Clinical trial NCT02600507
Conditions: Bipolar Depression
Sponsor: Intra-Cellular Therapies, Inc.
Start date: 2016-03-07; Completion date: 2020-07-02
Enrollment: 529 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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

Detailed description:

Arms: arm 1: Lumateperone 28 mg (ITI-007 40 mg tosylate) administered orally as capsules once daily for 6 weeks arm 2: Lumateperone 42 mg (ITI-007 60 mg tosylate) administered orally as capsules once daily for 6 weeks arm 3: Placebo administered orally as visually-matched capsules once daily for 6 weeks
Interventions: intervention 1: Lumateperone (ITI-007) intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
NCT02600507 
 
 
Study ID: ITI-007-402 
 
 
Title: A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multi-Center Study to Assess the 
Efficacy and Safety of ITI-007 Adjunctive to Lithium or Valproate in the Treatment of Patients With Major 
Depressive Episodes Associated With Bipolar I or II Disorder (Bipolar Depression) 
 
 
 
 
 
Protocol Amendment Version 1.5 Date: September 4, 2019 


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CLINICAL STUDY PROTOCOL 
ITI-007-402 
 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multi-Center 
Study to Assess the Efficacy and Safety of ITI-007 Adjunctive to Lithium 
or Valproate in the Treatment of Patients with Major Depressive Episodes 
Associated with Bipolar I or Bipolar II Disorder (Bipolar Depression) 
 
Confidential 


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Protocol: ITI-007-402 
 
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Version of Amended 
Protocol: 
Version 1.5 
Date of Amended Protocol: 
04 September 2019 
EudraCT No.: 
2018-002749-12 
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 to assess the efficacy and safety of 
ITI-007 adjunctive to lithium or valproate in the treatment of patients with major depressive 
episodes associated with bipolar I or bipolar II disorder (bipolar depression)” and the 
accompanying associated Investigator’s Brochure. 
I agree to supervise all aspects of the protocol and to conduct the clinical investigation in 
accordance with the Amended Protocol version 1.5, dated 04 September 2019, 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 (the Sponsor) 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 sub-investigator. 
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 the Sponsor. 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
Printed Name of Principal Investigator 
 
 
 
 


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Table of Contents 
Table of Contents .......................................................................................................................6 
List of Tables ............................................................................................................................10 
Protocol Synopsis..................................................................................................................... 11 
List of Abbreviations................................................................................................................29 
1 
Introduction ......................................................................................................................32 
2 
Study Objectives...............................................................................................................35 
2.1 
Primary Efficacy Objective .....................................................................................35 
2.2 
Key Secondary Efficacy Objective .........................................................................35 
 
 
2.4 
Safety Objectives ....................................................................................................36 
 
 
 
 
3 
Investigational Plan ..........................................................................................................38 
3.1 
Study Design ...........................................................................................................38 
3.1.1 
Rationale of Study Design .......................................................................39 
4 
Patient Selection and Withdrawal Criteria .......................................................................41 
4.1 
Selection of Study Population .................................................................................41 
4.1.1 
Inclusion Criteria .....................................................................................41 
4.1.2 
Exclusion Criteria ....................................................................................43 
4.2 
Withdrawal of Patients from the Study ...................................................................49 
4.2.1 
Reasons for Withdrawal/Discontinuation ................................................49 
4.2.2 
Handling of Patient Withdrawals or Patient Discontinuation of Study 
Intervention ..............................................................................................50 
4.2.3 
Replacements ...........................................................................................51 
5 
Study Treatments ..............................................................................................................52 
5.1 
Method of Assigning Patients to Treatment Groups ...............................................52 
5.2 
Treatments Administered ........................................................................................52 
 
 
5.4 
Management of Clinical Supplies ...........................................................................55 


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5.4.1 
Study Drug Packaging and Storage .........................................................55 
5.4.2 
Accountability Procedures for the Study Product....................................56 
5.5 
Overdose Management ...........................................................................................56 
5.5.1 
Treatment of Overdose ............................................................................56 
5.5.2 
Medication Errors ....................................................................................56 
5.5.3 
Treatment of Medication Errors ...............................................................57 
5.6 
Blinding...................................................................................................................57 
5.6.1 
Breaking the Blind ...................................................................................57 
5.7 
Treatment Compliance ............................................................................................57 
5.8 
Prior and Concomitant Therapy ..............................................................................58 
6 
Study Schedule .................................................................................................................60 
6.1 
Screening Assessments and Procedures ..................................................................64 
6.1.1 
Informed Consent ....................................................................................64 
6.1.2 
Medical History and Other Information ..................................................64 
6.1.3 
Modified Physical Examination...............................................................64 
6.1.4 
Electrocardiogram Assessments ..............................................................65 
6.1.5 
Vital Sign, Waist, Weight, and Height Measurements .............................65 
6.1.6 
Hepatitis Screening ..................................................................................66 
6.1.7 
HIV Screening .........................................................................................66 
6.1.8 
Urine Drug and Alcohol Screening ..........................................................66 
6.1.9 
Laboratory Assessments ..........................................................................66 
6.1.10 
Serum and Urine Pregnancy Tests ...........................................................66 
6.1.11 
Structured Clinical Interview ...................................................................67 
6.1.12 
Bipolarity Index .......................................................................................67 
6.1.13 
C-VISA ....................................................................................................68 
6.1.14 
Columbia Suicide Severity Rating Scale .................................................68 
6.1.15 
Young Mania Rating Scale ......................................................................69 
6.1.16 
Clinical Global Impression Scale of Bipolar Illness–Severity of Illness.69 
6.1.17 
Eligibility Adjudication............................................................................70 
6.2 
Efficacy Assessments and Procedures ....................................................................70 
6.2.1 
MADRS ...................................................................................................70 
6.2.2 
Clinical Global Impression of Bipolar Illness–Severity ..........................71 
6.2.3 
Sheehan Disability Scale .........................................................................71 


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6.2.4 
Quality of Life Enjoyment and Satisfaction Questionnaire – Short Form
 .................................................................................................................71 
6.2.5 
World Health Organization-5 Well-Being Index .....................................72 
6.2.6 
Neuroticism, Extraversion, and Openness to Experience-Five Factor 
Inventory ..................................................................................................72 
6.3 
Patient Placebo-Response Training.........................................................................72 
6.4 
Safety and Tolerability Assessments .......................................................................72 
6.4.1 
Adverse Events ........................................................................................73 
6.4.2 
Other Safety Assessments ........................................................................80 
6.5 
Safety Monitoring Committee ................................................................................83 
6.6 
 
 
 
 
 
 
 
 
 
6.8 
Pregnancy ................................................................................................................85 
7 
Statistical and Analytical Plan ..........................................................................................86 
7.1 
Analysis Endpoints .................................................................................................86 
7.1.1 
Primary Efficacy Endpoints .....................................................................86 
 
 
 
 
7.1.4 
Safety Endpoints ......................................................................................87 
 
 
 
 
7.2 
Sample Size Calculations ........................................................................................88 
7.3 
Analysis Sets ...........................................................................................................89 
7.4 
Description of Subgroups to be Analyzed ..............................................................90 
7.5 
Statistical Analysis Methodology ...........................................................................90 
7.5.1 
Patient Disposition, Analysis of Demographics and Other Baseline 
Characteristics ..........................................................................................91 
7.5.2 
Prior and Concomitant Medications ........................................................91 
7.5.3 
Study Medication Exposure and Treatment Compliance ........................92 
7.5.4 
Analysis of Primary Efficacy Endpoint ...................................................92 
7.5.5 
Analysis of Key Secondary Efficacy Endpoint .......................................94 


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7.5.6 
 
7.5.7 
 
7.5.8 
 
7.5.9 
 
7.6 
Estimand Framework ..............................................................................................97 
7.7 
Data Quality Assurance...........................................................................................97 
7.7.1 
Data Management ....................................................................................98 
8 
Ethics ................................................................................................................................99 
8.1 
Independent Ethics Committee or Institutional Review Board ..............................99 
8.2 
Ethical Conduct of the Study ..................................................................................99 
8.3 
Patient Information and Consent ............................................................................99 
9 
Investigator’s Obligations ..............................................................................................101 
9.1 
Confidentiality ......................................................................................................101 
9.2 
Financial Disclosure and Obligations ...................................................................101 
9.3 
Investigator Documentation ..................................................................................101 
9.4 
Study Conduct .......................................................................................................102 
9.5 
Adherence to Protocol...........................................................................................102 
9.6 
Adverse Events and Study Report Requirements .................................................103 
9.7 
Investigator’s Final Report ...................................................................................103 
9.8 
Records Retention .................................................................................................103 
9.9 
Publications ...........................................................................................................103 
10 Study Management .........................................................................................................104 
10.1 Monitoring ............................................................................................................104 
10.1.1 
External Data Monitoring Committee ...................................................104 
10.1.2 
Monitoring of the Study .........................................................................104 
10.1.3 
Inspection of Records ............................................................................104 
10.2 Management of Protocol Amendments and Deviations........................................104 
10.2.1 
Modification of the Protocol ..................................................................104 
10.2.2 
Protocol Deviations................................................................................105 
10.3 Premature Termination or Suspension of Study ...................................................105 
10.4 Halting Rules ........................................................................................................106 


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10.5 Final Report ..........................................................................................................106 
11 Reference List.................................................................................................................107 
List of Tables 
Table 5-1 
Study Medication and Dosing Schedule ......................................................... 53 
Table 5-2 
Tablet Composition ......................................................................................... 54 
Table 5-3  
Weekly Treatment Cards ................................................................................. 55 
Table 5-4 
Permitted Zolpidem and Lorazepam Use ....................................................... 59 
Table 6-1 
Schedule of Events .......................................................................................... 61 
Table 6-2 
Causality Categories ....................................................................................... 76 
Table 6-3 
Intensity Categories ........................................................................................ 77 
Table 6-4 
Number and Volume of Blood Samples .......................................................... 85 
 
 
 


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Protocol Synopsis 
Protocol Number: 
Title: 
Sponsor: 
Study Phase: 
Study Sites: 
Indication: 
Rationale: 
ITI-007-402 
A Phase 3, randomized, double-blind, placebo-controlled, 
multi-center study to assess the efficacy and safety of ITI-007 
adjunctive to lithium or valproate in the treatment of patients with 
major depressive episodes associated with bipolar I or bipolar II 
disorder (bipolar depression) 
Intra-Cellular Therapies, Inc. (ITI) 
Phase 3 
Approximately 93 study sites globally 
Major depressive episodes associated with bipolar I or bipolar II 
disorder (bipolar depression) 
Bipolar disorder is a serious psychiatric disorder associated with 
shifts in mood including manic or hypomanic episodes, depressed 
episodes, or mixed episodes. Every year bipolar disorder affects 
approximately 2.6% of the United States (US) population age 
18 years and older, according to the National Institute of Mental 
Health. Bipolar depression, the predominant presentation of bipolar 
disorder, remains a significantly underserved medical need, with 
only a few regulatory-approved treatment options available. 
Lithium and valproate have shown efficacy in treating the mania of 
bipolar disorder and are used as mood stabilizer monotherapy in 
first-line treatment for people with acute bipolar depression. 
However, monotherapy with mood stabilizers has been less 
effective in treating the depressive phase of the disease. Little 
evidence exists to guide adjunctive therapy of bipolar disorder, 
where drugs could be added to the mood stabilizers to treat the 
depressive symptoms of the disease. Antidepressants are commonly 
used as adjunctive therapy for patients with bipolar disorder, 
although concerns exist regarding their efficacy and their potential 
to induce manic switching or reduce cycle length. Hence, a 
significant need exists for an adjunctive agent that can be combined 
with mood stabilizers in patients with bipolar depression. 
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 
increases the phosphorylation of the NR2B, or GluN2B, subunit of 
N-methyl-D-aspartate channels in extrastriatal dopamine-rich brain


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regions (eg, nucleus accumbens), and indirectly modulates 
glutamatergic (NDMA and AMPA) activity downstream from 
dopamine 1 receptor activation. 
Evidence supports the use of D2 receptor antagonists in the 
treatment of bipolar disorder, including bipolar depression, 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-hydroxytryptomine 
2A (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. ITI-007’s 
indirect glutamatergic modulation in combination with serotonin 
reuptake inhibition predicts rapid-acting antidepressant response. 
Importantly, ITI-007 lacks potent off-target interactions that have 
been associated with side effects for other 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 histamine 1 (H1) or muscarinic cholinergic 
receptors, which predict favorable body weight and metabolic 
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 study. 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 (SERT) 
occupancy (average of 22%). Together, these data confirm a central 
mechanism for ITI-007 at dopaminergic and serotonergic brain 
targets. An additional PET study in patients with schizophrenia 
(ITI-007-008) demonstrated an average of approximately 40% 
striatal D2 receptor occupancy at 60 mg, at plasma steady state, 
lower than that observed with most antipsychotic drugs. Relatively 


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low striatal D2 receptor occupancy likely contributes to a relatively 
low liability for extrapyramidal side effects and hyperprolactinemia 
compared with most antipsychotic drugs. 
Clinical data from 3 well-controlled studies in patients with 
schizophrenia (ITI-007-005, ITI-007-301, and ITI-007-302) are 
consistent with respect to the pharmacological profile and 
prediction for antidepressant effects with favorable safety and 
tolerability. In these 3 studies, ITI-007 has been safely administered 
once daily for up to 42 days at doses ranging from 20 to 140 mg. 
Furthermore, the ITI-007 60 mg dose had a similar trajectory and 
magnitude of improvement in psychosis as demonstrated a 
reduction from baseline in the Positive and Negative Syndrome 
Scale (PANSS) total score in all 3 studies, which was statistically 
significant at Day 28 compared with placebo in 2 of these studies 
(ITI-007-005 and ITI-007-301). In addition to improving psychotic 
symptoms, ITI-007 also improved symptoms of depression in 
patients with schizophrenia and comorbid depression at baseline. 
Safety data from these and other trials with ITI-007 have shown 
that ITI-007, which has been administered to more than 1500 
individuals, is well tolerated across a dose range from 1 to 140 mg 
and administered once daily for up to 42 days with a safety profile 
similar to placebo. These clinical data together with the nonclinical 
data and the pharmacological profile support the development of 
ITI-007 for the treatment of bipolar depression. 
Objectives: 
Primary Objective 
The primary objective of this study is to compare the efficacy of 2 
doses of ITI-007 adjunctive to treatment with lithium or valproate, 
administered orally once daily, to that of placebo adjunctive to 
treatment with lithium or valproate as measured by mean change 
from baseline to Day 43 in the total score of the rater-administered 
Montgomery-Åsberg Depression Rating Scale (MADRS) in 
patients with bipolar depression. 
 
Key Secondary Efficacy Objective 
The key secondary efficacy objective of this study is to compare the 
efficacy of 2 doses of ITI-007 adjunctive to treatment with lithium 
or valproate, administered orally once daily to that of placebo 
adjunctive to lithium or valproate as measured by mean change 
from baseline to Day 43 in the Clinical Global Impression Scale-
Bipolar Version-Severity (CGI-BP-S)-Depression score in patients 
with bipolar depression. 






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Patient Population 
Patient Inclusion Criteria 
Each patient must meet all of the following criteria to be enrolled in 
this study: 
1. Is capable of understanding the written informed consent, 
provides signed and witnessed written informed consent, and 
agrees to comply with protocol requirements; 
2. Is between the ages of 18 and 75 years, inclusive, at the start of 
screening (both male and female patients are to be included); 
3. Meets the Diagnostic and Statistical Manual of Mental Disorder, 
5th Edition (DSM-5) criteria for Bipolar I or Bipolar II Disorder 
as confirmed by the Investigator or Sponsor-approved expert 
site-based rater by a Structured Clinical Interview for DSM-5 
Disorders–Clinical Trials Version (SCID-5-CT) (US sites only) 
or by the Mini International Neuropsychiatric Interview (MINI; 
non-US sites only) and meeting all of the following 6 criteria: 
a. The start of the current major depressive episode (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 CGI-BP-S-Depression score and CGI-BP-S 
Overall score each ≥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; 
f. A minimum of 28 days of treatment with either lithium (and 0.4 
to 1.5 mEq/L blood level at screening) or valproate (minimum 
25 µg/mL blood level at screening) and inadequate therapeutic 
response of depressive symptoms (confirmed by the treating 
health care provider or other reliable source).  A re-test of 


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lithium or valproate levels is not permitted; any patient who 
does not meet either of the two requirements must be screen-
failed. 
4. Has a body mass index (BMI) of 18 to 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% 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. 
 
Patient Exclusion Criteria 
Patients meeting any of the following criteria will be excluded from 
the study: 
1. The patient experiences a decrease in the rater-administered 
MADRS total score of ≥25% between screening and baseline 
visits. 
2. In the opinion of the Investigator, the patient has a significant 
risk for suicidal behavior during the course of his or her 
participation in the study or 
a. At screening, the patient scores “yes” on Items 4 or 5 in the 
Suicidal Ideation section of the C-SSRS with reference to a 6-
month period prior to screening; or 
b. At screening, the patient has had 1 or more suicidal attempts 
with reference to a 2-year period prior to screening; or 
c. At the baseline visit, the patient scores “yes” on Items 4 or 5 in 
the Suicidal Ideation section of the C-SSRS with reference to 
screening; or 
d. At screening or the baseline visit, scores ≥4 on Item 10 (suicidal 
thoughts) on the rater-administered MADRS; or 


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e. Considered to be an imminent danger to himself, herself, or 
others. 
3. The patient is pregnant or breast-feeding. Female patients of 
childbearing potential must have negative serum and urine 
pregnancy tests at Screening. On Day 1, female patients of 
childbearing potential must have a negative urine pregnancy 
test 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 (US sites only) or by the Mini International 
Neuropsychiatric Interview (MINI; non-US sites only), 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. Eating disorder; 
d. Primary diagnosis of obsessive-compulsive disorder; 
e. Moderate or severe substance use disorder (including for 
cannabis, excluding for nicotine); 
f. 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 Criterion 4. The presence of 
these symptoms should be reviewed with the Medical Monitor 
and adjudication team on a case-by-case basis prior to 
inclusion; 
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. 


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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; 
8. The patient is considered a rapid cycler, as 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 Food and Drug Administration (FDA)-
approved medications for bipolar depression (lurasidone, 
quetiapine, or Symbyax, depending on the region) at an 
adequate dose (per regulatory-approved label) for an adequate 
duration (at least 6 weeks); 
10. The patient is currently receiving formal cognitive or 
behavioral therapy, systematic psychotherapy, or plans to 
initiate such therapy during the study; 
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, 
(meth) amphetamines, alcohol, barbiturates, or hallucinogens 
or similar compounds; 
Note: Previous occasional use of alcohol or cannabis (but not 
synthetic marijuana/K2/Spice) or prescribed psychotropic (eg, 
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 


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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 one of the following agents under the 
specified conditions: 
a. Lifetime exposure to ITI-007 (ie, for US sites only, 
participation 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 short-acting anxiolytic medications within 1 week 
of the baseline visit or of long-acting anxiolytics within 5 half-
lives of the baseline visit; 
d. Drugs with known psychotropic properties or any non-
psychotropic drugs with known or potentially significant 
central nervous system effects within the last 28 days or 5 half-
lives before the baseline visit, whichever is less, as reviewed by 
the Medical Monitor, including, but not limited to: 
i. Sedative hypnotics (with the exception of zolpidem, 
zolpidem CR, or lorazepam as needed, no more than 3 times 
per week, allowed during the screening period and the first 
2 weeks of the treatment period). Note: If zolpidem, zolpidem 
CR, or lorazepam are not available in specific regions, 
another sedative hypnotic or benzodiazepine may be 
approved by the Medical Monitor. Medications may not be 
used in combination to treat insomnia. 
ii. Central opioid agonists/antagonists including tramadol 
(Ultram); 
iii. Anticonvulsants except valproate; 
iv. Mood stabilizers except lithium or valproate, antipsychotics, 
antidepressants; 
v. Methotrexate; 


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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 and medical foods are excluded unless 
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 × upper limit of 
normal (ULN); 
b. Alanine aminotransferase (ALT) >2.0 × ULN; 
c. Alkaline phosphatase >2.0 × ULN; 
d. Gamma-glutamyl transpeptidase >2.0 × ULN  
e. Total bilirubin >1.5 × ULN; 
f. Serum creatinine >1.5 × ULN; 
g. Blood urea nitrogen >1.5 × ULN; 
h. Thyroid-stimulating hormone (TSH) outside of the normal 
limits and clinically significant, as determined by the 
investigator. Free thyroxine levels may be measured if TSH 
level is abnormal. The patient will be excluded if the free 
thyroxine level is clinically significant; 
i. Any other clinically significant abnormal laboratory result at 
the time of the screening examination; 
j. 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 for males and females and/or heart 
rate ≤50 beats per minute, or evidence of clinically 
significant bundle-branch block. If a patient meets the QTcF 
and/or heart rate exclusion criteria during the screening 


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period, repeat ECG testing will not be permitted. 
Note: If it is the opinion of the Investigator that a lower 
heart rate is physiological in a well-fit subject or due to 
stable concomitant medications, this will be reviewed and 
approved by the Medical Monitor on a case by case basis. 
Note: Medical conditions that are stable with medication (eg, 
hypertension, high cholesterol, and hyperthyroidism) are 
allowed as long as the condition has been stable for at least 
3 months prior to screening, the medications are documented 
and kept stable during the study, and the condition is not 
thought to affect safe participation in the study in the opinion of 
the Investigator and confirmed by the Medical Monitor as part 
of the screening adjudication process. 
15. The patient has clinically significant cardiovascular (including 
but not limited to uncontrolled angina, or history of a 
myocardial infarction within 3 months prior to screening, or 
history of a clinically significant cardiac arrhythmia including 
antipsychotic drug-induced corrected QT interval 
prolongation), endocrine (including poorly controlled diabetes 
defined as glycated hemoglobin A1c [HbA1c] >53 mmol/mol 
[7.0%] at screening with no re-test allowed for HbA1c), hepatic, 
renal, pulmonary, gastrointestinal, neurological, malignancy 
(including any malignancy and/or chemotherapy within the 2 
years prior to screening; malignancy more than 2 years prior to 
screening must have been local and without metastasis and/or 
recurrence, and if treated with chemotherapy, without nervous 
system complications; some malignancies, such as basal cell 
carcinoma, may not preclude participation and will be 
individually reviewed), pheochromocytoma, metabolic, 
psychiatric or other condition that might be detrimental to the 
patient if he or she participates in the study (in the opinion of 
the Investigator); 
16. The patient has a history of human immunodeficiency virus 
(HIV) infection or has HIV antibodies in blood at screening; 
17. The patient has a history of hepatitis B or hepatitis C infection 
(or is tested positive for hepatitis B surface antigen or hepatitis 
C antibodies) AND at screening has evidence of active disease 
defined as elevated ALT, AST, or bilirubin levels as specified in 
Exclusion Criterion 14; 
18. The patient is an employee of the Investigator or study site, or 
immediate family (ie, spouse, parent, child, or sibling, whether 






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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 along with their 
concomitant dose of lithium or valproate. 
Statistical Methods 
Sample Size: 
Approximately 520 patients will be randomly assigned in a 1:1:1 
ratio to 1 of the 3 treatment arms (ITI-007 40 mg, ITI-007 60 mg, 
and placebo). Assuming a common drop-out rate of 15% and a 
common correlation of 0.7, the sample size of 173 patients per 
treatment group will provide approximately 90% statistical power 
for the effect size of 0.4 for the primary efficacy endpoint in the 
ITI-007 60 mg treatment group. .  
Analysis Sets: 
The All Patients Enrolled (ENR) Set will contain all patients who 
signed the informed consent for this study. 
The All Patients Randomized (RND) Set will contain all patients 
who signed the informed consent and were randomized to study 
medication. 
The Intent-to Treat (ITT) Set will contain all randomly assigned 
patients who received at least 1 dose of study medication and who 
had a valid baseline (pre-dose) measurement and at least 1 valid 
post-baseline measurement of MADRS. 
The Sensitivity Set will contain all randomly assigned patients who 
received at least 1 dose of study medication and who had a valid 
baseline (pre-dose) measurement MADRS total score. 
The Safety Set will be used for analysis of safety endpoints. The 
Safety Set will contain all patients who took at least 1 dose of study 
medication. All analyses using the Safety Set will classify patients 
according to treatment actually received. 
The PK Set will contain all patients who received study medication, 
had a valid baseline (pre-dose) measurement, had at least 1 valid 
post-baseline measurement of MADRS, and had at least 1 PK 
sample collected and analyzed. 
 
Patient Disposition, Demographics, and Other Baseline Data 
Patient disposition will be summarized by treatment group, when 
applicable, and overall, and by study visit when applicable, 
including incidence of screening failure and incidence of treatment 
or study discontinuation and the corresponding reasons. Time to 
treatment discontinuation due to all reasons, AEs (all, AEs 
associated with worsening of bipolar depression, and AEs not 


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associated with worsening of bipolar depression), lack of efficacy, 
or due to any other reason of special interest will be evaluated using 
the Kaplan-Meier method. The Log-rank test will be used to 
compare the time to discontinuation between each treatment group 
and the placebo group. 
Demographic and baseline characteristics, including bipolar 
disorder diagnosis and baseline efficacy measures, will be listed 
and summarized by treatment group and overall using descriptive 
statistics. 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 
and treatment group using frequencies and percentages.  
Additionally, the number and percent of patients receiving 
concomitant medications of special interest, such as lithium, 
valproate, zolpidem, zolpidem CR, or lorazepam, 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 with ITI-007 
 
Study Medication Exposure and Treatment Compliance 
Exposure to study medication and treatment compliance will be 
presented for the Safety Analysis and ITT Sets. Duration of 
exposure (days) and dosing compliance (%) will be calculated and 
summarized by treatment group. In addition, the number and 
percentage of patients exposed to study medication will be 
presented by planned study week. 
 
Analysis of the Primary Efficacy Endpoint 
The treatment effect on the primary efficacy endpoint will be 
evaluated using a mixed-effect 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 group, site (or 
pooled site), and the stratification variables (first-line treatment 
[lithium or valproate] and Bipolar Disorder type at Screening [I or 
II]), and the interaction term for treatment group-by-visit as fixed 
effects, the baseline MADRS total score and the interaction term of 
baseline MADRS-by-visit as covariates. An unstructured 
covariance matrix will be used to model the covariance of within-
patient scores. The Kenward-Roger approximation (Kenward and 






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List of Abbreviations 
Abbreviation 
Definition 
5-HT2A 
5-hydroxytryptomine 2A (receptor) 
AE 
adverse event 
AIMS 
Abnormal Involuntary Movement Scale 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AR 
autoregressive 
ARH 
heterogeneous autoregressive 
AST 
aspartate aminotransferase 
BARS 
Barnes Akathisia Rating Scale 
BMI 
body mass index 
BPI 
Bipolarity Index 
CFR 
Code of Federal Regulations 
CGI-BP-S 
Clinical Global Impression Scale of Bipolar Illness – Severity of Illness 
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 
FA0(q) 
No Diagonal Factor Analytic 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
H1 
histamine 1 (receptor) 
HbA1c 
glycated hemoglobin A1c 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 


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IEC 
IRB 
Independent Ethics Committee 
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 
LSM 
least-squares mean 
MADRS 
Montgomery-Åsberg Depression Rating Scale  
MDE 
major depressive episode 
MedDRA 
Medical Dictionary for Regulatory Activities 
MINI 
Mini International Neuropsychiatric Interview 
MMRM 
Mixed-effect model repeated measures  
NEO-FFI 
Neuroticism, Extraversion, and Openness to Experience-Five Factor 
Inventory 
PET 
positron emission tomography 
PK 
pharmacokinetic 
PP 
per-protocol 
Q-LES-Q-SF 
Quality of Life Enjoyment and Satisfaction Questionnaire – Short Form 
QTcB 
corrected QT interval using the Bazett formula 
QTcF 
corrected QT interval using the Fridericia formula 
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 
SIGMA 
Structured Interview Guide for the MADRS 
TEAE 
treatment-emergent adverse event  
TOEP 
Toeplitz structure 
TOEPH 
heterogeneous Toeplitz structure 
ULN 
upper limit of normal 


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US 
United States 
WHO-5 
World Health Organization-5 Well-being Index 
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 (MDEs). Bipolar 
disorder affects approximately 5.7 million adult Americans, or about 2.6% of the United 
States (US) population aged 18 years and older, every year according to the National Institute 
of Mental Health, with a similar prevalence worldwide. 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 
regulatory-approved treatment options available. 
Lithium and valproate have shown efficacy in treating the mania of bipolar disorder and are 
used as mood stabilizer monotherapy in first-line treatment for people with acute bipolar 
depression. However, monotherapy with mood stabilizers has been less effective in treating 
the depressive phase of the disease (Van Lieshout, 2010). Little evidence exists to guide 
adjunctive therapy of bipolar disorder, where drugs could be added to the mood stabilizers to 
treat the depressive symptoms of the disease (Loebel, 2014a). Antidepressants are commonly 
used as adjunctive therapy for patients with bipolar disorder, although concerns exist 
regarding their efficacy and potential to induce manic switching or reduce cycle length 
(Sidor, 2011; Vázquez, 2013). Hence, a significant need exists for an adjunctive agent that 
can be combined with mood stabilizers in patients with bipolar depression (Loebel, 2014a). 
Intra-Cellular Therapies (ITI), the Sponsor, is developing ITI-007, a new chemical entity, for 
the treatment of patients with MDEs associated with bipolar I or bipolar II disorder (bipolar 
depression) and for the treatment of agitation associated with dementia, including 
Alzheimer’s disease. ITI-007 is currently in Phase 3 clinical development in the US for the 
treatment of schizophrenia. 
ITI-007 is a novel small molecule therapeutic agent designed specifically to combine 
serotonergic, dopaminergic, and glutamatergic modulation in a dose-dependent manner. 
ITI-007 is a potent serotonin 5-hydroxytryptomine 2A (5-HT2A) receptor antagonist with 
mesolimbic/mesocortical selective modulation of phosphoprotein pathways downstream of 
dopamine receptors, serotonin reuptake inhibition, and indirect glutamatergic modulation 


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(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 D2 receptors in vivo, with mesolimbic/mesocortical selectivity. ITI-007 also 
increases the phosphorylation of the NR2B, or GluN2B, subunit of N-methyl-D-aspartate 
channels in extrastriatal dopamine-rich brain regions (eg, nucleus accumbens), and indirectly 
modulates glutamatergic (NDMA and AMPA) activity downstream from dopamine 1 receptor 
activation. 
Evidence supports the use of D2 receptor antagonists in the treatment of bipolar disorder, 
including bipolar depression (Young, 2013; Loebel, 2014a; Loebel, 2014b), as both 
monotherapy and adjunctive therapy to mood stabilizers. The pharmacologic profile of 
ITI-007 includes both the post-synaptic D2 antagonism that appears efficacious in bipolar 
disorder and other pharmacological properties that may confer better safety 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. ITI-007’s indirect glutamatergic modulation in combination 
with serotonin reuptake inhibition predicts rapid-acting antidepressant response. Importantly, 
ITI-007 lacks potent off-target interactions that have been associated with side effects for 
other 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 histamine 1 
(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 Investigator’s Brochure 
(June 2018). 
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. 


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Brain receptor target engagement was confirmed in healthy male volunteers in the 
ITI-007-003 positron emission tomography (PET) Phase 1 clinical study (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. An 
additional PET study in patients with schizophrenia (ITI-007-008) demonstrated an average 
of approximately 40% striatal D2 receptor occupancy at 60 mg, at plasma steady state, lower 
than that observed with most antipsychotic drugs. Relatively low striatal D2 receptor 
occupancy likely contributes to a relatively low liability for extrapyramidal side effects and 
hyperprolactinemia compared with most antipsychotic drugs. 
Clinical data from 3 well-controlled studies in patients with schizophrenia (ITI-007-005, 
ITI-007-301, and ITI-007-302) are consistent with respect to the pharmacological profile and 
prediction for antidepressant effects with favorable safety and tolerability. In these 3 studies, 
ITI-007 has been safely administered once daily for up to 42 days at doses ranging from 20 
to 140 mg. Furthermore, the ITI-007 60 mg dose had a similar trajectory and magnitude of 
improvement in psychosis as demonstrated a reduction from baseline in the Positive and 
Negative Syndrome Scale (PANSS) Total Score in all 3 studies, which was statistically 
significant at Day 28 compared with placebo in 2 of these studies (ITI-007-005 and 
ITI-007-301). In addition to improving psychotic symptoms, ITI-007 also improved 
symptoms of depression in patients with schizophrenia and comorbid depression at baseline. 
Safety data from these and other trials with ITI-007 have shown that ITI-007, which has been 
administered to more than 1500 individuals, is well tolerated across a dose range from 1 to 
140 mg and administered once daily for up to 42 days with a safety profile similar to placebo. 
These clinical data together with the nonclinical data and the pharmacological profile support 
the development of ITI-007 for the treatment of bipolar depression. Details on the profile of 
ITI-007 can be found in the ITI-007 Investigator’s Brochure. 


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2 Study Objectives 
 Primary Efficacy Objective 
The primary objective of this study is to compare the efficacy of 2 doses of ITI-007 
adjunctive to treatment with lithium or valproate, administered orally once daily, to that of 
placebo adjunctive to treatment with lithium or valproate as measured by mean change from 
baseline to Day 43 in the total score on the rater-administered Montgomery-Åsberg 
Depression Rating Scale (MADRS) in patients with bipolar depression. 
 Key Secondary Efficacy Objective 
The key secondary efficacy objective of this study is to compare the efficacy of 2 doses of 
ITI-007 adjunctive to treatment with lithium or valproate, administered orally once daily to 
that of placebo adjunctive to lithium or valproate as measured by mean change from baseline 
to Day 43 in the Clinical Global Impression Scale-Bipolar Version-Severity (CGI-BP-S)-
Depression score in patients with bipolar depression. 


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 Safety Objectives 
The safety objectives of this study are to determine the safety and tolerability of 2 doses of 
ITI-007 adjunctive to treatment with lithium or valproate via: 
• Incidence of adverse events (AEs); 
• Physical examination and neurological findings; 
As well as change from baseline in the following safety assessments: 
• Young Mania Rating Scale (YMRS); 


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• 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. 


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3 Investigational Plan 
 Study Design 
This is a Phase 3, randomized, double-blind, parallel-group, placebo-controlled study 
comparing the efficacy and safety of ITI-007 versus placebo administered orally once daily 
in patients with bipolar depression who have had inadequate response to their depression 
symptoms and are currently taking one of the mood stabilizers, lithium or valproate. 
The study consists of the following periods: screening period, on-treatment period, and safety 
follow-up period. 
Screening Period (2 Weeks) 
Eligible patients will be evaluated during a Screening Period up to 2 weeks in duration to 
ensure sufficient washout of prior and/or restricted medications. Extension of the Screening 
Period may be approved by the Sponsor or its representative on a case-by-case basis. 
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 
and must remain on-treatment with lithium or valproate for the duration of the study. 
 
 
 
 
At Baseline (Visit 2), patients who continue to meet all eligibility criteria, including 
therapeutic levels of lithium or valproate, will be randomly assigned to either adjunctive 
ITI-007 or placebo in 1 of the 3 treatment arms for a 6-week, double-blind treatment period. 
Patients will be randomly assigned to one of the following groups in combination with 
lithium or valproate: 40-mg ITI-007, 60-mg ITI-007, or matching placebo. The random 
assignment will be stratified for both the first-line treatment (with lithium or valproate) and 
diagnosis at screening (Bipolar I or Bipolar II Disorder). 


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Double-blind On-treatment Period (6 Weeks) 
Patients will take their first dose of study medication the evening of their baseline visit. A 
single dose will be taken each day in the evening for the duration of the on-treatment period. 
Following randomization, patients will attend the clinic at Days 8, 15, 22, 29, 36, and 43. 
The on-study treatment period will be a total of 6 weeks. 
Safety Follow-up Period (2 Weeks) 
A return to the clinic for a safety follow-up visit will occur at Week 8, approximately 2 weeks 
following the last dose of study medication. If possible, patients who withdraw prematurely 
will be seen for an early termination visit (within 1 week of early termination, when possible) 
and will be asked to return to the clinic for a safety follow-up visit 2 weeks following 
withdrawal. 
3.1.1 Rationale of Study Design  
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 either to ensure washout of excluded medication with long 
half-life (eg, fluoxetine), under the supervision of the Investigator before baseline or to 
ensure minimum exposure of at least 28 days to mood stabilizer (lithium or valproate) that is 
required to have been started by the patients of their own will, under standard of care, before 
the start of screening. 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. The stratified randomization 
will ensure that all treatment groups are balanced with regards to first-line treatment (lithium 
or valproate) and with regards to bipolar disorder diagnosis at study entry. 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. 
Two ITI-007 doses, as adjunctive therapy with the mood stabilizers, lithium or valproate, 
were selected to deliver full occupancy of the cortical 5-HT2A receptors (>85% occupancy) at 


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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 the present study, ITI-007 40 mg and ITI-007 60 mg, 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. 
The placebo control group is needed to establish the efficacy of a new compound. 
The treatment duration of 6 weeks has been chosen because this is considered an acceptable 
period to demonstrate efficacy in this patient population. 


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4 Patient Selection and Withdrawal Criteria 
 Selection of Study Population 
Approximately 520 patients (173 patients/arm) will be enrolled at approximately 93 study 
sites globally. Patients will be randomly assigned to study treatment only if they meet all of 
the inclusion criteria and none of the exclusion criteria. 
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. 
Appropriateness of patient eligibility will be adjudicated as described in Section 3.1. Once a 
final decision is made, no waivers for exceptions will be provided. 
4.1.1 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) (US sites only) or by the 
Mini International Neuropsychiatric Interview (MINI; non-US sites only) and meeting 
all of the following 6 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 
CGI-BP-S Depression and Overall scores each ≥4 at the Screening and 
Baseline Visits; 


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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; 
f. A minimum of 28 days of treatment with either lithium (and 0.4 to 
1.5 mEq/L blood level at screening) valproate (minimum 25 µg/mL blood 
level at screening) and inadequate therapeutic response of depressive 
symptoms (confirmed by the treating health care provider or other reliable 
source). A re-test of lithium or valproate levels is not permitted; any patient 
who does not meet either of the two requirements must be screen failed. 
4. Has a body mass index (BMI) of 18 to 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% 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 
nonchildbearing 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. 


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4.1.2 Exclusion Criteria 
Patients meeting any of the following criteria will be excluded from the study: 
1. The patient experiences a decrease in the rater-administered MADRS total score of 
≥ 25% between screening and baseline visits; 
2. In the opinion of the Investigator, the patient has a significant risk for suicidal 
behavior during the course of his or her participation in the study or  
a. At screening, the patient scores “yes” on Items 4 or 5 in the Suicidal Ideation 
section of the C-SSRS with reference to a 6-month period prior to screening; or  
b. At screening, the patient has had 1 or more suicidal attempts with reference to 
a 2-year period prior to screening; or  
c. At the baseline visit, the patient scores “yes” on Items 4 or 5 in the Suicidal 
Ideation section of the C-SSRS with reference to screening; or 
d. At screening or the baseline visit, scores ≥4 on Item 10 (suicidal thoughts) on 
the rater-administered MADRS; or 
e. Considered to be an imminent danger to himself, herself, or others. 
3. The patient is pregnant or breast-feeding. Female patients of childbearing potential 
must have negative serum and urine pregnancy tests at screening. On Day 1, female 
patients of childbearing potential must have a negative urine pregnancy test 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, (US sites only) or by the Mini International Neuropsychiatric 
Interview (MINI; non-US sites only), 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. Eating disorder; 


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d. Primary diagnosis of obsessive-compulsive disorder; 
e. Moderate or severe substance use disorder (including for cannabis, excluding 
for nicotine); 
f. 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 Criterion 4. The presence of these symptoms should 
be reviewed with the Medical Monitor and adjudication team on a case-by-case basis 
prior to inclusion; 
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 Food and Drug 
Administration (FDA)-approved medications for bipolar depression (lurasidone, 
quetiapine, or Symbyax, depending on the region) at an adequate dose (per regulatory-
approved label) for an adequate duration (at least 6 weeks); 


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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; 
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; 
Note: Previous occasional use of alcohol or cannabis (but not synthetic 
marijuana/K2/Spice) or prescribed psychotropic (eg, 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 one of the following agents under the specified conditions: 
a. Lifetime exposure to ITI-007 (ie, for US sites only, participation 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 short-acting anxiolytic medications within 1 week of the baseline 
visit or of long-acting anxiolytics within 5 half-lives of the baseline visit; 
d. Drugs with known psychotropic properties or any non-psychotropic drugs 
with known or potentially significant central nervous system effects within 
the last 28 days or 5 half-lives before the baseline visit, whichever is less, as 
reviewed by the Medical Monitor, including, but not limited to: 


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i. Sedative hypnotics (with the exception of zolpidem, zolpidem CR, or 
lorazepam as needed, no more than 3 times per week, allowed during 
the screening period and the first 2 weeks of the treatment period); 
Note: If zolpidem, zolpidem CR, or lorazepam are not available in 
specific regions, another sedative hypnotic or benzodiazepine may be 
approved by the Medical Monitor. Medications may not be used in 
combination to treat insomnia; 
ii. Central opioid agonists/antagonists including tramadol (Ultram); 
iii. Anticonvulsants except valproate; 
iv. Mood stabilizers except lithium or valproate, antipsychotics, 
antidepressants; 
v. Methotrexate; 
vi. Any known 5-HT2A receptor antagonist or inverse agonist including 
but not limited to mianserin, mirtazapine, nefazodone, cyproheptadine, 
pimavanserin, or fluvoxamine; 
vii. Immunosuppressants; 
viii. Dietary supplements and medical foods are excluded unless 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 the 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 × upper limit of normal (ULN); 
b. Alanine aminotransferase (ALT) >2.0 × ULN; 
c. Alkaline phosphatase >2.0 × ULN; 
d. Gamma-glutamyl transpeptidase >2.0 × ULN; 
e. Total bilirubin >1.5 × ULN; 
f. Serum creatinine >1.5 × ULN; 
g. Blood urea nitrogen >1.5 × ULN; 


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h. Thyroid-stimulating hormone (TSH) outside of the normal limits and 
clinically significant, as determined by the Investigator. Free thyroxine levels 
may be measured if TSH level is abnormal. The patient will be excluded if 
the free thyroxine level is clinically significant; 
i. Any other clinically significant abnormal laboratory result at the time of the 
screening examination; 
j. 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 for 
males or females and/or heart rate ≤50 beats per minute, or evidence of 
clinically significant bundle-branch blocks. If a patient meets the QTcF 
and/or heart rate exclusion criteria during the screening period, repeat ECG 
testing will not be permitted. 
Note: If it is the opinion of the Investigator that a lower heart rate is 
physiological in a well-fit subject or due to stable concomitant medications, 
this will be reviewed and approved by the Medical Monitor on a case-by-case 
basis. 
Note: medical conditions that are stable with medication (eg, 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. The patient has a history of hepatitis B or hepatitis C infection (or is tested positive for 
hepatitis B surface antigen or hepatitis C antibodies) AND at screening has evidence of 
active disease defined as elevated ALT, AST, or bilirubin levels as specified in 
Exclusion Criterion 14; 
18. The patient is an employee of the Investigator or study site, or immediate family (ie, 
spouse, parent, child, or sibling, whether biological or legally adopted) of such 
employees, the Investigator, the Sponsor, or contract research organizations (CROs) 
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) or unable to safely continue on current treatment with lithium or 
valproate; 
20. The patient is judged by the Investigator to be inappropriate for the study. 


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 Withdrawal of Patients from the Study 
The planned overall duration of the study for each patient is up to approximately 10 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. 
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; 
3. A serious or intolerable AE that, in the Investigator’s opinion, requires withdrawal 
from the study; 
4. Laboratory safety assessments that reveal clinically significant hematological or 
biochemical changes from baseline values, or baseline laboratory safety assessments 
that are returned after randomization but reveal clinically significant hematological or 
biochemical changes from screening; 
5. Symptoms or an intercurrent illness not consistent with the protocol requirements or 
that justify withdrawal; 
6. Lost to follow-up; 
7. Other (eg, pregnancy, development of contraindications of use of study medication); 
8.  The Investigator or Sponsor decides to discontinue the patient’s participation in the 
study; 


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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 Sponsor 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 Patient Withdrawals or Patient Discontinuation of 
Study Intervention 
Patients are free to withdraw from the study or study treatment at any time. Patient 
participation in the study may be stopped at any time at the discretion of the Investigator or at 
the request of the Sponsor. 
Patients who discontinue study treatment or active participation in the study will no longer 
receive study medication. When a patient withdraws from the study, the reason(s) for 
withdrawal shall be recorded by the Investigator on the relevant screen of the electronic case 
report form (eCRF). Whenever possible, all patients who discontinue study treatment or 
withdraw from the study prematurely will undergo all end-of-study assessments. Patients 
who fail to return for final assessments will be contacted by the study site (2 documented 
telephone calls followed by 1 registered letter) 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 
adverse event (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. 


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4.2.3 Replacements 
Patients who have been randomly assigned to study medication and prematurely discontinue 
from the study will not be replaced. 
A patient who fails to satisfy inclusion criteria and exhibits any of the exclusion criteria at 
screening may be rescreened with the permission of the Medical Monitor. Any patient who is 
rescreened within 28 days of an initial screen may have some screening procedures waived 
by the Medical Monitor on a case-by-case basis; any patient who is rescreened more than 
28 days following the previous screening (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 
 Method of Assigning Patients to Treatment Groups 
At Baseline (Visit 2), patients who continue to meet all eligibility criteria, including 
therapeutic levels of lithium or valproate, will be randomly assigned to one of the following 
groups in combination with lithium or valproate: 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 based on both treatment with 
either lithium or valproate and Bipolar I or Bipolar II diagnosis at screening. 
The dose of mood stabilizer will be adjusted to maintain a serum level in the range of 
0.4 to 1.5 mEq/L for lithium or minimum 25 µg/mL for valproate throughout the study as 
clinically appropriate per Investigator judgment. 
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 site personnel, confirming the 
patient data that were entered. The IVRS/IWRS notifications should be filed securely at the 
study site. 
 Treatments Administered 
Patients will be assigned to receive either ITI-007 (40- or 60-mg doses) or placebo in 
combination with their standard of care lithium or valproate. Study site personnel will receive 
a treatment card number from the IVRS/IWRS for each patient at each treatment dispensing 
clinic visit, to ensure that the correct investigational product is dispensed. Patients will self-
administer all doses orally, once daily, at home, in the evening for the duration of the on-


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treatment period. Treatment will be administered with or without food in the evening, and 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 along with their 
concomitant dose of lithium or valproate. 
 Identity of Investigational Product 
ITI-007 will be supplied as 20- and 60-mg over-encapsulated tablets (capsules) (see 
Table 5-1). 
 
 
 
Table 5-1 
Study Medication and Dosing Schedule 
 
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. 
Study Medication 
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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Placebo tablets are identical in appearance to ITI-007 and have the same excipient 
ingredients as ITI-007 but do not contain the active compound. 


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 Management of Clinical Supplies 
5.4.1 Study Drug Packaging and Storage 
ITI-007 and matching placebo will be prepared according to current Good Manufacturing 
Practice standards in carded blister strips and shipped under ambient conditions 
 
 Each treatment card will contain a sufficient quantity 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.  
Table 5-3  
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 1×8 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 medication must be stored in a secure area (eg, 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 to 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. Patients will be instructed to bring the weekly 
treatment card to the study site at the next visit to assess compliance. 


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5.4.2 Accountability Procedures for the Study Product 
The Investigator will maintain accurate records of receipt of all test articles, including dates 
of receipt. In addition, accurate records will be kept regarding when and how much test 
article is dispensed and used by each patient in the study. Reasons for departure from the 
expected dispensing regimen must also be recorded. At the completion of the study, to satisfy 
regulatory requirements regarding drug accountability, all study medication will be 
reconciled and retained or destroyed according to applicable regulations. 
 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 studies have evaluated ITI-007 in healthy volunteers with single doses up to 
and including 40 mg, multiple doses up to and including 20 mg administered once daily for 
5 days, and multiple doses up to and including 30 mg administered once daily for 7 days in 
healthy geriatric volunteers. Previous clinical studies 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 (not 
taking 2 capsules per dose, taking too many capsules per dose,), losing medication, or 
administration at the wrong time of day. Medication adherence will be emphasized at every 


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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. 
 Blinding 
The study will be performed in a double-blind manner. All study medication will be supplied 
in identical treatment cards and packaging, and will be similar in color, smell, taste, and 
appearance, thereby enabling double-blind conditions. 
5.6.1 Breaking the Blind 
A patient’s treatment assignment will not be broken until the end of the study unless medical 
treatment of the patient depends on knowing the study treatment the patient received. In the 
event that the blind needs to be broken because of a medical emergency, the Investigator may 
unblind an individual patient’s treatment allocation. As soon as possible, the Investigator 
should first contact the Medical Monitor to discuss the medical emergency and the reason for 
revealing the actual treatment received by that patient. The treatment assignment will be 
unblinded through IVRS/IWRS. Reasons for treatment unblinding must be clearly explained 
and justified in the eCRF. The date on which the code was broken together with the identity 
of the person responsible must also be documented. 
Any patients whose treatment assignment is unblinded will discontinue 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. 
 Treatment Compliance 
Patient compliance will be assessed by capsule counts of unused study medication at each 
visit during the double-blind treatment phase (Table 6-1). 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. 


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Any exceptions due to unusual circumstances should be discussed on a case-by-case basis 
with the Medical Monitor to determine whether a patient may continue despite apparent 
treatment compliance issues. 
Dispensing study treatment to be taken by patients in an outpatient study increases risk for 
medication errors. All errors in medication dispensing or administration must be carefully 
documented. These errors may include, but are not limited to, providing the wrong dose (not 
taking 1 capsule per dose or taking too many capsules per dose), losing medication, or 
administration at the wrong time of day. Medication adherence will be emphasized at every 
visit. Written instructions will be provided to the patients with the weekly medication card in 
order to minimize medication error. Additional adherence procedures may be implemented. 
 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, any short-acting anxiolytic, or any drugs with known psychotropic 
properties, or any non-psychotropic drugs with potential central nervous system effects. The 
only exceptions are zolpidem, zolpidem CR, and lorazepam, which may be taken no more 
than 3 times per week, allowed only during the Screening Period and taken within the first 2 
weeks of the Treatment Period (Section 4.1.2, Exclusion Criterion 13). Table 5-4 presents the 
permitted use of zolpidem, zolpidem CR, and lorazepam. If zolpidem, zolpidem CR, or 
lorazepam are not available in specific regions, another sedative hypnotic or benzodiazepine 
may be approved by the Medical Monitor.
Medications may not be used in combination to treat insomnia. If a patient is not able to 
discontinue use of zolpidem, zolpidem CR, or lorazepam (or equivalent) by the end of the 
first 2 weeks of the treatment period, the Investigator must contact the Sponsor or Sponsor’s 
representative to discuss the patient’s appropriateness to continue in the study. 
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Table 5-4 
Permitted Zolpidem and Lorazepam Use 
Concomitant 
Medication 
Dose 
Indication 
Study Period 
Allowance 
Assessment 
Restrictions 
Zolpidem  
Up to 10 mg/day 
(bedtime)  
Insomnia 
During screening 
and first 2 weeks 
of the treatment 
period 
Prohibited at 
least 8 hours 
prior to any 
psychiatric 
assessments 
Zolpidem CR 
Up to 12.5 mg/day 
(bedtime) 
Insomnia 
Lorazepam 
Up to 2mg/day 
Insomnia, 
agitation, anxiety 
Note: Zolpidem, zolpidem CR, and lorazepam should be used sparingly and for symptoms severe enough to 
require treatment as per the Investigator’s judgment. Prophylactic use is not allowed. If zolpidem, zolpidem CR, 
or lorazepam are not available regionally, then an alternative sedative hypnotic or benzodiazepine up to an 
equivalent maximum dose may be approved for use by the Medical Monitor. 
 
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 medication with longer half-life 
(eg, fluoxetine) under the supervision of the Investigator before baseline. 
Use of all concomitant medications, including lithium and valproate, 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 Schedule 
Before participating in any study procedures, all potential study patients must sign an 
informed consent form (ICF). Patients will have the opportunity to have any questions 
answered before signing the ICF. The Investigator must address all questions raised by the 
patient. The Investigator will also sign the ICF and a signed copy will be provided to the 
patient. 
The schedule of events for the study is presented in Table 6-1. Detailed instructions for the 
conduct of study assessments and procedures will be provided in the study reference manual. 
 


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 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 schedule of events in Table 6-1; assessments can be conducted on different days within 
the Screening Period. 
6.1.1 Informed Consent 
Before any study-related activities the patient must sign and date an ICF approved by the 
responsible institutional review board (IRB)/Independent Ethics Committee (IEC). The 
format and content of the ICF must have been agreed upon by the Investigator, the 
appropriate IRB/IEC, and the Sponsor. 
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. Note: Use of DupCheck applies to US patients only. 
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: appearance 
and skin; head and neck; eyes, ears, nose, and throat; chest and lungs; heart; abdomen; and 


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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 
Each ECG assessment will be a single 10-second epoch from 12-lead ECGs. 
Electrocardiogram parameters to be measured include heart rate and QRS, PR, QT, QTcB, 
QTcF, and RR intervals. 
The ECG recordings will be made on ECG machines supplied by a central ECG laboratory. 
Electrocardiogram data will be transferred to the central ECG laboratory on the same day as 
collected and interpretation will be provided to the study site within approximately 48 hours. 
If any 12-lead ECG recording shows an arrhythmia other than a sinus arrhythmia, sinus 
tachycardia, or sinus bradycardia, an additional 12-lead ECG will be recorded to confirm the 
original tracing. Any other clinically significant treatment-emergent cardiac conduction 
abnormalities will be followed until no longer deemed necessary by the Investigator. 
Central interpretations of ECG recordings obtained at screening will be the basis for 
determination that a patient is eligible for inclusion in the study. Similarly, central 
interpretations of ECG recordings at baseline and other visits will be included in the final 
study data. However, given that interpretations of recordings will not be available for up to 
48 hours, Investigators are to use machine generated parameters and clinical judgment to 
assess cardiac function for the purposes of immediate safety concerns.  
6.1.5 Vital Sign, Waist, Weight, and Height Measurements 
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 56). It is 
recommended that vital signs, waist circumference, and weight are always measured after 
conducting the ECGs, as applicable, and prior to any other assessments, including needle 
sticks for laboratory or PK samples scheduled for the same visit. Each patient’s BMI will be 
calculated before Day 1 to ensure that the patient meets the BMI inclusion criterion. 
Vitals sign measurements should also be collected, if feasible, at the time of an AE such as 
vertigo, dizziness, fall, or any sign or symptom that might indicate a fall in blood pressure. 


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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. Details regarding sample 
collection, processing, and shipping can be found in the study reference manual. 
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 
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, excluding prescription 
benzodiazepines, prescription opiates, and cannabinoids, or alcohol at screening will be 
excluded from participating in the study. 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 6.4.2.9. 
6.1.10 Serum and Urine Pregnancy Tests 
Female patients who are of childbearing potential will undergo serum and urine pregnancy 
tests at the study clinic at Screening, at the Baseline Visit (Day 1), and, at the discretion of 
the Investigator, at an Unscheduled Visit. Serum pregnancy testing will be performed using 
blood collected as part of protocol-specified sample; urine pregnancy testing will use a urine 
dipstick. 


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If the urine and serum pregnancy tests at screening are positive, the patient will not be 
eligible to participate in the study. If a urine pregnancy test is negative and the associated 
serum pregnancy test is positive, the patient will be discontinued from the study. Further 
details regarding sample collection and processing can be found in the study reference 
manual. 
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 either the SCID-5-CT, a semi-structured interview for making 
the major DSM-5 Axis I diagnosis (First, 2014) to be used by US sites only, or by the 
MINI 7.0.2 (08 August 2016 version) by Dr. David V. Sheehan (Sheehan et al, 1998), to be 
used by non-US sites. These assessments will be used in this study at screening only to 
confirm the diagnosis of bipolar depression in patients evaluated for inclusion in the study. 
The diagnostic assessment will be completed by the Investigator or an expert site-based rater 
approved by the Sponsor. 
6.1.12 Bipolarity Index  
The Bipolarity Index (BPI) was designed to provide a measure of quantitative measure of 
diagnostic confidence by mapping the known information about an individual patient on 5 
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 
BPI 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. The patient’s responses to the BPI and the BPI score generated by the BPI 
may be reviewed by an independent expert as a component of the systematic patient 
adjudication process. 
The BPI was developed by a group of bipolar disorder experts including Gary Sachs (Sachs, 
2004). The scoring system is divided into 5 dimensions including episode characteristics, age 
of onset (first affective episode), course of illness/associated features, response to treatment, 
and family history. Each dimension is given a score of 0 to 20 based on its correlation with 
bipolar disorder characteristics, and the scores are added to derive the BPI score. The 


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maximum score is 100. The score represents how close the patient is to having bipolar 
disorder. 
The BPI has been used to evaluate diagnostic confidence for patients entering global clinical 
studies. This assessment will be used by US sites only in conjunction with the SCID-5-CT. 
6.1.14 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. 
The C-SSRS will be administered by the Investigator or an expert site-based rater, as 
indicated in the schedule of events (Table 6-1). 
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. 


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6.1.15 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 
remaining 7 items rated on a 0 to 4 scale. The total score is appropriate both for assessing 
baseline severity of manic symptoms and for assessing treatment-emergent manic symptoms 
in patients with Bipolar I or Bipolar II Disorder with depression. It will be completed by the 
Investigator or an expert site-based rater. 
Note: Computer-based assessments will be utilized at sites that initiated under Version 1.3 of 
this protocol or prior versions. Assessments completed at sites initiated with Version 1.4 and 
any future versions of the protocol will be paper-based. 
At each visit with a YMRS assessment, the rater-administered YMRS interviews will be 
audio recorded (this applies to computer-administered assessment only); at each visit after 
the screening visit, a computer-administered interview will also be completed by patients. 
Where computer-administered assessments are not being used, the assessment completed by 
the patient will be paper-based. 
6.1.16 Clinical Global Impression Scale of Bipolar Illness–Severity of 
Illness 
The Clinical Global Impressions Scale has been modified specifically for use in assessing 
global illness severity and change in patients with bipolar disorder (CGI-BP-S) (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 by the 
Investigator or another Sponsor-approved expert site-based rater. The Depression score is 
based on the clinician’s assessment of depression symptom severity; the Mania score is based 
on the clinician’s assessment of mania symptom severity; and the Overall score is based on 
the clinician’s overall impression of illness severity.  


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 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 Sponsor-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. The MADRS is 
administered using a structured interview to ensure reliability and completeness. The format 
of the interview varies by region based on use of either Structured Interview Guide for the 
MADRS (SIGMA; when paper forms are used) or a similar interview structure when 
electronic tablets are used for scoring. 
Note: Computer-based assessments will be utilized at sites that initiated under Version 1.3 of 
this protocol or prior versions. Assessments completed at sites initiated with Version 1.4 and 
any future versions of the protocol will be paper-based. 
Remission of depression based on the MADRS is generally defined as a patient with a 
MADRS total score of ≤12 at endpoint. A response based 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. 
At each visit with a MADRS assessment, the rater-administered MADRS interview will be 
audio recorded (note: audio-recording applies to computer-based assessments only). At each 


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visit after screening, 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. Where paper scales are used, the SIGMA 
will be used to collect data for scoring MADRS. 
6.2.2 Clinical Global Impression of Bipolar Illness–Severity 
The CGI-BP-S, described in Section 6.1.16, will be a clinical efficacy assessment by the 
Investigator of each patient’s severity of illness. The Clinical Global Impression Scale is a 
widely accepted measure of illness severity in a variety of psychiatric disorders. The CGI-
BP-S will be assessed at Baseline/Visit 2, Visits 3-8, and Visit 9/ET. Details related to the 
statistical analysis of the CGI-BP-S scores are provided in Sections 7.5.5 and 7.5.6. 
6.2.3 Sheehan Disability Scale 
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. Note: This scale is to be administered to US 
patients only. 
6.2.4 Quality of Life Enjoyment and Satisfaction Questionnaire – Short 
Form 
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. here are an additional 2 stand-alone items (1 for medication 


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satisfaction and the other for overall life satisfaction). The total raw score is converted to a 
percent score. 
6.2.5 World Health Organization-5 Well-Being Index  
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 studies (Topp, 2015). 
Note: This scale is to be administered to US patients only. 
6.2.6 Neuroticism, Extraversion, and Openness to Experience-Five Factor 
Inventory 
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 5 dimensions of personality: neuroticism (N), extraversion 
(E), conscientiousness (C), openness (O), and agreeableness (A). Note: This scale is to be 
administered to US patients only. 
 Patient Placebo-Response Training 
A brief training explaining the use of placebo in this study will be provided to all patients at 
Baseline (Visit 2). In addition, site staff will receive a brief training defining the placebo 
response in clinical drug trials. Completion of placebo-response training will be documented 
for both patient and site staff. 
 Safety and Tolerability Assessments 
All patients who receive study medication 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 and neurological 
examinations. 


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6.4.1 Adverse Events 
The Investigator is responsible for reporting all AEs that are observed or reported during the 
study, regardless of their relationship to study medication or their clinical significance. 
6.4.1.1 Definition of Adverse Event 
An AE is any untoward medical occurrence in a study patient administered a study 
medication, 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 medication, without any judgment of causality. 
The AE may be: 
• A new illness; 
• A worsening sign or symptom of the condition under treatment, or of a concomitant 
illness; 
• An effect of the study medication, including comparator; or 
• A combination of 2 or more of these factors. 
No causal relationship with the study medication or with the clinical study itself is implied by 
the use of the term AE. 
Surgical procedures themselves are not AEs; they are therapeutic measures for conditions 
that require surgery. The condition for which the surgery is required may be an AE. Planned 
surgical measures, if permitted by the clinical study protocol and the conditions leading to 
those measures are not AEs. 
All AEs fall into the categories of “nonserious” or “serious” (Sections 6.4.1.2 and 6.4.1.3). 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (eg, 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. 


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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. 
6.4.1.2 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 Investigator believes that any event is serious, the event must be 
considered and evaluated by the Sponsor for possible expedited reporting. 
Clarification of the difference between "serious" and "severe": 
The term “severe” is often used to describe the intensity (severity) of a specific event (as in 
mild, moderate, or severe myocardial infarction); the event itself, however, may be of 
relatively minor medical significance (such as a severe headache). This is not the same as 


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“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. 
6.4.1.3 Nonserious Adverse Event 
A nonserious AE is any AE not meeting the SAE criteria.  
6.4.1.4 Definition of Relationship to Study Medication 
By definition, any AE that starts before the first dose of study medication administration is 
considered to be “unrelated.” 
The Investigator will assess the causality/relationship between the study medication and the 
AE (Table 6-2). 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 6-2 
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 (eg, concomitant disease, environmental factors, or 
other drugs or chemicals). 
1 Dechallenge is when a drug suspected of causing an adverse event (AE) is discontinued. If the symptoms of 
the AE disappear partially or completely, within a reasonable time from drug discontinuation, this is termed a 
positive dechallenge. If the symptoms continue despite withdrawal of the drug, this is termed a negative 
dechallenge. Note that there are exceptions when an AE does not disappear upon discontinuation of the drug, 
yet drug-relatedness clearly exists (eg, bone marrow suppression, fixed drug eruptions, tardive dyskinesia). 


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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. 
6.4.1.5 Definition of Intensity 
The Investigator will assess all AEs for intensity (severity) in accordance with the following 
standard ratings (Table 6-3): 
Table 6-3 
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.  
6.4.1.6 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. 


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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. 
6.4.1.7 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, ie, 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 medication 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). 
6.4.1.8 Notification About Serious or Unexpected Adverse Events 
The Investigator will review each SAE (Section 6.4.1.2) and evaluate the intensity and the 
causal relationship of the event to study medication. 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 medication or not, that a patient experiences during 
their participation in study within 24 hours of becoming aware of the event. 


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As a minimum requirement, the initial notification should provide the following information: 
• Study number; 
• Patient number; 
• Gender; 
• Date of birth; 
• Name of Investigator and full study site address; 
• Details of SAE; 
• Criterion for classification as “serious”; 
• Study medication code, or name if unblinded, and treatment start date and stop date, 
if applicable; 
• Date of SAE onset; 
• Causality assessment (if sufficient information is available to make this 
classification). 
The Sponsor will request clarification of omitted or discrepant information from the initial 
notification. The Investigator or an authorized delegate is responsible for 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 (eg, 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. 


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The SAE reporting contact information will be provided to all participating study sites by the 
CRO before study initiation. 
6.4.1.9 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 6.4.1.2, 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. 
6.4.1.10 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 medication administration. A follow-up 
visit to the study site may occur for those patients with an ongoing AE which the Investigator 
believes to be possibly related to study medication 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. 
6.4.2 Other Safety Assessments 
6.4.2.1 C-SSRS 
The C-SSRS will be completed at screening, baseline, and at every subsequent scheduled 
clinic visit (Table 6-1). Details of the C-SSRS are presented in Section 6.1.13. 
6.4.2.2 YMRS 
The YMRS will be completed at screening, baseline, and at every subsequent scheduled 
clinic visit (Table 6-1). Details of the YMRS are presented in Section 6.1.15. 


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6.4.2.3 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 (ie, the scores are not averaged). Additionally, overall 
severity is scored on the basis of severity of abnormal movements and incapacitation due to 
abnormal movements. The patient’s awareness of and distress caused by the abnormal 
movements are also noted. The AIMS is to be completed at baseline and periodically 
throughout the study as specified in the schedule of events (Table 6-1). 
6.4.2.4 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). 
6.4.2.5 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 (eg, 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). 


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6.4.2.6 Vital Sign Measurements 
Vital signs will be measured at screening and at every subsequent scheduled clinic visit 
(Table 6-1). Details of the vital sign measurements are presented in Section 6.1.5. 
6.4.2.7 ECG Assessments 
The ECG assessments will be performed at screening and periodically throughout the study, 
as scheduled (Table 6-1). Details of the ECG assessments are presented in Section 6.1.4. 
6.4.2.8 Physical and Neurological Examination 
The physical and neurological examinations will be conducted at screening and periodically 
throughout the study, as scheduled (Table 6-1). Details of the physical and neurological 
examinations are presented in Section 6.1.3. 
6.4.2.9 Laboratory Analyses 
Blood and urine samples collected from patients will be forwarded to a central laboratory for 
analysis. The Investigator must review all laboratory results for all patients. If a laboratory 
value is reported as deleted, cancelled, unable to perform, or otherwise missing, the test must 
be repeated as soon as possible. If the Investigator determines that the missing value does not 
require an immediate repeat, he/she must provide clinical reasoning to the Sponsor or its 
representative. 
Additional 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), after any scheduled ECG or vital signs have been recorded, and prior to dosing 
with study medication. Samples for clinical laboratory analysis will be used only for the 
evaluation of safety and tolerability. 
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 


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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. Thyroid panel 
(thyroid-stimulating hormone) will be assayed at Screening (Visit 1) and at Visit 8 (end of 
Treatment Period) or at Visit 9 (Early Discontinuation). 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). 
Drug Assays: Lithium and valproate blood levels will be assessed at screening and at each 
specified visit to assess maintenance within the respective therapeutic ranges. 
 Safety Monitoring Committee 
No safety monitoring committee will be used for the study. 


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 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. To 
ensure patient safety, each pregnancy must be reported to the Sponsor within 2 weeks of 
learning of its occurrence. The pregnancy must be followed up to determine outcome 
(including spontaneous miscarriage, elective termination, normal birth, or congenital 
abnormality) and status of mother and child, 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. 
Completion of the pregnancy form is not required for screen-failed patients who have had 
positive pregnancy test(s). 
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 the Sponsor. 


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7 Statistical and Analytical Plan 
A formal and detailed statistical analysis plan (SAP) will be finalized prior to the planned 
interim analysis and will provide further details regarding the definition of analysis 
endpoints, analysis methodology, and the interim analysis to address all study objectives. 
Changes made to the data analysis methods as described in this protocol will be documented 
in the SAP and will not necessitate a protocol amendment. All departures from the statistical 
analyses described in the approved protocol, whether made before or after unblinding, will be 
documented, and justified in the final clinical study report. 
A blinded data review will be conducted prior to unblinding the patients’ treatment 
assignments for assessing the accuracy and completeness of the study database and defining 
analysis sets.  
 Analysis Endpoints 
7.1.1 Primary Efficacy Endpoints 
The primary efficacy endpoint is the change from baseline to Day 43 in the 
rater-administered MADRS total score.  
7.1.2 Key Secondary Efficacy Endpoint 
The key secondary efficacy endpoint is the mean change from baseline to Day 43 in the 
CGI-BP-S-Depression score. 


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7.1.4 Safety Endpoints 
• AEs; 
• YMRS total score; 
• C-SSRS scores; 
• AIMS scores; 


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• BARS scores; 
• SAS score; 
• Physical examination and neurological findings; 
• Vital signs (blood pressure, heart rate), weight, and waist circumference; 
• ECGs; 
• Clinical laboratory evaluations. 
 Sample Size Calculations 
The sample size calculation of the study is based on the primary efficacy endpoint, the 
change from baseline to Day 43 in MADRS total score. Adjusting for multiple comparisons 
of two ITI-007 treatment groups with placebo by using the fixed sequence procedure (test the 
60 mg vs placebo first, and if statistically significant then proceed to test the 40 mg placebo 
vs placebo), a sample size of approximately 520 patients (173 per group) will provide 
approximately 90% power to detect an effect size of 0.4. This sample size estimation also 
assumes a common dropout rate of 15% at Day 43, and a common within-patient correlation 
of 0.7 for the change from baseline in MADRS total scores at Days 8, 15, 22, 29, 36, and 43. 


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 Analysis Sets 
The following analysis sets will be used in the statistical analyses: 
All Enrolled (ENR) Set: The ENR Set will contain all patients who signed the informed 
consent 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 medication. Patients will be classified 
according to randomized treatment; 
Intent-to-treat (ITT) Set: The ITT Set will contain all randomly assigned patients who 
received at least 1 dose of study medication and who had a valid baseline (pre-dose) 
measurement and at least 1 valid post-baseline measurement of MADRS. All analyses using 
the ITT Set will classify patients according to randomized treatment, regardless of the 
treatment actually received during the course of the study; 
Sensitivity Set: The Sensitivity Set will contain all randomly assigned patients who received 
at least 1 dose of study medication and who had a valid baseline (pre-dose) measurement 
MADRS total score.  All analyses using the Sensitivity Set will classify patients according to 
randomized treatment, regardless of the treatment actually received during the course of the 
study. 
Safety Set: The Safety Set will contain all patients who received at least 1 dose of study 
medication. All analyses using the Safety Set will classify patients according to treatment 
actually received; 
PK Set: The PK Set will contain all patients who received study medication, a baseline as 
well as at least 1 valid post-baseline MADRS measurement and had at least 1 PK sample 
collected and analyzed. Protocol deviations (eg, dosing errors) and AEs (eg, emesis) will be 
considered when assigning patients to the PK Set; patients who experience such events may 
be excluded from the PK Set on a case-by-case basis. 
Unless otherwise specified, the ITT Set will be used for analysis of efficacy endpoints and 
the Safety Set will be used for analysis of safety endpoints. 


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 Description of Subgroups to be Analyzed 
In addition to the ITT Set, efficacy measures will be analyzed by a subgroup defined by the 
concomitant treatment (lithium or valproate). Other subgroup analyses of efficacy and safety 
variables may be conducted as deemed appropriate and will be detailed in the SAP. 
 Statistical Analysis Methodology 
Categorical variables (eg, AEs) will be summarized using the number and percentage of 
patients in specified categories. Unless otherwise specified, the calculation of percentages 
will be based on the number of patients in the analysis set of interest. Continuous variables 
(eg, MADRS scores) will be summarized using descriptive statistics, including number of 
patients, mean, standard deviation, median, minimum, and maximum. 
First treatment with study medication and baseline assessments are scheduled for Visit 2 on 
Day 1. For analysis purposes, baseline is defined as the last non-missing assessment before 
the first treatment with study medication. Assessments on Day 1 for which the time is 
recorded will be considered baseline if the assessment time is before the time of the first 
treatment. Assessments on Day 1 for which the time is missing, and are, according to the 
study schedule of events, supposed to be collected prior to treatment, will be considered 
baseline. 
Safety, efficacy, and quality of life data will be listed for all treated patients and summarized 
by treatment group and visit, unless stated otherwise in the SAP. All total and subscale scores 
will be derived from available individual items. In case of missing items, the total and 
subscale scores will be considered missing. Plasma concentrations below the limit of 
quantification will be flagged in the data listings and will be set to 0 in the calculation of 
summary statistics of concentration values and derivations of PK parameters. 
Unless stated otherwise, statistical tests will be 2-sided significant level of 0.05, leading to 
95% (2-sided) confidence intervals (CIs). 
All investigative sites with fewer than 6 ITI-007 patients will be pooled as follows: the 
largest site with fewer than 2 patients per treatment group will be pooled with the smallest 
site with fewer than 2 patients per treatment group within the same country or geographic 
region. If this results in a pooled site still having fewer than 2 patients per treatment group, 
this site will be pooled together with the next smallest investigative site within the same 


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country or geographic region, if one exists; otherwise, no further pooling is needed. If the 
primary efficacy analysis model presents convergence issues due to the too small number of 
patients per site, including pooled sites, the same site pooling algorithm will be applied 
again, but this time pooling sites with fewer than a pre-specified larger number of ITI-007 
patients per site within each country or geographic region, as described in the SAP.  The 
pooled investigative sites, as determined based on the primary efficacy variable, will be used 
for any analysis model that includes site as a fixed effect. The actual investigative site 
numbers will be included in the listings. 
Additional details regarding the statistical analysis methodology will be provided in the SAP. 
All statistical analysis will be performed using SAS® software Version 9.4 or higher. 
7.5.1 
Patient Disposition, Analysis of Demographics and Other Baseline 
Characteristics 
Patient disposition will be summarized by treatment group, when applicable, and overall, and 
by study visit when applicable, including incidence of screening failure and incidence of 
treatment or study discontinuation and the corresponding reasons. The number and 
percentage of randomized patients who discontinued due to an AE associated with worsening 
of bipolar depression will be summarized. Similarly, the number and percentage of 
randomized patients who discontinued due to an AE not associated with worsening of bipolar 
depression will also be presented. Time to treatment discontinuation due to all reasons, AEs 
(all, AEs associated with worsening of bipolar depression, and AEs not associated with 
worsening of bipolar depression), lack of efficacy, or due to any other reason of special 
interest will be evaluated separately using the Kaplan-Meier method. The Log-rank test will 
be used to compare the time to discontinuation between each treatment group and the placebo 
group. 
Demographic and baseline characteristics, including bipolar disorder diagnosis and baseline 
efficacy measures, will be listed and summarized by treatment group and overall. 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 


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and treatment group. 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 lithium, valproate, zolpidem, zolpidem CR, or 
lorazepam, as described in Section 5.8 and detailed in Table 5-4. The number and percent of 
patients in the ITT Set receiving any of these medications 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 with ITI-007. 
7.5.3 
Study Medication Exposure and Treatment Compliance 
Exposure to study medication and treatment compliance will be presented for the ITT and 
Safety Sets. Duration of exposure (days) and dosing compliance (%) will be calculated and 
summarized by treatment group. In addition, the number and percentage of patients exposed 
to study medication will be presented by study week, defined by the planned visits. 
7.5.4 Analysis of Primary Efficacy Endpoint 
The study is designed to evaluate the efficacy profile of ITI-007 40 mg and 60 mg based on 
the change from baseline to Day 43 in the MADRS total score. 
The treatment effect on the primary efficacy endpoint will be evaluated using a mixed-effect 
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 group, site (or pooled site), and the stratification 
variables, first-line treatment (lithium or valproate) and Bipolar Disorder type at screening 
(I or II), and interaction term for treatment group-by-visit interaction as fixed effects, and the 
baseline MADRS total score and baseline MADRS total score-by-visit interaction as 
covariates. The patient term will be included in the model as a random effect and other terms 
as fixed effects. The treatment group-by-site (or pooled site) interaction term will not be 
included in the MMRM model for the primary efficacy analysis. Rather, it will be examined 
as part of the exploratory analysis. An unstructured covariance matrix will be used to model 
the correlation among repeated measurements within patient. In the event the convergence 
cannot be attained with the unstructured correlation matrix, the following alternative 
structures will be attempted in the specified order: heterogeneous Toeplitz structure 
(TOEPH), heterogeneous autoregressive (1) (ARH[1]), heterogeneous compound symmetry, 


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No Diagonal Factor Analytic (FA0(q), with q equal to the number of time points), Toeplitz 
structure (TOEP), autoregressive (1) (AR[1]), and compound symmetry. Model parameters 
will be estimated using restricted maximum likelihood. The Kenward-Roger approximation 
will be used to estimate the denominator degrees of freedom. The treatment group and 
treatment group-by-visit interaction terms allow for comparisons of the treatment groups at 
each of the following: Days 8, 15, 22, 29, 36, and 43. Treatment differences will be evaluated 
via contrasts for the treatment group-by-visit factor. This methodology will be used to 
compare each of the ITI-007 doses, 40 mg and 60 mg, to placebo for change from baseline at 
each day. Estimates of model parameters will be presented, as well as LSM estimates for 
change from baseline in MADRS total score, standard errors and 95% CIs for LSMs will be 
presented by treatment group and day. Contrast estimates (LSMs) for between-group 
comparisons, the corresponding standard errors, 95% CIs, effect sizes, and p-values will be 
presented for day. 
A number of sensitivity analyses of the primary efficacy endpoint will be performed to 
explore the robustness of the MMRM results under a different assumption on the mechanism 
of missing data. All sensitivity analyses will be performed based on the Sensitivity Set. The 
MMRM method assumes a missing-at-random mechanism for missing data. That is, the 
probability that measurements are missing depends on the set of observed measurements but 
is unrelated to the specific unobserved missing values that, in principle, should have been 
obtained.  Sensitivity analyses will be conducted to assess the impact of missing data under 
different assumptions on the mechanism of missing data and will be detailed in the SAP. 
Additionally, as a supportive analysis of the primary efficacy variable, the change from 
baseline to Day 43 in MADRS total score will be evaluated using analysis of covariance 
(ANCOVA) model with last observation carried forward (LOCF) based on the ITT Set. The 
model will contain the main effects of treatment group, site (or pooled site), the baseline 
value of MADRS total score, and the stratification variables (first-line treatment - lithium or 
valproate) and the bipolar disorder at screening [I or II]). Analysis of the LOCF Day 43 
endpoint will provide an estimate of efficacy attributable to ITI-007 compared with 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. LSMs for each 
treatment, the LSM difference between treatment groups, the associated standard errors and 
2-sided 95% CIs for the differences between the treatment groups, and p-values for between-
treatment tests of differences will be presented. 


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7.5.5 Analysis of Key Secondary Efficacy Endpoint 
The key secondary efficacy endpoint of the study is the change from baseline to Day 43 in 
the CGI-BP-S-Depression score. The key secondary efficacy endpoint will be analyzed using 
the similar MMRM model as for the primary efficacy endpoint. Details will be provided in 
the SAP. 
A fixed sequence procedure will be employed to control the overall type I error rate for 
multiple comparisons across the primary and the key secondary efficacy endpoints for the 
60-mg and 40 mg treatment groups. Specifically, the primary and the key secondary efficacy 
endpoints will be tested in the following specified order: 
 
#1: ITI-007 60 mg vs placebo comparison for change from baseline in MADRS total 
score at Day 43; 
 
#2: ITI-007 40 mg vs placebo comparison for change from baseline in MADRS total 
score at Day 43; 
 
#3: ITI-007 60 mg vs placebo comparison for change from baseline in CGI-BP-S 
score at Day 43; 
#4: ITI-007 40 mg vs placebo comparison for change from baseline in CGI-BP-S score at 
Day 43. 
All tests will be performed at the 0.05 level. Once one hypothesis fails to achieve statistical 
significance, all subsequent tests will not have p-values reported as nominal and will not be 
used to suggest statistical significance. 


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7.5.7 Safety Analyses 
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 treatment group 
and visit. When appropriate, out-of-range values will be flagged in data listings and 


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tabulated. Shift tables will be prepared for pre-specified safety measures, such as selected 
laboratory parameters, ECG, and BMI, based on markedly abnormal criteria. 
Reported AE terms will be coded using the latest version of MedDRA. Treatment-emergent 
AEs will be defined as any AEs, regardless of the relationship to study medication, that occur 
or worsen in severity after the first dose of study medication and before the last dose of study 
medication. Treatment-related TEAEs will be defined as any TEAEs that are considered by 
the Investigator to be either possibly, probably, or definitely related to study medication. If 
relationship to study medication is missing, the TEAE will be considered as treatment-
related. Severity of TEAEs will also be determined by the Investigator. All TEAEs, 
treatment-related TEAEs, and serious TEAEs will be summarized by treatment group, 
primary system organ class, and preferred terms and will be further broken down by severity 
and relationship to study medication.  If a patient reports the same TEAE more than once 
within the same system organ class and preferred term, the event with the worst-case 
relationship to study medication will be used in the corresponding relationship summaries. 
Similarly, if a patient reports a TEAE more than once within the same system organ class and 
preferred term, the event with the worst-case severity will be used in the corresponding 
severity summaries. The TEAEs occurring in at least 5% of patients in any treatment group 
will be summarized. Additional summaries of TEAEs will be presented as deemed necessary 
and will be specified in the SAP. 
Patients who discontinue study or study medication due to AEs will be listed and 
summarized by system organ class and preferred term. 
Treatment-emergent AEs will be categorized to monitor signals of potential abuse of ITI-007 
and the number and percentage of patients with at least 1 abuse-related TEAE will be 
summarized by the pre-specified categories. 
Laboratory assessments, including hematology and chemistry, vital signs, and ECGs, will be 
listed and summarized by treatment group and visit. Summaries may include actual and 
change from baseline, incidence of abnormal values according to normal range criteria, shift 
from baseline to each visit according to markedly abnormal criteria, and listing of patients 
meeting markedly abnormal criteria. Certain chemistry results, including but not limited to 
blood levels of fasting glucose, total cholesterol, triglycerides, and insulin will be evaluated 
for whether there is a difference between ITI-007 and placebo, using ANCOVA with LOCF. 
Any comparison between the treatment groups will be considered exploratory. 


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The observed values and changes from baseline in the scores of the rating scales (YMRS, 
C-SSRS, AIMS, BARS, and SAS) will be summarized by treatment group and study visit. 
7.5.9 Blinded Sample Size Re-estimation 
A blinded sample size re-estimation may be performed when 70% of randomized patients 
have either completed the study or discontinued to obtain an estimate of the pooled standard 
deviation on change from baseline to Day 43 in the MADRS total score. If the estimated 
pooled standard deviation is larger than the assumed pooled standard deviation in the sample 
size calculation , sample sizes may be increased to ensure an adequate power. The number of 
patients in each treatment arm will be capped at 200. 
Details on the blinded sample size re-estimation will be provided in the SAP. 
 Estimand Framework 
An estimand framework will also be employed to assess the efficacy of ITI-007 and its detail 
will be presented in the SAP of this study. 
 Data Quality Assurance 
To ensure compliance with Good Clinical Practice (GCP) and all applicable regulatory 
requirements, ITI  (the Sponsor) 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 


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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. 
7.7.1 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 or MINI (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 (eg, laboratory data). 
Clinical data management will be performed in accordance with applicable Sponsor 
standards and data-cleaning procedures to ensure the integrity of the data, eg, removing 
errors and inconsistencies in the data. Adverse events and concomitant medication terms will 
be coded using MedDRA, and an internal validated medication dictionary, respectively. 
After database lock, each study site will receive an electronic data storage device containing 
all of their study site- specific eCRF data as entered into the EDC, including full discrepancy 
and audit history. Additionally, an electronic copy of all of the study site’s data will be 
created and sent to the Sponsor for storage. The CRO will maintain a duplicate electronic 
copy for their records. In all cases, patient initials will not be collected or transmitted to the 
Sponsor. 


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8 Ethics 
 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/IEC before participation of human patients in research 
studies. Before study onset, the protocol, informed consent, advertisements to be used for the 
recruitment of study patients, and any other written information regarding this study to be 
provided to the patient or the patient’s legal guardian must be approved by the IRB/IEC. 
Documentation of all IRB/IEC approvals and of the IRB/IEC compliance with ICH 
harmonised tripartite guideline E6(R1) GCP will be maintained by the study site and will be 
available for review by the Sponsor or its designee. 
All IRB/IEC approvals should be signed by the IRB/IEC chairman or designee and must 
identify the IRB/IEC name and address; the clinical protocol by title, or protocol number, or 
both; and the date approval or a favorable opinion was granted. 
The Investigator is responsible for providing written summaries of the progress and status of 
the study at intervals not exceeding 1 year or otherwise specified by the IRB/IEC. The 
Investigator must promptly supply the Sponsor or its designee, the IRB/IEC, and, where 
applicable, the institution, with written reports on any changes significantly affecting the 
conduct of the study or increasing the risk to patients. 
 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. 
 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 
modifications to study-related procedures are proposed or made by the study site, the consent 
should be reviewed by the Sponsor, its designee, or both before IRB/IEC submission. Once 
reviewed, the consent will be submitted by the Investigator to his or her IRB/IEC for review 


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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/IEC and will 
not result in protocol amendments. 
 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/IEC. 
The Investigator and all employees and coworkers involved with this study may not disclose 
or use for any purpose other than performance of the study any data, record, or other 
unpublished, confidential information disclosed to those individuals for the purpose of the 
study. Prior written agreement from the Sponsor or its designee must be obtained for the 
disclosure of any said confidential information to other parties. 
 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. 
 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: 


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•  IRB/IEC approval 
• Original Investigator-signed Investigator agreement page of the protocol 
• Form FDA 1572, fully executed, and all updates on a new fully executed Form FDA 
1572 
• Curriculum vitae for the Investigator and each sub-investigator listed on Form 
FDA 1572 
• Financial disclosure information to allow the Sponsor to submit complete and 
accurate certification or disclosure statements required under 21 CFR 54. In addition, 
the Investigators must provide to the Sponsor a commitment to promptly update this 
information if any relevant changes occur during the course of the investigation and 
for 1 year after study completion. 
•  IRB/IEC-approved informed consent, samples of study 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 
 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 registries before enrollment of patients begins. 
 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. 


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 Adverse Events and Study Report Requirements 
By participating in this study, the Investigator agrees to submit reports of SAEs according to 
the timeline and method outlined in the protocol. In addition, the Investigator agrees to 
submit annual reports to the study site IRB/IEC, as appropriate. 
 Investigator’s Final Report 
Upon completion of the study, the Investigator, where applicable, should inform the 
institution; the Investigator/institution should provide the IRB/IEC with a summary of the 
study’s outcome and the Sponsor and regulatory authority(ies) with any required reports. 
 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. 
 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. 
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 
 Monitoring 
10.1.1 External Data Monitoring Committee 
There will not be an external DMC for this study. 
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/IEC 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 (eg, 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. 
 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 


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designee. Amendments to the protocol must be submitted in writing to the Investigator’s 
IRB/IEC 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/IEC approval. As soon as possible after such an occurrence, the 
implemented deviation or change, the reasons for it, and any proposed protocol amendments 
should be submitted to the IRB/IEC for review and approval, to the Sponsor for agreement, 
and to the regulatory authorities, if required. 
A deviation from the protocol is an unintended or unanticipated departure from the 
procedures or processes approved by the Sponsor and the IRB/IEC and agreed to by the 
Investigator. A significant deviation occurs when there is nonadherence to the protocol by the 
patient or Investigator that results in a significant, additional risk to the patient. Significant 
deviations can include nonadherence to inclusion or exclusion criteria, enrollment of the 
patient without prior Sponsor approval, or nonadherence to FDA regulations or ICH GCP 
guidelines, and will lead to the patient being withdrawn from the study (Section 4.2). 
Protocol deviations will be documented by the clinical monitor throughout the course of 
monitoring visits. Principal Investigators will be notified in writing by the monitor of 
deviations. The IRB/IEC should be notified of all protocol deviations in a timely manner. 
 Premature Termination or Suspension of Study 
This study may be suspended or prematurely terminated by the Sponsor. Written notification, 
documenting the reason for study suspension or termination, will be provided by the 
suspending or terminating party to the Investigator, and regulatory authorities. If the study is 
prematurely terminated or suspended, the Investigator will promptly inform the IRB/IEC and 
will provide the reason(s) for the termination or suspension.  
Circumstances that may warrant termination include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to patients; 
• Insufficient adherence to protocol requirements; 


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• Data that are not sufficiently complete and/or evaluable; 
• Determination of futility. 
 Halting Rules 
Individual patient participation in the study may be stopped at any time at the discretion of 
the Investigator (see Section 4.2). Individual patient participation may also be stopped at any 
time at the request of the Sponsor. Additionally, the Sponsor may place a temporary or 
permanent suspension of enrollment at any site or for the entire study. Reasons for stopping 
or suspending patient participation and/or enrollment include, but are not limited to, violation 
of inclusion/exclusion criteria, major protocol deviation(s), or safety concerns. 
Review of serious, unexpected, and related AEs by the IRB/IEC, the Sponsor, or the FDA or 
relevant local regulatory authorities may also result in suspension of further study 
interventions/administration of study product at a site. The FDA or other local regulatory 
authorities and study Sponsor retain the authority to suspend additional enrollment and study 
interventions/administration of study product for a site or the entire study, as applicable. 
Although the Sponsor has every intention of completing the study, the Sponsor reserves the 
right to discontinue the study at any time for clinical or administrative reasons. 
 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 agencies as required by the 
applicable regulatory requirements. 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 registries. 


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11  Reference List 
Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiatry. 1989;154:672-6. 
Costa PTJ, McCrae RR. Revised NEO Personality Inventory (NEO-PI-R) and NEO Five-
Factor Inventory (NEO-FFI) Professional Manual. Psychological Assessment Resources Inc.: 
Odessa, FL. 1992. 
Davis RE, Vanover KE, Zhou Y, et al. ITI-007 demonstrates brain occupancy at serotonin 
5-HT2A and dopamine D2 receptors and serotonin transporters using positron emission 
tomography in healthy volunteers. Psychopharmacology (Berl). 2015;232(15):2863-72. 
First MB, Williams JBW, Karg RS, Spitzer RL. Structured Clinical Interview for DSM-5 
Disorders – Clinical Trials Version (SCID-5-CT, 2014), Arlington, VA: American 
Psychiatric Association. 
Guy W, editor. ECDEU Assessment Manual for Psychopharmacology. Rockville: U.S. 
Department of Health Education, and Welfare; 1976. 616 p. 
Loebel A, Cucchiaro J, Silva R, et al. Lurasidone monotherapy in the treatment of bipolar I 
depression: a randomized, double-blind, placebo-controlled study. Am J Psychiatry. 
2014a;171(2):160-8. 
Loebel A, Cucchiaro J, Silva R, et al. Lurasidone as adjunctive therapy with lithium or 
valproate for the treatment of bipolar I depression: a randomized, double-blind, placebo-
controlled study. Am J Psychiatry. 2014b;171(2):169-77.  
Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: initial 
validity and internal consistency findings from three multisite studies with adolescents and 
adults. Am J Psychiatry 2011;168(12):1266-77. 
Sachs GS. Strategies for improving treatment of bipolar disorder: integration of measurement 
and management. Acta Psychiatr Scand Suppl 2004;422:717. 
Sheehan DV, Lecrubier Y, Harnett-Sheehan K, Amorim P, Janavs J, Weiller E, Hergueta T, 
Baker R, Dunbar G. The Mini International Neuropsychiatric Interview (M.I.N.I.): The 
Development and Validation of a Structured Diagnostic Psychiatric Interview. J Clin 
Psychiatry. 1998;59(suppl 20):22-33. 
Simpson GM, Angus JW. A rating scale for extrapyramidal side effects. Acta Psychiat Scand 
Suppl. 1970;212:11–9. 
Sidor MM, MacQueen GM: Antidepressants for the acute treatment of bipolar depression: a 
systematic review and meta-analysis. J Clin Psychiatry 2011;72(2):156–67. 


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Snyder GL, Vanover KE, Zhu H, et al. Functional profile of a novel modulator of serotonin, 
dopamine, and glutamate neurotransmission. Psychopharmacology (Berl). 
2015;232(3):605-21. 
Spearing MK, Post RM, Leverich GS, et al. Modification of the Clinical Global Impressions 
(CGI) Scale for use in bipolar illness (BP): the CGI-BP. Psychiatry Res. 1997;73(3):159-71. 
Svenningsson P, Greengard P. p11 (S100A10) – an inducible adaptor protein that modulates 
neuronal functions. Curr Opin Pharmacol. 2007;7(1):27-32. 
Topp CW, Østergaard SD, Søndergaard S, et al. The WHO-5 Well-Being Index: a systematic 
review of the literature. Psychother Psychosom. 2015;84(3):167-76. 
Van Lieshout RJ, MacQueen GM. Efficacy and acceptability of mood stabilisers in the 
treatment of acute bipolar depression: systematic review. Br J Psychiatry. 2010; 
196(4):266-73. 
Vázquez GH, Tondo L, Undurraga J, et al. Overview of antidepressant treatment of bipolar 
depression. Int J Neuropsychopharmacol. 2013; 6(7):1673–85. 
Young RC, Biggs JT, Ziegler VE, et al. A rating scale for mania: reliability, validity and 
sensitivity. Br J Psychiatry. 1978;133:429–35. 
Young AH, Calabrese JR, Gustafsson U, et al. Quetiapine monotherapy in bipolar II 
depression: combined data from four large, randomized studies. Int J Bipolar Disord. 
2013;1:10. 

SAP_001.pdf: 
NCT02600507 
 
 
Study ID: ITI-007-402 
 
 
Title: A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multi-Center Study to Assess the 
Efficacy and Safety of ITI-007 Adjunctive to Lithium or Valproate in the Treatment of Patients With Major 
Depressive Episodes Associated With Bipolar I or II Disorder (Bipolar Depression) 
 
 
 
 
 
Statistical Analysis Plan Date: August 11, 2020 
















 
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1. LIST OF ABBREVIATIONS
AE
Adverse Event
AIMS
Abnormal Involuntary Movement Scale
ANCOVA
Analysis of Covariance
AR(1)
Autoregressive(1)
ARH(1)
Heterogeneous autoregressive(1)
BARS
Barnes Akathisia Rating Scale
BLQ
Below the limit of quantification
BMI
Body mass index
BPI
Bipolarity Index
C SSRS
Columbia ʹ Suicide Severity Rating Scale
CGI BP S
Clinical Global Impression Scale, Bipolar Version ʹ Severity
CI
Confidence interval
COVID 19
Coronavirus Disease 2019
DMC
Data Monitoring Committee
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
ENR
All Patients Enrolled
FA0(q)
No diagonal factor analytic
HIV
human immunodeficiency virus
HR
Heart rate
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ITCI
Intra Cellular Therapies, Inc. (Sponsor)
ITT
Intent to Treat
LOCF
Last observation carried forward
LS
Least squares
MADRS
Montgomery Åsberg Depression Rating Scale
MAR
Missing at random
MedDRA
Medical Dictionary for Regulatory Activities
MI
Multiple imputation
MMRM
Mixed Effect Model Repeated Measure
MNAR
Missing not at random
NEO FFI
Neuroticism, Extraversion and Openness to Experience Five Factor Inventory
PK
Pharmacokinetic(s)
PR
PR interval of the electrocardiogram; time duration between the P and R waves
PT
Preferred Term
Q LES Q SF
Quality of Life Enjoyment and Satisfaction Questionnaire ʹ Short Form
QRS
QRS interval of the electrocardiogram; duration of the QRS complex
QT
QT interval of ECG, duration between the Q and T waves
QTcB
QT interval of ECG corrected for heart rate using Bazett͛s formula
QTcF
QT interval of ECG corrected for heart rate using Fridericia͛s formula
RND
All Patients Randomized
RR
Time duration between two consecutive R waves of the electrocardiogram
SAE
Serious Adverse Event
SAF
Safety Analysis
SAP
Statistical Analysis Plan
SAS
Simpson Angus Scale
SAS®
Statistical Analysis Software


 
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SD
Standard deviation
SDS
Sheehan Disability Scale
SMQs
Standard MedDRA Queries
SOC
System Organ Class
TEAE
Treatment emergent adverse event
TOEPH
Heterogeneous Toeplitz structure
TOEP
Toeplitz structure
WHO
World Health Organization
YMRS
Young Mania Rating Scale
2. INTRODUCTION
This document describes the rules and conventions to be used in the presentation and analysis
of efficacy, safety, and pharmacokinetic (PK) data for Protocol ITI 007 402. It describes the data
to be summarized and analyzed, including specifics of the statistical analyses to be performed.
This statistical analysis plan (SAP) is based on protocol version 1.6, dated 23Mar2020.
Exploratory analyses of biomarkers will be described in a separate analysis plan.
3. STUDY OBJECTIVES
3.1. 
PRIMARY EFFICACY OBJECTIVE
The primary objective of this study is to compare the efficacy of 2 doses of ITI 007 adjunctive to
treatment with lithium or valproate, administered orally once daily, to that of placebo
adjunctive to treatment with lithium or valproate as measured by mean change from baseline
to Day 43 in the total score on the rater administered Montgomery Åsberg Depression Rating
Scale (MADRS) in patients with bipolar dipression.
3.2.
SECONDARY OBJECTIVES
3.2.1. KEY SECONDARY EFFICACY OBJECTIVE
The key secondary objective of this study is to compare the efficacy of 2 doses of ITI 007
adjunctive to treatment with lithium or valproate, administered orally once daily to that of
placebo adjunctive to lithium or valproate as measured by mean change from baseline to Day
43 in Clinical Global Impression Scale Bipolar Version Severity (CGI BP S) Depression score in
patients with bipolar depression.






















































 
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See Appendix 2 for handling of partial or completely missing dates for AEs. In the case where it
is not possible to define an AE as treatment emergent or not, the AE will be classified as the
worst case, i.e., treatment emergent.
An overall summary of the number of patients within each of the categories described in the
sub sections 16.1.1 and 16.1.2 below will be provided as specified in the TLF shells.
Listings will include all adverse events, TEAEs and Non TEAEs.
16.1.1. 
AES AND TEAES
The incidence of TEAEs will be presented by SOC and PT and also broken down further by
maximum severity and relationship to study medication.
The number and percentage of patients with at least one TEAE and total number of patients
having events for each PT and SOC will be summarized. A summary of TEAEs will be provided
with only PTs and a separate summary for only SOCs. An additional summary of TEAEs will be
provided for PTs occurring in at least 5% of patients in any treatment group (ITI 007 60 mg, ITI
007 40 mg, or placebo). This summary will be repeated for TEAEs related (possibly, probably, or
definitely) to study drug. Within each patient, multiple reports of events that map to a common
MedDRA PT and/or SOC will be condensed into a single AE for incidence counts. Summaries will
be presented by treatment group and in decreasing frequency by decreasing dose group (ITI
007 60 mg, ITI 007 40 mg) and placebo group. AEs which occur during the follow up period will
be summarized by PT and SOC and treatment group.
The relative risk of at least one TEAE and for each PT and SOC will also be presented along with
95% CIs and p values obtained by the Chi square test for association.
Intensity is classed as ͞mild͟, ͞moderate͟, ͞severe͟, or ͞life threatening͟ (increasing severity).
AEs and TEAEs with a missing severity will be classified as ͞not specified͟. If a patient reports a
TEAE more than once within the same PT and SOC, the event with the worst case severity will
be used in the corresponding severity summaries.
Relationship, as indicated by the Investigator, is classed as ͞unrelated͟, ͞unlikely to be related͟,
͞possibly related͟, ͞probably related͟, or ͞definitely related͟ (increasing severity of
relationship). A ͞related͟ TEAE is defined as a TEAE with a relationship to study medication as
͞possibly related͟, ͞probably related͟, or ͞definitely related͟ to study medication. TEAEs with a
missing relationship to study medication will be classified as ͞related͟. If a patient reports the
same AE more than once within the same PT and SOC, the AE with the worst case relationship
to study medication will be used in the corresponding relationship summaries. A summary of
related TEAEs by SOC and PT will be presented.
AEs leading to early withdrawal or discontinuation of study medication will be identified by
using the Adverse Events page of the eCRF, where item ͚Action taken with study treatment͛
indicates permanent discontinuation of study medication, i.e., ͞Drug withdrawal͟. AEs leading




























 
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