Clinical trial NCT04285515
Conditions: Bipolar Depression Major Depressive Disorder
Keywords: Mixed Features
Sponsor: Intra-Cellular Therapies, Inc.
Start date: 2020-02-27; Completion date: 2022-11-30
Enrollment: 488 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of lumateperone monotherapy in the treatment of patients with major depressive episodes associated with Bipolar I or Bipolar II Disorder (Bipolar Depression) or major depressive disorder (MDD) who also meet the Diagnostic and Statistical Manual of Mental Disorder, 5th Edition (DSM-5) criteria for mixed-features. The study consists of a Screening Period, a Double-blind Treatment Period, and a Safety Follow-up Period.

Detailed description:

Arms: arm 1: Lumateperone 42mg administered once daily in the evening arm 2: Matching placebo administered once daily in the evening
Interventions: intervention 1: Lumateperone intervention 2: Placebos
Intervention descriptions: intervention 1: Lumateperone 42mg oral capsule intervention 2: Placebo oral capsule

Protocol documents:
Prot_000.pdf: 
NCT04285515 
 
 
 
 
Study ID: ITI-007-403 
 
 
 
Title: A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multi-Center Study to 
Assess the Efficacy and Safety of Lumateperone Monotherapy in the Treatment of Patients 
with Major Depressive Episodes Associated with Bipolar I or Bipolar II Disorder 
(Bipolar Depression) or Major Depressive Disorder 
 
Protocol Amendment 4.0 Date: January 27, 2023 


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A Phase 3, Randomized, Double-Blind, Placebo-
Controlled, Multi-Center Study to Assess the Efficacy 
and Safety of Lumateperone Monotherapy in the 
Treatment of Patients with Major Depressive Episodes 
Associated with Bipolar I or Bipolar II Disorder 
(Bipolar Depression) or Major Depressive Disorder 
ITI-007-403 
 
Sponsor: Intra-Cellular Therapies, Inc. (ITI) 
Original Protocol Version 1.0:  
November 7, 2019 
Amendment 2.0:  
November 2, 2020 
Amendment 3.0 
August 30, 2021 
Amendment 4.0: 
January 27, 2023 
STATEMENT OF COMPLIANCE 
The study will be conducted in accordance with the International Conference on 
Harmonisation guidelines for Good Clinical Practice (ICH E6) and the Code of Federal 
Regulations Title 45: Public Welfare, part 46 (45 CFR Part 46) on the Protection of Human 
Subjects. 
CONFIDENTIAL 
All financial and nonfinancial support for this study will be provided by Intra-Cellular 
Therapies, Inc. (ITI or ITCI). The concepts and information contained in this document or 
generated during the study are considered proprietary and may not be disclosed in whole 
or in part without the expressed, written consent of ITI.


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INVESTIGATOR SIGNATURE PAGE 
Study Title: A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multi-Center 
Study to Assess the Efficacy and Safety of Lumateperone Monotherapy in the Treatment 
of Patients with Major Depressive Episodes Associated with Bipolar I or Bipolar II Disorder 
(Bipolar Depression) or Major Depressive Disorder 
Protocol Number:  ITI-007-403 
Amendment 4.0 Date: 
27 Jan 2023 
The signature below constitutes the approval of this protocol and attachments and 
provides the necessary assurances that this trial will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable US federal and/or 
local regulations and ICH guidelines. 
I will not supply the investigational product 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 Intra-Cellular Therapies, Inc. (the Sponsor). 
Principal Investigator: 
Signed: 
 
Date:  
 
Name:  
 
Title:  


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TABLE OF CONTENTS 
PAGE 
INVESTIGATOR SIGNATURE PAGE ............................................................................. II 
KEY SPONSOR ROLES AND CONTACT INFORMATION ........................................... III 
TABLE OF CONTENTS ................................................................................................. IV 
LIST OF ABBREVIATIONS ........................................................................................... VII 
1 
PROTOCOL SYNOPSIS AND SCHEDULE OF EVENTS ....................................... 1 
2 
INTRODUCTION ..................................................................................................... 9 
2.1 
Background Information ............................................................................... 9 
2.2 
Rationale .................................................................................................... 12 
2.3 
Potential Risks and Benefits ....................................................................... 13 
3 
STUDY OBJECTIVES ........................................................................................... 14 
3.1 
Primary Efficacy Objective .......................................................................... 14 
3.2 
Secondary Efficacy Objectives ................................................................... 14 
3.2.1 Key Secondary Efficacy Objective ................................................... 14 
3.2.2 Additional Secondary Efficacy Objectives ........................................ 15 
3.3 
Safety Objectives ........................................................................................ 15 
4 
STUDY DESIGN ................................................................................................... 16 
5 
STUDY ENROLLMENT AND WITHDRAWAL ....................................................... 18 
5.1 
Patient Inclusion Criteria ............................................................................. 18 
5.2 
Patient Exclusion Criteria ........................................................................... 19 
5.3 
Strategies for Recruitment .......................................................................... 23 
5.4 
Treatment Assignment Procedures ............................................................ 24 
5.4.1 Randomization Procedures.............................................................. 24 
5.4.2 Masking Procedures ........................................................................ 24 
5.4.3 Breaking the Blind ............................................................................ 24 
5.5 
Discontinuation of Patients ......................................................................... 25 
5.6 
Premature Study Termination or Study Suspension ................................... 26 
5.7 
Patient Replacement Procedures ............................................................... 26 
6 
STUDY TREATMENTS ......................................................................................... 27 
6.1 
Study Drug Description ............................................................................... 27 
6.1.1 Formulation, Packaging, and Labeling ............................................. 28 
6.1.2 Product Storage and Stability .......................................................... 29 
6.2 
Dosage and Administration of Study Drug .................................................. 29 
6.3 
Modification of Study Treatment Administration ......................................... 29 
6.4 
Study Drug Accountability Procedures ....................................................... 30 
6.5 
Assessment of Patient Compliance with Study Drug Administration .......... 30 
6.6 
Concomitant Medications/Treatments ........................................................ 30 
7 
STUDY SCHEDULE.............................................................................................. 32 
7.1 
Screening (Visit 1) ...................................................................................... 32 


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7.2 
Baseline (Visit 2, Day 1) ............................................................................. 33 
7.3 
Visit 3, Day 8 ± 1 ........................................................................................ 33 
7.4 
Visit 4, Day 15 ± 1 ...................................................................................... 34 
7.5 
Visit 5, Day 22 ± 1 ...................................................................................... 34 
7.6 
Visit 6, Day 29 ± 1 ...................................................................................... 35 
7.7 
Visit 7, Day 36 ± 1 ...................................................................................... 35 
7.8 
Visit 8/Early Termination Visit, Day 43 ± 1 .................................................. 36 
7.9 
Follow-up Visit (Visit 9), Day 57 ± 1 ............................................................ 36 
8 
EFFICACY, SAFETY, AND OTHER ASSESSMENTS .......................................... 37 
8.1 
Diagnostic and Other Screening Period Assessments ............................... 37 
8.1.1 Mini International Neuropsychiatric Interview ................................... 37 
8.1.2 Young Mania Rating Scale .............................................................. 37 
8.1.3 Medical History and Other Information ............................................ 37 
8.1.4 Eligibility Review Process ................................................................ 37 
8.1.5 Patient Placebo Questionnaire and Training .................................... 38 
8.2 
Efficacy Assessments ................................................................................. 38 
8.2.1 Montgomery-Åsberg Depression Rating Scale (MADRS) ................ 38 
8.2.2 Clinical Global Impression–Severity (CGI-S) ................................... 38 
8.3 
Safety Assessments ................................................................................... 38 
8.3.1 Adverse Events ................................................................................ 39 
8.3.2 Pregnancy ........................................................................................ 44 
8.3.3 ECG Assessments ........................................................................... 44 
8.3.4 Vital Sign Assessments ................................................................... 45 
8.3.5 Clinical Laboratory Evaluations ........................................................ 45 
8.3.6 Other Safety Assessments .............................................................. 47 
9 
STATISTICAL CONSIDERATIONS ...................................................................... 50 
9.1 
Sample Size Considerations ...................................................................... 52 
9.2 
Planned Interim Analyses ........................................................................... 52 
9.3 
Analysis Sets .............................................................................................. 53 
9.4 
Statistical Analysis Methodology ................................................................ 53 
9.4.1 Patient Disposition, Analysis of Demographics and Other Baseline 
Characteristics ................................................................................. 54 
9.4.2 Prior and Concomitant Medications ................................................. 55 
9.4.3 Study Drug Exposure and Treatment Compliance ........................... 55 
9.4.4 Analysis of Primary and Key Secondary Efficacy Endpoints............ 55 
9.4.5 Analysis of Additional Secondary Efficacy Endpoints ...................... 57 
9.4.6 Safety Analyses ............................................................................... 58 
9.5 
Protocol Deviations ..................................................................................... 59 
10 
ETHICS/PROTECTION OF HUMAN SUBJECTS ................................................. 61 
10.1 
Institutional Review Board and Independent Ethics Committee ................. 61 
10.2 
Ethical Conduct of the Study ...................................................................... 61 


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10.3 
Information and Informed Consent ............................................................. 61 
10.4 
Patient Confidentiality ................................................................................. 62 
11 
INVESTIGATOR OBLIGATIONS .......................................................................... 63 
11.1 
Documentation ........................................................................................... 63 
11.2 
Performance ............................................................................................... 63 
11.3 
Use of Investigational Materials .................................................................. 64 
11.4 
Study Records Retention ............................................................................ 64 
11.5 
Clinical Site Monitoring ............................................................................... 64 
12 
DATA HANDLING AND RECORD KEEPING ....................................................... 65 
12.1 
Data Monitoring .......................................................................................... 65 
12.2 
Data Recording and Documentation ........................................................... 66 
13 
PUBLICATION/DATA SHARING POLICY ............................................................ 68 
14 
LITERATURE REFERENCES .............................................................................. 69 
LIST OF TABLES 
Table 1-1: Schedule of Events ........................................................................................ 6 
Table 6-1: Study Drug Dosage and Composition—Original Supply .............................. 27 
Table 6-2: Study Drug Dosage and Composition—New Supply ................................... 28 
Table 6-3: Weekly Study Drug Cards—Original Supply ................................................ 29 
Table 6-4: Weekly Study Drug Cards—New Supply ..................................................... 29 
Table 8-1: Adverse Event Causality Categories ............................................................ 41 
Table 8-2: Adverse Event Severity Categories .............................................................. 42 
Table 9-1: Overview of Statistical Data Analyses .......................................................... 51 
 
LIST OF FIGURES 
Figure 4-1: Schematic of Study Design ......................................................................... 16 
 


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LIST OF ABBREVIATIONS 
5-HT2A 
5-Hydroxytryptomine 2A Receptor 
AE 
adverse event 
AIMS 
Abnormal Involuntary Movement Scale 
ALT 
alanine aminotransferase 
ARH 
Heterogeneous Autoregressive 
AST 
aspartate aminotransferase 
BARS 
Barnes Akathisia Rating Scale 
bITT 
Bipolar Intent-to-treat 
BMI 
body mass index 
bpm 
beats per minute 
C-SSRS 
Columbia Suicide Severity Rating Scale  
CFR 
Code of Federal Regulations 
CGI-S 
Clinical Global Impression Scale–Severity  
CI 
confidence interval 
CRF 
case report form 
CRO 
Contract Research Organization 
CSR 
clinical study report 
D2 
dopamine 2 receptor 
DSM-5 
Diagnostic and Statistical Manual, 5th Edition 
eCRF 
electronic Case Report Form 
EAF 
Eligibility Assessment Form 
ECG 
electrocardiogram 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HbA1C 
glycated hemoglobin A1C 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ITI 
Intra-Cellular Therapies, Inc. 
ITT 
Intent-to-treat 
IVRS 
Interactive Voice Response System 


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IWRS 
Interactive Web Response System 
LDL 
low-density lipoprotein 
MADRS 
MAR 
Montgomery-Åsberg Depression Rating Scale 
Missing at random 
MDD 
Major Depressive Disorder 
MDE 
major depressive episode 
MedDRA 
Medical Dictionary for Regulatory Activities 
MINI 
Mini International Neuropsychiatric Interview  
mITT 
Modified Intent-to-treat 
MMRM 
Mixed-effect Model for Repeated Measures 
msec 
Millisecond 
PCS 
PET 
Potentially Clinically Significant 
Positron Emission Tomography 
QTcB 
corrected QT Interval Using the Bazett Formula 
QTcF 
corrected QT Interval Using the Fridericia Formula 
SAE 
serious adverse event 
SAS 
Simpson Angus Scale 
SERT 
serotonin transporter 
SAP 
Statistical Analysis Plan 
TEAE 
treatment-emergent adverse event 
TOEP 
Toeplitz Structure 
TOEPH 
Heterogeneous Toeplitz Structure 
ULN 
upper limit of normal 
US 
United States 
YMRS 
Young Mania Rating Scale  


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1 PROTOCOL SYNOPSIS AND SCHEDULE OF EVENTS 
Title: 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled, 
Multi-Center Study to Assess the Efficacy and Safety of 
Lumateperone Monotherapy in the Treatment of Patients with 
Major Depressive Episodes Associated with Bipolar I or 
Bipolar II Disorder (Bipolar Depression) or Major Depressive 
Disorder 
Study Design: 
This is a Phase 3, randomized, double-blind, placebo-controlled, 
multicenter study to evaluate the efficacy and safety of 
lumateperone monotherapy in the treatment of patients with 
major depressive episodes (MDEs) associated with Bipolar I or 
Bipolar II Disorder (Bipolar Depression) or major depressive 
disorder (MDD) who also meet the Diagnostic and Statistical 
Manual of Mental Disorder, 5th Edition (DSM-5) criteria for 
mixed-features. The study consists of a Screening Period, a 
Double-blind Treatment Period, and a Safety Follow-up Period. 
Screening Period (2 Weeks) 
Potential patients will be evaluated during a Screening Period 
lasting up to 2 weeks. 
After obtaining written informed consent, diagnostic interviews 
and physical examinations will be conducted, vital signs and 
ECGs will be assessed, and blood samples for laboratory 
assessments will be collected. Patients considered potentially 
eligible for participation will be required to discontinue their 
current antidepressant treatment and/or other psychotropic 
drugs. 
At Baseline (Visit 2), patients who continue to meet all eligibility 
criteria will be randomly assigned in a 1:1 ratio to 1 of the 
2 treatment arms (lumateperone 42 mg or placebo) for a 
6-week, double-blind treatment period. 
Double-blind Treatment Period (6 Weeks) 
Patients will take their first dose of study drug the evening of 
their randomization visit. A single dose will be taken each day in 
the evening for the duration of the on-treatment period. 
Following randomization, patients will attend clinic visits on 
Days 8, 15, 22, 29, 36, and 43. 
The Double-blind Treatment Period will be a total of 6 weeks. 


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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 
drug. Patients who withdraw prematurely should be seen for an 
early termination visit and will be asked to return to the clinic for 
a safety follow-up visit approximately 2 weeks after Visit 8/Early 
Termination (ET). 
Objectives: 
Primary Objective: 
The primary objective of this study is to confirm the efficacy of 
lumateperone 42 mg administered orally once daily compared 
with that of placebo as measured by mean change from baseline 
to Day 43 in the Montgomery-Åsberg Depression Rating Scale 
(MADRS) total score in patients with bipolar depression with 
mixed features or MDD with mixed features. 
 
Secondary Objectives 
 
Key Secondary Objective: 
The key secondary objective of this study is to confirm the 
efficacy of lumateperone 42 mg administered orally once daily 
compared with that of placebo as measured by mean change 
from baseline to Day 43 in Clinical Global Impression Scale–
Severity (CGI-S) score in patients with bipolar depression with 
mixed features or MDD with mixed features. 
 
Safety Objective: 
The safety objective of this study is to determine the safety and 
tolerability of lumateperone administered orally once daily 
compared with that of placebo in patients with bipolar 
depression or MDD as assessed by adverse events (AEs); 
clinical 
laboratory 
results; 
vital 
sign 
measures; 
electrocardiogram (ECG) results; suicidality as assessed by the 
Columbia-Suicide Severity Rating Scale (C-SSRS); manic 
symptoms as assessed by the Young Mania Rating Scale 
(YMRS); and extrapyramidal symptoms (EPS) as assessed by 
Abnormal Involuntary Movement Scale (AIMS), Barnes 
Akathisia Rating Scale (BARS), and Simpson Angus Scale 
(SAS) scales. 


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Population: 
Male and female patients between the ages of 18 and 75 years, 
inclusive, with a diagnosis of Bipolar I or Bipolar II Disorder with 
mixed features or major depressive disorder (MDD) with mixed 
features who are experiencing a major depressive episode 
(MDE) and who meet the following criteria may be eligible for 
participation in the study: 
• The start of the current MDE is at least 2 weeks but no more 
than 6 months prior to Screening (Visit 1); 
• The patient has at least moderate severity of illness as 
measured by MADRS total score ≥ 24 and CGI-S score ≥ 4 
at Screening (Visit 1) and Baseline (Visit 2); 
• The patient has sufficient history and/or independent report 
verifying that the current MDE is causing clinically significant 
distress or impairment in social, occupational, or other 
important areas of functioning; 
• The patient has a YMRS total score between 4 and 16, 
inclusive, at Screening (Visit 1) and Baseline (Visit 2). 
Patients will be enrolled in multiple countries globally. 
Phase: 
3 
Number of Sites: 
Up to 60 sites, approximately 
Description of 
Intervention: 
Patients will be randomized to receive either lumateperone 
42 mg or placebo. Patients will self-administer doses orally, 
once daily, each evening at home for the duration of the Double-
blind Treatment Period. Study drug will be provided in blister 
cards containing capsules, and patients will be instructed to take 
1 capsule per dose. 
Study Duration: 
For each patient completing the study, the study will last up to 
approximately 10 weeks (9 visits), including a Screening Period, 
a Double-blind Treatment Period, and a Safety Follow-up 
Period. 
Statistical 
Methods: 
Efficacy Analyses 
The primary efficacy endpoint is the change from baseline to 
Day 43 in MADRS total score. 
The analysis of the primary efficacy endpoint will be performed 
using a mixed-effects model for repeated measures (MMRM) 
with the change from baseline in the MADRS total score at each 
pre-specified postbaseline time point as the response variable; 
treatment group, visit, site (or pooled site), the stratification 
factor at screening (Bipolar Disorder or MDD diagnosis), and 
treatment group-by-visit interaction as factors; and the baseline 


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MADRS total score and visit-by-baseline MADRS total score 
interaction as covariates. An unstructured covariance matrix will 
be used to estimate the covariance among repeated 
measurements within patient. This analysis will be performed 
based on all post-baseline scores using only the observed cases 
without imputation of missing values. This primary efficacy 
analysis will first be performed based on the combined patient 
population of Bipolar Disorder with mixed features and of MDD 
with mixed features. If this primary analysis based on the 
combined population is statistically significant at 0.05 level, then 
by using a similar MMRM model the primary efficacy analyses 
will be performed separately for the subpopulation of Bipolar 
Disorder with mixed features and for the subpopulation of MDD 
with mixed features. 
The key secondary efficacy endpoint is the change from 
baseline to Day 43 in CGI-S score. This endpoint will be 
analyzed using an MMRM model similar to the one proposed for 
the analysis of the primary efficacy endpoint replacing MADRS 
total score with CGI-S score for the baseline and baseline-by-
visit interaction terms as covariates in the model. The key 
secondary efficacy analysis will first be performed based on the 
combined patient population of Bipolar Disorder with mixed 
features and of MDD with mixed features. If the key secondary 
analysis is statistically significant at 0.05 level, then by using a 
similar MMRM model, the key secondary efficacy analyses will 
be performed separately for the subpopulation of Bipolar 
Disorder with mixed features and for the subpopulation of MDD 
with mixed features.  
Multiple comparisons for the primary and key secondary efficacy 
endpoints 
will 
be 
addressed 
using 
a 
fixed-sequence 
(hierarchical) gatekeeping strategy combined with Hochberg 
procedure. The key secondary efficacy endpoint will be tested 
and its 2-sided p-value compared with 0.05 level for statistical 
significance only if the comparison for the primary efficacy 
endpoint is significant for the combined and two separate 
subpopulations at 2-sided α = 0.05 overall level. Otherwise, the 
p-value for the key secondary efficacy endpoint will be reported 
as nominal. 
The efficacy conclusion will be based on the analyses using the 
modified Intent-to-Treat (mITT) Analysis Set. The mITT Analysis 
Set is defined as all randomized patients enrolled after the 
implementation of Amendment 2.0 (dated 02 Nov 2020) who 
received at least 1 dose of study drug and had baseline and at 
least 1 post-baseline assessment of MADRS total score.  


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Descriptive analyses of the efficacy endpoints will be performed 
for patients enrolled before the implementation of Amendment 
2.0 (dated 02 Nov 2020).  
Safety Analyses 
Safety data such as reported and observed AEs and SAEs, 
clinical laboratory results, vital signs, physical and neurological 
examination findings, ECGs, YMRS, EPS as measured by 
AIMS, BARS, and SAS, and C-SSRS, will be summarized 
descriptively by treatment group and visit. When appropriate, 
out-of-range values will be flagged in data listings and tabulated. 
Shift tables will be prepared for pre-specified safety measures. 
The safety analysis will be performed using the Safety Analysis 
Set, defined as all randomized patients who received at least 1 
dose of study drug.  
A statistical analysis plan (SAP) will be finalized prior to 
unblinding patients’ treatment assignments. 
Sample Size: 
The assumed effect size (treatment-group difference relative to 
pooled standard deviation) of 0.37 for lumateperone is based on 
a treatment difference of 3.3 units with a common pooled 
standard deviation of 9 for the primary efficacy parameter, 
change from baseline to Day 43 in MADRS total score. A sample 
size of 350 patients (175 per treatment group) enrolled after the 
implementation of Amendment 2.0 (dated 02 Nov 2020) will be 
needed to provide 90% power for primary analysis for the 
combined population of Bipolar Disorder with mixed features 
and MDD with mixed features based on a mixed-effect model 
for repeated measures (MMRM) using simulation method 
(Lu, 2012). The simulation assumes a correlation of 0.7 between 
the repeated measures and a dropout rate of 10% based on 
historical data.  
The sample size and statistical power for the primary analyses 
in the subpopulations are presented in Section 9.1. 
The study randomized approximately 100 patients under the 
original protocol before the implementation of Amendment 2.0 
(dated 02 Nov 2020); therefore, the total enrollment for the study 
will be approximately 450 patients. 


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2 INTRODUCTION 
2.1 
Background Information 
Major depressive disorder (MDD) is a serious psychiatric disorder characterized by the 
presence of one or more major depressive episodes (MDE) without a history of manic, 
mixed, or hypomanic episodes. Major depressive episodes may begin at any age; 
however, the average age of onset is in the mid-20s. The lifetime risk for MDD is 
estimated at 5% to 12% for men and 10% to 25% for women. MDD has a high mortality 
rate and up to 15% of patients with severe major depressive episodes die by suicide. In 
addition, individuals with MDD have high medical morbidity and are often plagued with 
more pain and physical illness than the general population. 
Bipolar Disorder is a serious psychiatric disorder that may also result in major depressive 
episodes but is additionally characterized by manic or hypomanic episodes. Bipolar I 
Disorder is defined by the presence of mania with or without mixed features whereas 
Bipolar II Disorder is defined by the presence of hypomania, but both are often associated 
with MDEs. Bipolar Disorder affects approximately 5.7 million adult Americans a year, or 
about 2.6% of the U.S. population age 18 and older, according to the National Institute of 
Mental Health, with similar prevalence worldwide. Depressive episodes associated with 
Bipolar Disorder tend to last longer, recur more often, and are associated with worse 
prognosis than manic/hypomanic episodes. Bipolar Depression, the predominant 
presentation of Bipolar Disorder, remains a significantly underserved medical need, with 
only a few approved treatment options available. 
In both MDD and Bipolar Disorder, MDEs may include some symptoms of hypomania or 
mania that do not meet the criteria for a manic or hypomanic episode. The recognition of 
this presentation has been noted in the DSM-5 (2013) as the specifier of “mixed features.” 
Mixed features associated with MDD have been noted to be a risk factor for the 
development of Bipolar I or Bipolar II disorder, highlighting the clinical utility of this 
specifier. Additionally, these “subsyndromic hypomanic” patients with either MDD or 
Bipolar Disorder may suffer from greater symptom severity, increased recurrence of mood 
episodes, higher comorbidity, and increased risk of suicidality. These poorer outcomes 
emphasize the need for effective treatments in this population. 
Lumateperone (trade name CAPLYTA®) was approved by the Food and Drug 
Administration (FDA) on December 20, 2019, under NDA 209500 for the treatment of 
schizophrenia in adults. Intra-Cellular Therapies, Inc. (ITI, the Sponsor) is exploring the 
utility of lumateperone (ITI-007) for the treatment of MDEs with mixed features associated 
with Bipolar I or Bipolar II Disorder (bipolar depression) and MDD. 
Lumateperone is a novel small molecule therapeutic agent designed specifically to 
combine serotonergic, dopaminergic, and glutamatergic modulation in a dose-dependent 


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manner. Lumateperone is a potent serotonin 5-HT2A receptor antagonist with 
mesolimbic/mesocortical selective modulation of phosphoprotein pathways downstream 
of dopamine receptors, serotonin reuptake inhibition, and indirect glutamatergic 
modulation (Snyder et al, 2015). As a dopamine receptor protein phosphorylation 
modulator, lumateperone has dual properties, acting as post-synaptic antagonist and as 
a pre-synaptic partial agonist at dopamine 2 (D2) receptors in vivo, with 
mesolimbic/mesocortical selectivity. Lumateperone 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 (NMDA and AMPA) activity downstream from dopamine 1 receptor 
activation. 
Evidence supports the use of D2 receptor antagonists in the treatment of Bipolar Disorder, 
including bipolar depression (Young et al, 2013; Loebel et al, 2014a; 2014b), as both 
monotherapy and adjunctive therapy to mood stabilizers. In addition, studies have also 
shown the potential for D2 receptor antagonists in the treatment of MDEs with mixed 
features in MDD (Suppes et al, 2016; Swann et al, 2017) as well as mixed features in 
Bipolar Depression (McIntyre et al, 2015; McIntyre et al, 2020). The pharmacologic profile 
of lumateperone includes both the post-synaptic D2 antagonism that appears efficacious 
in Bipolar Disorder and other pharmacological properties that may confer efficacy and 
better safety and tolerability than other D2 antagonists. As a 5-HT2A receptor antagonist 
and serotonin reuptake inhibitor, lumateperone is predicted to have antidepressant 
efficacy with fewer side effects than selective serotonin reuptake inhibitors (Meltzer et al, 
1989). Lumateperone’s indirect glutamatergic modulation in combination with serotonin 
reuptake inhibition predicts rapid-acting antidepressant response. Importantly, 
lumateperone lacks potent off-target interactions that have been associated with side 
effects of other antipsychotic drugs approved for the treatment of bipolar depression. For 
example, lumateperone shows relatively weak affinity for 5-HT2C and no measurable 
affinity for H1 or muscarinic cholinergic receptors, which predict favorable body weight 
and metabolic profile responses to the extent that these receptors mediate such effects. 
Additional details on the pharmacologic profile of lumateperone are provided in the 
Investigator’s Brochure. 
Nonclinical data also suggest that lumateperone may have the potential to treat 
depression (Snyder et al, 2015). Antidepressant-like activity of lumateperone 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, lumateperone 1 mg/kg, 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 Study ITI-007-003, the 


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positron emission tomography (PET) Phase 1 clinical trial (Davis et al, 2015). PET 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 
lumateperone administration. Lumateperone 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 the 10 mg dose (>85% occupancy). 
A dose of lumateperone 40 mg 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 lumateperone at dopaminergic and serotonergic brain 
targets. An additional PET study in patients with schizophrenia (Study 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 (Studies 
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 addition to improving psychotic symptoms, lumateperone also improved 
symptoms of depression in patients with schizophrenia and comorbid depression at 
baseline. Safety data from these studies and other trials with lumateperone, which has 
been administered to more than 1500 individuals, show lumateperone to be well tolerated 
across a dose range from 0.7 to 98 mg, administered once daily for up to 42 days with a 
safety profile similar to placebo. 
In previously conducted bipolar depression studies (Studies ITI-007-401, ITI-007-404, 
and ITI-007-402) lumateperone was well-tolerated with a favorable safety profile. Studies 
ITI-007-401 and ITI-007-404 were randomized, double-blind, fixed-dose, placebo-
controlled, outpatient clinical trials designed to evaluate lumateperone as monotherapy in 
patients with major depressive episodes associated with either Bipolar I or II Disorder. 
Study ITI-007-402 was a randomized, double-blind, fixed-dose, placebo-controlled, 
outpatient clinical trial designed to evaluate lumateperone as adjunctive to lithium or 
valproate in patients with major depressive episodes associated with either Bipolar I or II 
Disorder. 
In Study ITI-007-404, which was conducted globally, once-daily lumateperone 42 mg met 
the primary endpoint with statistically significant improvement over placebo at Week 6 
(study endpoint), as measured by change from baseline in MADRS total score. 
Lumateperone 42 mg also met the key secondary endpoint of statistically significant 
improvement on the CGI-BP-S total score and demonstrated statistically significant 
improvement on the CGI-BP-S subscale that specifically assesses depression. Positive 


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effects were demonstrated in patients with either Bipolar I or Bipolar II Disorder. 
Additionally, a post hoc analysis of patients with 4 ≤ YMRS ≤ 12 showed statistically 
significant improvement over placebo at Week 6, as measured by change from baseline 
in MADRS and CGI-BP-S total score. 
In Study ITI-007-402, which was conducted globally, once-daily lumateperone 42 mg 
adjunctive to lithium or valproate met the primary endpoint with statistically significant 
improvement over placebo at Week 6 (study endpoint), as measured by change from 
baseline in MADRS total score. Lumateperone 42 mg also met the key secondary 
endpoint of statistically significant improvement on the CGI-BP-S depression subscale. 
In Study ITI-007-401, which was conducted solely in the United States, neither 
lumateperone dose (28 mg or 42 mg) met the primary endpoint of statistical separation 
from placebo as measured by change from baseline in MADRS total score. There was a 
high placebo response in this trial. 
The purpose of this study is to confirm the efficacy of lumateperone 42 mg administered 
orally once daily compared with that of placebo as measured by mean change from 
baseline to Day 43 in the MADRS total score in patients with bipolar depression with 
mixed features or MDD with mixed features. 
2.2 
Rationale 
The screening phase permits evaluation of diagnosis of Bipolar I or Bipolar II Disorder 
with mixed features or MDD with mixed features. Laboratory and ECG assessments 
enable confirmation of eligibility for inclusion into the study. Unless an extension of 
screening is approved by the Medical Monitor or Sponsor designee, the screening phase 
will be no longer than 2 weeks (14 days). 
At Baseline (Visit 2), patients will be randomly assigned in a 1:1 ratio to 1 of 2 treatment 
groups (lumateperone 42 mg or placebo) and will receive treatment for up to 6 weeks. In 
order to ensure patient safety, a mandatory follow-up visit will be performed approximately 
2 weeks after Visit 8/ Early Termination (ET). 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. 
Lumateperone 42 mg was selected to evaluate the efficacy seen with this dose in bipolar 
depression studies ITI-007-404 and ITI-007-402. This dose delivers full occupancy of the 
cortical 5-HT2A receptors (>85% occupancy) with modest striatal D2 receptor occupancy 
and SERT occupancy. Data from human PET brain receptor occupancy studies with 
lumateperone indicate that a dose as low as 10 mg is associated with >85% occupancy 
of cortical 5-HT2A receptors, while the 42-mg dose demonstrates approximately 40% 
striatal D2 receptor occupancy. SERT occupancy has been demonstrated to be 
comparable to D2 receptor occupancy. Moreover, in patients with schizophrenia and 


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bipolar depression, once-daily oral administration of lumateperone 42 mg has been well 
tolerated with no dose titration needed and with a safety profile similar to placebo with up 
to 6 weeks’ treatment duration. There is evidence that MDD patients with mixed features 
respond to similar doses of D2 receptor antagonists as bipolar depression patients with 
mixed features (Suppes et al, 2016; Swann et al, 2017). Therefore, a fixed-dose design 
will be employed in this study with once daily oral administration of lumateperone 42 mg 
(or placebo). 
A placebo control group is needed to establish the efficacy of a new compound. 
The treatment period duration of 6 weeks was chosen because it is considered an 
acceptable period to demonstrate efficacy in this patient population. 
The hypothesis of this study is that lumateperone 42 mg will demonstrate efficacy based 
on a 2-sided test for the treatment of MDEs associated with Bipolar I or II Disorder or with 
MDD, with statistically significant superiority vs placebo on the primary outcome measure: 
mean change from baseline to Day 43 in MADRS total score in patients with bipolar 
depression or MDD who meet DSM-5 criteria for mixed features. 
2.3 
Potential Risks and Benefits 
Patients will be monitored carefully for their mental health status and general health. 
Symptoms of bipolar depression may or may not improve during participation in this study; 
approximately half of the patients in this study will receive placebo. However, the 
information obtained from this study may help to treat people with bipolar depression in 
the future. More detailed information about the known and expected benefits and risks 
and reasonably expected AEs is provided in the lumateperone Investigator’s Brochure. 


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3 STUDY OBJECTIVES 
3.1 
Primary Efficacy Objective 
The primary objective of this study is to confirm the efficacy of lumateperone 42 mg 
administered orally once daily compared with that of placebo as measured by mean 
change from baseline to Day 43 in the MADRS total score in patients with bipolar 
depression with mixed features or MDD with mixed features. 
 
This study will evaluate the efficacy of lumateperone 42 mg based on the following three 
sets of patients: 
1. All patients enrolled after the implementation of Amendment 2.0, which includes 
all patients associated with Bipolar Depression with mixed features and all patients 
associated with MDD with mixed features;  
2. All patients with Bipolar Disorder (I or II) with mixed features enrolled after the 
implementation of Amendment 2.0;  
3. All patients associated with MDD with mixed features.  
3.2 
Secondary Efficacy Objectives 
 
 
 
 
 
 
 
 


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3.3 
Safety Objectives 
The safety objective of this study is to determine the safety and tolerability of 
lumateperone 42 mg administered orally once daily compared with that of placebo in 
patients with bipolar depression and MDD as assessed by AEs; clinical laboratory results; 
vital sign measures; ECG results; suicidality as assessed by the C-SSRS; manic 
symptoms as assessed by the YMRS; and extrapyramidal symptoms (EPS) as assessed 
by Abnormal Involuntary Movement Scale (AIMS), Barnes Akathisia Rating Scale 
(BARS), and Simpson Angus Scale (SAS) scales. 


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4 STUDY DESIGN 
This is a Phase 3, randomized, double-blind, placebo-controlled, multicenter study to 
evaluate the efficacy and safety of lumateperone monotherapy in the treatment of patients 
with MDEs associated with Bipolar Disorder with mixed features or MDD with mixed 
features. The study consists of a Screening Period, Double-blind Treatment Period, and 
a Safety Follow-up Period.  
Figure 4-1 presents the study-design schematic. The numbers of patients enrolled and 
randomized are based on the patients to be enrolled after the implementation of 
Amendment 2.0. 
Figure 4-1: Schematic of Study Design 
Visit 1 
Screening 
 
 
 
 
 
 
 
 
 
 
Visit 2 
(Day 1) 
 
 
 
Visits 3-8 
(Days 8-43) 
 
 
 
Visit 9 
(Day 57) 
 
 
 
 
luma = lumateperone 
Total N ~525: Obtain informed consent. Screen potential patients by inclusion and 
exclusion criteria; obtain history, perform eligibility review. 
Perform baseline assessments per Schedule of Events. 
Dispense initial study drug. 
Follow Up 
Perform safety measures per 
Schedule of Events. 
N ~ 350 Randomized 
Placebo 
N ~ 175 
luma 42 mg  
N ~ 175 
Double-Blind Treatment Period 
Perform weekly assessments per Schedule of Events 


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Screening Period (2 Weeks) 
Potential patients will be evaluated during a Screening Period lasting up to 2 weeks unless 
an extension of the Screening Period is approved by the Medical Monitor or Sponsor 
Designee.  
After obtaining written informed consent, diagnostic interviews and physical examinations 
will be conducted, vital signs and ECGs will be assessed, and blood samples will be 
collected for laboratory assessments. Patients considered potentially eligible for 
participation will be required to discontinue their current antidepressant treatment and/or 
other psychotropic drugs. 
At Baseline (Visit 2), patients who continue to meet all eligibility criteria will be randomized 
to 1 of the 2 treatment arms (lumateperone 42 mg or matching placebo) for a 6-week, 
double-blind treatment period. 
Double-blind Treatment Period (6 Weeks) 
Patients will take their first dose of study drug on the evening of Baseline (Visit 2, Day 1). 
A single dose will be taken each day in the evening, with or without food, for the duration 
of the 6-week Double-blind Treatment Period. 
Following randomization, patients will attend outpatient study visits on Days 8, 15, 22, 29, 
36, and 43. 
With approval from the Sponsor or Sponsor’s representative, sites will be permitted to 
conduct remote visits if the patient is unable to travel to the site for an in-person visit or if 
the site is unable to schedule an in-person visit. However, all Screening and Baseline 
(Visit 2) assessments must be performed in person. 
A patient will be defined as a treatment completer if the patient completed the double-
blind treatment period (all scheduled visits up to and including Visit 8). 
Safety Follow-up Period (2 Weeks) 
All patients should return to the clinic for the Safety Follow-up Visit approximately 2 weeks 
after Visit 8/ET. 


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5 STUDY ENROLLMENT AND WITHDRAWAL 
5.1 
Patient Inclusion Criteria 
Each patient must meet all of the following criteria to be enrolled in this study: 
1. Is capable of understanding the written informed consent, provides signed and 
witnessed written informed consent, and agrees to comply with protocol 
requirements; 
2. Male and female patients between the ages of 18 and 75 years, inclusive, at the 
start of screening; 
3. Meets the Diagnostic and Statistical Manual of Mental Disorder, 5th Edition 
(DSM-5) criteria for Bipolar I or Bipolar II Disorder with mixed features or MDD with 
mixed features, as confirmed by the Investigator or Sponsor-approved rater using 
the Mini-International Neuropsychiatric Interview (MINI) and meets all of the 
following 4 criteria: 
a. The start of the current MDE is at least 2 weeks but no more than 
6 months prior to the Screening (Visit 1); 
b. Has at least moderate severity of illness, as measured by a rater-
administered MADRS total score ≥24 and corresponding to a CGI-S 
score of ≥ 4 at Screening (Visit 1) and Baseline (Visit 2); 
c. Has 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. Has a rater-administered YMRS total score between 4 and 16, inclusive, 
at Screening (Visit 1) and Baseline (Visit 2). 
4. Has a body mass index (BMI) of 19–35 kg/m2, inclusive; 
5. Either must agree to use highly effective methods of birth control (defined as those, 
alone or in combination, that result in a failure rate less than 1 percent per year 
when used consistently and correctly) for at least 2 weeks prior to randomization 
(starting with signing informed consent) through 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. 


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5.2 
Patient Exclusion Criteria 
Patients meeting any of the following criteria will be excluded from the study: 
1. The patient experiences a ≥ 25% decrease in the rater-administered MADRS total 
score between Screening (Visit 1) and Baseline (Visit 2); 
2. In the opinion of the Investigator, the patient has a significant risk for suicidal 
behavior during the course of his/her participation in the study or  
a. At Screening (Visit 1), 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 (Visit 1), the patient has had 1 or more suicidal attempts with 
reference to a 2-year period prior to screening; or 
c. At Baseline (Visit 2), 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 (Visit 1) or Baseline (Visit 2), scores ≥ 4 on Item 10 (suicidal 
thoughts) on the rater-administered MADRS; or 
e. Considered to be an imminent danger to himself/herself or others; 
3. The patient is pregnant or breast-feeding. Female patients of childbearing potential 
must have negative urine and serum pregnancy tests at Screening (Visit 1). On 
Day 1 (Baseline/Visit 2), female patients of childbearing potential must have a 
negative urine pregnancy test prior to study drug administration; 
4. Within 12 months of screening, the patient has a confirmed DSM-5 psychiatric 
diagnosis other than Bipolar Disorder or MDD, including: 
a. Schizophrenia or other psychotic disorder; 
b. Anxiety disorders such as panic disorder, obsessive-compulsive disorder, 
general anxiety disorder, or post-traumatic stress disorder as a primary 
diagnosis (however, anxiety symptoms may be allowed, if secondary to 
Bipolar Disorder or MDD, provided these symptoms do not require current 
treatment); 
c. Eating disorder; 
d. Personality disorder; 
e. Moderate or severe substance use disorder (including for cannabis, 
excluding for nicotine); 
f. Any other psychiatric condition (other than Bipolar Disorder or MDD) that 
has been the main focus of treatment within 12 months of screening; 


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5. Patients who have experienced hallucinations, delusions, or any other psychotic 
symptomatology in the current depressive episode may be allowed as long as these 
symptoms are not attributable to a primary DSM-5 diagnosis other than Bipolar 
Disorder or MDD, as described in Exclusion Criterion #4; 
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 prior to study enrollment 
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 his/her lifetime.  
8. For patients with bipolar depression, the patient has had at least 4 major 
depressive, manic, hypomanic, or mixed episodes during the previous year. These 
episodes must be demarcated either by a partial or full remission of at least 
2 months' duration or by a switch to an episode of opposite polarity. Each MDE 
must have lasted at least 2 weeks, each manic or mixed episode must have lasted 
at least 1 week, and each hypomanic episode must have lasted at least 4 days, as 
validated by a reliable informant; 
Note: This criterion is included to avoid spontaneous remission during participation 
in the study that might confound treatment results. 
9. The patient is considered treatment-resistant, defined as having a lifetime history 
of treatment resistance (no remission) to ≥ 2 treatments with medications approved 
for the treatment of MDD or medications approved for the treatment of bipolar 
depression at an adequate dose (per locally-approved label) for an adequate 
duration (at least 6 weeks); 
10. The patient is currently receiving formal cognitive behavioral therapy (CBT), or 
plans to initiate such therapy during the study; 
11. The patient presents with a lifetime history of epilepsy, seizure or convulsion, or 
electroencephalogram with clinically significant abnormalities, delirium, dementia, 
amnestic, or other cognitive disorder or significant brain trauma; 


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12. The patient has a positive test for drugs of abuse or alcohol at Screening (Visit 1) 
or presents evidence of either withdrawal from or acute intoxication with cocaine, 
opiates, amphetamines (including methamphetamine), alcohol, barbiturates, or 
hallucinogens or similar compounds. A negative urine drug screen/test is required 
for study enrollment. Repeat testing is prohibited for positive alcohol, cocaine, 
phencyclidine, and amphetamine results; 
13. The patient has used 1 of the following agents under the specified conditions: 
a. Any previous exposure to lumateperone (including participation in previous 
clinical study of lumateperone) 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 
Baseline/Visit 2 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 which may be 
taken as needed, but no more than 3 times per week during the 
screening period and the first 2 weeks of the treatment period); 
Note: If zolpidem is not available in specific regions, another sedative 
hypnotic may be approved by the Medical Monitor. 
ii. Central opioid agonists/antagonists including tramadol; 
iii. Anticonvulsants; 
iv. Mood stabilizers, antipsychotics, antidepressants; 
v. Methotrexate; 
vi. Any known 5-HT2A receptor antagonist or inverse agonist including 
but 
not 
limited 
to 
mianserin, 
mirtazapine, 
nefazodone, 
cyproheptadine, pimavanserin, or fluvoxamine; 
vii. Immunosuppressants; 


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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 including, but not limited to: 
a. Aspartate aminotransferase (AST) >2.0 × the 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 T3 and free T4 
will be measured if TSH level is out of range. The patient will be excluded if 
the free T3 or T4 level is clinically significant; 
i. Any other clinically significant abnormal laboratory result at the time of the 
screening examination; 
Note: medical conditions that are stable with medication (eg, diabetes, 
hypertension, high cholesterol, and thyroid abnormalities) 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. 
15. 12-lead ECG (in a supine position after a rest of approximately 10 minutes at the 
screening visit) corrected QT interval using the Fridericia formula (QTcF) 
>450 msec for males or females, corrected QT interval using the Bazett formula 
(QTcB) >450 msec for males or >470 msec for females, and/or heart rate ≤ 50 bpm, 
or evidence of clinically significant bundle-branch blocks. Repeat ECG testing will 
not be permitted; 


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16. 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] > 7.0% [>53 mmol/mol] at screening with no HbA1c re-test allowed); 
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/she 
participates in the study (in the opinion of the Investigator); 
17. The patient has a known history of human immunodeficiency virus (HIV) infection; 
18. The patient has a positive test for hepatitis B surface antigen and/or hepatitis B core 
antibody immunoglobulin M at screening; 
19. The patient has a positive hepatitis C antibody at screening, with the exception of 
a patient for whom the reflex HCV RNA test is negative 
20. 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); 
21. The patient is judged by the Investigator to be inappropriate for the study; 
22. 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. 
5.3 
Strategies for Recruitment 
Strategies for recruitment will be determined by individual participating clinical study sites 
using Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved 
recruitment materials consistent with ICH guidelines. Patients may be compensated for 
study participation as reviewed and approved by the IRB/IEC and consistent with 
customary regional practices and ICH guidelines. Patient compensation (if regionally 
allowed) will be described in the informed consent form. 


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5.4 
Treatment Assignment Procedures 
At Baseline/Visit 2, patients who continue to meet all eligibility criteria will be randomly 
assigned to 1 of the 2 treatment arms (lumateperone 42 mg or matching placebo) for a 
6-week Double-blind Treatment Period. 
5.4.1 Randomization Procedures 
An interactive voice response system (IVRS)/interactive web response system (IWRS) 
(English only) will be used to administer the randomization schedule. Unblinded 
biostatistics personnel not participating in the conduct of the study will generate a 
permuted block randomization schedule using SAS software Version 9.4 or newer for 
IVRS/IWRS, which will link sequential patient randomization numbers to treatment codes. 
In the event that the blind needs to be broken because of a medical emergency, the 
Investigator may unblind an individual patient’s treatment allocation (Section 5.4.3). 
Patients will be stratified based on their Bipolar Disorder or MDD diagnosis. Also, patients  
with Bipolar Disorder will be further stratified by Bipolar I or Bipolar II diagnosis. 
Each patient will be assigned a randomization number at the time of randomization, which 
will be separate from the patient identification number. Once a randomization number has 
been allocated to a patient, it may not be assigned to another patient. 
The IVRS/IWRS will send visit notifications to the study site personnel confirming that 
patient data were entered. The IVRS/IWRS notifications should be filed securely at the 
study site. 
5.4.2  Masking Procedures 
The study will be performed in a double-blind manner. All study drug will be supplied in 
identical treatment cards and packaging, and will be similar in color, smell, taste, and 
appearance, thereby enabling double-blind conditions. 
5.4.3 Breaking the Blind 
A patient’s treatment assignment will not be broken until after the end of the study unless 
medical treatment of the patient depends on knowing the study drug 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 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. The date on which the code was broken together with the identity of 
the person responsible must also be documented. 


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The overall randomization code will be broken only for study reporting purposes and will 
occur after all final clinical data have been entered into the database and all data queries 
have been resolved. 
5.5 
Discontinuation of Patients 
A premature discontinuation will occur when a patient who signed the ICF ceases 
participation in the study, regardless of circumstances, before the completion of all study 
visits and procedures. Patients can be prematurely discontinued from the study after 
careful consideration for one of the following reasons: 
• Death 
• AE or SAE 
• Lack of efficacy  
• Lost to follow-up  
• Pregnancy 
• Physician decision 
• Protocol violation 
• Study terminated by Sponsor 
• Withdrawal by subject or withdrawal of consent 
NOTE: If a patient discontinues due to withdrawal of consent and either a concurrent AE 
was reported or concurrent lack of efficacy was documented, the study site should query 
and confirm the primary reason for discontinuation and record the primary reason for 
discontinuation on the electronic case report form (eCRF). 
All patients who prematurely discontinue from the study regardless of cause should be 
seen for final assessments as soon as possible at Visit 8/ET. All patients who prematurely 
discontinue from the study should also return for the Safety Follow-up Visit (Visit 9). 
Patients who discontinue from the study and do not return to the study site for the ET Visit 
must be requested in writing to return to the study site for a final assessment. A copy of 
the letter, together with the source documentation, will be kept in the Investigator’s files. 
The reason for premature discontinuation from the study will be recorded on the Study 
Termination Page of the eCRF. Study site staff may be contacted by the Sponsor after 


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each premature discontinuation to ensure that proper characterization of the reason for 
discontinuation is recorded. 
5.6 
Premature Study Termination or Study Suspension 
The Sponsor reserves the right to terminate the study in its entirety or at a specific study 
site before study completion. 
5.7 
Patient Replacement Procedures 
Patients who prematurely discontinue from the study during the Double-blind Treatment 
Period will not be replaced. 


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6 STUDY TREATMENTS 
6.1 
Study Drug Description 
Lumateperone 42 mg and placebo will be supplied as capsules. Placebo capsules are 
identical in appearance to lumateperone and have the same excipient ingredients as 
lumateperone but do not have the active compound. 
 
 
 
  
Descriptions of study drug supplies and formulation for the original supply (lumateperone 
Swedish orange opaque capsule) and for the new supply (lumateperone white opaque 
capsule) are provided in Table 6-1 and Table 6-2, respectively. 
Table 6-1: Study Drug Dosage and Composition—Original Supply 
Study drug 
Lumateperone 42 mg 
Placebo 
Dose frequency 
Once daily in the evening 
Once daily in the evening 
 
Composition (mg) 
Lumateperone dose 
42  
(60 mg lumateperone tosylate) 
0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 6-2: Study Drug Dosage and Composition—New Supply 
Study drug 
Lumateperone 42 mg 
Placebo 
Dose frequency 
Once daily in the evening 
Once daily in the evening 
 
Composition (mg) 
Lumateperone dose 
42  
(60 mg lumateperone tosylate) 
0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
6.1.1 Formulation, Packaging, and Labeling 
Lumateperone and matching placebo will be prepared according to current Good 
Manufacturing Practice standards in blister cards and shipped under ambient conditions. 
Each blister card will contain a sufficient quantity of capsules for 1 patient for 1 week: 
• The original supply contains 7 doses, plus 1 extra dose, to be dispensed at every 
visit during the 6-week treatment period. 
• The new supply will contain 7 doses, plus 3 extra doses, to be dispensed at every 
visit during the 6-week treatment period. 
The blister card for study drug in the original supply contains one 1×8 strips of 
capsules; the blister card for study drug in the new supply will contain one 1×10 strips of 
capsules (see Table 6-3 and Table 6-4). 


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Table 6-3: Weekly Study Drug Cards—Original Supply 
Treatment 
Card Contents 
Lumateperone 42 mg 
One 1×8 strip of lumateperone 42-mg capsule  
Placebo 
One 1×8 strip of lumateperone-matched placebo 
Note: Each card will hold 8 capsules. 
Table 6-4: Weekly Study Drug Cards—New Supply 
Treatment 
Card Contents 
Lumateperone 42 mg 
One 1×10 strip of lumateperone 42-mg capsule  
Placebo 
One 1×10 strip of lumateperone-matched 
placebo 
Note: Each card will hold 10 capsules. 
Each lumateperone dosing container will be labeled according to local laws and 
regulations. 
6.1.2 Product Storage and Stability 
Study drug must be stored in a secure area (eg, a locked cabinet) while in storage at the 
study site, protected from moisture, and kept at room temperature. Patients will be 
instructed to store the blister card at room temperature at home, out of the reach of 
children. 
6.2 
Dosage and Administration of Study Drug 
Patients will be randomized to receive either lumateperone 42 mg or placebo. Study site 
personnel will receive a treatment card number from the IVRS/IWRS for each patient at 
every clinic visit (eg, at Baseline/Day 1, Visit 3/Day 8, Visit 4/Day 15, Visit 5/Day 22, 
Visit 6/Day 29, and Visit 7/Day 36) to ensure that the correct study drug is dispensed.  
Patients will be instructed to take 1 capsule per dose. Patients will self-administer study 
drug orally, once daily in the evening for the duration of the Double-blind Treatment 
Period. Study drug should be administered with or without food and at approximately the 
same time each evening. 
6.3 
Modification of Study Treatment Administration 
Patients who do not tolerate the study drug should be discontinued from the study. No 
dose modifications are allowed. See Section 5.5 for details regarding patient 
discontinuation. 


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6.4 
Study Drug Accountability Procedures 
The Investigator will maintain accurate records of receipt of all study drug, including dates 
of receipt. In addition, accurate records will be kept regarding when and how much study 
drug is dispensed and used by each patient in the study. Reasons for deviation from the 
expected dispensing regimen must also be recorded. At the completion of the study, to 
satisfy regulatory requirements regarding drug accountability, all study drug will be 
reconciled and retained or destroyed according to applicable regulations. 
6.5 
Assessment of Patient Compliance with Study Drug Administration 
Patient compliance will be assessed by capsule counts of unused study drug at each visit 
during the double-blind treatment period. Any irregularities in medication adherence 
should be discussed with the patient. Any exceptions to non-compliance with the study 
drug regimen due to unusual circumstances should be discussed with the Medical 
Monitor. 
All errors in medication dispensing or administration must be carefully documented. 
These errors may include providing the wrong dose, not taking dose as prescribed, or 
losing medication. Medication adherence will be emphasized at every visit. Written 
instructions will be provided to the patients with the weekly medication card in order to 
minimize medication error. Additional adherence procedures may be implemented. 
6.6 
Concomitant Medications/Treatments 
Use of the following products during the study is prohibited: 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. 
Zolpidem may be taken no more than 3 times per week during the screening period and 
the first 2 weeks of the double-blind treatment period only (Section 5.2, Exclusion 13). If 
zolpidem is not available in specific regions, another sedative hypnotic may be approved 
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. 
Use of all concomitant medications will be recorded in the patient’s eCRF. Drug name 
and dates of administration must be recorded for all prescription drugs, herbal products, 
vitamins, minerals, and over-the-counter medications. Any changes in concomitant 


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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 complete details regarding the medication are recorded in the eCRF. 


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7 STUDY SCHEDULE 
Before participating in any study procedures, all potential study patients must sign an 
informed consent form (ICF). Patients will have the opportunity to have any questions 
answered before signing the ICF. The investigator must address all questions raised by 
the patient. The Investigator will also sign the ICF and a signed copy will be provided to 
the patient. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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8 EFFICACY, SAFETY, AND OTHER ASSESSMENTS 
8.1 
Diagnostic and Other Screening Period Assessments 
8.1.1 Mini International Neuropsychiatric Interview 
To be included in this study, a patient must meet the DSM-5 criteria for diagnosis of 
Bipolar I or Bipolar II Disorder with mixed features or MDD with mixed features, as 
confirmed by the MINI (7.0.2; 8/8/16 version). The MINI is a validated clinical tool 
(Sheehan et al, 1998) that will be used at screening only and will be completed by a 
Sponsor-approved rater. 
8.1.2 Young Mania Rating Scale 
The YMRS is an 11-item, clinician-administered mania rating scale with established 
reliability, validity, and sensitivity that assesses the severity of manic symptoms (Young 
et al, 1978). Four of the YMRS items are rated on a 0 to 8 scale, with the remaining 
7 items rated on a 0 to 4 scale. The YMRS total score assesses baseline severity of manic 
symptoms and treatment-emergent manic symptoms in patients. It will be completed by 
the Sponsor-approved rater. 
8.1.3 Medical History and Other Information 
Medical history information will be collected at screening and should include demographic 
information, current and past medical conditions, and current and past medications. Prior 
to study drug administration, medical history must be documented in the patient’s study 
chart and also recorded in the appropriate eCRF. In addition to medical history, 
information pertaining to the patient’s average alcohol and caffeine consumption and 
average tobacco and cannabis usage should be recorded in the eCRF. 
Patients will be checked for previous participation in an ITI-007 clinical study and for 
duplicate enrollment by study site staff through Verified Clinical Trials (VCT). 
 
 
 
 
 
 
 
 
 


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8.1.5 Patient Placebo Questionnaire and Training 
A brief training module will be provided describing placebo response at Baseline (Visit 2). 
placebo response questionnaire will be administered to assess the patient’s perception 
of likelihood their symptoms will improve as well as their perception at the end of the study 
whether they received placebo or active investigational drug. 
8.2 Efficacy Assessments 
8.2.1 Montgomery-Åsberg Depression Rating Scale (MADRS) 
The MADRS is a 10-item checklist designed to measure the overall severity of depressive 
symptoms (Montgomery and Åsberg, 1979). Individual items are rated by the Investigator 
or Sponsor-approved rater on a scale of 0 to 6 in which a score of 6 represents the most 
severe symptoms for each item assessed. The MADRS total score ranges from 0 to 60. 
The MADRS total score at screening is a major inclusion criterion for in the study, as well 
as the primary outcome measure for the study. 
8.2.2 Clinical Global Impression–Severity (CGI-S) 
The Clinical Global Impressions Scale-Severity provides the clinician’s assessment of the 
overall severity of the patient’s psychopathology (Guy, 1976). The CGI-S asks the 
clinician: “Considering your total clinical experience with this particular population, how 
mentally ill is the patient at this time?” which is rated on the following seven-point scale: 
1=normal, not at all ill; 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly 
ill; 6=severely ill; 7=among the most extremely ill patients. The CGI-S will be completed 
by a Sponsor-approved rater. 
8.3 Safety Assessments 
All patients who receive study drug will be evaluated for safety. Safety assessments will 
include incidence of AEs, C-SSRS assessment for suicidality, YMRS assessment of 
manic symptoms, EPS assessments as measured by AIMS, BARS, and SAS scales, 
clinical laboratory evaluations, ECG evaluations, vital sign measurements, and physical 
examination and neurological findings. Additional details pertaining to safety 
assessments are provided in the Schedule of Events (Table 1-1). 


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8.3.1 Adverse Events 
8.3.1.1 
Definition of Adverse Event 
An AE is any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug-related. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding, for example), symptom, or 
disease temporally associated with the use of a medicinal product, whether or not it is 
considered related to the medicinal product (ICH-E2A; 21 CFR 312.32[a]). 
NOTE: Medical procedures scheduled prior to obtaining informed consent but occurring 
during the study should not be captured as AEs but the medical reason for the procedure 
should be listed in the medical history if related to a pre-existing condition. 
8.3.1.2 
Definition of Serious Adverse Event 
An SAE is defined as any untoward medical occurrence that at any dose: 
• Results in death; 
• Is life threatening; 
Note: The term “life threatening” refers to an event in which the patient is at risk of 
death at the time of the event. 
• Requires hospitalization or prolongation in existing hospitalization; 
• Results in persistent or significant disability or incapacity; or 
• Is a congenital anomaly or birth defect. 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based on appropriate medical judgment, 
they may jeopardize the patient and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in patient hospitalization, or the 
development of study medication dependency or drug abuse. 
Emergency room visits that do not result in hospitalization should be evaluated for one of 
the other serious outcomes to determine whether they qualify as SAEs. 


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Pre-planned hospitalizations (eg, elective procedures for pre-existing conditions that did 
not worsen, such as cosmetic surgery and hysterectomy) are excluded from SAE 
reporting. 
Expectedness of SAEs 
The Sponsor or designee will be responsible for determining whether an SAE is expected 
or unexpected. An SAE will be considered unexpected if the nature, severity, or frequency 
of the event is not consistent with the risk information previously described for the 
intervention as documented in the Investigator’s Brochure. 
8.3.1.3 
Classification of Adverse Events and Serious Adverse Events 
8.3.1.3.1 Causality Assessment 
By definition, any AE that starts before the first dose of study drug administration is 
considered to be “unrelated.” 
The Investigator will assess the causality/relationship between the study drug and the AE. 
Table 8-1 presents the AE causality categories, one of which should be selected based 
on medical judgment and all contributing factors. 


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Table 8-1: Adverse Event Causality Categories 
Category 
Definition 
Definitely related 
A clinical event, including laboratory test abnormality, occurs in a plausible 
time relationship to treatment administration, and which concurrent disease or 
other drugs or chemicals cannot explain. The response to withdrawal of the 
treatment (dechallenge1) should be clinically plausible. The event must be 
definitive pharmacologically or phenomenologically, using a satisfactory 
rechallenge2 procedure if necessary. 
Probably related 
A clinical event, including laboratory test abnormality, with a reasonable time 
sequence to administration of the treatment, unlikely to be attributed to 
concurrent disease or other drugs or chemicals, and which follows a clinically 
reasonable response on withdrawal (dechallenge). Rechallenge information is 
not required to fulfill this definition. 
Possibly related 
A clinical event, including laboratory test abnormality, with a reasonable 
possibility that the adverse event may have been caused by the treatment. 
Information on treatment withdrawal may be lacking or unclear. 
Unlikely to be 
related 
A clinical event, including laboratory test abnormality, with a temporal 
relationship to treatment administration which makes a causal relationship 
improbable, and in which other drugs, chemicals or underlying disease provide 
plausible explanations. 
Unrelated 
A clinical event, including laboratory test abnormality, with little or no temporal 
relationship with treatment administration. May have negative dechallenge and 
rechallenge information. Typically, explained by extraneous factors (eg, 
concomitant disease, environmental factors, or other drugs or chemicals). 
1 Dechallenge is when a drug suspected of causing an 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). 
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. 


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8.3.1.3.2 Severity 
The Investigator will provide an assessment of the severity of each AE by recording a 
severity rating on the appropriate AE reporting page of the patient’s eCRF. Severity, 
which is a description of the intensity of manifestation of the AE, is distinct from 
seriousness, which implies a patient outcome or AE-required treatment measure 
associated with a threat to life or functionality (Section 8.3.1.2). Severity will be assessed 
according to the following scale (Table 8-2): 
Table 8-2: Adverse Event Severity Categories 
 
Category 
Definition 
Mild 
A type of adverse event that is usually transient and may require only 
minimal treatment or therapeutic intervention. The event does not generally 
interfere with usual activities of daily living. 
Moderate 
A type of adverse event that is usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual activities of daily 
living, causing discomfort but poses no significant or permanent risk of 
harm to the research 
Severe 
A type of adverse event that interrupts usual activities of daily living, or 
significantly affects clinical status, or may require intensive therapeutic 
intervention. 
Any change in intensity of signs and symptoms will be captured by recording a new AE 
with the amended intensity grade and the date of the change in intensity. If changes in 
AE intensity occur more than once a day, the maximum intensity of the AE should be 
recorded for that day. 
8.3.1.4 
Time Period and Frequency of AE Assessment and Follow-up 
The Investigator will report all AEs and SAEs from the time informed consent was 
obtained until 30 days after the final protocol-defined study visit or the last known dose of 
study drug (if the final visit does not occur). 
All AEs must be 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 clinically 
stable. 


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8.3.1.5 
Adverse Event Reporting Procedures 
8.3.1.5.1 Reporting Adverse Events 
All AEs, including overdose of study medication or other medication, must be recorded 
on the appropriate AE reporting page of the patient’s eCRF whether or not they are 
considered causally related to study medication. For every AE, the Investigator must: 
• Provide an assessment of the seriousness of the event (ie, is it an SAE?), as well 
as the severity and casual relationship. See Section 8.3.1.2 for the definition of 
SAEs and Section 8.3.1.5.2 for SAE reporting procedures. 
• Document all actions taken with regard to study medication 
• Detail any other treatment measures taken for the AE 
Any AEs that are ongoing at the time of the final protocol-defined study visit will be 
followed until the condition returns to pre-study status, has resolved or stabilized, or can 
be explained as being unrelated to study medication.  
8.3.1.5.2 Reporting Serious Adverse Events 
The Sponsor is required to inform regulatory authorities of SAEs that meet specific 
criteria. Therefore, the Sponsor must be notified immediately regarding any SAE that 
occurs after informed consent is obtained. 
For the initial SAE report, the Investigator will complete, sign, and date a Serious Adverse 
Event Form and submit via fax or email within 24 hours of becoming aware of the event. 
As a minimum requirement, the initial notification should provide the following information: 
• Study number 
• Patient number 
• Gender 
• Date of birth 
• Name of investigator and full study site address 
• Details of SAE 
• Criterion for classification as “serious” 
• Study drug code, or name if unblinded, and treatment start date and stop date, if 
applicable 


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• Date of SAE onset 
• Causality assessment (if sufficient information is available to make this classification) 
The Sponsor will request clarification of omitted or discrepant information from the initial 
notification. The Investigator or an authorized delegate is responsible for providing the 
requested information to the sponsor within 24 hours of the Sponsor’s request. 
Initial reports of SAEs must be followed later with detailed descriptions, including clear 
photocopies of other documents as necessary (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 provided to the Sponsor within 24 hours of receipt of the information. If a 
new SAE Report Form is provided, then the Investigator must sign and date the form.  
The SAE reporting contact information will be provided to all participating study sites by 
the contract research organization (CRO) on behalf of the Sponsor before study initiation. 
8.3.2 Pregnancy 
Pregnancy is not regarded as an AE unless there is a suspicion that an investigational 
product may have interfered with the effectiveness of a contraceptive medication. Any 
pregnancy that occurs in a patient or partner of a patient during study participation must 
be reported by completing a Pregnancy Reporting Form. The patient must stop study drug 
immediately after pregnancy is discovered and have an ET visit as soon as possible. 
Additionally, each pregnancy must be reported to ITI within 2 weeks of learning of its 
occurrence. The pregnancy must be followed up to determine outcome (including 
spontaneous miscarriage, elective termination, normal birth, or congenital abnormality) 
and status of mother and child, even if the patient was discontinued from the study. 
Pregnancy complications and elective terminations for medical reasons should not be 
reported as an AE or SAE. If the pregnancy is associated with an SAE (eg, spontaneous 
miscarriage or if the mother is hospitalized for hemorrhage), a separate SAE form must 
be filed as described in Section 8.3.1.5.2 with the appropriate serious criterion (eg, 
hospitalization) indicated in addition to the Pregnancy Reporting Form. 
8.3.3 ECG Assessments 
A 12-lead ECG will be performed during the Double-blind Treatment Period at the visits 
specified in the Schedule of Evaluations (Section 1). ECGs will be performed and 
electronically transmitted to a central ECG laboratory for analysis according to the 
instructions provided by the central ECG laboratory. Measurements (in msec) will be 
recorded for the following parameters: PR interval, QRS duration, and uncorrected QT 


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interval; QTcB (Bazett corrected QT interval) and QTcF (Fridericia corrected QT interval) 
will be calculated. 
The overall interpretation and determination of the clinical significance of ECG findings 
using the interpretation from the central ECG laboratory will be the responsibility of the 
Investigator and will be recorded in the patient’s eCRF. For eligibility criteria, the values 
reported on the central ECG interpretation report, not the values that are printed on the 
tracing itself, are used. 
8.3.4 Vital Sign Assessments 
Vital signs (pulse rate, systolic and diastolic blood pressure [BP], body temperature, body 
weight, and waist circumference) will be assessed at every visit. Height will be assessed 
at Screening/Visit 1 only; BMI will be calculated at Screening/Visit 1 and Visit 8/ET. 
BP and radial pulse rate will be measured twice: once in the supine position for at least 5 
minutes followed by once in the standing position. The standing measurements should 
be assessed after at least 2 minutes to allow the BP to equilibrate in the standing state. 
BP may be measured manually or by machine, but radial pulse rate should only be 
measured manually and for a sufficient time to acquire an accurate measurement. 
Patients should be instructed not to wear clothing with tight sleeves when they come for 
clinic visits. Additionally, patients should be kept as calm and undisturbed as possible 
while BP and pulse rate measurements are taken (eg, there should be no talking while 
the BP is being measured). The same arm and BP cuff (appropriate to the arm 
circumference) should be used for all BP measurements. 
Whenever possible, the patient’s weight should be measured at the same time of day; the 
patient should wear his/her usual indoor clothing but take off his/her jacket and shoes. 
For each patient, body weight should be determined using the same equipment during 
the study after ensuring its proper calibration. 
8.3.5 Clinical Laboratory Evaluations 
Blood and urine samples for clinical laboratory tests will be collected during the study as 
detailed in the Schedule of Evaluations (Table 1-1). During screening, the 
Investigator/sub-Investigator should assess the clinical significance of any values that are 
outside the reference ranges provided by the central laboratory; patients with 
abnormalities judged to be clinically significant will be excluded from the study. Laboratory 
results should be reviewed by the Investigator/sub-investigator throughout the study. 


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Patients are required to fast overnight (≥ 10 hours) before arriving at the study site for 
appointments involving the collection of clinical laboratory blood tests. 
The following clinical laboratory analytes will be evaluated: 
Hematology: hematocrit; hemoglobin; HbA1c (Screening/Visit 1 and Visit 8/ET); red blood 
cell count with indices (mean corpuscular volume, mean corpuscular hemoglobin, and 
mean corpuscular hemoglobin concentration); reticulocytes; white blood cell count and 
differential (neutrophils, lymphocytes, monocytes, eosinophils, and basophils) reported 
as percent (%) and absolute values; and platelet count. 
Clinical chemistry: albumin; alkaline phosphatase; blood urea nitrogen; gamma-
glutamyl transferase; calcium; creatinine; glucose; insulin; cholesterol (high-density 
lipoprotein [HDL] and low-density lipoprotein [LDL] [calculated] and LDL will be reported, 
and LDL will be reflexed if a patient’s triglycerides are >400 mg/dL); triglycerides; 
phosphate; potassium; prolactin; ALT; AST; lactate dehydrogenase; sodium; chloride; 
bilirubin (total, direct); total protein; uric acid; creatine phosphokinase; and TSH (reflex 
free T3 and free T4 at Screening/Visit 1 and at Visit 8/ET only). 
Urinalysis: macroscopic (pH, specific gravity, glucose, protein, ketones, nitrates, blood) 
and microscopic (red blood cells/high-power field, white blood cells/high-power field, 
casts, epithelial cells, crystals, granulation). 
8.3.5.1 
Hepatitis Screening 
Blood samples will be collected at screening from all patients in order to perform 
hepatitis B surface antigen, hepatitis B core antibody IgM, and hepatitis C antibody 
(immunoglobulin G) testing. Test results will be sent to the study site and must be 
reviewed before Baseline (Visit 2, Day 1). Any patient who tests positive for hepatitis B 
surface antigen and/or hepatitis B core antibody IgM or positive hepatitis C antibody with 
a positive confirmatory hepatitis C RNA result will be excluded from participating in the 
study. Details regarding sample collection, processing, and shipping are provided in the 
Laboratory Manual. 
8.3.5.2 
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 alcohol or any drug, excluding prescription 
benzodiazepines, prescription opiates, and cannabinoids, at screening will be excluded 
from participating in the study. Positive drug screen results may undergo confirmative 


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testing. Repeat testing is prohibited for positive alcohol, cocaine, phencyclidine, and 
amphetamine results. 
Additional information regarding sample collection, processing, and shipping is provided 
in the Laboratory Manual. 
8.3.5.3 
Urine and Serum Pregnancy Test 
Female patients who are of childbearing potential will undergo serum and urine 
pregnancy tests at the study clinic at Screening (Visit 1), at Baseline (Visit 2, Day 1), and, 
at the discretion of the Investigator, at an Unscheduled Visit. At Visit 5 and Visit 8/ET, 
urine pregnancy tests will be administered. 
Serum pregnancy testing will be performed using blood collected as part of protocol-
specified sample; urine pregnancy testing will use a urine dipstick. 
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. 
8.3.6 Other Safety Assessments 
8.3.6.1 
Extrapyramidal Scales 
8.3.6.1.1 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” 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 in the study according to Schedule of Events (Table 1-1). 
8.3.6.1.2 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 


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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 in the study according to 
Schedule of Events (Table 1-1). 
8.3.6.1.3 Simpson-Angus Scale 
The SAS is a measure of extrapyramidal side effects (Simpson and Angus 1970). Ten 
items including rating gait, arm dropping, shoulder shaking, elbow rigidity, wrist rigidity, 
leg pendulousness, head dropping, 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 in the study according 
to Schedule of Events (Table 1-1). 
8.3.6.2 
C-SSRS 
The C-SSRS is a clinician-rated instrument that reports the severity of both suicidal 
ideation and behavior (Posner, 2011). Suicidal ideation is classified on a 5-item scale: 
• 1 (wish to be dead) 
• 2 (nonspecific active suicidal thoughts) 
• 3 (active suicidal ideation with any methods [not plan] without intent to act) 
• 4 (active suicidal ideation with some intent to act, without specific plan); and 
•  5 (active suicidal ideation with specific plan and intent). 
The C-SSRS also captures information about the intensity of ideation, specifically the 
frequency, duration, controllability, deterrents, and reasons for the most severe types of 
ideation.  
Suicidal behavior categories are: 
• Actual attempt 
• Interrupted attempt 
• Aborted attempt 
• Preparatory acts or behavior 
• Presence of suicidal behavior 


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More than 1 classification can be selected provided it represents separate episodes. For 
actual attempts only, the actual or potential lethality is classified for the initial, most lethal, 
and most recent attempts. 
The C-SSRS will be completed at all study visits. At Screening (Visit 1), the C-SSRS will 
be completed for the patient’s lifetime history of suicidal ideation and behavior 
(“Baseline/Screening” version). At all other visits, the C-SSRS will be completed for 
suicidal ideation and behavior since the previous visit (“Since Last Visit” version). Before 
the patient leaves the study site, the Investigator or appropriately qualified designee will 
assess the patient’s C-SSRS results. 
The patient should not be released from the study center until the results of the C-SSRS 
are reviewed and the patient is not considered to be at risk. If there is doubt about whether 
a patient is at risk, the Investigator must obtain appropriate psychiatric consultation. The 
results of the C-SSRS will be recorded in the eCRF. 
8.3.6.3 
Modified Physical and Neurological Examination  
A modified physical examination, including neurological and excluding genital/rectal 
examinations, will be performed. The examination should include evaluation of height (m; 
at Screening/Visit 1 only); body weight (kg); waist circumference (cm); appearance and 
skin; head and neck; eyes, ears, nose, and throat; chest and lungs; heart; abdomen; and 
extremities. Neurological findings will also be recorded. All physical examination findings 
must be documented in the patient’s study chart and also recorded in the eCRF. 


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9 STATISTICAL CONSIDERATIONS 
A statistical analysis plan (SAP) will be finalized prior to unblinding the patients’ treatment 
assignments and will provide further details regarding the definition of analysis endpoints 
and analysis methodology to address all study objectives. Changes made to the data 
analysis methods as described in the protocol will be documented in the SAP and will not 
necessitate a protocol amendment. All departures from the statistical analyses described 
in the approved protocol, whether made before or after unblinding, will be documented, 
and justified in the final clinical study report. 
The study randomized 100 patients with Bipolar Disorder (Bipolar I or Bipolar II) before 
Amendment 2.0 (dated 02 Nov 2020). The efficacy data of these 100 patients will be 
combined with those of patients with Bipolar Disorder enrolled after Amendment 2.0 as a 
separate analysis.  
 
Table 9-1 presents an overview of the statistical data analyses planned for all patients 
enrolled in the study.  


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Table 9-1: Overview of Statistical Data Analyses 
Analysis 
Patients 
Randomized 
before Protocol 
Amendment 2.0 
Patients Randomized after Protocol 
Amendment 2.0 
All Bipolar 
Patients 
(randomized 
before or after 
Amendment 2.0) 
All Patients 
randomized 
before or after 
Amendment 2.0 
Bipolar 
Disorder 
with Mixed 
Features 
MDD with 
Mixed 
Features 
All Patients 
Randomized 
after Protocol 
Amendment 2.0 
Patient Disposition 
Yes 
Yes 
Yes 
Yes 
Yes 
Yes 
Protocol Deviation 
Yes 
Yes 
Yes 
Yes 
 
Yes 
Demographic and 
baseline characteristics 
Yes 
Yes 
Yes 
Yes 
Yes 
Yes 
Bipolar Diagnosis, 
Psychiatric Diagnosis 
and History 
Yes 
Yes 
Yes 
Yes 
— 
— 
Medical History 
Yes 
Yes 
Yes 
Yes 
— 
— 
Prior/Concomitant 
Medication 
Yes 
Yes 
Yes 
Yes 
— 
— 
Exposure/ Compliance 
Yes 
Yes 
Yes 
Yes 
Yes 
Yes 
Primary and Key 
Secondary Efficacy 
Yes1 
Yes 
Yes 
Yes 
Yes 
Yes 
AE 
Yes 
Yes 
Yes 
Yes 
Yes 
Yes 
Labs 
— 
Yes 
Yes 
Yes 
Yes 
Yes 
Vital Signs 
— 
Yes 
Yes 
Yes 
Yes 
Yes 
ECG 
— 
Yes 
Yes 
Yes 
Yes 
Yes 
C-SSRS 
— 
Yes 
Yes 
Yes 
Yes 
Yes 
YMRS 
Yes 
Yes 
Yes 
Yes 
Yes 
Yes 
AIMS, BARS, and SAS2 
— 
Yes 
Yes 
Yes 
Yes 
— 
AE = adverse event; AIMS = Abnormal Involuntary Movement Scale; BARS = Barnes Akathisia Rating Scale; C-SSRS = Columbia Suicide 
Severity Rating Scale; ECG = electrocardiogram; SAS = Simpson-Angus Scale; YMRS = Young Mania Rating Scale. 
1 
Descriptive statistics only. 
2 
AIMS, BARS, and SAS assessments were added after implementation of Protocol Amendment 2.0. 
 


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Blinded data reviews will be conducted prior to unblinding the patients’ treatment 
assignments for assessing the accuracy and completeness of the study database and 
defining analysis sets, patient evaluability, and appropriateness of the planned statistical 
methods. 
9.1 
Sample Size Considerations 
The assumed effect size (treatment group difference relative to pooled SD) of 0.37 for 
lumateperone is based on a treatment difference of 3.3 units with a common pooled SD 
of 9 for the primary efficacy parameter, change from baseline to Day 43 in MADRS total 
score. A sample size of 350 patients (175 per treatment group) will need to be enrolled 
after the implementation of Amendment 2.0 (dated 02 Nov 2020) to provide 90% power 
for primary analysis for the combined population of Bipolar Disorder with mixed features 
and MDD with mixed features based on an MMRM model using simulation method 
(Lu, 2012). The simulation assumed a correlation of 0.7 between the repeated measures 
and a dropout rate of 10% based on historical data.  
The assumed values of drop-out rate of 10%, correlation of 0.7, and standard deviation 
of 9 are approximate estimates from a previous successful study of lumateperone for 
bipolar depression. The assumed treatment difference of 3.3 used to obtain the power of 
90% is considered appropriate as the generated sample size can cover a wide range of 
clinically relevant treatment difference to be detected as statistically significant. 
The study will enroll approximately equal number of patients (175) for the Bipolar Disorder 
with mixed features and for MDD with mixed features following Amendment 2.0. 
Assuming an effect size of 0.45, and same assumptions of drop-out rate and correlation 
between the repeated measures, this sample size (approximately 87 patients in each 
treatment group) for each of the two subpopulations is expected to provide approximately 
80% statistical power for the primary efficacy analysis with the adjustment of multiplicity 
for the testing of the primary analysis in each of the subpopulations.  
The study randomized approximately 100 patients under the original protocol before the 
implementation of Amendment 2.0 (dated 02 Nov 2020); therefore, the total enrollment 
for the study will be approximately 450 patients. 
9.2 
Planned Interim Analyses 
No interim analysis is planned. 


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9.3 
Analysis Sets 
All Enrolled Set will contain all patients who signed the informed consent for the study. 
All Patients Randomized Set will contain all patients who signed the informed consent 
and were randomized to study drug. 
Intent-to-treat (ITT) Analysis Set will contain all randomized patients who received at 
least 1 dose of study drug and who had a non-missing (pre-dose) baseline assessment 
and at least 1 non-missing post-baseline assessment of MADRS total score. 
 
Modified Intent-to-treat (mITT) Analysis Set will contain all randomized patients who 
received at least 1 dose of study drug and who had a valid (pre-dose) baseline 
assessment and at least 1 valid post-baseline assessment of MADRS total score and 
were enrolled after the implementation of Amendment 2.0 (dated 02 Nov 2020). Patients 
enrolled before the implementation of Amendment 2.0 will not be included in the mITT 
Analysis Set. 
Sensitivity Set will contain all patients randomized after the implementation of Amendment 
2.0 (dated 02 Nov 2020) and who received at least 1 dose of study drug and who had a 
valid (pre-dose) baseline assessment of MADRS total score. Patients enrolled before the 
implementation of Amendment 2.0 will not be included in the Sensitivity Set. 
The Bipolar Intent-to-treat (bITT) Analysis Set will contain all randomized Bipolar Disorder 
patients who received at least 1 dose of study drug and had baseline assessment and at 
least 1 post-baseline assessment of MADRS total score. The bITT Analysis Set will be 
based on patients enrolled before the implementation of Amendment 2.0 as well as the 
patients of Bipolar Disorder with mixed features enrolled after the implementation of 
Amendment 2.0.Safety Analysis Set will contain all patients who received at least 1 dose 
of study drug. 
9.4 
Statistical Analysis Methodology 
Categorical variables (eg, AEs) will be summarized using the number and percentage of 
patients in specified categories. Unless otherwise stated, the calculation of percentages 
will be based on the number of patients in the analysis set of interest. Continuous 
variables (eg, MADRS total score) will be summarized using descriptive statistics 
including number of patients, mean, standard deviation, median, minimum, and 
maximum. 
For analysis purposes, baseline is defined as the last non-missing measurement before 
the first dose of study drug. Assessments on Day 1 for which times are recorded will be 


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considered baseline if the assessment time is before the time of the first dose of study 
drug. 
Unless stated otherwise, statistical tests will be performed at a 2-sided significance level 
of 0.05, leading to 95% (2-sided) confidence intervals (CIs). 
For efficacy analyses in which study site is a factor, a small site will be defined as a site 
with less than 2 patients in at least one treatment group for each specific analysis set (ie, 
the mITT Set, the Bipolar Disorder with mixed features based on mITT Set, the MDD with 
mixed feature based on mITT Set, and the bITT Set). Small sites in each specific analysis 
set will be pooled to form pseudo-sites so that each treatment group includes at least 
2 patients within the site. Pooling will be performed separately for each analysis set but 
using the same algorithm described as the following: 
Based on the number of patients, small sites will be ordered from the largest to the 
smallest, and sites of the same size will be ordered from the largest site code to the 
smallest site code. The pooling process starts with the largest small site from the top, 
which will be pooled with the smallest from the bottom until a non-small site is formed. 
The process will be repeated using the small sites left out after the first pass. If any sites 
are left out at the end of the process, they will be pooled with the smallest pseudo site. If 
there is more than 1 smallest pseudo site, the pseudo site with the smallest site code will 
be selected. In case the pseudo site formed by pooling all small sites is still a small site, 
it will be pooled with the smallest non-small site. If there is more than 1 smallest non-
small site, the one with the smallest site code will be selected. 
All statistical analysis will be performed using SAS® software Version 9.4 or newer. 
Additional details regarding the statistical analysis methodology will be provided in the 
SAP. 
9.4.1 Patient Disposition, Analysis of Demographics and Other Baseline 
Characteristics 
Patient disposition will be summarized by treatment group, when applicable, and overall, 
including 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 or MDD will be summarized.  
Demographic and baseline characteristics, including Bipolar Disorder or MDD diagnosis 
and baseline efficacy parameters, will be listed and summarized by treatment group as 
outlined in Table 9-1 for the Safety Analysis Set. No inferential statistics will be presented. 


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9.4.2 Prior and Concomitant Medications 
Prior, concomitant, and post-treatment medications, defined by start and stop dates 
relative to study drug administration, will be summarized by Anatomical Therapeutic 
Chemical (ATC) code, preferred term and treatment group for the Safety Analysis Set as 
outlined in Table 9-1. Patients with multiple occurrences of a medication in the same 
preferred term will only be counted once within the preferred term. 
During the study, a patient may be treated with zolpidem as described in Section 6.6. The 
number and percent of patients in the Safety Analysis Set receiving zolpidem and the 
total number of days on zolpidem will be summarized by treatment group for the 
Screening Period, for each week during the Double-blind Treatment Period and for post-
treatment with lumateperone. 
9.4.3 Study Drug Exposure and Treatment Compliance 
Exposure to study drug and treatment compliance will be presented using the Safety 
Analysis Set as outlined in Table 9-1. Duration of exposure (days) and dosing compliance 
(%) will be calculated and summarized by treatment group. Additionally, the number and 
percentage of patients exposed to study drug will be presented by study week, defined 
by the planned visits. 
9.4.4 Analysis of Primary and Key Secondary Efficacy Endpoints 
The study is designed to evaluate the efficacy of lumateperone 42 mg based on the 
following primary and key secondary efficacy endpoints: 
• Primary Endpoint – Change from baseline to Day 43 in the MADRS total score. 
• Key Secondary Endpoint – Change from baseline to Day 43 in the CGI-S score. 
The treatment effect on the primary efficacy endpoint will be evaluated in the combined 
population of Bipolar Disorder with mixed features and MDD with mixed features using a 
mixed-effect model for repeated measures (MMRM) method based on the mITT Set. The 
model will include the change from baseline at each pre-specified time point in the 
MADRS total score as the response variable; treatment group (lumateperone 42 mg and 
placebo), visit, site (or pooled site), the stratification factor at screening (Bipolar I, 
Bipolar II, or MDD), and treatment group-by-visit interaction as factors; and the baseline 
MADRS total score and visit-by-baseline MADRS total score interaction as covariates. An 
unstructured covariance matrix will be used to estimate the covariance 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 


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autoregressive(1) (ARH(1)), heterogeneous compound symmetry (CSH), 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 (CS). Model parameters 
will be estimated using restricted maximum likelihood. The Kenward-Roger approximation 
will be used to estimate the denominator degrees of freedom. 
The MMRM method described above will also be used for the primary efficacy analyses 
based on the subpopulation of Bipolar Disorder with mixed features in the mITT Set and 
based on the subpopulation of MDD with mixed features in the mITT Set.  
The key secondary efficacy endpoint, change from baseline to Day 43 in the CGI-S score, 
will be analyzed based on the mITT Set using an MMRM method similar to the one 
specified for the analysis of the primary efficacy endpoint, but replacing MADRS total 
score with CGI-S score for the baseline and baseline-by-visit interaction terms as 
covariates in the model. 
The MMRM method for the key secondary efficacy endpoint will also be applied to the 
key secondary efficacy analyses based on the subpopulations of Bipolar Disorder with 
mixed features in the mITT Set and based on the MDD with mixed features in the mITT 
Set. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 


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9.4.6 Safety Analyses 
All safety parameters will be summarized using the Safety Analysis Set as outlined in 
Table 9-1.  
Safety data such as reported and observed AEs, treatment emergent AEs (TEAEs) and 
SAEs, clinical laboratory results, vital signs, physical examinations and neurological 
findings, ECGs, YMRS, AIMS, BARS, SAS, and C-SSRS) will be summarized by treatment 
group and by visit when appropriate. When appropriate, out-of-range values will be flagged 
in data listings and tabulated. Shift tables will be prepared for pre-specified safety measures, 
such as laboratory parameters and ECG. Parameters collected in duplicate or triplicate will 
be analyzed as an average of the measures for the relevant time point, including baseline. 
Reported AE terms will be coded using the latest version of the Medical Dictionary for 
Regulatory Activities (MedDRA). TEAEs are defined as any AEs, regardless of the 
relationship to study drug, that occur or worsen in severity after the first dose of study 
medication and on or before the date of last dose of study medication plus one day. 
Treatment-related TEAEs will be defined as any TEAEs that are considered by the 
investigator to be either possibly, probably, or definitely related to study drug. If relationship 
to study drug is missing, the TEAE will be considered as treatment-related. Severity of 
TEAEs will also be determined by the Investigator. All TEAEs, treatment-related TEAEs, and 
SAEs will be summarized by treatment group, primary system organ class categories, and 


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preferred terms. If a patient reports the same TEAE more than once within the same system 
organ class and preferred term, the event with the worst-case relationship to study drug will 
be used in the corresponding relationship summaries. Similarly, if a patient reports a TEAE 
more than once within the same system organ class and preferred term, the event with the 
worst-case severity will be used in the corresponding severity summaries. 
Patients who discontinue study or study drug due to AEs will be listed and summarized 
by system organ class and preferred term. TEAEs will be categorized to monitor signals 
of potential abuse of lumateperone and the number and percentage of patients with at 
least one 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 potentially clinically significant (PCS)  values 
during the Double-blind Treatment Period according to normal range criteria  and shifts 
from baseline to the end of Double-blind Treatment Period . Listings may be provided for 
patients meeting the PCS criteria.  
For the C-SSRS, the number and percentage of patients who have suicidal ideation or 
suicidal behaviors will be summarized by treatment group. Supportive listings will be 
provided that include treatment group, assessment date, lifetime history, and 
postbaseline values for each patient. Intensity of suicidal ideation, suicidal behavior type, 
and lethality of suicidal behavior will also be included in these listings. 
The observed and change from baseline in YMRS, AIMS, BARS, and SAS will be 
summarized by treatment group and by visit. 
Additional details for analyses on safety assessments will be provided in the SAP. 
9.5 
Protocol Deviations 
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 or have 
any impact on the efficacy analyses. Significant deviations can include nonadherence to 
inclusion or exclusion criteria, enrollment of the patient without prior sponsor approval, or 
nonadherence to FDA or local regulations or ICH GCP guidelines and may lead to the 
patient being withdrawn from the study (Section 5.5). 
The Investigator or designee must document and explain in the patient’s source 
documentation any deviation from the approved protocol. The Investigator may 


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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. 
The IRB/IEC should be notified of all protocol deviations in a timely manner, according to 
local requirements. 
Major protocol deviations observed during the Double-blind Treatment Period will be 
summarized by treatment group as outlined in Table 9-1 using the ITT Set. 


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10 ETHICS/PROTECTION OF HUMAN SUBJECTS 
10.1 
Institutional Review Board and Independent Ethics Committee  
Federal regulations and the International Conference on Harmonisation (ICH) guidelines 
require that approval be obtained from an IRB or IEC before participation of human 
patients in research studies. 
The protocol, informed consent form(s), recruitment materials, and all patient materials 
will be submitted to the IRB/IEC and local regulatory authorities (where applicable) for 
review and approval. Approval of both the protocol and the consent form must be obtained 
before any patient is enrolled. Any amendment to the protocol will require review and 
approval by the IRB/IEC as well as local regulatory authorities before the changes are 
implemented in the study. 
Documentation of all IRB/IEC approvals and of the IRB/IEC compliance with ICH 
harmonised tripartite guideline E6(R1): GCP will be maintained by the study site and will 
be available for review by the sponsor or its designee. 
All IRB/IEC approvals should be signed by the IRB/IEC chairman or designee and must 
identify the IRB/IEC name and address; the clinical protocol by title, protocol number, or 
both; and the date approval or a favorable opinion was granted. 
The Investigator is responsible for providing written summaries of the progress and status 
of the study at intervals not exceeding 1 year or otherwise specified by the IRB/IEC. The 
Investigator must promptly supply the sponsor or its designee, the IRB/IEC, and, where 
applicable, the institution, with written reports on any changes significantly affecting the 
conduct of the study or increasing the risk to patients. 
10.2 
Ethical Conduct of the Study 
The study will be performed in accordance with the ethical principles that have their origin 
in the Declaration of Helsinki, ICH GCP, and all applicable regulations. 
10.3 
Information and Informed Consent 
A written informed consent in compliance with US Title 21 Code of Federal Regulations 
(CFR) Part 50 shall be obtained from each patient before entering the study or performing 
any nonroutine procedure that involves risk to the patient. An informed consent template 
will be provided by the Sponsor to clinical study sites. If any institution-specific 
modifications to study-related procedures are proposed or made by the study site, the 
consent should be reviewed by the Sponsor, its designee, or both before IRB/IEC 
submission. Once reviewed, the consent will be submitted by the Investigator to his or 


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her IRB/IEC for review and approval before the start of the study. If the ICF is revised 
during the course of the study, all active participating patients must sign the revised form. 
Before any screening procedure, a consent form describing in detail the study procedures 
and risks will be given to the patient. The patient is required to read and review the 
document or have the document read to him/her. The Investigator or designee will explain 
the research study to the patient and answer any questions that may arise. Once the 
Investigator is assured that the patient understands the implications of participating in the 
study, the patient will be asked to give consent to participate in the study by signing the 
ICF prior to any study-related assessments or procedures. Patients will be given the 
opportunity to discuss the study with their surrogates or think about it prior to agreeing to 
participate. They may withdraw consent at any time throughout the course of the study. 
A copy of the signed informed consent document will be given to patients for their records. 
The rights and welfare of the patients will be protected by emphasizing to them that the 
quality of their clinical care will not be adversely affected if they decline to participate in 
this study. 
The consent process will be documented in the clinical or research record. 
The Investigator shall retain the signed original ICF(s) and give a copy of the signed 
original form to the patient. 
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. 
10.4 
Patient Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in 
a manner designed to maintain patient confidentiality. All records will be kept in a secure 
storage area with limited access. Clinical information will not be released without the 
written permission of the patient, except as necessary for monitoring and auditing by the 
Sponsor, its designee, the US FDA or other local regulatory authorities, or the IRB/IEC. 
The Investigator and all employees and coworkers involved with this study may not 
disclose or use for any purpose other than performance of the study any data, record, or 
other unpublished, confidential information disclosed to those individuals for the purpose 
of the study. Prior written agreement from the Sponsor or its designee must be obtained 
for the disclosure of any said confidential information to other parties. 


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11 INVESTIGATOR OBLIGATIONS 
11.1 
Documentation 
Prior to beginning the study, the Investigator will be asked to comply with ICH E6(R1) 8.2 
and Title 21 of the US Code of Federal Regulations by providing to the Sponsor the 
following essential documents, including but not limited to: 
• A completed and signed Form FDA 1572. If, during the course of the study, any 
changes are made that are not reflected on Form FDA 1572, a new Form 
FDA 1572 must be completed and returned to the Sponsor for submission to 
the FDA 
• A fully executed contract 
• The curricula vitae for the Investigator and all sub-investigators listed on Form FDA 
1572, including a copy of each physician’s license 
• Financial disclosure agreement completed and signed by the Investigator and all 
Sub-investigators listed on Form FDA 1572. The Investigator and all sub-
investigators will provide an updated financial disclosure agreement to the Sponsor 
1 year after the completion of the study. 
• A copy of the original IRB/IEC approval for conducting the study. If the study is 
ongoing, renewals must be submitted at yearly intervals. All subsequent 
modifications must be submitted and approved by the IRB/IEC. 
• A copy of the IRB/IEC-approved ICF 
• A copy of the HIPAA authorization form, or other applicable local privacy forms 
• A list of the IRB/IEC members or the US Department of Health and Human 
Services general assurance number 
• A copy of the laboratory certifications and reference ranges 
• The Investigator’s Signature page in this protocol signed and dated by the 
Investigator 
11.2 
Performance 
The Investigator must demonstrate reasonable efforts to recruit qualified patients for the 
study. 


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11.3 
Use of Investigational Materials 
The Investigator will acknowledge on the Investigator Signature page that the study drug 
supplies are investigational and as such must be used strictly in accordance with the 
protocol and only under the supervision of the Investigator or Sub-investigators listed on 
Form FDA 1572. Study drug supplies must be stored in a secured place and must be 
locked. At study initiation, a representative from the Sponsor will inventory the study drug 
supplies at the study center. The Investigator must maintain adequate records 
documenting the receipt and disposition of all study supplies as well as daily temperature 
logs. The Sponsor may supply forms on which to record the date the study drug was 
received and a dispensing record in which to record each patient’s use. All unused study 
drug must be returned to the Sponsor-designated central depot. 
11.4 
Study Records Retention 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. However, if required 
by the applicable regulatory requirements or by an agreement with the Sponsor, these 
documents should be retained for a longer period. It is the responsibility of the Sponsor 
to inform the Investigator/institution as to when these documents no longer need to be 
retained. 
11.5 
Clinical Site Monitoring 
All aspects of the study will be carefully monitored by the Sponsor or its designee to 
ensure compliance with applicable government regulations, current GCP, and current 
standard operating procedures. 
The Clinical Monitor, as a representative of the Sponsor, is obligated to closely monitor 
the study. In doing so, the monitor will visit the Investigator and study site at periodic 
intervals, in addition to maintaining necessary contact with the Investigator and study site. 
The Clinical Monitor will maintain current knowledge of the study through observation, 
review of study records and source documentation, and discussion of study conduct with 
the Investigator and study site personnel. 


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12 DATA HANDLING AND RECORD KEEPING 
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 MINI, laboratory reports, and ECG 
tracings. 
After database lock, each study site will receive documentation containing all of their 
study site-specific eCRF data as entered into the electronic data capture (EDC) system, 
including full discrepancy and audit history. Additionally, documentation of all of the study 
site’s data will be created and sent to the Sponsor for storage. The CRO will maintain 
duplicate copy for its records.  
In all cases, patient initials and other protected patient information will not be collected or 
transmitted to the Sponsor. 
12.1 
Data Monitoring 
Before any patient enters the study, a representative of the Sponsor will meet with the 
Investigator and the study center personnel to review the procedures to be followed 
during the study. EDC functionality training is provided via computer-based training to 
train Investigators and authorized designees on recording the data in the eCRFs using 
the EDC system. 
The Investigator will maintain complete source documents (eg, signed ICFs, written or 
electronic medical records, pharmacy records). Source documents provide evidence for 
the existence of study patients and substantiate the integrity of the data collected in the 
eCRF. The Investigator will make available to the Clinical Monitor or designee source 
documents (written notes and electronic medical records, if used), signed ICFs, and all 
other study-related documents. 
Clinical Monitors, appointed by the Sponsor, will perform ongoing source document 
verification to confirm that data entered into the eCRF are accurate, complete, and 
verifiable from source documents; that the safety and rights of patients are protected; and 
that the study is conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. After the 
first patient is enrolled, the Clinical Monitor or designee, will periodically monitor the 
progress of the study by conducting on-site visits. In addition to on-site source document 
verification, Clinical Monitors will review study progress remotely, possibly warranting 


Intra-Cellular Therapies, Inc. Confidential 
66 
ITI-007-403 Protocol        
27 Jan 2023 
 
more frequent communication and/or study center visits. Details of monitoring activities 
are provided in the Clinical Operations Plan. 
12.2 
Data Recording and Documentation 
Data collection will involve the use of the EDC system, to which only authorized personnel 
will have access. Patient data are to be entered into the EDC system by the Investigator 
or designee using their assigned EDC user account. The Investigator or designee will 
record all patients’ study data in the eCRF, unless the data are transmitted to the Sponsor 
electronically (eg, laboratory data). Data entered in the eCRF must be consistent with the 
source documents or the discrepancies must be explained. The Investigator is 
responsible for verifying that all data entries are accurate and correct. The Investigator 
may need to request previous or external medical records to support study data. 
The Sponsor is responsible for the data management of this study, including quality 
checking of the data. The Sponsor or designee will review study data for completeness, 
logic, and protocol adherence, using a combination of manual review and programmatic 
edit checks. After data entry into the EDC system by the Investigator or designee, a 
combination of manual and programmatic edit checks will be used to review the data for 
completeness, logic, and adherence to study protocol. As a result of these edit checks, 
data monitoring, and reviews, queries may be electronically issued to the study center 
and should be answered electronically via the EDC system. Each query will carry 
identifying information (assigned username, date, and time) to assist the Sponsor and the 
Investigator on the origin of the data clarification request and the response provided by 
the Investigator. All data changes made to the patient’s data via a data query will be 
approved by the Investigator prior to final database lock. 
The Investigator or designee will be responsible for approving all changes to the data and 
endorsing the patient data within the EDC system. This approval method will include 
applying an electronic signature linked to a uniquely assigned username and password 
that together will represent a traditional handwritten signature. After all data have been 
reviewed and all issues have been resolved, the database will be locked. 
All data collected in the context of this study will be stored and evaluated per regulatory 
requirements and applicable guidance for electronic records. Also, data will be stored and 
evaluated in such a way as to guarantee patient confidentiality in accordance with the 
legal stipulations applying to confidentiality of data. Study records (eg, copies of eCRFs, 
laboratory reports, and regulatory documents) will be retained at the study center, along 
with adequate source documentation, according to FDA and ICH requirements. All study 
records must be available for inspection by the Sponsor, its authorized representatives, 
the FDA, or other health authorities. 


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ITI-007-403 Protocol        
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Source documents will be used at the study centers and may include a patient’s medical 
record, hospital charts, clinic charts, the Investigator’s patient study files, as well as the 
results of diagnostic tests such as laboratory tests, ECGs, etc. A centralized clinical 
laboratory will be used for the analysis of all blood samples. Additional information on the 
collection and handling of samples is detailed in the Laboratory Procedure Manual. 


Intra-Cellular Therapies, Inc. Confidential 
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27 Jan 2023 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Intra-Cellular Therapies, Inc. Confidential 
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ITI-007-403 Protocol        
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14 LITERATURE REFERENCES 
Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiatry. 1989.154:672-6. 
Davis RE, Vanover KE, Zhou Y, et al. ITI-007 demonstrates brain occupancy at 
serotonin 5-HT2A and dopamine D2 receptors and serotonin transporters using positron 
emission tomography in healthy volunteers. Psychopharmacology (Berl). 
2015;232(15):2863-72. 
Guy W, editor. ECDEU Assessment Manual for Psychopharmacology. Rockville: US 
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.  
Lu K. Sample size calculations with multiplicity adjustment for longitudinal clinical trials 
with missing data. Statist Med. 2012; 31:19-28. 
McIntyre RS, Suppes T, Earley W, et al. Cariprazine efficacy in bipolar I depression with 
and without concurrent manic symptoms: post hoc analysis of 3 randomized, placebo-
controlled studies. CNS Spectrums. 2020; 25(4):502-510. 
McIntyre RS, Cucchiaro J, Pikalov A, et al. Lurasidone in the treatment of bipolar 
depression with mixed (subsyndromal hypomanic) features: post hoc analysis of a 
randomized placebo-controlled trial. J Clin Psychiatry. 2015; 76(4):398-405. 
Montgomery SA and Åsberg M. A new depression scale designed to be sensitive to 
change. Br J Psychiatry. 1979;134:382-389. 
Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: 
initial validity and internal consistency findings from three multisite studies with 
adolescents and adults. Am J Psychiatry. 2011;168(12):1266-77. 
Sheehan DV, Lecrubier Y, Harnett-Sheehan K, Amorim P, et al. 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. 


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Simpson GM. Angus JW. A rating scale for extrapyramidal side effects. Acta Psychiat 
Scand Suppl. 1970;212:11–9. 
Snyder GL, Vanover KE, Zhu H, et al. Functional profile of a novel modulator of 
serotonin, dopamine, and glutamate neurotransmission. Psychopharmacology (Berl). 
2015;232(3):605-21. 
Suppes T, Silva R, Cucchiaro J, et al. Lurasidone for the Treatment of Major Depressive 
Disorder With Mixed Features: A Randomized, Double-Blind, Placebo-Controlled Study. 
Am J Psychiatry. 2016; 173(4):400-407. 
Swann AC, Fava M, Tsai J, et al. Lurasidone for major depressive disorder with mixed 
features and irritability: a post-hoc analysis. CNS Spectrums. 2017; 22, 228–235. 
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: 
NCT04285515 
 
 
 
 
Study ID: ITI-007-403 
 
 
 
Title: A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multi-Center Study to 
Assess the Efficacy and Safety of Lumateperone Monotherapy in the Treatment of Patients 
with Major Depressive Episodes Associated with Bipolar I or Bipolar II Disorder 
(Bipolar Depression) or Major Depressive Disorder 
 
SAP Date: 31 Jan 2023 


A Phase 3, Randomized, Double-blind, Placebo-controlled, 
Multi-Center Study to Assess the Efficacy and Safety of 
Lumateperone Monotherapy in the Treatment of Patients 
with Major Depressive Episodes Associated with Bipolar I or 
Bipolar II Disorder (Bipolar Depression) or Major 
Depressive Disorder 
Statistical Analysis Plan 
Protocol Number: 
Version: 
ITI-007-403 
Final 
Date: 
31 Jan 2023 
Compound: 
Lumateperone 
Study Phase: 
3 
Sponsor: 
Intra-Cellular Therapies, Inc. 
Alexandria Center for Life Science 
430 East 29th Street, Suite 900 
New York, NY 10016 
Confidentiality Statement 
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 Intra-Cellular Therapies, Inc. 


 
 
 
Page 2 of 44 
TABLE OF CONTENTS 
TABLE OF CONTENTS ................................................................................................................ 2 
1. 
LIST OF ABBREVIATIONS .............................................................................................. 4 
2. 
INTRODUCTION ............................................................................................................... 6 
3. 
STUDY OBJECTIVES ...................................................................................................... 11 
3.1 
Primary Efficacy Objective ............................................................................................ 11 
3.2 
Secondary Efficacy Objectives ...................................................................................... 11 
3.2.1 
Key Secondary Efficacy Objective ......................................................................... 11 
 
 
4. 
ANALYSIS SETS ............................................................................................................. 12 
4.1 
All Enrolled Set .............................................................................................................. 12 
4.2 
All Patients Randomized Set .......................................................................................... 12 
4.3 
Safety Analysis Set......................................................................................................... 12 
4.4 
Intent-to-Treat Analysis Set ........................................................................................... 12 
 
 
 
 
 
 
5. 
PATIENTS DISPOSITION ............................................................................................... 13 
 
 
7. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ............................ 15 
8. 
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE .................................. 16 
8.1 
Extent of Exposure ......................................................................................................... 16 
8.2 
Treatment Compliance ................................................................................................... 16 
9. 
EFFICACY ANALYSES .................................................................................................. 17 
9.1 
Primary Efficacy Parameter ........................................................................................... 18 
 
 
9.3 
Additional Efficacy Parameters ..................................................................................... 20 
10. 
SAFETY ANALYSES....................................................................................................... 23 
10.1 
Adverse Events ............................................................................................................... 23 
10.2 
Clinical Laboratory Parameters ...................................................................................... 24 
10.3 
Vital Signs ...................................................................................................................... 27 
10.4 
Electrocardiograms......................................................................................................... 28 


 
 
 
Page 3 of 44 
10.5 
Other Safety Parameters ................................................................................................. 29 
10.5.1 
Columbia-Suicide Severity Rating Scale (C-SSRS) ............................................... 29 
10.5.2 
Young Mania Rating Scale (YMRS) ...................................................................... 30 
10.5.3 
Abnormal Involuntary Movement Scale (AIMS) ................................................... 30 
10.5.4 
Barnes Akathisia Rating Scale (BARS) .................................................................. 30 
10.5.5 
Simpson Angus Scale (SAS) .................................................................................. 31 
11. 
INTERIM ANALYSIS ...................................................................................................... 32 
12. 
SAMPLE SIZE CONSIDERATION ................................................................................. 33 
13. 
STATISTICAL SOFTWARE ............................................................................................ 34 
14. 
DATA HANDLING CONVENTIONS ............................................................................. 35 
14.1 
Visit Time Windows ...................................................................................................... 35 
14.2 
Derived Efficacy Variables ............................................................................................ 35 
14.3 
Repeated or Unscheduled Assessments of Safety Parameters ....................................... 35 
14.4 
Missing Date of the Last Dose of Study Drug ............................................................... 36 
14.5 
Missing Severity Assessment for Adverse Events ......................................................... 36 
14.6 
Missing Relationship to Study Drug for Adverse Events .............................................. 36 
14.7 
Missing Dates Information for Adverse Events ............................................................. 36 
14.8 
Missing Date Information for Adverse Events .............................................................. 36 
14.9 
Missing Date Information for Prior or Concomitant Medications ................................. 37 
14.9.1 
Incomplete Start Date ............................................................................................. 37 
14.9.2 
Incomplete Stop Date .............................................................................................. 38 
 
 
 
 
 
 
17. 
REFERENCES .................................................................................................................. 44 


 
 
 
Page 4 of 44 
1. 
LIST OF ABBREVIATIONS 
AE 
adverse event 
AIMS 
abnormal involuntary movement scale 
ALT 
alanine aminotransferase  
ALP 
alkaline phosphatase 
AST 
aspartate aminotransferase 
ATC 
anatomical therapeutic chemical 
ANCOVA 
analysis of covariance 
BARS 
Barnes akathisia rating scale  
bITT 
bipolar intent-to-treat 
BMI 
body mass index 
BP 
blood pressure  
BPM 
beats per minute 
CGI-S 
clinical global impression scale-severity 
CI 
confidence interval 
C-SSRS 
Columbia-suicide severity rating scale 
DBTP 
double-blind treatment period 
ECG 
electrocardiogram, electrocardiographic 
ET 
early termination 
eCRF 
electronic case report form 
GCP 
Good Clinical Practice 
ICE 
intercurrent event 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ICH 
international council on harmonization  
ITT 
intent-to-treat 
LLN 
lower limit of normal 
LOE 
lack of efficacy 
MADRS 
Montgomery-Åsberg Depression Rating Scale 
MAR 
missing at random 
MDD 
major depressive disorder 
MDE 
major depressive episode  
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified intent-to-treat 
MMRM 
mixed model with repeated measure 


 
 
 
Page 5 of 44 
MNAR 
missing not at random 
msec 
millisecond(s) 
PCS 
potentially clinically significant 
PMM 
pattern mixture model 
PT 
preferred term 
QTc 
QT interval corrected for heart rate 
QTcB 
QT interval corrected for heart rate using the Bazett formula 
QTcF 
QT interval corrected for heart rate using the Fridericia formula  
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
Simpson angus scale 
SD 
standard deviation 
SFUP 
safety follow-up period 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
TSH 
Thyroid-stimulating hormone 
ULN 
upper limit of normal 
WHO 
World Health Organization  
YMRS 
Young Mania Rating Scale 
 
 


 
 
 
Page 6 of 44 
2. 
INTRODUCTION 
This statistical analysis plan (SAP) provides a technical and detailed elaboration of the statistical 
analyses of the efficacy and safety data as outlined and specified in the Protocol Amendment 4.0 
of Study ITI-007-403 (dated 27 Jan 2023). Specifications of tables, figures, and data listings are 
contained in a separate document.  
This study was originally designed as a Phase 3, randomized, double-blind, placebo-controlled, 
multicenter study to evaluate the efficacy and safety of lumateperone as monotherapy in the 
treatment of patients with Major Depressive Episodes (MDEs) associated with bipolar I or bipolar 
II disorder. After the study started, Study ITI-007-402 (a Phase 3, randomized, double-blind, 
placebo-controlled, multicenter study to evaluate the efficacy and safety of lumateperone 
adjunctive to lithium or valproate in the treatment of patients with MDEs associated with bipolar I 
or bipolar II disorder) reported its results and demonstrated lumateperone successfully reduced 
MDEs associated symptoms based on treatment difference in change from baseline to Day 43 in 
MADRS total score for lumateperone vs placebo. As a result, there was no need for an additional 
pivotal study for the treatment of patients with MDEs associated with bipolar I or bipolar II 
disorder.  
Therefore, Study ITI-007-403 was repositioned for the treatment of patients with MDEs associated 
with bipolar disorder with mixed features or major depressive disorder (MDD) with mixed 
features. This change was described in Protocol Amendment 2.0 (dated 02 Nov 2020). A total of 
100 patients had been randomized under the original protocol before the implementation of 
Protocol Amendment 2.0. Protocol Amendment 2.0 plans for an additional enrollment of 
350 patients with approximately equal number of patients for bipolar disorder with mixed features 
and for MDD with mixed features.  
For data analysis, the main difference between the original protocol before Protocol Amendment 
2.0 and after Protocol Amendment 2.0 is in the patient populations: Original Protocol before 
Protocol Amendment 2.0 enrolled patients with MDE associated with bipolar I or bipolar II 
disorder; while after Protocol Amendment 2.0, the study enrolled patients with MDEs associated 
with bipolar disorder with mixed features or MDD with mixed features.  
Both the Original Protocol and Protocol Amendment 2.0 consist of the same study design of a 
Screening Period, Double-blind Treatment Period (DBTP), and a Safety Follow-up Period (SFUP) 
with the same planned assessments. 
Screening Period (2 Weeks) 
Potential patients will be evaluated during a Screening Period lasting up to 2 weeks unless an 
extension of the Screening Period is approved by the Medical Monitor or Sponsor Designee.  
After obtaining written informed consent, diagnostic interviews and physical examinations will be 
conducted, vital signs and electrocardiogram (ECGs) will be assessed, and blood samples will be 
collected for laboratory assessments. Patients considered potentially eligible for participation will 
be required to discontinue their current antidepressant treatment and/or other psychotropic drugs. 


 
 
 
Page 7 of 44 
At Baseline (Visit 2), patients who continue to meet all eligibility criteria will be randomized to 
1 of the 2 treatment arms (lumateperone 42 mg or matching placebo) for a 6-week DBTP. 
Double-blind Treatment Period (6 Weeks) 
Patients will take their first dose of study drug on the evening of Baseline (Visit 2, Day 1). A single 
dose will be taken each day in the evening, with or without food, for the duration of the 6-week 
DBTP. 
Following randomization, patients will attend outpatient study visits on Days 8, 15, 22, 29, 36, and 
43. 
With approval from the Sponsor or Sponsor’s representative, sites will be permitted to conduct 
remote visits if the patient is unable to travel to the site for an in-person visit or if the site is unable 
to schedule an in-person visit. However, all Screening and Baseline (Visit 2) assessments must be 
performed in person. 
A patient will be defined as a treatment completer if the patient completed the double-blind 
treatment period (all scheduled visits up to and including Visit 8). 
Safety Follow-up Period (2 Weeks) 
All patients should return to the clinic for the Safety Follow-up Visit approximately 2 weeks after 
Visit 8/ET. 
The Schedule of Evaluations for this Study is in Table 2-1. 
 


 
 
Page 8 of 44 


 
 
 
Page 9 of 44 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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3. 
STUDY OBJECTIVES 
3.1 
Primary Efficacy Objective 
Following Protocol Amendment 2.0, the primary objective of this study is to confirm the efficacy 
of lumateperone 42 mg administered orally once daily compared with that of placebo as measured 
by mean change from baseline to Day 43 in the Montgomery-Åsberg Depression Rating Scale 
(MADRS) total score in patients with MDEs associated with bipolar depression with mixed 
features or MDD with mixed features.  
Based on the primary efficacy objective, this study will evaluate the efficacy of lumateperone 
42 mg based on the following three sets of patients: 
1. All patients randomized after Protocol Amendment 2.0, which includes all patients 
associated with bipolar depression with mixed features and all patients associated with 
MDD with mixed features;  
2. All patients with bipolar disorder (I or II) with mixed features randomized after Protocol 
Amendment 2.0; 
3. All patients with MDD with mixed features. 
3.2 
Secondary Efficacy Objectives 
3.2.1 Key Secondary Efficacy Objective 
Following Protocol Amendment 2.0, the key secondary efficacy objective of this study is to 
confirm the efficacy of lumateperone 42 mg administered orally once daily compared with that of 
placebo as measured by mean change from baseline to Day 43 in the Clinical Global Impression 
Scale-Severity (CGI-S) score in patients with MDEs associated with bipolar depression with 
mixed features or associated with MDD with mixed features. 
The key secondary efficacy objective will be assessed using the same three sets of patients defined 
for the primary efficacy objective. 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 


 
 
 
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4. 
ANALYSIS SETS 
4.1 
All Enrolled Set 
All Enrolled Set will contain all patients who signed the informed consent form (ICF) for the study. 
4.2 
All Patients Randomized Set 
All Patients Randomized Set will contain all patients who signed the informed consent and were 
randomized to study drug. 
4.3 
Safety Analysis Set 
Safety Analysis Set will contain all patients who received at least 1 dose of study drug. 
4.4 
Intent-to-Treat Analysis Set 
Intent-to-treat (ITT) Analysis Set will contain all randomized patients who received at least 1 dose 
of study drug and who had a non-missing (pre-dose) baseline assessment and at least 1 non-missing 
post-baseline assessment of MADRS total score. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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5. 
PATIENTS DISPOSITION 
The number of patients in the All Patients Randomized Set, Safety Analysis Set, mITT Analysis 
Set, bITT Analysis Set and ITT Analysis Set will be summarized by treatment group and study 
site. patients in the All Enrolled Set will only be summarized overall by study site. 
Screen failures (ie, patients who are screened but not randomized) and the associated reasons for 
failure to be randomized will be tabulated overall for all screened patients. The number and 
percentage of patients who complete the DBTP, patients who prematurely discontinue from the 
DBTP and patients who enter the SFUP, patients who complete the SFUP, patients who 
discontinue from the SFUP will be presented by treatment group for the Safety Analysis Set as 
outlined in Table 2-2. The reasons for premature discontinuation during the DBTP and SFUP as 
recorded on the disposition pages of the electronic case report forms (eCRFs) will be summarized 
(number and percentage) by treatment group for the Safety Analysis Set as outlined in Table 2-2. 


 
 
 
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7. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic parameters (eg, age, sex, race, ethnicity, weight, body mass index calculated as 
weight [kg]/(height [m])2) and other baseline characteristics will be summarized by treatment 
group and by overall for the Safety, and ITT Analysis Sets. 
Demographic and baseline characteristics will also be summarized separately for patients 
randomized before Protocol Amendment 2.0 in the Safety and ITT Analysis Sets, for patients 
randomized after Protocol Amendment 2.0 in the Safety and mITT Analysis Sets, for two 
subpopulations of bipolar disorder with mixed features and MDD with mixed features in the mITT 
Analysis Set, and for patients in the bITT Analysis Set. 
Medical and surgical history/physical findings will be summarized by treatment group, system 
organ class (SOC), and preferred term (PT) separately for patients randomized before Protocol 
Amendment 2.0, and for patients randomized after Protocol Amendment 2.0 separately for the 
Safety Analysis Set. Bipolar and psychiatric diagnosis and history will be summarized by 
treatment group and by overall for the Safety Analysis Set and will include current diagnosis, 
whether the current major depressive episode has psychotic features or whether patient meets 
criteria for anxious distress, age of patient at first diagnosis of bipolar disorder or MDD, number 
of lifetime depressive and manic/hypomanic/mixed episodes, number of depressive and 
manic/hypomanic/mixed episodes within the past year, whether and how many times patient has 
been hospitalized for any psychiatric related issues.  
Baseline efficacy parameters will be summarized by treatment group for patients randomized 
before Protocol Amendment 2.0 in the ITT Analysis Set, for patients in the mITT Analysis Set and 
for patients in the bITT Analysis Set. Baseline efficacy parameters will also be summarized by 
treatment group for patients randomized after Protocol Amendment 2.0, and for two 
subpopulations of bipolar disorder with mixed features and of MDD with mixed features in the 
ITT Analysis Set. 
Prior medication is defined as any medication which started and stopped before the date of the 
first dose of double-blind study drug. Prior Concomitant medication is defined as any medication 
which started before the date of the first dose of double-blind study drug and stopped or is ongoing 
after the date of the first dose of double-blind study drug. Concomitant medication is defined as 
any medication taken on or after the date of the first dose of double-blind study drug and on or 
before the date of the last dose of double-blind study drug. The World Health Organization (WHO) 
Drug Dictionary, version MAR21 or newer, will be used to code medications.  
Prior medication, prior concomitant medication, and concomitant medication will be summarized 
by treatment group and Anatomical Therapeutic Chemical (ATC) code and preferred term for  the 
Safety Analysis Set as outlined in Table 2-2. Each patient will be counted only once for each ATC 
code and preferred term.  
Any concomitant medication started after the date of the last dose of double-blind study drug will 
not be included in the summary but will be included in the patient data listings. 
Prior medication, prior concomitant medication, concomitant medication, and prior concomitant 
or concomitant use of Zolpidem and other protocol permitted rescue medication during the study 
will be summarized by treatment group for patients randomized before Protocol Amendment 2.0, 
for patients randomized after Protocol Amendment 2.0 and for two subpopulations of bipolar 
disorder with mixed features and of MDD with mixed features in the Safety Analysis Set. 


 
 
 
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8. 
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE 
8.1 
Extent of Exposure 
Exposure to study drug during the DBTP will be based on treatment duration, calculated as the 
number of days from the date of first dose of double-blind study drug to the date of last dose of 
double-blind study drug, inclusive. Descriptive statistics (number of patients, mean, standard 
deviation (SD), median, minimum, and maximum) will be presented by treatment group for the 
Safety Analysis Set as outlined in Table 2-2. 
Patient-years during the DBTP, defined as total exposure to study drug in years, will be 
summarized by treatment group.  
8.2 
Treatment Compliance 
Dosing compliance for the DBTP is defined as the number of capsules actually taken by a patient 
during that phase divided by the number of capsules prescribed to be taken during the DBTP 
multiplied by 100. The total number of capsules actually taken during the DBTP is calculated as 
the sum of capsules taken during the DBTP as obtained from the study drug record. The number 
of capsules prescribed to be taken for the DBTP is calculated by multiplying the number of days 
in the DBTP by the number of capsules prescribed per day. 
Descriptive statistics for study drug compliance will be presented by treatment group for the entire 
DBTP for the Safety Analysis Set as outlined in Table 2-2. 


 
 
 
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9. 
EFFICACY ANALYSES 
All efficacy analyses will be performed in the following analysis sets: the mITT Analysis Set, the 
patients with bipolar disorder with mixed features in the mITT Analysis Set, the patients with 
MDD with mixed feature in the mITT Analysis Set, and the bITT Analysis Set. Baseline for 
efficacy parameters will be defined as the last non-missing efficacy measurement prior to the first 
dose of double-blind study drug. All statistical hypothesis tests will be performed at the 2-sided 
significance level of 5% for main effects. All confidence intervals (CIs) will be 2-sided 95% CIs, 
unless stated otherwise. 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The efficacy analyses will be performed based on the treatment to which the patient is randomized 
regardless of the actual treatment received.  
The efficacy analyses of MADRS assessments will be based on the rater-administered MADRS. 


 
 
 
Page 18 of 44 
9.1 
Primary Efficacy Parameter 
The primary efficacy parameter will be the change from baseline in MADRS total score at the end 
of Week 6 (Day 43). The MADRS contains 10 items that assess depression, with scores for each 
item ranging from 0 (absence of symptoms) to 6 (symptoms of maximum severity). The MADRS 
total score is the sum of the 10 individual items.  
The primary efficacy analysis will be performed based on the mITT Analysis Set using the mixed 
model with repeated measures (MMRM) with terms for treatment, pooled study site, stratification 
variable (bipolar I, bipolar II, or MDD), visit, baseline, and treatment-by-visit and baseline-by-
visit interactions. An unstructured covariance matrix will be used to model the covariance of 
within-patient scores. The Kenward-Roger approximation will be used to estimate denominator 
degrees of freedom (Kenward et al, 1997). This analysis will only use the observed post-baseline 
scores without imputation of missing values. The treatment difference for lumateperone 42 mg vs 
placebo will be estimated and reported along with the corresponding 95% CI and p-value. 
In the case that the MMRM with unstructured covariance fails to converge then the Fisher scoring 
algorithm will be used to provide better initial values of the covariance parameters. In the rare 
event that model still does not converge after using those initial values, the following alternative 
structures will be attempted in the specified order until convergence is achieved: heterogeneous 
Toeplitz structure (TOEPH), heterogeneous autoregressive(1) (ARH(1)), heterogeneous 
compound symmetry (CSH), 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 
(CS). 
The primary efficacy analysis will also be performed based on subpopulation of patients associated 
with bipolar depression with mixed features and patients associated with MDD with mixed features 
in the mITT Analysis Set. The same MMRM described above will be applied to subpopulation of 
bipolar disorder and subpopulation of MDD without the stratification at screening as a factor. 
 
 
 
 
 
 
 
 
 
 
 
 
  
 


 
 
 
Page 19 of 44 
9.2 
Secondary Efficacy Parameters 
The key secondary efficacy parameter will be the change from baseline to Day 43 in CGI-S score. 
The key secondary efficacy analysis will be performed based on the mITT Analysis Set using a 
MMRM similar to those for the primary efficacy parameter. The treatment difference for 
lumateperone 42 mg vs placebo will be estimated and reported along with the corresponding 95% 
CI and p-value.  
The key secondary efficacy analysis will also be performed based on subpopulation of patients 
associated with bipolar depression with mixed features and patients associated with MDD with 
mixed features in the mITT Analysis Set. The same MMRM described above will be applied to 
the subpopulation of bipolar disorder and the subpopulation of MDD without the stratification at 
screening as a factor. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




 
 
 
Page 21 of 44 
To examine the consistency of the treatment effect of lumateperone vs placebo based on the change 
from baseline to Day 43 in MADRS total score across demographic and baseline characteristic 
subgroup categories, subgroup analyses will be performed whenever applicable based on the mITT 
Analysis Set, the subpopulation of bipolar disorder with mixed features in the mITT Analysis Set, 
and the subpopulation of MDD with mixed features in the mITT Analysis Set for the following: 
• Region (US; Non-US) 
• Baseline disease severity (Baseline MADRS total score < 32; Baseline MADRS total score 
≥ 32) 
• Sex (Male; Female) 
• Age group (≤ 40 years; > 40 years) 
• Race group (White; Non-White) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
Exploratory analysis of the primary endpoint will be performed in the subgroups of bipolar I and 
bipolar II of the mITT Analysis Set. 
 
 
 
Descriptive statistics (n, mean, SD, minimum, median, and maximum) and change from baseline 
value of the MADRS total score and CGI-S score will be presented by treatment group at each 
assessment point and performed for patients randomized before Protocol Amendment 2.0 in the 
ITT Analysis Set. 


 
 
 
Page 22 of 44 
 
 
 


 
 
 
Page 23 of 44 
10. 
SAFETY ANALYSES 
The safety analysis will be performed as outlined in Table 2-2 based on the Safety Analysis Set. 
Safety variables will include adverse events (AE), clinical laboratory, vital signs, and ECG; 
suicidality as assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS); manic symptoms 
as assessed by the Young Mania Rating Scale (YMRS); and extrapyramidal symptoms (EPS) as 
assessed by Abnormal Involuntary Movement Scale (AIMS), Barnes Akathisia Rating Scale 
(BARS), and Simpson Angus Scale (SAS) scales. For each safety parameter, the last assessment 
made before the first dose of double-blind study drug will be used as the baseline for all analyses 
of that safety parameter. 
10.1 
Adverse Events 
AEs will be coded using the Medical Dictionary for Regulatory Activities, version 20.1 or newer. 
Treatment emergent AEs (TEAE) are defined as any AEs, regardless of the relationship to study 
drug, that occur or worsen in severity after the first dose of study drug and on or before the date of 
last dose of study drug plus one day. An event that occurs is referring to an event that did not occur 
before, or it started 2 days or more after the end date of the previous event for the same preferred 
term. Severity increases is referring to an increase in severity for a continuous event during the 
DBTP. 
The number and percentage of patients reporting TEAEs in each treatment group will be tabulated 
by SOC and PT; by SOC, PT, and severity; and by SOC, PT, and relationship to study drug. If 
more than 1 AE is coded to the same PT for the same patient, the patient will be counted only once 
for that PT using the most severe and most related occurrence for the summarization by severity 
and by relationship to study drug, respectively. 
The incidence of common (≥ 5% of patients in any treatment group) TEAEs will be summarized 
by PT and treatment group and sorted by decreasing frequency for the lumateperone 42 mg group. 
The incidence of serious adverse events (SAEs) and of AEs leading to premature discontinuation 
of study drug will also be summarized by SOC, PT, and treatment group and will be sorted by 
decreasing frequency for lumateperone 42 mg group. Listings will be presented for patients with 
SAEs, patients with AEs leading to premature discontinuation of study drug, patients who died (if 
any) and patients who died (if any) with AEs.   
 
 
 
 
 


 
 
 
 
 
10.2 
Clinical Laboratory Parameters 
Descriptive statistics (n, mean, SD, minimum, median, and maximum) for clinical laboratory 
values (in SI and conventional units) and change from baseline values will be presented by 
treatment group at each assessment timepoint (including the end of the DBTP) for the following 
clinical laboratory parameters: 
Hematology: 
Hematocrit, hemoglobin, HbA1c, red blood cell count, mean 
corpuscular volume, mean corpuscular hemoglobin, mean 
corpuscular hemoglobin concentration, reticulocytes, white blood 
cell count, absolute neutrophils, absolute lymphocytes, absolute 
monocytes, 
absolute 
eosinophils, 
absolute 
basophils,                        
neutrophils/leukocytes 
(%), 
lymphocytes/leukocytes 
(%), 
monocytes/leukocytes 
(%), 
 
eosinophils/leukocytes 
(%), 
basophils/leukocytes (%), and platelets,  
Chemistry: 
Albumin, alkaline phosphatase (ALP), aspartate transaminase 
(AST), alanine aminotransferase (ALT), total bilirubin, direct 
bilirubin, blood urea nitrogen, gamma-glutamyl transferase, 
calcium, creatinine, glucose, insulin, cholesterol, triglycerides, 
phosphate, potassium, Prolactin, lactate dehydrogenase, sodium, 
chloride, total protein, uric acid, creatine phosphokinase, and 
Thyroid-stimulating hormone (TSH) (reflex T3 and T4), 


 
 
 
Page 25 of 44 
Urinalysis: 
Specific gravity, pH, protein, glucose, ketones, nitrates, blood, red 
blood cells, white blood cells, casts, epithelial cells, crystals, and 
granulation.  
 
Clinical laboratory values will be considered to be potentially clinically significant (PCS) if they 
meet either the low or high PCS criteria listed in Table 10-2. The number and percentage of patients 
who have PCS post-baseline clinical laboratory values will be tabulated by treatment group for the 
DBTP. The percentages will be calculated relative to the number of patients with available non-
PCS baseline values and at least one post-baseline assessment. The numerator is the total number 
of patients with available non-PCS baseline values and at least one PCS post-baseline value.  
A supportive listing of patients with PCS post-baseline values will be provided including the 
patient ID, baseline, and post-baseline values (including non-PCS values). A listing of all AEs for 
patients with PCS clinical laboratory values will also be provided. 
Shift tables from baseline to end of the DBTP for clinical laboratory parameters will be presented 
by treatment group for the following categories: low, normal, and high, which are provided by the 
laboratory vendor. 
Criteria for potential Hy’s Law cases is defined by a postbaseline elevation of alanine 
aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 3 × ULN, along with total bilirubin 
(TBL) ≥ 2 × ULN and a non-elevated alkaline phosphatase (ALP) < 2 × ULN, all based on blood 
draws collected within a 24-hour period. Patients who meet the potential Hy’s Law criteria during 
the DBTP will be summarized. Support listings will also be provided. 


 
 
 
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Table 10-2: Criteria for Potentially Clinically Significant Clinical Laboratory Tests 
Laboratory Parameter 
SI Unit 
Conversion 
Factora 
Conventional 
Unit 
PCS Criteriab 
Low Values 
PCS Criteriab High 
Values 
Hematology 
Hemoglobin 
g/L 
0.1 
g/dL 
     ≤ 0.9 × LLN 
— 
Hematocrit 
% 
1 
% 
     ≤ 0.9 × LLN 
— 
Abs Neutrophils (ANC) 
109/L 
1 
109/L  
< 1.0 
— 
Platelet count 
109/L 
1 
109/L  
≤ 75 
≥ 700 
White cell count 
109/L 
1 
109/L  
≤ 2.5 
≥ 15 
Chemistry 
Albumin 
g/L 
0.1 
g/dL 
< 2.5 
 
Alkaline phosphatase 
U/L 
1 
U/L 
— 
≥ 2 × ULN 
ALT  
U/L 
1 
U/L 
— 
≥ 3 × ULN 
AST  
U/L 
1 
U/L 
— 
≥ 3 × ULN 
Blood urea nitrogen 
(BUN) 
mmol/L 
2.8003 
mg/dL 
— 
≥ 30 
Calcium 
mmol/L 
4.008 
mg/dL 
< 7 
> 12 
Chloride 
mmol/L 
1 
mg/dL 
< 90 
> 115 
Total Cholesterol (fasting) 
mmol/L 
38.6698 
mg/dL 
— 
≥ 300 
CPK 
U/L 
1 
U/L 
— 
≥ 5 × ULN 
Creatinine 
 
mcmol/L 
0.0113 
mg/dL 
— 
> 1.3 × ULN 
Glucose (fasting) 
mmol/L 
18 
mg/dL 
< 45 
> 160 
LDL Cholesterol (fasting) 
mmol/L 
38.6698 
mg/dL 
— 
> 200 
Potassium 
mmol/L 
1 
mEq/L 
< 3 
> 5.5 
Prolactin 
mIU/L  
21.2766 
ng/ml  
 
> 200 
Sodium 
mmol/L 
1 
mEq/L 
< 130 
> 150 
Total bilirubin 
 mcmol/L 
0.0585 
mg/dL 
— 
≥ 2 × ULN 
Triglycerides (fasting) 
mmol/L 
88.6 
mg/dL 
— 
≥ 300 
Urinalysis 
Protein 
 
— 
— 
— 
At least 2 + 
Glucose 
 
— 
— 
— 
At least 2 + 
Blood 
 
— 
— 
— 
At least 2 + 
a 
Conversion factor from SI units to traditional units. 
b 
Criteria refer to conventional units. 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK=creatine phosphokinase; LLN = lower limit of normal 
of laboratory reference range; PCS = potentially clinically significant; SI = Le Système International d'Unités (International 
System of Units); ULN = upper limit of normal of laboratory reference range. 


 
 
 
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10.3 
Vital Signs 
Descriptive statistics (n, mean, SD, minimum, median, and maximum) for vital signs assessments 
(systolic and diastolic blood pressures, pulse rate, weight, temperature, BMI and waist) and 
changes from baseline values at each assessment visit and at the end of DBTP will be presented 
by treatment group. For systolic and diastolic blood pressure and pulse rate, measurements will be 
measured after at least 5 minutes in the supine position and after at least 2 minutes in the standing 
position. Descriptive statistics for systolic and diastolic blood pressure and pulse rate in the supine 
position and in the standing position will be presented separately. 
Vital sign values will be considered to be PCS if they meet both the observed value criteria and 
the change from baseline value criteria that are detailed in Table 10-3. The number and percentage 
of patients who have PCS post-baseline vital sign values will be tabulated by treatment group for 
the DBTP. The percentages will be calculated relative to the number of patients who have available 
baseline values and at least 1 post-baseline assessment. The numerator will be the total number of 
patients with available baseline values and at least 1 PCS post-baseline value.  
A listing of all patients with PCS post-baseline values will be provided and will include the patient 
ID, baseline, all post-baseline (including non-PCS) value and change from baseline. In addition, a 
listing of all AEs for patients who had PCS vital sign values will be provided. 
The number and percentage of patients with orthostatic hypotension will be provided by treatment 
group. Orthostatic hypotension is defined as a reduction of ≥ 20 mm Hg in systolic BP or a 
reduction of ≥ 10 mm Hg in diastolic BP measured when the patient changes from the supine 
position to the standing position. Standing measurements should be taken after sufficient amount 
of time has been given to allow the blood pressure to equilibrate in the standing state. 
A supportive listing of patients with orthostatic hypotension will be provided including the 
Patient ID, baseline and post-baseline systolic and diastolic BP values (supine and standing). 
Table 10-3: Criteria for Potentially Clinically Significant Vital Signs 
Vital Sign, unit 
Flag 
Criterion Valuea 
Change From Baselinea 
Systolic blood pressure, mm Hg 
High 
≥ 180 
Increase of ≥ 20 
Low 
≤ 90 
Decrease of ≥ 20 
Diastolic blood pressure, mm Hg 
High 
≥ 105 
Increase of ≥ 15 
Low 
≤ 50 
Decrease of ≥ 15 
Pulse rate, bpm 
High 
≥ 120 
Increase of ≥ 15 
Low 
≤ 50  
Decrease of ≥ 15 
Weight, kgb 
High 
— 
Increase of ≥ 7% 
Low 
— 
Decrease of ≥ 7% 
a 
A post-baseline value will be considered potentially clinically significant if it meets both criterion value and change from 
baseline value. 
b 
Weight change is relative to baseline. 
bpm = beats per minute. 
 


 
 
 
Page 28 of 44 
10.4 
Electrocardiograms 
Descriptive statistics (n, mean, SD, minimum, median, and maximum) for 12-lead ECG 
assessments (eg, heart rate, QRS duration, PR interval, RR interval, uncorrected QT interval, and 
corrected QT [QTc] intervals) and changes from baseline values at each assessment visit and at 
the end of DBTP will be presented by treatment group. QTc interval will be calculated using both 
Bazett (QTcB = QT/(RR)½) and Fridericia (QTcF = QT/(RR)⅓) corrections; if RR is not available, 
it will be replaced with 60/heart rate in the correction formula.  
ECG parameter values will be considered PCS if they meet or exceed the criterion value or the 
change from baseline value listed in Table 10-4. The number and percentage of patients who have 
PCS post-baseline ECG values will be tabulated by treatment group for the DBTP. The percentages 
will be calculated relative to the number of patients with available non-PCS baseline values and at 
least 1 post-baseline assessment for PCS criteria based on the actual values and the percentages 
will be calculated relative to the number of patients who have available baseline values and at least 
1 post-baseline assessment for PCS criteria based on changes. The numerator will be the total 
number of patients with available non-PCS baseline values and at least 1 PCS post-baseline value.  
A listing of all patients with PCS post-baseline values will be provided and will include the patient 
ID, baseline, all post-baseline (including non-PCS) values, and change from baseline. In addition, 
a listing showing all AEs that occurred in patients who had post-baseline PCS ECG values will be 
provided. 
A shift table from baseline to the end of study in the  overall interpretation of the ECG will be 
presented by treatment group for the following categories: normal; abnormal, not clinically 
significant; abnormal, clinically significant. A listing showing patients with post-baseline 
clinically significant ECG abnormalities according to the overall interpretation will be provided. 
 
 


 
 
 
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Table 10-4: Criteria for Potentially Clinically Significant Electrocardiographic Values 
Parameter 
Unit 
Criterion Value a 
Change from Baseline a 
QRS duration 
msec 
≥ 150 
— 
PR interval 
msec 
≥ 250 
— 
QTcB 
msec 
≥ 480  
— 
QTcB 
msec 
≥ 500 
 
QTcF 
msec 
≥ 480  
— 
QTcF 
msec 
≥ 500 
 
QTcB  
msec 
--- 
Increase of >30 and ≤60 
QTcB  
msec 
--- 
Increase of > 60 
QTcF 
msec 
--- 
Increase of >30 and ≤60 
QTcF 
msec 
--- 
Increase of > 60 
a 
A post-baseline value will be considered potentially clinically significant if it meets the criterion value or the change from 
baseline value. 
PCS = potentially clinically significant; QTcB = QT interval/(RR)½; QTcF = QT interval/(RR)⅓. 
10.5 
Other Safety Parameters 
Other safety parameters include the C-SSRS, YMRS, AIMS, BARS and SAS. 
10.5.1 Columbia-Suicide Severity Rating Scale (C-SSRS) 
The number and percentage of patients with suicidal ideation and suicidal behavior as recorded on 
the C-SSRS will be summarized by treatment group for lifetime history (assessed at the screening 
visit), during the DBTP and during the post DBTP. The distribution of responses for most severe 
suicidal ideation and most severe suicidal behavior will be also presented by treatment group for 
lifetime history, during the DBTP and during the post DBTP. The baseline of suicidal ideation and 
suicidal behavior is defined as the last non-missing “since last visit” assessment before the first 
dose of double-blind study drug. The severity of suicidal ideation will be presented in a decreasing 
order as below:  
• Active suicidal ideation with specific plan and intent 
• Active suicidal ideation with some intent to act, without specific plan 
• Active suicidal ideation with any methods (not plan) without intent to act 
• Non-specific active suicidal thoughts 
• Wish to be dead  
The severity of suicidal behavior will also be presented in a decreasing order as below: 
• Completed Suicide 
• Actual attempt 


 
 
 
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• Interrupted attempt 
• Aborted attempt 
• Preparatory acts or behavior 
For the distribution of responses, each patient will be counted only once under the most severe 
category across all visits during the specific period for suicidal ideation and separately for suicidal 
behavior.  
Supportive listing for patients with suicidal ideation or with suicidal behavior during the study will 
be provided and will include the Patient ID, treatment group, visit number, lifetime history, and 
post-baseline values for each patient. A listing of all AEs for patients with suicidal ideation or 
suicidal behavior will also be provided. 
In addition, the number and percentage of patients with the following emergence of suicidal 
ideation or of suicidal behavior during the DBTP will be summarized by treatment group: 
• Emergence of suicidal ideation (no suicidal ideation at Baseline, and any type of suicidal 
ideation post-Baseline) 
• Emergence of serious suicidal ideation (no suicidal ideation at Baseline, and any serious 
suicidal ideation [Active suicidal ideation with specific plan and intent, or Active suicidal 
ideation with some intent to act, without specific plan] post-Baseline) 
• Worsening of suicidal ideation (most severe suicidal ideation post-Baseline was more 
severe than it was at Baseline)  
• Emergence of suicidal behavior (no suicidal behavior at Baseline, and any type of suicidal 
behavior post-Baseline) 
10.5.2 Young Mania Rating Scale (YMRS) 
Descriptive statistics (n, mean, SD, minimum, median, and maximum) for YMRS assessments and 
changes from baseline values at each assessment visit and at the end of the DBTP will be presented 
by treatment group. 
10.5.3 Abnormal Involuntary Movement Scale (AIMS) 
Descriptive statistics (n, mean, SD, minimum, median, and maximum) for AIMS assessments and 
changes from baseline values at each assessment visit and at the end of the DBTP will be presented 
by treatment group. 
10.5.4 Barnes Akathisia Rating Scale (BARS) 
Descriptive statistics (n, mean, SD, minimum, median, and maximum) for BARS assessments and 
changes from baseline values at each assessment visit and at the end of the DBTP will be presented 
by treatment group. 


 
 
 
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10.5.5 Simpson Angus Scale (SAS) 
Descriptive statistics (n, mean, SD, minimum, median, and maximum) for SAS assessments and 
changes from baseline values at each assessment visit and at the end of the DBTP will be presented 
by treatment group. 
 
 
 
 
 
 


 
 
 
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11. 
INTERIM ANALYSIS 
No interim analysis is planned for this study. 
 
 


 
 
 
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12. 
SAMPLE SIZE CONSIDERATION 
The sample size for this study is based on assumed effect size (treatment group difference relative 
to SD) of 0.37. This assumed effect size of 0.37 for lumateperone is based on a treatment difference 
of 3.3 units with a common pooled SD of 9 for the primary efficacy parameter, change from 
baseline to Day 43 in MADRS total score. A sample size of 350 patients (175 per treatment group) 
will be needed to be enrolled after Protocol Amendment 2.0 to provide 90% statistical power for 
primary analysis based on an MMRM using a simulation method (Lu 2012). The simulation 
assumed a correlation of 0.7 between the repeated measures and a dropout rate of 10% based on 
historical data.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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13. 
STATISTICAL SOFTWARE 
Statistical analyses of efficacy and safety parameters will be performed using version 9.4 of SAS.  
 


 
 
 
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14. 
DATA HANDLING CONVENTIONS 
14.1 
Visit Time Windows 
Table 14-1 presents the visits assigned for efficacy and safety analyses and the corresponding 
range of treatment days (window) during which an actual visit may occur. 
Table 14-1: Windows for Analysis Visits 
Derived Visit 
Scheduled Visit (Daya) 
Windowb 
Baseline 
Week 0 (Day 1) 
Days ≤ 1 
Week 1 
Week 1 (Day 8) 
                                Days [2, 11] 
Week 2 
Week 2 (Day 15) 
                                Days [12, 18] 
Week 3 
Week 3 (Day 22) 
                                Days [19, 25] 
Week 4 
Week 4 (Day 29) 
                                Days [26, 32] 
Week 5 
Week 5 (Day 36) 
                                Days [33, 39] 
Week 6 
Week 6 (Day 43) 
Days ≥ 40 and within double-blind treatment period 
End of Double-blind 
Treatment Period 
Final or termination visit during the double-blind treatment period 
Week 8 
               Week 8 (Day 57) 
              Within the safety follow-up period 
a. Relative to the date of the first dose of double-blind study drug. For example, Day 1 = the date of the first dose of double-blind 
study drug. 
b. Visit day is calculated as visit date − date of the first dose of double-blind study drug + 1 if the visit date is on or after the date 
of the first dose of double-blind study drug. Otherwise, it is calculated as visit date – date of the first dose of double-blind study 
drug. 
 
If a patient has 2 or more non-missing assessment within the same window, the assessment closest 
to the target day will be used for analysis; if the 2 closet assessments are equidistant to the target 
day, the later one will be used for analysis. 
14.2 
Derived Efficacy Variables 
The MADRS total score at a particular visit will be calculated using (sum of scores from non-
missing items) × (total number of items) / (number of non-missing items) only if the number of 
missing items is ≤ 2. Otherwise, the MADRS total score will be set equal to missing.  
14.3 
Repeated or Unscheduled Assessments of Safety Parameters 
If a patient has repeated assessments before the first dose of double-blind study drug, then the 
results from the final non-missing assessment made before the first dose of double-blind study 
drug will be used as baseline. If end-of-treatment assessments are repeated or if unscheduled visits 
occur, the last non-missing post-baseline assessment will be used as the end-of-treatment 
assessment for generating summary statistics. However, all post-baseline assessments will be used 
for PCS value determinations, and all assessments will be presented in the data listings. 


 
 
 
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14.4 
Missing Date of the Last Dose of Study Drug 
When the date of the last dose of double-blind study drug in the study is missing for a patient, all 
efforts should be made to obtain the date from the Investigator. If it is still missing after all efforts, 
then the last available dosing date in the DBTP will be used as the last dose date. 
14.5 
Missing Severity Assessment for Adverse Events 
If severity is missing for an AE that occurred before the date of the first dose of double-blind study 
drug, then a severity of mild will be assigned. If the severity is missing for an AE that occurred on 
or after the date of the first dose of double-blind study drug, then a severity of severe will be 
assigned. The imputed values for severity will be used for the incidence summary; the actual values 
will be presented in data listings. 
14.6 
Missing Relationship to Study Drug for Adverse Events 
If the relationship to study drug is missing for an AE that occurred after the date of the first dose 
of double-blind study drug, then a causality of Yes will be assigned. The imputed values for 
relationship to study drug will be used for the incidence summary; the actual values will be 
presented in data listings. 
14.7 
Missing Dates Information for Adverse Events 
The following imputation rules apply only to cases in which the start date is incomplete (i.e, 
partially missing) for AEs and prior/concomitant medications. 
14.8 
Missing Date Information for Adverse Events 
The following imputation rules only apply to cases in which the start date for AEs is incomplete 
(i.e., partly missing). 
Missing month and day 
• If the year of the incomplete start date is the same as the year of the first dose of double-
blind study drug, the month and day of the first dose of double-blind study drug will be 
assigned to the missing fields  
• If the year of the incomplete start date is before the year of the first dose of double-blind 
study drug, December 31 will be assigned to the missing fields 
• If the year of the incomplete start date is after the year of the first dose of double-blind 
study drug, January 1 will be assigned to the missing fields 
Missing month only 
• If only the month is missing, the day will be treated as missing and both the month and the 
day will be replaced according to the above procedure 


 
 
 
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Missing day only 
• If the month and year of the incomplete start date are the same as the month and year of 
the first dose of double-blind study drug, the day of the first dose of double-blind study 
drug will be assigned to the missing day 
• If either the year of the incomplete start date is before the year of the date of the first dose 
of double-blind study drug or if both years are the same but the month of the incomplete 
start date is before the month of the date of the first dose of double-blind study drug, the 
last day of the month will be assigned to the missing day 
• If either the year of the incomplete start date is after the year of the date of the first dose of 
double-blind study drug or if both years are the same but the month of the incomplete start 
date is after the month of the date of the first dose of double-blind study drug, the first day 
of the month will be assigned to the missing day 
If the stop date is complete and the imputed start date as above is after the stop date, the start date 
will be imputed by the stop date. 
If the start date is completely missing and the stop date is complete, the following algorithm will 
be used to impute the start date: 
• If the stop date is after the date of the first dose of double-blind study drug, the date of the 
first dose of double-blind study drug will be assigned to the missing start date 
• If the stop date is before the date of the first dose of double-blind study drug, the stop date 
will be assigned to the missing start date 
14.9 
Missing Date Information for Prior or Concomitant Medications 
For prior or concomitant medications, incomplete (ie, partly missing) start dates and/or stop dates 
will be imputed. When the start date and the stop date are both incomplete for a patient, the start 
date will be imputed first.  
14.9.1 Incomplete Start Date 
The following rules will be applied to impute the missing numeric fields for an incomplete prior 
or concomitant medication start date. If the stop date is complete (or imputed) and the imputed 
start date is after the stop date, the start date will be imputed using the stop date. 
Missing month and day 
• If the year of the incomplete start date is the same as the year of the first dose of double-
blind study drug, the month and day of the first dose of double-blind study drug will be 
assigned to the missing fields 
• If the year of the incomplete start date is before the year of the first dose of double-blind 
study drug, December 31 will be assigned to the missing fields 
• If the year of the incomplete start date is after the year of the first dose of double-blind 
study drug, January 1 will be assigned to the missing fields 


 
 
 
Page 38 of 44 
Missing month only 
• If only the month is missing, the day will be treated as missing and both the month and the 
day will be replaced according to the above procedure  
Missing day only 
• If the month and year of the incomplete start date are the same as the month and year of 
the first dose of double-blind study drug, the day of the first dose of double-blind study 
drug will be assigned to the missing day 
• If either the year of the incomplete start date is before the year of the date of the first dose 
of double-blind study drug or if both years are the same but the month of the incomplete 
start date is before the month of the date of the first dose of double-blind study drug, the 
last day of the month will be assigned to the missing day. 
• If either the year of the incomplete start date is after the year of the date of the first dose of 
double-blind study drug or if both years are the same but the month of the incomplete start 
date is after the month of the date of the first dose of double-blind study drug, the first day 
of the month will be assigned to the missing day 
14.9.2 Incomplete Stop Date 
The following rules will be applied to impute the missing numeric fields for an incomplete prior 
or concomitant medication stop date. If the imputed stop date is before the start date (imputed or 
non-imputed start date), the imputed stop date will be equal to the start date. 
Missing month and day 
• If the year of the incomplete stop date is the same as the year of the last dose of double-
blind study drug, the month and day of the last dose of double-blind study drug will be 
assigned to the missing fields 
• If the year of the incomplete stop date is before the year of the last dose of double-blind 
study drug, December 31 will be assigned to the missing fields 
• If the year of the incomplete stop date is after the year of the last dose of double-blind study 
drug, January 1 will be assigned to the missing fields 
Missing month only 
• If only the month is missing, the day will be treated as missing and both the month and the 
day will be replaced according to the above procedure 
Missing day only 
• If the month and year of the incomplete stop date are the same as the month and year of 
the last dose of double-blind study drug, the day of the last dose of double-blind study drug 
will be assigned to the missing day 
• If either the year of the incomplete stop date is before the year of the date of the last dose 
of double-blind study drug or if both years are the same but the month of the incomplete 
stop date is before the month of the date of the last dose of double-blind study drug, the 
last day of the month will be assigned to the missing day 


 
 
 
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• If either the year of the incomplete stop date is after the year of the date of the last dose of 
double-blind study drug or if both years are the same but the month of the incomplete stop 
date is after the month of the date of the last dose of double-blind study drug, the first day 
of the month will be assigned to the missing day. 
 
 


 
 
 
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15. 
CHANGES TO ANALYSES SPECIFIED IN THE PROTOCOL 
There are no changes to the analyses specified in the protocol. 
 
 
 


 
 
 
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