments. 
9.1 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 the IRB. 
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. 
9.2 Financial Disclosure and Obligations 
Investigators are required to provide financial disclosure information to allow the sponsor to 
submit the complete and accurate certification or disclosure statements required under 
21 CFR 54.  In addition, the investigator 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 following the completion of the study. 
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. 

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9.3 Investigator Documentation 
Prior to beginning the study, the investigator will be asked to comply with ICH E6(R1) 8.2 
and Title 21 of the CFR by providing the following essential documents, including but not 
limited to: 
• 
IRB 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-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 
9.4 Study Conduct 
The investigator agrees that the study will be conducted according to the principles of 
ICH E6(R1).  The investigator will conduct all aspects of this study in accordance with all 
national, state, and local laws or regulations.  Study information from this protocol will be 
posted on publicly available clinical trial registers before enrollment of patients begins. 

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9.5 Adherence to Protocol 
The investigator agrees to conduct the study as outlined in this protocol in accordance with 
ICH E6(R1) and all applicable guidelines and regulations. 
9.6 Adverse Events and Study Report Requirements 
By participating in this study, the investigator agrees to submit reports of SAEs according to 
the time line and method outlined in the protocol.  In addition, the investigator agrees to 
submit annual reports to the study site IRB, as appropriate. 
9.7 Investigator’s Final Report 
Upon completion of the study, the investigator, where applicable, should inform the 
institution; the investigator/institution should provide the IRB with a summary of the study’s 
outcome and the sponsor and regulatory authority(ies) with any required reports. 
9.8 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. 
9.9 Publications 
After completion of the study, the data may be considered for reporting at a scientific 
meeting or for publication in a scientific journal.  In these cases, the sponsor will be 
responsible for these activities and will work with the investigators to determine how the 
manuscript is written and edited, the number and order of authors, the publication to which it 
will be submitted, and other related issues.  The sponsor has final approval authority over all 
such issues. 

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Data are the property of the sponsor and cannot be published without prior authorization 
from the sponsor, but data and publication thereof will not be unduly withheld. 

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10  Study Management 
10.1 Monitoring 
10.1.1 External Data Monitoring Committee 
There will be an external DMC for this study which will review the unblinded interim 
efficacy and safety data. Additional details regarding the DMC will be provided in the SAP 
the DMC Charter.   
10.1.2 Monitoring of the Study 
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. 
10.1.3 Inspection of Records 
Investigators and institutions involved in the study will permit study-related monitoring, 
audits, IRB review, and regulatory inspections by providing direct access to all study records.  
In the event of an audit, the investigator agrees to allow the sponsor, representatives of the 
sponsor, or a regulatory agency (e.g., FDA or other regulatory agency) access to all study 
records. 
The investigator should promptly notify the sponsor and the CRO of any audits scheduled by 
any regulatory authorities and promptly forward copies of any audit reports received to the 
sponsor. 

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10.2 Management of Protocol Amendments and Deviations 
10.2.1 Modification of the Protocol 
Any changes in this research activity, except those necessary to remove an apparent, 
immediate hazard to the patient, must be reviewed and approved by the sponsor or its 
designee.  Amendments to the protocol must be submitted in writing to the investigator’s IRB 
for approval before patients can be enrolled into an amended protocol. 
10.2.2 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 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 for review and approval, to the sponsor for agreement, and to 
the regulatory authorities, if required. 
A deviation from the protocol is an unintended or unanticipated departure from the 
procedures or processes approved by the sponsor and the IRB 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 regulations or ICH 
GCP guidelines, and will lead to the patient being withdrawn from the study (Section 4.1.3). 
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 should be notified of all protocol deviations in a timely manner. 

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10.3 Study Termination 
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.  
The end of the study is defined as the date on which the last patient completes the last visit 
(includes follow-up visit).  
10.4 Final Report 
Whether the study is completed or prematurely terminated, the sponsor will ensure that the 
clinical study reports are prepared and provided to the regulatory agency(ies) as required by 
the applicable regulatory requirement(s).  The sponsor will also ensure that the clinical study 
reports in marketing applications meet the standards of the ICH harmonised tripartite 
guideline E3: Structure and content of clinical study reports. 
Upon completion of the clinical study report, the study results will be posted on publicly 
available clinical trial registers. 

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