Conditions: Major Depressive Disorder
Keywords: Adjunctive MDD Therapy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 485
Healthy volunteers: no

Brief summary:
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group, fixed-dose study in patients with a primary diagnosis of MDD according to criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) who have an inadequate response to ongoing ADT.

Detailed description:
The study will be conducted in three periods:

* Screening Period (up to 2 weeks) during which patient eligibility will be assessed;
* Double-blind Treatment Period (6 weeks) in which all patients will be randomized to receive placebo or lumateperone 42mg/day in 1:1 ratio.
* Safety Follow-up Period (1 week) in which all patients will return to the clinic for a safety follow-up visit approximately one week after the last dose of study treatment.

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: Lumateperone intervention 2: Placebo
Intervention descriptions: intervention 1: Lumateperone 42 mg capsules administered orally, once daily. intervention 2: Matching capsules administered orally, once daily.

Protocol document:
Prot_000.pdf: 
NCT04985942 
 
 
 
 
Study ID: ITI-007-501 
 
 
 
Title: A Randomized, Double-Blind, Placebo-controlled Multicenter Study to Assess the 
         Efficacy and Safety of Lumateperone as Adjunctive Therapy in the Treatment of 
         Patients with Major Depressive Disorder 
 
 
 
 
Protocol Amendment 2 Date: 20 Aug 2021 




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PROTOCOL AMENDMENT #2: MAJOR CHANGES 
Protocol Amendment 2 for Study ITI-007-501, dated 20 Aug 2021, provides revisions and 
clarifications to the Protocol Amendment 1 (dated 08 Jun 2021). Major changes to the protocol are 
summarized in the table below. 
Editorial corrections and minor revisions for consistent terminology usage are not summarized in 
this table. 
Major changes to previous Protocol Amendment 1 are presented in Appendix II. 
Protocol Section 
Revision  
Rationale 
Section 5.1.1 Primary 
Objective, 3rd paragraph after 
Table 5-1  
Updated statistical methodology: “An 
additional estimand…” 
Based on feedback from 
FDA on ITI-007-501 
protocol  
Section 6.3.2 Exclusion 
Criterion #21e 
Modified hepatic exclusion criterion to 
specify exclusion of patients with moderate 
or severe hepatic impairment 
Based on feedback from 
FDA on ITI-007-501 
protocol  
Section 6.4 Stopping Criteria  
Updated the section title;  modified 
discontinuation and patient-level stopping 
criteria (Section 6.4.1); and added a 
subsection for study stopping criteria 
(Section 6.4.2);  
Based on feedback from 
FDA on ITI-007-501 
protocol  
Section 7.2 Study Treatment: 
Supply, Storage, and 
Accountability of Study Drug 
Updated study treatment supply and storage 
information 
Clarifications 
Section 8.1.4 Eligibility Review 
Process and Section 8.5.1 
Screening 
Changed EAF to PEER form 
Clarification of the 
screening assessment form 
used for the MDD 
program. 
Section 8.3.4 Clinical 
Laboratory Determination; 
Section 8.4 Pharmacokinetic 
Assessments; Section 10.3.2 
Data Recording and 
Documentation  
Changed Laboratory Procedure Manual to 
Laboratory Manual 
Revised to be consistent 
with nomenclature for 
study site materials. 
Section 9.4.5.1.1 Primary 
Efficacy Analysis, last 
paragraph 
Added statistical methodology: “In case the 
…” 
Based on feedback from 
FDA on ITI-007-501 
protocol  
Section 9.4.5.1.3 Additional 
Analysis 
Added subsection “Additional Analysis” 
Based on feedback from 
FDA on ITI-007-501 
protocol 
Section 9.4.5.2.2 Supportive 
Key Secondary Analysis 
Updated statistical methodology: “The 
analyses will…” 
Based on feedback from 
FDA on ITI-007-501 
protocol 
Section 12 REFERENCES 
Added Lu 2010 reference 
To support statistical 
approach to the primary 
efficacy analysis. 


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PROTOCOL APPROVAL—SPONSOR SIGNATORIES 
Protocol Title: 
A 
Randomized, 
Double-blind, 
Placebo-controlled 
Multicenter Study to Assess the Efficacy and Safety of 
Lumateperone as Adjunctive Therapy in the Treatment of 
Patients with Major Depressive Disorder 
Protocol Number: 
ITI-007-501 
Original Protocol Date: 
20 Aug 2021 
DocuSign Envelope ID: E26472E7-C23A-486A-B8EF-3AAD431B0C53


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TABLE OF CONTENTS 
PROTOCOL AMENDMENT #2: MAJOR CHANGES ................................................................ 2 
PROTOCOL APPROVAL—SPONSOR SIGNATORIES ............................................................ 3 
TABLE OF CONTENTS ................................................................................................................ 4 
LIST OF TABLES .......................................................................................................................... 8 
LIST OF FIGURES ........................................................................................................................ 8 
LIST OF ABBREVIATIONS ......................................................................................................... 9 
1 PROTOCOL SYNOPSIS AND SCHEDULE OF EVALUATIONS ..................................... 12 
2 ETHICAL CONSIDERATIONS ............................................................................................ 18 
2.1 
Institutional Review Board and Independent Ethics Committee ................................... 18 
2.2 
Ethical Conduct of the Study ......................................................................................... 18 
2.3 
Patient Information and Informed Consent .................................................................... 18 
3 INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ............................. 19 
4 INTRODUCTION .................................................................................................................. 20 
5 STUDY OBJECTIVES ........................................................................................................... 23 
5.1 
Efficacy Objectives ........................................................................................................ 23 
5.1.1 
Primary Objective ....................................................................................................... 23 
5.1.2 
Key Secondary Efficacy Objective ............................................................................. 25 
5.1.3 
Additional Efficacy Objectives .................................................................................. 26 
5.2 
Safety Objectives............................................................................................................ 26 
6 INVESTIGATIONAL PLAN ................................................................................................. 27 
6.1 
Overall Study Design and Plan ...................................................................................... 27 
6.2 
Scientific Rationale for Study Design ............................................................................ 28 
6.2.1 
Study Design............................................................................................................... 28 
6.2.2 
Separate Open-label Safety Study .............................................................................. 29 
6.2.3 
Dose Selection ............................................................................................................ 29 
6.3 
Study Population ............................................................................................................ 29 
6.3.1 
Inclusion Criteria ........................................................................................................ 29 
6.3.2 
Exclusion Criteria ....................................................................................................... 31 
6.4 
Stopping Criteria ............................................................................................................ 35 
6.4.1 
Discontinuation of Patients from Therapy or Assessment: Patient-level Stopping 
Criteria 35 
6.4.2 
Study Stopping Criteria .............................................................................................. 36 


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6.5 
Patient Replacement Procedures .................................................................................... 36 
6.6 
Changes in the Conduct of the Study ............................................................................. 36 
7 STUDY TREATMENTS ........................................................................................................ 37 
7.1 
Treatment Administered ................................................................................................. 37 
7.2 
Supply, Storage, and Accountability of Study Treatment .............................................. 37 
7.2.1 
Storage of Study Treatment ........................................................................................ 38 
7.2.2 
Study Treatment Accountability ................................................................................. 38 
7.3 
Method of Assigning Patients to Treatment Groups ...................................................... 38 
7.4 
Blinding .......................................................................................................................... 39 
7.5 
Unblinding ...................................................................................................................... 39 
7.6 
Monitoring Treatment Compliance ................................................................................ 39 
7.7 
Prior and Concomitant Medications ............................................................................... 39 
7.7.1 
Prior Medications ....................................................................................................... 40 
7.7.2 
Prohibited Medications ............................................................................................... 40 
7.7.3 
Rescue Medication ..................................................................................................... 40 
7.8 
Treatment After Discontinuation ................................................................................... 40 
8 EFFICACY, SAFETY AND OTHER ASSESSMENTS ....................................................... 41 
8.1 
Diagnostic and Other Screening Period Assessments .................................................... 41 
8.1.1 
MINI International Neuropsychiatric Interview ......................................................... 41 
Medical History and Other Information ................................................................................. 41 
8.1.2 
Eligibility Review Process.......................................................................................... 41 
8.1.3 
Patient Placebo Questionnaire and Training .............................................................. 41 
8.1.4 
Quick Inventory for Depressive Symptomatology-Self Report (QIDS-SR-16) ......... 42 
8.2 
Efficacy Assessments ..................................................................................................... 42 
8.2.1 
Montgomery-Åsberg Depression Rating Scale (MADRS) ........................................ 42 
8.2.2 
Clinical Global Impression-Severity (CGI-S) ............................................................ 42 
8.2.3 
Generalized Anxiety Disorder-7 item (GAD-7) ......................................................... 42 
8.3 
Safety .............................................................................................................................. 42 
8.3.1 
Adverse Events ........................................................................................................... 43 
8.3.2 
Potential Hy’s Law Cases ........................................................................................... 46 
8.3.3 
Pregnancy ................................................................................................................... 47 
8.3.4 
Clinical Laboratory Determinations ........................................................................... 48 


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8.3.5 
Vital Signs .................................................................................................................. 49 
8.3.6 
Electrocardiograms ..................................................................................................... 50 
8.3.7 
Columbia–Suicide Severity Rating Scale (C-SSRS) .................................................. 50 
8.3.8 
Extrapyramidal Scales ................................................................................................ 51 
8.3.9 
Modified Physical Examination ................................................................................. 51 
8.4 
Pharmacokinetic Assessments........................................................................................ 52 
8.5 
Schedule of Assessments ............................................................................................... 52 
8.5.1 
Screening .................................................................................................................... 52 
8.5.2 
Double-blind Treatment Period (Visit 2-8/Weeks 0-6) .............................................. 53 
8.5.3 
Safety Follow-up Visit (Visit 9/Day 50 ±3) ............................................................... 56 
9 STATISTICAL METHODS ................................................................................................... 57 
9.1 
General Considerations .................................................................................................. 57 
9.2 
Determination of Sample Size........................................................................................ 57 
9.3 
Analysis Populations ...................................................................................................... 57 
9.4 
Statistical Analyses ........................................................................................................ 58 
9.4.1 
Patient Disposition ...................................................................................................... 58 
9.4.2 
Demographics and Other Baseline Characteristics .................................................... 58 
9.4.3 
Prior and Concomitant Medication ............................................................................. 58 
9.4.4 
Extent of Exposure and Treatment Compliance ......................................................... 59 
9.4.5 
Efficacy Analyses ....................................................................................................... 59 
9.4.6 
Multiple Comparisons/Multiplicity ............................................................................ 65 
9.4.7 
Safety Analyses .......................................................................................................... 65 
9.4.8 
PHARMACOKINETIC ANALYSES ........................................................................ 67 
9.5 
INTERIM ANALYSIS .................................................................................................. 67 
9.6 
Data and Safety Monitoring Board ................................................................................ 67 
9.7 
Protocol Deviations ........................................................................................................ 67 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL MONITORING ............. 68 
10.1 
Study Termination .......................................................................................................... 68 
10.2 
Investigator Obligations ................................................................................................. 68 
10.2.1 
Documentation ........................................................................................................ 68 
10.2.2 
Performance ............................................................................................................ 68 
10.2.3 
Use of Investigational Materials ............................................................................. 68 


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10.2.4 
Case Report Forms .................................................................................................. 69 
10.2.5 
Retention and Review of Records........................................................................... 69 
10.2.6 
Patient Confidentiality ............................................................................................ 69 
10.3 
Data Quality Assurance .................................................................................................. 70 
10.3.1 
Data Monitoring ...................................................................................................... 70 
10.3.2 
Data Recording and Documentation ....................................................................... 70 
10.4 
Reporting and Publication .............................................................................................. 71 
11 
APPENDICES ................................................................................................................... 72 
Appendix I. 
Elements Of Informed Consent ........................................................................... 72 
Appendix II. Protocol Amendment 1: Major Changes ................................................................. 74 
12 
REFERENCES .................................................................................................................. 76 
13 
INVESTIGATOR SIGNATURE PAGE ........................................................................... 78 


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LIST OF TABLES 
Table 1-1: Schedule of Evaluations .............................................................................................. 16 
Table 5-1: Primary Estimand and Intercurrent Events—Hypothetical Strategy .......................... 23 
Table 7-1: Study Treatment Dosage and Composition ................................................................. 37 
Table 7-2: Weekly Study Treatment Cards .................................................................................. 38 
Table 9-1: Primary Estimand and Intercurrent Events—Hypothetical Strategy .......................... 60 
Table 9-2: Supportive Estimand and Intercurrent Events—Treatment Policy Strategy Eliminating 
New ADT Effect ........................................................................................................................... 61 
Table 9-3: Additional Estimand and Intercurrent Events—Treatment Policy Strategy Including 
Possible New ADT Effect ............................................................................................................. 62 
Table 9-4: Key Secondary Estimand and Intercurrent Events—Hypothetical Strategy ............... 64 
LIST OF FIGURES 
Figure 6-1: Schematic of Study Design ........................................................................................ 27 
 


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LIST OF ABBREVIATIONS 
ADT 
antidepressant therapy 
AE 
adverse event 
AIMS 
Abnormal Involuntary Movement Scale 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ATRQ 
Antidepressant Treatment Response Questionnaire 
BMI 
body mass index 
BP 
blood pressure 
bpm 
beats per minute 
CFR 
Code of Federal Regulations 
C-SSRS 
Columbia–Suicide Severity Rating Scale 
CGI-BP-S 
Clinical Global Impression Scale, Bipolar version, 
 
Severity 
CRO 
Contract research organization 
CSR 
Clinical study report 
D2 
dopamine 2 receptor 
DSM-5 
Diagnostic and Statistical Manual, 5th edition 
ECG 
electrocardiogram, electrocardiographic 
eCRF 
electronic case report form 
ECT 
electroconvulsive therapy 
EDC 
electronic data capture 
ET 
early termination 
FDA 
Food and Drug Administration 
RF 
Federal Register 
GAD-7 
Generalized Anxiety Disorder-7 item 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act
 
of 1996 
HIV 
human immunodeficiency virus 
ICE 
intercurrent event 
ICF 
informed consent form 


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ICH 
International Council on Harmonisation of 
Technical  
Requirements for Registration of Pharmaceuticals 
for  
Human Use 
IEC 
International Ethics Committee 
IND 
Investigational New Drug (application) 
ITI 
Intra-Cellular Therapies, Inc. 
ITT 
intent-to-treat 
IWRS 
interactive web response system 
MADRS 
Montgomery-Åsberg Depression Rating Scale 
MDD 
major depressive disorder 
MDE 
major depressive episode 
MedDRA 
Medical Dictionary for Regulatory Activities 
MINI 
Mini International Neuropsychiatric Interview 
MMRM 
Mixed-effect Model for Repeated Measures 
msec 
millisecond 
PCS 
potentially clinically significant 
PEER 
 
Pre-Enrollment Eligibility Review 
PET 
positron emission tomography 
PK  
pharmacokinetic 
PMM 
pattern-mixture model 
QIDS-SR-16 
Quick Inventory of Depressive Symptomatology-
 
Self-Report-16 item 
QTc 
QT interval corrected for heart rate 
QTcB 
QT interval corrected for heart rate using the Bazett 
 
formula (QTcB = QT/<RR>½) 
QTcF 
QT interval corrected for heart rate using the 
 
Fridericia formula (QTcF = QT/<RR>⅓) 
SAE 
serious adverse event 
SAS 
Simpson Angus Scale 
SAP  
statistical analysis plan 
SERT 
serotonin transporter 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
UDS 
urine drug screen 


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ULN 
upper limit of normal 
US 
United States 
 


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1 PROTOCOL SYNOPSIS AND SCHEDULE OF EVALUATIONS 
CLINICAL STUDY SYNOPSIS: Study ITI-007-501 
Title of Study 
A Randomized, Double-blind, Placebo-controlled Multicenter Study to 
Assess the Efficacy and Safety of Lumateperone as Adjunctive Therapy in 
the Treatment of Patients with Major Depressive Disorder. 
Study Centers (Country) 
Approximately 60 study centers (United States and globally).  
Development Phase 
3 
Objectives 
Primary Objective 
• 
To evaluate the efficacy of lumateperone 42 mg administered once 
daily compared with placebo as adjunctive treatment to 
antidepressant therapy in patients with Major Depressive Disorder 
(MDD) who have an inadequate response to ongoing antidepressant 
therapy (ADT) as measured by change from baseline to Day 43 in 
the Montgomery-Åsberg Depression Rating Scale (MADRS) total 
score. 
Key Secondary Efficacy Objective 
• 
To evaluate the efficacy of lumateperone 42 mg administered once 
daily compared with placebo as adjunctive treatment to ADT in 
patients with MDD who have an inadequate response to ongoing 
ADT as measured by change from baseline to Day 43 in the Clinical 
Global Impression Scale-Severity (CGI-S). 
Study Design 
This is an international, multicenter, randomized, double-blind, placebo-
controlled, parallel-group, fixed-dose study in patients with a primary 
diagnosis of MDD according to criteria of the Diagnostic and Statistical 
Manual of Mental Disorders, Fifth Edition (DSM-5) who have an 
inadequate response to ongoing ADT. 
The study will be conducted in three periods:  
• 
Screening Period (up to 2 weeks) during which patient eligibility 
will be assessed; 
• 
Double-blind Treatment Period (6 weeks) in which all patients will 
be randomized to receive placebo or lumateperone 42 mg/day in 1:1 
ratio. 
• 
Safety Follow-up Period (1 week) in which all patients will return 
to the clinic for a safety follow-up visit approximately one week 
after the last dose of study treatment. 
Number of Patients 
Approximately 470 patients (235 per treatment group) are planned to be 
enrolled in the Double-blind Treatment Period. 
Diagnosis and Main Criteria for 
Inclusion and Exclusion 
Main Inclusion Criteria 
Patients will be eligible for study participation if they meet the following 
inclusion criteria: 
1. Provides written informed consent; 
2. Male or female patients between the ages of 18 and 65 years, 
inclusive;  
3. Meets DSM-5 criteria for MDD (MDD with psychotic features 
will be acceptable) as confirmed by the Investigator or Sponsor-
approved rater using the MINI and meets all of the following 
criteria: 


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a. 
The start of the current major depressive episode (MDE) is at 
least 8 weeks but not more than 18 months prior to Screening 
(Visit 1); 
b. Has at least moderate severity of illness based on rater-
administered MADRS total score ≥ 24 at Screening (Visit 1) 
and at Baseline (Visit 2); 
c. 
Has at least moderate severity of illness based on CGI-S 
score ≥ 4 at Screening (Visit 1) and at Baseline (Visit 2);  
d. Has a Quick Inventory of Depressive Symptomatology-Self 
Report-16 item (QIDS-SR-16) score ≥ 14 at Screening 
(Visit 1) and at Baseline (Visit 2); 
e. 
Has sufficient history and medical record confirmation 
verifying the ADT and the current MDE is causing clinically 
significant distress or impairment in social, occupational, or 
other important areas of functioning. 
4.  Currently having an inadequate response to ADT (less than 50% 
improvement) as confirmed by the Investigator using the 
Antidepressant Treatment Response Questionnaire (ATRQ) and 
taking at least the minimum effective dose (per package insert) of 
one of the following antidepressants as monotherapy treatment for 
at least 6 weeks duration: 
a. 
citalopram/escitalopram 
b. fluoxetine  
c. 
paroxetine 
d. sertraline 
e. 
duloxetine 
f. 
levomilnacipran/milnacipran (if locally approved for MDD) 
g. venlafaxine/desvenlafaxine 
h. bupropion 
i. 
vilazodone 
j. 
vortioxetine 
All Inclusion Criteria are presented in Section 6.3.1. 
Main Exclusion Criteria 
Patients who meet any of the following exclusion criteria will not be able 
to participate in the study: 
1. Within the patient’s lifetime, has a confirmed DSM-5 psychiatric 
diagnosis other than MDD, including: 
a. 
Schizophrenia, Schizoaffective Disorder, Schizophreniform 
Disorder or other psychotic disorder; 
b. Bipolar Disorder; 
2. Within 6 months of Screening, has a confirmed DSM-5 psychiatric 
diagnosis other than MDD including: 
a. 
Anxiety disorders such as Panic Disorder or Generalized 
Anxiety Disorder; Obsessive-compulsive Disorder; 
Posttraumatic Stress Disorder as primary diagnoses. Note: 
Anxiety symptoms may be allowed if secondary to MDD, 
provided these symptoms do not require concurrent treatment; 
b. Eating disorder; 
c. 
Substance use disorders (excluding nicotine); 
d. Personality disorder of sufficient severity to have a major 
impact on the patient’s psychiatric status; 




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Statistical Methods 
The primary efficacy endpoint will be change from Baseline to Day 43 in 
MADRS total score. Based on the primary hypothetical estimand strategy 
which assumes patients are on study treatment up to the primary time point 
(Day 43), efficacy data collected after discontinuation of study treatment 
(ie, efficacy assessment performed more than 3 days after last dose of study 
treatment) and/or after starting new ADT will be set to missing and will not 
be included in the primary analysis. Instead, these missing data will be 
assumed as missing at random. The primary analysis to estimate and 
compare the treatment effects of lumateperone vs placebo as defined by the 
primary estimand will be performed using a mixed-effects model for 
repeated measures (MMRM) with change from baseline at each study visit 
as the response variable, and treatment group, study site (or pooled site) 
and study visit as factors, baseline MADRS total score as covariate, and 
interaction terms for baseline MADRS total score-by-study visit and 
treatment group-by-study visit. An unstructured covariance matrix will be 
used to model the covariance of within-patient scores. The Kenward-Roger 
approximation will be used to estimate the denominator degrees of 
freedom. Treatment difference will be estimated via contrast based on 
treatment group and treatment group-by-study visit factors. 
The key secondary efficacy parameter will be the change from baseline to 
Day 43 in CGI-S score. The key secondary efficacy parameter will be 
analyzed using a similar MMRM as used for the primary analysis with the 
baseline CGI-S score for the covariate. 
A fixed sequence testing procedure will be used to control the overall 
Type I error of 0.05 with the primary endpoint tested first at the 2-sided 
0.05 level, and if significant, the key secondary endpoint will be tested at 
the 2-sided 0.05 level. 
Primary efficacy analyses will be based on the modified Intent-to-Treat 
(mITT) Population, defined as all randomized patients who received at least 
1 dose of study treatment, have an evaluable baseline assessment of 
MADRS total score, and have at least one evaluable post-baseline, on-
treatment assessment of the MADRS total score (on-treatment MADRS 
assessments are those performed no later than 3 days after the last dose of 
study treatment). 
Key secondary efficacy analyses will also be based on the mITT Population. 
An estimation and comparison of the treatment effects of lumateperone vs 
placebo for the key secondary endpoint are based on the hypothetical 
estimand (similar to that defined for the primary analysis, using assessed 
CGI-S score up to 3 days after last study dose and not including those 
assessed after new ADT). 
All safety parameters will be summarized descriptively. Safety analyses 
will be based on the Safety Population defined as all randomized patients 
who received at least one dose of investigational product.  
Individual plasma concentrations will be listed and summarized by visit. 
Plasma concentrations will be analyzed using a population PK approach. 
The results from the population PK analyses will be presented in a separate 
report. 
Approximately 470 patients will be randomly assigned to 1 of the 2 
treatment groups (lumateperone 42 mg or matching placebo). Assuming a 
common drop-out rate of 20% and a common correlation of 0.7 between 
the repeated measures, the sample size of 235 patients per treatment group 
will provide approximately 90% statistical power for the effect size of 0.33 
(treatment difference of 3.3 and common pooled standard deviation of 10) 
for the primary efficacy endpoint. 






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2 ETHICAL CONSIDERATIONS 
2.1 
Institutional Review Board and Independent Ethics Committee 
Approval by the Institutional Review Board (IRB) and Independent Ethics Committee (IEC) is 
required before the start of the study. A copy of the approval letter will be supplied to Intra-Cellular 
Therapies, Inc. (the Sponsor) or its designee along with a roster of IRB/IEC members. During the 
course of the study, the Investigator will provide timely and accurate reports to the IRB/IEC on 
the progress of the study, at intervals not exceeding 1 year (or as appropriate) and will notify the 
IRB/IEC of serious adverse events (SAEs) or other significant safety findings. The study protocol, 
informed consent form (ICF), information sheet advertisements, and amendments (if any) will be 
approved by the IRBs/IECs at the study centers in conformance with US CFR, Title 21, Part 56 
and applicable local regulations. 
2.2 
Ethical Conduct of the Study 
This clinical study will be conducted in accordance with the ethical principles that have their 
origins in the Declaration of Helsinki. This clinical study will comply with the ICH Guidance on 
General Considerations for Clinical Trials (ICH-E8; 62 FR 66113, 17 Dec 1997) and GCP (ICH-
E6; 62 FR 25692, March 2018), as well as CFR Part 312 and applicable local regulations. 
2.3 
Patient Information and Informed Consent 
A written informed consent in compliance with US Title 21 Code of Federal Regulations (CFR) 
Part 50 regulations and relevant country regulations shall be obtained from each patient before 
entering the study or performing any study-specific procedure that involves risk to the patient. If 
the ICF is revised during the study, all active participating patients must sign the revised form. The 
informed consent statement shall contain all the elements of informed consent listed in Appendix I. 
Before any screening procedures, each prospective patient will be given a full explanation of the 
study and be allowed to read the approved ICF. After receiving an explanation of study procedures, 
patients will have the opportunity to have any questions answered before signing the ICF. The 
Investigator must address all questions raised by the patient. Each patient will read, assent to an 
understanding of, and sign the ICF or other locally applicable authorization form. Each patient will 
be made aware that he/she may withdraw from the study at any time. 
The Investigator will also sign the ICF and provide a copy of the ICF to the patient. 


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3 INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE 
A list of Sponsor personnel responsible for study oversight is provided in the Study Reference 
Manual. 


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4 INTRODUCTION 
Major depressive disorder (MDD) is a serious psychiatric disorder characterized by the presence 
of one or more major depressive episodes (MDE). 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. Depression can have damaging effects on 
health and wellbeing, and leave one at risk for social withdrawal, alcohol abuse, and disrupted 
work, family, and social life (Kupferberg et al, 2016). 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. 
Despite a number of approved antidepressants, a substantial percentage of individuals with MDD 
have inadequate response to conventional antidepressants alone or in various combinations (Little, 
2009). In STAR*D (Sequenced Treatment Alternatives to Relieve Depression), the largest 
randomized trial of the treatment of MDD, a representative sample of outpatients with MDD 
received one to four successive acute treatment steps. Those who did not achieve remission at each 
treatment step were able to move to the next step. Only 36.8% of patients achieved remission at 
step 1, the first course of antidepressant treatment (Rush et al, 2005). More than 20% of those who 
failed to improve with the first treatment stopped taking medication, primarily within the first 2 
weeks (Warden, 2007). Depressed patients who have an inadequate response to ADT represent a 
particularly vulnerable, at risk 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. 
ITI, the Sponsor, is exploring the utility of lumateperone as adjunctive therapy in the treatment of 
MDD.  
Lumateperone is a novel small molecule therapeutic agent designed specifically to combine 
serotonergic, dopaminergic, and glutamatergic modulation in a dose-dependent 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 (D1) receptor activation.  
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 may also play a role in antidepressant response. Importantly, 
lumateperone lacks potent off-target interactions that have been associated with side effects of 
other antipsychotic drugs approved as adjunctive treatment of MDD. For example, lumateperone 
shows relatively weak affinity for 5-HT2C and no measurable affinity for H1 or muscarinic 


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cholinergic receptors, which predict favorable body weight and metabolic profile responses to the 
extent that these receptors mediate such effects. 
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 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. 
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. Similar improvements in depression 
symptoms were also seen in a one-year open label study of lumateperone in patients with 
schizophrenia (ITI-007-303). In this study, the favorable safety and tolerability profile was 
sustained.  
Clinical data from 3 well-controlled bipolar depression studies (Studies ITI-007-401, ITI-007-404, 
and ITI-007-402) demonstrated efficacy in bipolar depression and confirmed lumateperone’s 
tolerability and favorable safety profile.  
In Study ITI-007-404, 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 Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Lumateperone 
42 mg also met the key secondary endpoint of statistically significant improvement on the Clinical 
Global Impression Scale, Bipolar version, Severity (CGI-BP-S) total score and demonstrated 
statistically significant improvement on the CGI-BP-S depression. 
In Study ITI-007-402, 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.  


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In Study ITI-007-401, 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. 
Patients who completed Study ITI-007-401 were eligible to participate in an optional, 6-month 
open-label extension. On average, patients improved and did not worsen on lumateperone 42 mg 
with respect to their depressive symptoms. 
Safety data from these studies and other trials with lumateperone, which has been administered to 
more than 3300 individuals for up to one year, show lumateperone to be well tolerated across a 
dose range from 0.7 to 126 mg, with a safety profile similar to placebo.  
The purpose of the current study is to confirm the efficacy, safety and tolerability of lumateperone 
as adjunctive therapy for the treatment of patients with MDD. Patients will be monitored carefully 
for their mental health status and general health. Symptoms of 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 
depression in the future. More detailed information about the known and expected benefits and 
risks and reasonably expected AEs is provided in the current lumateperone Investigator’s 
Brochure. 










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6 INVESTIGATIONAL PLAN 
6.1 
Overall Study Design and Plan 
Study ITI-007-501 is a Phase 3, randomized, double-blind, placebo-controlled, multicenter study 
to evaluate the efficacy, safety, and tolerability of lumateperone as adjunctive therapy for the 
treatment of patients with MDD. This study will be performed at approximately 60 study centers 
in the United States and globally.  
The study will be conducted as follows: 
• A Screening Period of up to 2 weeks 
• A 6-week Double-blind Treatment Period 
• A 1-week Safety Follow-up (SFU) Period 
The maximum study duration for each patient will be approximately 9 weeks. 
The study design schematic is provided in Figure 6-1. The Schedule of Evaluations is presented in 
Table 1-1. Detailed descriptions of the procedures conducted at each study visit are provided in 
Section 8.5. 
Figure 6-1: Schematic of Study Design 
 
ADT = antidepressant treatment; ET = early termination; SFU = Safety Follow-up. 
a Eligible patients who complete 6 weeks of double-blind treatment and provide informed consent to rollover into 
the Open-label Safety Study will not enter the SFU Period. 


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6.2 
Scientific Rationale for Study Design 
6.2.1 
Study Design 
Screening Period (up to 2 Weeks)  
Potential patients will be evaluated during a Screening Period lasting up to 14 days. With approval 
from the Sponsor or designee, short extensions to the Screening Period may be granted in 
exceptional circumstances. After obtaining written informed consent, diagnostic interviews, 
determination of inadequate response to current ADT, 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 will be required to continue their 
current ADT but will be required to discontinue other psychotropic drugs.  
Evaluation of diagnostic validity and eligibility of each patient will be undertaken by the Sponsor 
or designee. 
At Baseline (Visit 2), patients who continue to meet all eligibility criteria will be randomized to 
1 of 2 treatment arms, lumateperone 42 mg or matching placebo, and will enter the 6-week, double-
blind treatment period.  
Double-blind Treatment Period (6 Weeks)  
Patients will self-administer his/her first dose of study treatment on the evening of the Baseline 
visit (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. Antidepressant treatment will also 
continue as previously prescribed. The dose and frequency of ADT must not change during the 
Screening Period or for the duration of the Double-blind Treatment Period. 
Patients will attend outpatient study visits on Days 8, 15, 22, 29, 36, and 43. With approval from 
the Sponsor or designee, sites will be permitted to conduct remote visits if a site-based visit is not 
feasible. However, all Screening (Visit 1) and Baseline (Visit 2) assessments must be performed 
in person. 
A patient will be defined as a treatment completer if the patient completes the Double-blind 
Treatment Period (all scheduled visits up to and including Visit 8). Patients who withdraw 
prematurely should be seen for an Early Termination (ET) visit as soon as possible and will also 
be asked to return for a safety follow-up visit approximately one week after Visit 8/ET. 
Safety Follow-up Period (1 Week)  
All patients should return to the clinic for the SFU visit approximately 1 week after Visit 8/ET. 
Any ongoing AEs at the SFU visit must be followed until resolution, until the AE stabilizes, until 
it is determined to be not clinically significant, or until the patient is lost to follow-up. 


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6.2.2 
Separate Open-label Safety Study  
Patients who complete the 6-week Double-blind Treatment Period, who are considered to be 
appropriate by the Investigator, and who meet eligibility criteria may enroll in the 6-month Open-
label Safety Study at the Visit 8/Week 6 visit. This rollover visit to the Open-label Safety Study at 
Visit 8/Week 6 must be in person. A patient who enters the Open-label Safety Study will not have 
a SFU visit (Visit 9/Week 7). 
6.2.3 
Dose Selection 
Lumateperone 42 mg was selected based on 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 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. 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 indication. The 6-week 
treatment period duration 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 MDD, with statistically significant 
superiority vs placebo on the primary outcome measure: Change from baseline to Day 43 in 
MADRS total score in patients with MDD. 
6.3 
Study Population 
6.3.1 
Inclusion Criteria 
To be eligible to participate in the study, patients must meet the following inclusion criteria: 
1. Provide written informed consent obtained from the patient before the initiation of any study 
specific procedures. See Appendix I for informed consent requirements; 
2. Male or female patients between the ages 18 and 65 years; inclusive; 
3. Meet DSM-5 diagnostic criteria for MDD (a diagnosis of MDD with psychotic features will 
be acceptable) as confirmed by the Investigator or Sponsor-approved rater using the Mini-
International Neuropsychiatric Interview (MINI), and meet all the following criteria:  
a. The start of the current MDE is at least 8 weeks but no more than 18 months prior 
to the Screening (Visit 1);  


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b. Has at least moderate severity of illness, based on rater administered MADRS total 
score ≥ 24 at Screening (Visit 1) and at Baseline (Visit 2); 
c. Has at least moderate severity of illness based on CGI-S score of ≥ 4 at Screening 
(Visit 1) and at Baseline (Visit 2);  
d. Has a QIDS-SR-16 score of >14 at Screening (Visit 1) and at Baseline (Visit 2); 
e. Has sufficient history and medical record confirmation (as defined in the Study 
Reference Manual) verifying ADT and the current MDE is causing clinically 
significant distress or impairment in social, occupational, or other important areas 
of functioning; 
4. Currently having an inadequate response to ADT (less than 50% improvement) as confirmed 
by the Investigator using ATRQ and is taking at least the minimum effective dose (per package 
insert) of one of the following antidepressants as monotherapy treatment for at least 6 weeks 
duration, and: 
a. citalopram/escitalopram 
b. fluoxetine  
c. paroxetine 
d. sertraline 
e. duloxetine 
f. levomilnacipran/milnacipran (if locally approved for MDD) 
g. venlafaxine/desvenlafaxine 
h. bupropion 
i. vilazodone 
j. vortioxetine 
5. Is currently an outpatient, and is anticipated to maintain outpatient status for the duration of 
the study; 
6. Has a body mass index (BMI) of 19–40 kg/m2, inclusive; 
7. Ability to follow study instructions and likely to complete all required visits. 


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6.3.2 
Exclusion Criteria 
Patients who meet any of the following exclusion criteria will not be eligible to participate in the 
study. 
Psychiatric Criteria: 
1. Within the patient’s lifetime, has a confirmed DSM-5 psychiatric diagnosis other than MDD, 
including: 
a. 
Schizophrenia, Schizoaffective Disorder, Schizophreniform Disorder or other 
psychotic disorder;  
b. 
Bipolar Disorder. 
2. Within 6 months of Screening, has a confirmed DSM-5 psychiatric diagnosis other than MDD, 
including: 
a. 
Anxiety disorders such as Panic Disorder or Generalized Anxiety Disorder; Obsessive-
compulsive Disorder; Posttraumatic Stress Disorder as primary diagnoses. Note: 
anxiety symptoms may be allowed if secondary to MDD, provided these symptoms do 
not require concurrent treatment; 
b. 
Eating disorder;  
c. 
Substance use disorders (excluding nicotine) 
d. 
Personality disorder of sufficient severity to have a major impact on the patient’s 
psychiatric status; 
e. 
Within 12 months of Screening, has had any other psychiatric condition (other than 
MDD) that has been the main focus of treatment. 
3. The patient experiences a ≥ 25% decrease in the MADRS total score between Screening 
(Visit 1) and Baseline (Visit 2); 
4. The patient experiences a ≥ 25% decrease in the QIDS-SR-16 total score between Screening 
(Visit 1) and Baseline (Visit 2); 
5. In the opinion of the Investigator, the patient has a significant risk for suicidal behavior during 
his/her participation in the study or  
a. 
At Screening (Visit 1), the patient scores “yes” on Suicidal Ideation Items 4 or 5 of 
the C-SSRS within 6 months prior to Screening or, at Baseline (Visit 2), the patient 
scores “yes” on Suicidal Ideation Items 4 or 5 since the Screening Visit; 
b. 
At Screening (Visit 1), the patient has had 1 or more suicidal attempts within the 2 
years prior to Screening; or  
c. 
At Screening (Visit 1) or Baseline (Visit 2), the patient scores ≥ 5 on MADRS Item 10 
(Suicidal Thoughts); or  
d. 
The patient is considered to be an imminent danger to him/herself or others. 
6. The patient has a first MDE at age 60 years or older. 
 


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Treatment Criteria: 
7. In the current MDE, the patient has had > 2 ADTs administered at adequate dose (per product 
label) and for an adequate duration (at least 6 weeks); 
8. In the current MDE, the patient has not responded to treatment with an antipsychotic for MDD 
administered at an adequate dose (per product label) and for an adequate duration (at least 
3 weeks); 
9. The patient is considered treatment-resistant, defined as having a lifetime history of treatment 
resistance (no remission) to > 3 treatments with medications approved for the treatment of 
MDD at an adequate dose (per product label) and for an adequate duration of at least 6 weeks 
for monotherapy and 3 weeks for adjunctive therapy);  
10. The patient has received electroconvulsive therapy (ECT), vagal nerve stimulation, or 
repetitive trans-cranial magnetic stimulation within the past 5 years or had a failure in response 
to ECT at any time; 
11. The patient has known hypersensitivity or intolerance to lumateperone, or to any of the 
excipients;  
12. The patient is currently participating in psychotherapy, or has plans to initiate psychotherapy 
therapy during the study; 
13. The patient has used 1 of the following agents under the specified conditions: 
a. Any strong cytochrome P450 3A4 inhibitor or any P450 3A4 inducer within 7 days 
prior to the baseline visit; 
b. Monoamine oxidase inhibitors within 14 days prior to the baseline visit; 
c. Other drugs with known psychotropic properties or any non-psychotropic drugs 
with known or potentially significant central nervous system effects as reviewed by 
the Sponsor or designee, taken after screening, including, but not limited to: 
i. Benzodiazepines or sedative hypnotics (exceptions for zolpidem and other 
alternative treatments for insomnia are described in Section 7.7.3-Rescue 
Medications);  
ii. Central opioid agonists/antagonists including tramadol; 
iii. Anticonvulsants, mood stabilizers, antidepressants other than background 
antidepressant 
treatment, 
stimulants, 
antipsychotics, 
and 
non-
benzodiazepine anxiolytics; 
iv. Dietary supplements and medical foods unless approved by the Sponsor or 
designee. Daily multivitamin use is not excluded; 
14. The patient has participated in a previous clinical trial with lumateperone, or has had exposure 
to any investigational product within 3 months of the baseline visit or participated in the past 
3 years in > 2 clinical studies of an investigational product with a central nervous system 
indication; 
15. The patient is unable to be safely discontinued from prohibited psychotropic or non-
psychotropic medication (in the opinion of the Investigator). 


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Other Medical Criteria: 
16.  The patient is male, or female of childbearing potential, and does not agree to use a highly 
effective method of birth control (defined as those methods, alone or in combination, that result 
in a failure rate less than 1 percent per year when used consistently and correctly) beginning 
with signing the Informed Consent Form through the end-of-study follow-up period. (Females 
of non-childbearing potential (defined as either permanently sterilized) or post-menopausal 
females (defined as at least one year with no menses without an alternative medical 
explanation) are exempt from the birth control requirement; 
17. The patient is breast-feeding or pregnant. Female patients of childbearing potential must have 
a negative serum pregnancy test 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 
treatment administration; 
18. The patient has a positive test for drugs of abuse (eg, amphetamines, barbiturates, 
benzodiazepines, cannabinoids, cocaine metabolites, methadone, opiates, or phencyclidine) at 
Screening (Visit 1). Exceptions may include prescription treatments (eg, opioids, 
benzodiazepines) if the use is not chronic and is able to be discontinued as per the Investigator 
with the concurrence of the Sponsor or designee. A repeat drug test is allowed with the 
approval of the Sponsor or designee. A negative urine drug screen (UDS) is required for 
randomization. 
19. The patient has abnormal laboratory values or clinical findings at Screening (Visit 1) that are 
judged to be clinically significant including, but not limited to: 
a. 
Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) > 2 × the 
upper limit of normal (ULN);  
b. Total bilirubin > 1.5 × ULN; 
c. 
Hemoglobin < 8 g/dL (80 g/L) for females and < 9 g/dL (90 g/L) for males; 
d. Absolute neutrophil count (ANC) < 1200 cells/µL (1.2 × 109/L); 
e. 
Thyroid-stimulating hormone (TSH) outside of normal reference range AND free 
T3 or free T4 outside of the reference range. Free T3 and Free T4 will only be 
evaluated if TSH is outside of reference range; 
f. 
HbA1c >7.5% [>58 mmol/mol]; 
g. Positive test for hepatitis B surface antigen and/or hepatitis B core antibody 
immunoglobulin M at screening; positive hepatitis C antibody at screening 
(Visit 1), with the exception of a patient for whom the reflex HCV RNA test is 
negative; 
h. Any other clinically significant abnormal laboratory result obtained at Screening 
(Visit 1); 


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20. The patient has corrected QT interval using the Fridericia formula (QTcF) >450 msec for males 
or > 470 msec for 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; 
21. The patient has any of the following conditions: 
a. Cardiac: 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);  
b. Malignancy: Any diagnosis of cancer (except basal or squamous cell skin 
carcinoma), unless in remission for at least 5 years; 
c. Gastrointestinal: history of gastric bypass or any other condition that results in 
malabsorption; 
d. Endocrine: hypo- or hyperthyroidism unless treated and stable with no medication 
changes for at least three months prior to screening, diabetes, unless considered 
stable with no changes in treatment for at least three months prior to screening; 
e. Hepatic: Hepatitis B or Hepatitis C; moderate or severe hepatic impairment 
(Child-Pugh B or C);  
f. Pulmonary: history of diagnosed and untreated obstructive sleep apnea; 
g. Neurological: history of epilepsy, seizure or convulsion, or electroencephalogram 
with clinically significant abnormalities, delirium, dementia, amnestic, or central 
sleep apnea, or significant brain trauma, or other cognitive disorder; 
h. Infectious: History of human immunodeficiency virus (HIV) infection. 
Note: Any other medical condition, or medical conditions that are stable with treatment (eg, 
hypertension, hypercholesterolemia, or thyroid abnormalities) are allowed as long as the 
condition has been stable for at least 3 months prior to Screening (Visit 1); treatments for 
these conditions are documented, kept stable, and are expected to be unchanged during the 
study; and the condition is not thought to affect safe participation in the study or relevant 
study outcomes in the opinion of the Investigator and confirmed by the Sponsor or 
designee. 
 
Other Criteria: 
22. The patient is judged by the Investigator to be inappropriate for the study;  
23. 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. 


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6.4 
Stopping Criteria  
This section describes the patient-level discontinuation or stopping criteria as well as study-
stopping criteria. 
6.4.1 
Discontinuation of Patients from Therapy or Assessment: Patient-level Stopping 
Criteria 
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 treatment period for one of the following 
reasons: 
• Death 
• AE 
• Lack of efficacy (patients whose MDD symptoms worsen or are determined by the 
Investigator to not be adequately controlled prior to completing the double-blind treatment 
period may be withdrawn from the study to start appropriate treatment at the Investigator’s 
discretion) 
• Protocol violation 
• Study terminated by Sponsor 
• Site terminated by Sponsor 
• Withdrawal by subject or withdrawal of consent 
• Lost to follow-up (every effort must be made to contact the patient; a certified/traceable 
letter must be sent) 
• Pregnancy 
• Other (such as physician decision, administrative reasons, etc) 
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). 
Patients who discontinue from the study and do not return to the study center for final assessments 
must be requested in writing to return to the study center for a final assessment. A copy of the 
letter, together with the source documentation, will be kept in the Investigator’s files. The reason 
for premature discontinuation from the study will be recorded on the Study Termination Page of 
the eCRF. Study center staff may be contacted by the Sponsor or designee after each premature 
discontinuation to ensure that proper characterization of the reason for discontinuation is captured. 
All patients who prematurely discontinue from the study regardless of cause should be seen for a 
final assessment at an ET Visit. All patients who prematurely discontinue from the study should 
return for the safety follow-up visit 


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6.4.2 
Study Stopping Criteria 
This study will be regularly monitored for safety and tolerability based on routine review of safety 
data. On a quarterly basis during study conduct, all safety data (adverse events, clinical laboratory 
measures, vital signs, ECGs, and C-SSRS) will be reviewed in a blinded manner. If the Study 
Physician determines at any point during the double-blind treatment period that the risk of study 
continuation outweighs the benefits, a determination to stop the study can occur in conjunction 
with discussions with the Head of Clinical Development or designee, the Head of Drug Safety and 
Pharmacovigilance, and the Chief Medical Officer. 
6.5 
Patient Replacement Procedures 
Patients who prematurely discontinue from the study during the double-blind treatment period will 
not be replaced. 
6.6 
Changes in the Conduct of the Study 
Any amendment to this protocol will be provided by the Sponsor in writing to the Investigator. No 
protocol amendment may be implemented before it has been approved by the IRB/IEC and 
Competent Authorities (if applicable), and the signature page, signed by the Investigator, has been 
received by the Sponsor. If the protocol is amended to eliminate or reduce the risk to patients, the 
amendment may be implemented before IRB/IEC and Competent Authority review and approval. 
However, the IRB/IEC and the Competent Authority must be informed in writing of such an 
amendment, and approval must be obtained within reasonable time limits. Administrative changes, 
such as changes in study personnel, will be specified in the Study Reference Manual. 
Administrative changes will not require a protocol amendment.  




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Table 7-2: Weekly Study Treatment Cards 
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. 
 
7.2.1 
Storage of Study Treatment 
Study treatment must be stored in a secure area, eg, a locked cabinet, protected from moisture, and 
kept at room temperature . Sites must report any temperature excursions as described in the Study 
Reference Manual or contact the Sponsor or its designee for further instructions. Patients will be 
instructed to store the blister card at room temperature at home, out of the reach of children. 
7.2.2 
Study Treatment Accountability 
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 treatment 
is dispensed and used by each patient in the study. Reasons for deviation from the expected 
dispensing regimen must also be recorded. 
At the end of the study, all study treatment must be accounted for. In addition, at the end of the 
study, all unused study treatment and empty study treatment packages should be returned to the 
Sponsor or designee or destroyed, as per instructions provided by the Sponsor. 
7.3 
Method of Assigning Patients to Treatment Groups 
After a patient signs the ICF at Screening (Visit 1), site personnel will register the patient in the 
interactive web response system (IWRS). 
Study treatment will be labeled with medication kit numbers. The IWRS will provide the study 
center with the specific medication kit number(s) for each patient at the time of randomization. 
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 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 7.5). 
Study center personnel will dispense study treatment according to the IWRS instructions. Study 
center personnel will also log onto the IWRS at subsequent visits to obtain a study treatment kit 
number for dispensing study treatment. Study centers will receive the IWRS confirmation 
notifications for each transaction. All notifications are to be maintained with the study source 
documents. 


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7.4 
Blinding 
The study will be performed in a double-blind manner. All study treatment will be supplied in 
identical treatment cards and packaging, and will be similar in color, smell, taste, and appearance, 
thereby enabling double-blind conditions. 
7.5 
Unblinding 
Unblinding at the study center should be done only in an emergency that requires the study 
treatment to be identified for the medical management of the patient. The Investigator must notify 
the Sponsor or designee immediately and a full written explanation must be provided if the blind 
is broken. Before study treatment is unblinded, every attempt should be made to discuss the case 
with the Sponsor or designee. Breaking the code at the study center will immediately disqualify 
the patient from further participation in the study. 
Treatment codes may be broken by Drug Safety for regulatory reporting purposes. In such cases, 
the study center staff will be kept blinded and the patient will not need to be disqualified from the 
study. 
For IWRS Unblinding 
In an emergency, the Investigator can obtain the treatment assignment of any patient at his/her 
study center through the IWRS. In an emergency, the Investigator will access the IWRS to break 
the blind. 
7.6 
Monitoring Treatment Compliance 
Study treatment adherence will be emphasized at every visit. Study treatment compliance during 
any period will be closely monitored. Compliance is based on the number of capsules prescribed 
and number of capsules taken. At every visit, study staff will count the number of capsules 
remaining in the blister pack. Any irregularities in study treatment adherence should be discussed 
with the patient. All errors in study treatment dispensing or administration must be carefully 
documented. These errors may include providing the wrong dose, not taking the dose as prescribed, 
or losing medication. 
In addition, at every visit, study staff will ask the patient about compliance with prescribed ADT 
dosing regimen.  
Any exceptions to non-compliance due to unusual circumstances should be discussed with the 
Sponsor or designee. 
7.7 
Prior and Concomitant Medications 
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 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, eg, limited, acute prescribed 


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opioid use. However, it is the responsibility of the Investigator to ensure that complete details 
regarding the medication are recorded in the eCRF. 
7.7.1 
Prior Medications 
Tapering and discontinuation of psychotropic medications, with the exception of the ongoing 
antidepressant, will take place during the Screening Phase lasting up to 2 weeks. A washout is not 
required for non-psychotropic medications; however, certain medications do have stability 
requirements as presented in the eligibility criteria. Medication history, including the use of 
psychotropic medication or of any other medication, should be recorded at Screening (Visit 1). 
Thereafter, any changes in concomitant medications or new medications should be recorded in the 
eCRF.  
7.7.2 
Prohibited Medications 
Use of the following products during the study is prohibited: alcohol, cannabis, illicit drugs, any 
known 5-HT2A receptor antagonist or inverse agonist, any strong cytochrome P450 3A4 inhibitor 
or inducer, or any drugs with known psychotropic properties or any non-psychotropic drugs with 
potential central nervous system effects. 
Patients who have been taking a low dose of quetiapine (< 50 mg) for the treatment of insomnia 
must discontinue quetiapine at the Screening Visit (Visit 1). 
7.7.3 
Rescue Medication 
Medications for the acute treatment of extrapyramidal symptoms and akathisia are allowed.  
Zolpidem may be taken for insomnia, in the evening at bedtime and prior to midnight, but no more 
than 3 times per week during the screening period and the first 2 weeks of the double-blind 
treatment period only (Section 6.3.2, Exclusion 13) for the treatment of insomnia. If zolpidem is 
not available in specific regions, another sedative hypnotic may be approved by the Sponsor or 
designee. 
The date and time of each dose of rescue medication administration as well as the name and dosage 
regimen of the rescue medication must be recorded on the eCRF. 
7.8 
Treatment After Discontinuation 
Patients whose depressive symptoms worsen or are determined by the Investigator not to be 
adequately controlled prior to completing the Double-blind Treatment Period may, at the 
Investigator’s discretion, be discontinued from the Double-blind Treatment Period in order to start 
appropriate treatment. This new treatment will not be provided by the Sponsor. Patients who 
initiate a new treatment during the study must be discontinued from the study and should also 
return for a Safety Follow-up visit. 
All patients who prematurely discontinue from the Double-blind Treatment Period regardless of 
cause should be seen for a final assessment at the ET Visit. All patients who prematurely 
discontinue from the Double-blind Treatment Period should return for the Safety Follow-up visit. 


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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 Major 
Depressive Disorder, as confirmed by the MINI (7.0.2; 8/8/16 version). The MINI is a validated 
clinical diagnostic tool (Sheehan et al, 1998) that will be used at the Screening visit only and will 
be completed by a Sponsor-approved rater. 
MGH Antidepressant Treatment Response Questionnaire (ATRQ) 
The Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (ATRQ) 
(Chandler et al, 2010) is a clinician-administered scale used to determine treatment resistance in 
Major Depressive Disorder. The scale defines 6 weeks on an adequate dose of antidepressant 
medication as an adequate duration of treatment. It also provides specific operational criteria for 
adequate dosage for each of the most commonly used antidepressants. 
Medical History and Other Information 
Medical history information will be collected at screening and should include demographic 
information (as allowed by local country legislation), current and past medical conditions, and 
current and past medications. Prior to study treatment administration, medical history must be 
documented in the patient’s study chart and also recorded in the appropriate 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). 
8.1.2 
Eligibility Review Process 
Eligibility of potential patients will be confirmed by the Sponsor or designee through a review of 
screening data, including safety and laboratory assessments, medical and psychiatric history, 
including the ATRQ, and psychiatric status, including DSM-5 diagnosis of MDD, as confirmed 
by the MINI, and MADRS, CGI-S and QIDS-SR-16 scores. Further information regarding the 
eligibility review process and the Pre-Enrollment Eligibility Review (PEER) Form are provided 
in the Study Reference Manual. 
8.1.3 
Patient Placebo Questionnaire and Training 
A brief training module will be provided describing placebo response at Baseline (Visit 2) prior to 
randomization. A placebo response questionnaire will be administered at Baseline (Visit 2) prior 
to randomization 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 study 
treatment. 


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8.1.4 
Quick Inventory for Depressive Symptomatology-Self Report (QIDS-SR-16) 
The QIDS-SR-16 is a 16-item patient-rated scale of symptom severity in depression. It assesses 
nine key symptoms of depression: insomnia/hypersomnia, low mood, appetite/weight changes, 
impaired self-perception, concentration difficulties, loss of interest/pleasure, suicidal ideation, 
psychomotor agitation and fatigue. Respondents use a 4-point Likert-type scale (0-3) to assess 
their behaviors and mood over the course of the past week. The total score ranges from 0-27, with 
higher scores indicating more severe depression.  
8.2 
Efficacy Assessments 
8.2.1 Montgomery-Åsberg Depression Rating Scale (MADRS) 
The MADRS is a 10-item scale 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. Patients are rated on items assessing feelings of sadness, lassitude, pessimism, 
inner tension, suicidality, reduced sleep or appetite, difficulty in concentration, and lack of interest. 
The MADRS total score ranges from 0 to 60. The MADRS total score at screening is a major 
inclusion criterion of the study, as well as the primary outcome measure for the study. The MADRS 
will be completed by a Sponsor-approved rater. 
8.2.2 
Clinical Global Impression-Severity (CGI-S) 
The Clinical Global Impression 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. 
8.2.3 
Generalized Anxiety Disorder-7 item (GAD-7) 
The GAD-7 is a 7-item self-reported questionnaire for measuring severity of symptoms of anxiety 
associated with Generalized Anxiety Disorder (Spitzer, et al 2006). Items assess 1) nervousness; 
2) inability to stop worrying; 3) excessive worry; 4) restlessness; 5) difficulty in relaxing; 
6) irritation; and 7) fear of something awful happening. Assessment is based on the total score. 
Each item is rated on a scale of Not at all (0 points); Several days (1 point); More than half the 
days (2 points); and Nearly every day (3 points). 
8.3 
Safety  
All patients who receive study treatment will be evaluated for safety. Safety assessments will 
include incidence of AEs, C-SSRS assessment for suicidality, EPS assessment as measured by 
AIMS, BARS, and SAS scales, clinical laboratory evaluations, ECG evaluations, vital sign 
measurements, and physical examination. Additional details pertaining to safety assessments are 
provided in the Schedule of Evaluations (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 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 and for a pre-existing condition which did not worsen 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 any untoward medical occurrence that at any dose: 
• Results in death 
• Is life threatening 
NOTE: An AE is considered "life-threatening" if, in the view of either the Investigator or Sponsor, 
its occurrence places the patient at immediate risk of death. It does not include an AE that, had it 
occurred in a more severe form, might have caused death. 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity, or 
• Is a congenital anomaly/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 treatment 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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8.3.1.3 
Classification of Adverse Events and Serious Adverse Events 
8.3.1.3.1 Severity 
The Investigator will provide an assessment of the severity of each AE by recording a severity 
rating on the appropriate AE reporting page of the 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: 
Mild: 
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities 
of daily living. 
Moderate: 
A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research 
patient. 
Severe: 
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention. 
8.3.1.3.2 Causality Assessment 
For each reported AE and SAE, the Investigator must provide an assessment of causal relationship 
to study treatment. Causal relationship must be assessed by answering the following question: 
Is there a reasonable possibility the study treatment caused the event? 
Yes: 
There is evidence to suggest a causal relationship between the study treatment and 
adverse event, ie: 
• There is a reasonable temporal relationship between the study treatment and the event, 
and/or  
• The event is unlikely to be attributed to underlying/concurrent disease, other 
investigational products, or other factors, and/or 
• Positive dechallenge and/or rechallenge exist 
OR 
No: 
There is no evidence to suggest a causal relationship between the study treatment and 
adverse event, ie: 
• There is no reasonable temporal relationship between the study treatment and the event, or 
• The patient did not take the study treatment, or 


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• The event is likely to be attributed to underlying/concurrent disease, other investigational 
products, or other factors. 
There may be situations in which an SAE has occurred, and the Investigator has minimal 
information to include in the initial report to the Sponsor. However, it is important that the 
Investigator always makes an assessment of causality for every event before the initial 
transmission of the SAE data to the Sponsor. The Investigator may change his/her opinion of 
causality in light of follow-up information and send an SAE follow-up report with the updated 
causality assessment. 
For each AE/SAE, the Investigator must document in the medical notes that he/she has reviewed 
the AE/SAE and has provided an assessment of causality. The causality assessment must be 
recorded on the appropriate AE reporting page of the patient’s eCRF. 
8.3.1.4 
Time Period and Frequency of AE and SAE Reporting  
The Investigator will report all AEs from the time informed consent was obtained until the final 
protocol-defined study visit or last known dose date of study drug + 1 day, whichever is later.  
The Investigator will report all SAEs from the time informed consent was obtained until 30 days 
after the last known dose date of study drug. 
At each visit, patients are to be queried regarding any AEs that have occurred since the previous 
visit. Patients will be asked to volunteer information with a nonleading question such as, “How do 
you feel since your last visit?”  
8.3.1.5 
Adverse Event Reporting Procedures 
8.3.1.5.1 Reporting Adverse Events 
All AEs, including overdose with sequelae or intentional overdose of study treatment 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 treatment.  
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 treatment; 
• 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 treatment. If a follow-up visit is deemed necessary for appropriate safety 
surveillance, it will take place within 30 days of the final protocol-defined study visit. 


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8.3.1.5.2 Reporting Serious Adverse Events 
The Sponsor is required to inform worldwide 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. Within 24 hours of learning of any AE that meets one of the criteria 
for an SAE, study center personnel must report the event to ProPharma Group on the SAE Form. 
In addition to completing the SAE form, the Study Physician may also be notified by telephone. 
If, during follow-up, any nonserious AE worsens and eventually meets any SAE criterion, that AE 
should be recorded as a new SAE. 
Preplanned hospitalizations (eg, elective procedures for pre-existing conditions that did not 
worsen, such as cosmetic surgery and hysterectomy) are excluded from SAE reporting. 
The study center must email or fax the SAE form to the SAE email address below. Even if an 
initial report is made by telephone, the SAE form containing all available details must still be 
emailed or faxed within 24 hours of knowledge of the event at the study center. 
Supplemental information should be submitted as soon as available and may include laboratory 
results, radiology reports, progress notes, hospital admission and emergency room notes, holding 
and observation notes, discharge summaries, autopsy reports, and death certificates. 
The Investigator is expected to take all therapeutic measures necessary for resolution of the SAE. 
Any medications or procedures necessary for treatment of the SAE must be recorded on the 
appropriate pages of the patient’s eCRF. All SAEs will be followed until resolution or stabilization. 
The Sponsor may contact the study center to solicit additional information or follow up on the 
event. A response is required within 24 hours of the request. 
SAE Reporting E-mail: clinicalsafety@propharmagroup.com  
SAE Reporting Fax Number: +1 (866) 681-1063 
Medical Emergency Phone Number: US: +1 (512) 686-1256; outside of US: +44 118 936 4096. 
8.3.2 
Potential Hy’s Law Cases 
Study center personnel must report every patient who meets potential Hy’s Law criteria from the 
time the ICF is signed until 30 days after the final protocol-defined study visit or the last known 
dose of study treatment (if the final visit does not occur). 
The criteria for potential Hy’s law cases are as follows: 
• ALT or AST ≥ 3 × ULN and  
• Total bilirubin ≥ 2 × ULN and  
• Alkaline phosphatase < 2 × ULN 
Study center personnel must report every subject who meets these potential criteria. Typically, 
these analytes will be obtained from the same sample, but they may come from multiple samples 


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taken within a 24-hour period. This requirement applies from the time the ICF is signed for the 
study until 30 days after the last known dose of study treatment. 
A laboratory alert for potential Hy’s Laws cases will be in place, and the laboratory must notify 
Investigators and the Sponsor immediately when the above criteria have been met. The Sponsor 
must be notified of any potential Hy’s Law case as soon as possible (within 24 hours of learning 
of a potential Hy’s Law case). Refer to the SAE reporting procedures (Section 8.3.1.5.2) even if 
no AE has occurred. 
Every effort to determine the cause of the liver enzyme abnormalities must be made, and close 
monitoring should be initiated in conjunction with the Study Physician and in accordance with the 
FDA Guidance for Industry: Drug Induced Liver Injury—Pre-Marketing Clinical Evaluation, 
July 2009. 
8.3.3 
Pregnancy 
Female patients will not be eligible for inclusion in the study if they have a positive pregnancy test 
at the Screening or Baseline Visit. Any patient who becomes pregnant must be discontinued from 
the study. 
Study center personnel must report every pregnancy, including pregnancies in female partners of 
male study patients, from the time consent was obtained until the final protocol-defined study visit 
or last known dose of study treatment (if a final visit does not occur). 
Within 24 hours of learning of the pregnancy, study center personnel must report the event to the 
Sponsor on the Pregnancy Notification Form and email or fax it to the email address or fax number 
below even if no AE has occurred.  
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication 
or elective termination of a pregnancy for medical reasons will 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 8.2.1.5.2 with the appropriate serious criterion (eg, hospitalization) indicated in 
addition to the Pregnancy Notification/Outcome Form. 
• Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs and will be reported as such. 
Any pregnancy in a study patient or in a female partner of a male study patient/subject must be 
followed to term/termination. The outcome, including status of the mother and the child, must be 
reported to the Sponsor by completing a follow-up Pregnancy Outcome Form. 
Pregnancy Reporting E-mail: clinicalsafety@propharmagroup.com 
Pregnancy Reporting Fax Number: +1 (866) 681-1063. 


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8.3.4 
Clinical Laboratory Determinations 
Blood and urine samples for clinical laboratory tests will be collected as specified in the Schedule 
of Evaluations (Table 1-1). Patients are required to fast for at least 10 hours before the collection 
of clinical laboratory blood tests at designated visits.  
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 
abnormal screening laboratory results judged to be clinically significant will be excluded from the 
study. 
Laboratory results should be reviewed by the Investigator/sub-investigator throughout the study. 
For safety reasons or at the discretion of the Investigator, repeat laboratory assessments may be 
performed at an unscheduled visit. 
The following clinical laboratory levels will be measured: 
• Hematology: hematocrit; hemoglobin; 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.  
• Chemistry: albumin; alkaline phosphatase; ALT; AST; bilirubin (total, direct); blood urea 
nitrogen; calcium; chloride; cholesterol (high-density lipoprotein [HDL] and low-density 
lipoprotein [LDL] will be calculated and reported); creatinine; creatine phosphokinase; 
gamma-glutamyl transferase; glucose; insulin; lactate dehydrogenase; phosphate; 
potassium; prolactin; sodium; triglycerides; total protein; uric acid. HbA1c and TSH (reflex 
free T3 and free T4) will be measured at Screening/Visit 1 and Visit 8/ET only. 
 
• Urinalysis: macroscopic (pH, specific gravity, glucose, protein, ketones, bilirubin, nitrates, 
blood) and microscopic (red blood cells/high-power field, white blood cells/high-power 
field, casts, epithelial cells, crystals, granulation). 
• Urine Drug Screen (UDS): Urine drug tests for amphetamines, barbiturates, 
benzodiazepines, cannabinoids, cocaine metabolites, methadone, opiates, or phencyclidine 
will be performed. Any patient who tests positive for any drug at Screening, will be 
excluded from participating in the study. Exceptions may include  prescription treatments 
(eg, opioids, benzodiazepines) if the use is not chronic and is able to be discontinued as per 
the Investigator with the concurrence of the Sponsor or designee. A repeat drug test is 
allowed with the approval of the Sponsor or designee. A negative UDS is required for 
randomization. 
Additional information regarding sample collection, processing, and shipping is provided 
in the Laboratory Manual. 


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• Urine and serum pregnancy tests: Female patients who are of childbearing potential will 
undergo a serum pregnancy test at Screening (Visit 1) and a urine pregnancy test at 
Baseline (Visit 2) at the study clinic, and, at the discretion of the Investigator, at an 
Unscheduled Visit. Serum and urine pregnancy test will be administered at Visit 8 for 
patients who are rolling over into the Open-label Safety Study. 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 serum pregnancy test at screening is 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.  
• Hepatitis screening: Blood samples will be collected at Screening (Visit 1) from all 
patients in order to perform hepatitis B surface antigen, hepatitis B core antibody IgM, and 
hepatitis C antibody (immunoglobulin G) testing. Confirmatory testing will be undertaken 
as needed. 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. 
A central laboratory will be used to evaluate all urine and blood samples, which will be collected, 
processed, and stored according to the instructions provided in the Laboratory Manual. 
8.3.5 
Vital Signs 
Vital signs (pulse rate, systolic and diastolic blood pressure [BP], body temperature, and body 
weight will be assessed at every visit during the study as specified in the Schedule of Evaluations 
(Table 1-1). Height and BMI is assessed at Screen (Visit 1) only and waist circumference will be 
assessed at Screen (Visit 1) and Visit 8/ET.  
Blood pressure and pulse rate will be measured twice: once after the patient is resting quietly in 
the supine position followed by once after at least 2 minutes in the standing positions. BP may be 
measured either manually or by machine but using the same method consistently for each patient 
throughout the study. 
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 without jacket and shoes. For each patient, body weight 
and height should be determined using the same equipment during the study after ensuring its 
proper calibration. 


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8.3.6 
Electrocardiograms 
A 12-lead ECG will be performed as specified in the Schedule of Evaluations (Table 1-1). Each 
ECG assessment will be conducted after the patient has been resting quietly in the supine position 
and will comprise ten-second epochs from 12-lead ECGs. ECG parameters to be measured include 
HR, QRS, PR, QT, QTcB, QTcF and RR intervals. 
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. For 
eligibility criteria, the values reported on the central ECG interpretation report, not the values that 
are printed on the tracing itself, will be used. 
8.3.7 
Columbia–Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is a clinician-rated instrument that reports the severity of both suicidal ideation and 
behavior (Posner, 2011). The C-SSRS will be completed by a Sponsor-approved rater. 
 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: 
• Completed suicide 
• Actual attempt 
• Interrupted attempt 
• Aborted attempt, and 
• Preparatory acts or behavior 
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. 


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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. The C-SSRS will be completed by a trained and Sponsor-approved 
rater. 
8.3.8 
Extrapyramidal Scales 
8.3.8.1 
Abnormal Involuntary Movement Scale (AIMS) 
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. There are an 
additional 2 items on dental status that are answered yes or no. The AIMS is to be completed at 
Baseline (Visit 2) and Visits 4, 6 and 8/ET according to Schedule of Evaluations (Table 1-1). 
8.3.8.2 
Barnes Akathisia Rating Scale (BARS) 
The BARS is a rating scale for drug-induced akathisia developed by Barnes (Barnes 1989). It 
includes the rating of observable restless movements, the subjective awareness of restlessness, and 
the distress associated with the akathisia. There is also a global rating for severity. The scale is 
completed by the investigator or an expert site-based rater after a standard examination. Objective 
akathisia, subjective awareness and subjective distress are rated on a 4-point scale from 0 to 3, 
yielding a total score from 0 to 9. The Global Clinical Assessment of Akathisia is rated separately, 
on a 6-point scale from 0 to 5. The BARS is to be completed at Baseline (Visit 2) and Visits 4, 6 
and 8/ET according to Schedule of Evaluations (Table 1-1). 
8.3.8.3 
Simpson-Angus Scale (SAS) 
The SAS is a measure of extrapyramidal side effects (Simpson &Angus, 1970). The SAS is used 
for assessment of antipsychotic-induced parkinsonism in both clinical practice and research 
settings. 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 (Visit 2) and Visits 4, 6 and 8/ET according to Schedule of Evaluations (Table 1-1). 
8.3.9 
Modified Physical Examination  
A modified physical examination, excluding genital/rectal examinations, will be performed at the 
visits specified in the Schedule of Evaluations (Table 1-1). The examinations will be performed 
by a professionally trained physician or health professional licensed to perform physical 
examinations.  






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9.4 
Statistical Analyses 
9.4.1 
Patient Disposition 
The number of patients in each study population will be summarized by treatment group and study 
center as follows: 
• The number of patients who were screened will be summarized overall by study center.  
• The number of patients in the Safety and mITT populations will be summarized overall 
and by treatment group and study center.  
In addition, the number and percentage of patients who completed the Double-blind Treatment 
Period and who prematurely discontinue from the Double-blind Treatment Period will be 
summarized overall, by treatment group, and by reasons for premature discontinuation for the 
Double-blind Treatment Period. The reasons for premature discontinuation from the Double-blind 
Treatment period as recorded on the termination page of the eCRF will be summarized (number 
and percentage) by treatment group for the Safety Population. 
9.4.2 
Demographics and Other Baseline Characteristics 
Demographic parameters as allowed by local country legislation (eg, age, sex, race, ethnicity, 
weight, body mass index) and other baseline characteristics will be summarized by treatment group 
for the Safety and mITT populations. 
Prior medical and surgical history will be summarized by treatment group for the Safety 
Population. 
Baseline efficacy parameters will be summarized by treatment group for the mITT Population. 
9.4.3 
Prior and Concomitant Medication 
Prior medication is defined as any medication started and stopped before the date of the first dose 
of double-blind study treatment. A prior concomitant medication is any medication that started 
before the date of the first dose of double-blind study treatment and stopped or is ongoing after the 
date of the first dose of study treatment. Concomitant medication is defined as any medication 
taken on or after the date of the first dose of double-blind study treatment. Both prior and 
concomitant medication, including prior concomitant medication use, will be summarized as the 
number and proportion of patients in each treatment group who received each medication within 
each therapeutic class for the Safety Population. Multiple medications used by a patient will only 
be counted once. 
Any concomitant medication started after the date of the last dose of double-blind study treatment 
will not be included in the summary but will be included in the patient data listings. 


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9.4.4 
Extent of Exposure and Treatment Compliance 
9.4.4.1 
Extent of Exposure 
Exposure to study treatment for the Safety Population will be summarized for treatment duration, 
calculated as the number of days from the date of the first dose of double-blind study treatment 
taken to the date of the last dose taken, inclusive. The number and percentage of patients with each 
treatment duration of ≥ 1 day, ≥ 7 days, etc, will be summarized by treatment group, respectively. 
9.4.4.2 
Measurement of Treatment Compliance 
Dosing compliance for a specified period is defined as the total number of capsules of study 
treatment actually taken by a patient during the treatment period divided by the number of capsules 
of study treatment that were expected to be taken during the treatment period multiplied by 100. 
The total number of capsules actually taken during the treatment period will be calculated from 
the study treatment record. Descriptive statistics for study treatment dosing compliance together 
with compliance category will be summarized by treatment group for the Safety Population. 
9.4.5 
Efficacy Analyses 
The primary efficacy analyses and the sensitivity analysis will be based on the mITT and ITT 
Populations; other efficacy analyses will be based on the ITT Population, unless stated otherwise. 
The baseline for each specific efficacy endpoint is defined as the last measurement prior to the 
first dose of randomized treatment. All statistical hypothesis tests will be performed at the 2-sided 
5% significance level for main effects. All confidence intervals (CIs) will be 2-sided 95% CIs, 
unless stated otherwise. 
All investigative sites with fewer than 2 mITT patients per treatment group will be pooled as 
follows: The largest site with fewer than 2 mITT patients per treatment group will be pooled with 
the smallest site with fewer than 2 mITT patients per treatment group within the same country or 
geographic region. If this results in a pooled site still having fewer than 2 mITT patients per 
treatment group, this site will be pooled together with the next smallest investigative site within 
the same country or geographic region, if one exists; otherwise, no further pooling is needed. Sites 
with the same number of mITT patients will be ordered in ascending order of their numerical site 
identification number. This will serve as a tie‐breaker rule in case multiple sites have the same 
number of mITT patients. Should the primary efficacy analysis model present convergence issues, 
after testing the sequence of correlation structures, then the site effect will be reconsidered and 
may be dropped from the model. These pooled investigative sites, as determined based on the 
primary efficacy response variable, will be used for any analysis that has investigative site as a 
fixed effect in the model. The actual investigative site numbers will be included in the listings. For 
analyses that are based on the ITT Population and include site as a factor, additional pooling will 
be performed starting from the mITT pooled sites. Sites with patients who are in ITT Population 
but not the mITT Population will be pooled, using the same algorithm as outlined above.  














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9.4.7.2 
Clinical Laboratory Parameters 
Descriptive statistics for clinical laboratory values (in International System of Units [SI] and 
conventional units) and changes from baseline values at each assessment timepoint will be 
summarized by treatment group for each clinical laboratory parameter. 
The number and percentage of patients with potentially clinically significant (PCS) postbaseline 
clinical laboratory values will be tabulated by treatment group. The criteria for PCS laboratory 
values and details on additional laboratory analyses will be provided in the SAP. 
The number and percentage of patients with shifts from baseline according to normal range criteria 
(for quantitative and categorical measurements) at the end of treatment will be provided. In 
addition, the number and percentage of patients with shifts from baseline according to PCS criteria 
at the end of treatment will be provided. 
In addition, the number and percentage of patients meeting Hy’s law criteria during the double-
blind treatment period will be provided. 
9.4.7.3 
Vital Signs 
Descriptive statistics for vital signs (eg, pulse rate, systolic and diastolic BP, body weight) and 
changes from baseline values at each visit, and at the end of the treatment period, will be presented 
by treatment group. 
Vital sign values will be PCS if they meet the observed-value and the change-from-baseline-value 
criteria as detailed in the SAP. Details on additional vital sign analyses will be provided in the 
SAP. 
9.4.7.4 
Electrocardiogram 
Descriptive statistics for ECG parameters (eg, ventricular heart rate, QTc interval, QRS interval) 
and changes from baseline values at each assessment timepoint will be summarized by treatment 
group.  
The number and percentage of patients with PCS postbaseline ECG values will be summarized by 
treatment group. The criteria for PCS ECG values and details on additional analyses of ECG 
parameters will be provided in the SAP. 
9.4.7.5 
Other Safety Parameters 
Descriptive statistics for EPS scales (AIMS, BARS, SAS) and C-SSRS will be summarized overall 
and by treatment group for the Double-blind Treatment Period, based on the corresponding Safety 
Populations. 




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10 SUPPORTING DOCUMENTATION AND OPERATIONAL MONITORING 
10.1 
Study Termination 
The Sponsor reserves the right to terminate the study in its entirety or at a specific study center 
before study completion.  
10.2 
Investigator Obligations 
10.2.1 
Documentation 
The Investigator must provide the following to the Sponsor, before the start of the study: 
• A completed and signed Form FDA 1572 or equivalent form, if applicable. If, during the 
course of the study, any changes are made that are not reflected on Form FDA 1572 or 
equivalent form, if applicable, a new form must be completed and returned to the Sponsor. 
• A fully executed contract 
• The curricula vitae for the Investigator and all sub-investigators listed on Form FDA 1572 
or equivalent form, if applicable, 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 or equivalent form, if applicable  
• 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 
• 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 
• The Investigator’s Statement page in this protocol signed and dated by the Investigator. 
10.2.2 
Performance 
The Investigator must demonstrate reasonable efforts to recruit qualified patients for the study. 
10.2.3 
Use of Investigational Materials 
Study treatment must be stored in a secured place and must be locked. At study initiation, a 
representative from the Sponsor will inventory the study treatment at the study center. The 
Investigator must maintain adequate records documenting the receipt and disposition of all study 
supplies. The Sponsor may supply forms on which to record the date the study treatment was 
received and a dispensing record in which to record each patient’s use. All unused study treatment 
must be returned to the Sponsor-designated central depot. 


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10.2.4 
Case Report Forms 
All patient data relating to the study, except for data electronically transmitted (eg, central 
laboratory results), will be recorded on eCRFs to be provided by the Sponsor through the EDC 
system. The Investigator is responsible for verifying that all data entries in the eCRFs are accurate 
and correct by electronically signing the completed eCRFs submitted to the Sponsor. The 
Investigator must maintain and retain accurate documentation that supports the information 
entered into the EDC system for source document verification and possible regulatory inspection. 
10.2.5 
Retention and Review of Records 
Records and documents pertaining to the conduct of this study, including eCRFs, source 
documents (eg, medical records, laboratory reports), consent forms, regulatory documents, and 
medication inventory records must be retained by the Investigator for a period of at least 15 years 
after study completion unless local regulations or institutional policies require a longer retention 
period or otherwise notified in writing by the Sponsor. 
No study records shall be destroyed without notifying the Sponsor and providing the Sponsor the 
opportunity to arrange long-term storage for such study records or authorizing in writing the 
destruction of records after the required retention period. 
The Investigator must permit access to any documentation relating to the study upon request of 
the Sponsor or applicable regulatory authorities. If the Investigator for the study retires, relocates, 
or for other reasons withdraws from the responsibility of keeping the study records, custody must 
be transferred to a suitable alternate custodian employee of the institution or to a suitably qualified 
and responsible third party. The Sponsor must be notified in writing of the name and address of 
the new custodian in advance of the transfer. 
10.2.6 
Patient Confidentiality 
All patient records will be identified by patient identification number only. Patients’ names are not 
to be transmitted to the Sponsor. The Investigator will keep a master patient list on which the 
patient’s identification number and the full name, address, and telephone number are listed. 
However, the list will never leave the site and will be archived at the site after the end of the study.


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10.3 
Data Quality Assurance 
10.3.1 
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. Electronic 
data capture (EDC) functionality training is provided via computer-based training to train 
Investigators and authorized designees on recording the data in the eCRFs using the EDC system.  
The Investigator will maintain complete source documents (eg, signed ICFs, written or electronic 
medical records, pharmacy records). Source documents provide evidence for the existence of study 
patients and substantiate the integrity of the data collected in the eCRF. The Investigator will make 
available to the Sponsor or study monitor or designee source documents (written notes and 
electronic medical records, if used), signed ICFs, and all other study-related documents. 
Study monitors or designee, appointed by the Sponsor, will perform ongoing source document 
verification to confirm that data entered into the eCRF are accurate, complete, and verifiable from 
source documents; that the safety and rights of 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 randomized, the 
study monitor or designee will periodically monitor the progress of the study by conducting on-
site visits. In addition to on-site source document verification, study monitors will review study 
progress remotely, possibly warranting more frequent communication and/or study center visits. 
Details of monitoring activities are provided in the Monitoring Plan. 
10.3.2 
Data Recording and Documentation 
Data collection will involve the use of the EDC system, to which only authorized personnel will 
have access. Patient data are to be entered into the EDC system by the Investigator or his/her 
designee using his/her assigned EDC user account. The Investigator or his/her 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. 


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The Investigator or designee will be responsible for approving all changes performed on 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 used in the past. After all data have been reviewed 
and all issues have been resolved, the database will be locked. 
All data collected in the context of this study will be stored and evaluated per regulatory 
requirements and applicable guidance for electronic records. Also, data will be stored and 
evaluated in such a way as to guarantee 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. 
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 Manual. 
10.4 
Reporting and Publication 
All data generated in this study are the property of the Sponsor. An integrated clinical and 
statistical report will be prepared and submitted within one year after the completion of the study. 


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11 APPENDICES 
APPENDIX I. 
ELEMENTS OF INFORMED CONSENT 
Procedures will comply with 21 CFR, Parts 50 and 312. Signed informed consent will be obtained 
for each patient participating in a clinical research study. This consent must include the following 
items: 
• A statement that the study involves research and an explanation of the purposes of the 
research; a description of the procedures to be followed and the identification of any 
procedures that are experimental; and the expected duration of the patient’s participation 
• A description of any reasonably foreseeable risks or discomforts to the patient 
• A description of any benefits to the patient or to others that may reasonably be expected 
from the research. If the patient is to be paid for participating in the study, the consent form 
must state the amount that he/she will receive and the schedule of payment (to ensure 
neither coercion nor undue influence). 
• A disclosure of appropriate alternative procedures or courses of treatment, if any, that 
might be advantageous to the patient. 
• A statement describing the extent, if any, to which confidentiality of records identifying 
the patient will be maintained and noting the possibility that the FDA or other local health 
authority, the Sponsor, the IRB/IEC, or an authorized contract research organization may 
inspect the records 
• For research involving more than minimal risk, an explanation of whether any medical 
treatment is available if injury occurs and, if so, what it consists of or where further 
information may be obtained 
• An explanation of whom to contact, including the relevant telephone number, for answers 
to pertinent questions about the research and the research patient’s rights and whom to 
contact in the event of a research-related injury to the patient. (Note: In some cases, it may 
be necessary to identify a person other than the Investigator as the contact. The guidance 
of the IRB/IEC may be required.) 
• For EU countries, the ICF will include a statement of whom to contact, including relevant 
phone and email address, for questions about patient data confidentiality or data breach’ 
per GDPR. 
• A statement that participation is voluntary, that refusal to participate will involve no 
penalty or loss of benefits to which the subject/patient is otherwise entitled, and that the 
patient may discontinue participation at any time without penalty or loss of benefits to 
which the patient is otherwise entitled 
• A statement that the treatment or procedures may involve risks to the patient (or to the 
embryo or fetus if the patient is, or may become, pregnant) that are at present unforeseeable 
• The expected circumstances for which the patient’s participation may be terminated by the 
Investigator without regard to the patient’s consent 


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• Any additional costs to the patient that may result from participation in the research 
• The consequences of a patient’s decision to withdraw from the research and procedures for 
an orderly termination of the patient’s participation 
• A statement that significant new findings developed during the course of the research that 
may relate to the patient’s willingness to continue participation will be provided to the 
patient 
• The approximate number of patients involved in the study 
• A statement of permission, providing consent for the patient to participate (eg, “I agree to 
participate . . .”) 
• A place for the patient’s signature and date of signing of the ICF  
• A statement indicating that information about this study has been, or will be, entered into 
a databank that is publicly accessible at www.ClinicalTrials.gov. 
• A copy of the signed consent form must be given to the patient.  


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APPENDIX II. PROTOCOL AMENDMENT 1: MAJOR CHANGES 
Major changes previously specified in Protocol Amendment 1, dated 08 Jun 2021, are presented 
below. 
Protocol Section 
Revision  
Rationale 
Global 
Deleted “Medical Monitor” term and 
replaced with ‘Sponsor or designee” 
Clarification  
Global 
The neurological examination was deleted 
from descriptions related to Physical 
Examination assessments 
Revision 
Global 
Deleted references to IVRS; only IWRS 
will be used. 
Revision 
Title Page, 
Section 1-Synopsis 
Added “…to Assess the Efficacy and 
Safety…” to the study title. 
Clarification 
Section 1-Synopsis: Inclusion 
Criteria, 
Section 6.3.1-Inclusion Criteria  
Maximum age for study eligibility lowered 
from 75 years to 65 years. 
Modification of Inclusion 
Criterion #2 
Section 1-Synopsis: Inclusion 
Criteria, 
Section 6.3.1-Inclusion Criteria 
Added ATRQ to be used for Investigator 
confirmation of inadequate response to 
ADT 
Modification of Inclusion 
Criterion #4 
Section 1-Synopsis: Statistical 
Methods 
Updated the primary analysis, key 
secondary analysis, and the mITT 
definitions per estimand strategy. 
Modification per FDA 
comment and 
recommendation 
Section 5.1.1-Primary 
Objective 
Added estimand strategy for the primary 
objective 
Modification per FDA 
comment and 
recommendation 
Section 5.1.2-Key Secondary 
Efficacy Objective 
Added estimand strategy for the key 
secondary objective 
Modification per FDA 
comment and 
recommendation 
Section 6.3.2-Exclusion 
Criteria 
Added “methadone” and “phencyclidine” to 
list of substances to be evaluated in the 
Urine Drug Screen test. Deleted 
“hallucinogens or similar compounds” from 
list of substances to be evaluated. 
Modification of Exclusion 
Criterion #18 
Section 7.6-Monitoring 
Treatment Compliance 
Modified treatment compliance language 
Clarification 
Section 7.7.2-Prohibited 
Medications 
Deleted “moderate” from prohibited 
cytochrome P450 3A4 medications. 
Clarification 
Section 8.1.3-Medical History 
and Other Information 
Deleted “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.”  
Modification 


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Protocol Section 
Revision  
Rationale 
Section 8.3.1.4-Time Period 
and Frequency of AE and SAE 
Reporting 
• Specified that AE reporting will 
continue through the last study visit or 
the last known dose date study 
treatment was taken +1 day, or 
whichever is later. 
• Specified that SAE reporting will 
continue through 30 days after the last 
known dose date study treatment was 
taken. 
Clarification 
Section 8.3.3-Pregnancy 
Modified pregnancy reporting language 
Clarification 
Section 8.3.4-Clinical 
Laboratory Determinations: 
Urine Drug Screen 
UDS section revised for consistency. 
Deleted “Propoxyphene” and 
“hallucinogens or similar compounds” 
Clarification 
Section 8.3.5-Vital Signs, 
Section 8.5-Schedule of 
Assessments 
Respiratory rate assessment removed from 
all vital sign assessments  
Modification 
Section 9.3-Analysis 
Populations 
Section revised for ITT and mITT 
Populations to accommodate the estimand 
approach for FDA request.  
Modification 
Sections 9.4.1-Patient 
Disposition 
Revised to specify that the mITT Population 
will be used to summarize patient 
disposition 
Modification 
Section 9.4.2-Demographics 
and Other Baseline 
Characteristics  
Revised to specify that the mITT Population 
will be used to summarize demographic and 
baseline efficacy parameters 
Modification 
Section 9.4.5-Efficacy 
Analyses through Section 
9.4.5.3-Additional Efficacy 
Analyses 
Revised Primary, Key Secondary, and 
Additional analyses to accommodate the 
estimand approach for FDA request. 
Modifications 
Section 9.4.6-Multiple 
Comparisons/Multiplicity 
Revised to accommodate the estimand 
approach for FDA request. 
Modification 
 


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12 REFERENCES  
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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.  
Rush A, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed 
outpatients requiring one or several treatment steps: A STAR*D report. Am J Psychiatry. 2006: 
163: 1905-1917. 
Rush, A, Trivedi, MH, Ibrahim, HM, et al. The 16-item Quick Inventory of Depressive 
Symptomatology (QIDS), clinician rating (QIDS-C), and self-report (QIDS-SR): A psychometric 
evaluation in patients with chronic major depression. Biol Psychiatry, 2010; 54(5): 573-583. 


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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.  
Simpson GM. Angus JW. A rating scale for extrapyramidal side effects. Acta Psychiat Scand 
Suppl. 1970; 212:11–9. 
Spitzer RL, Kroenke, K, Williams, JB, et al. (2006). A brief measure for assessing generalized anxiety 
disorder. Arch Intern Med. 2006; 166(10), 1092-1097. 
Warden D, Trivedi MH, Wisniewski SR, et al. Predictors of attrition during initial (citalopram) 
treatment for depression: A STAR*D report. Am J Psychiatry. 2007: 164:1189-1197. 


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13 INVESTIGATOR SIGNATURE PAGE 
I agree to conduct the study in accordance with Amendment 2 to the Protocol for Study 
ITI-007-501, dated 20 Aug 2021, and with all applicable government regulations and GCP 
guidance, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable US federal and/or local regulations and ICH guidelines. 
I will not disclose information regarding this clinical investigation or publish results of the 
investigation without prior authorization from Intra-Cellular Therapies, Inc. 
_____________________________________ 
_____________________ 
Principal Investigator Signature 
Date 
_____________________________________ 
______________________ 
Principal Investigator Name (printed) 
Site Number 

SAP_001.pdf: 
NCT04985942 
 
 
 
 
Study ID: ITI-007-501 
 
 
 
Title: A Randomized, Double-Blind, Placebo-controlled Multicenter Study to Assess the 
         Efficacy and Safety of Lumateperone as Adjunctive Therapy in the Treatment of 
         Patients with Major Depressive Disorder 
 
 
 
 
Statistical Analysis Plan Version 2 Date: 08 Feb 2024 


Statistical Analysis Plan 
ITI-007-501
A Randomized, Double-Blind, Placebo-controlled Multicenter Study to Assess the Efficacy 
and Safety of Lumateperone as Adjunctive Therapy in the Treatment of Patients with 
Major Depressive Disorder 
Version: 
2.0  
Date: 
08 Feb 2024   
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. 


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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN AMENDMENT 1: MAJOR CHANGES ............................. 2 
TABLE OF CONTENTS ................................................................................................................ 3 
1. 
LIST OF ABBREVIATIONS .............................................................................................. 5 
2. 
INTRODUCTION ............................................................................................................... 7 
3. 
STUDY OBJECTIVES ...................................................................................................... 11 
3.1 
Efficacy Objectives and Estimands ................................................................................ 11 
3.1.1 
Primary Objective ................................................................................................... 11 
3.1.2 
Key Secondary Efficacy Objective ......................................................................... 14 
3.1.3 
 ................................................................................ 14 
3.2 
........................................................................................................... 14 
4. 
ANALYSIS POPULATIONS ........................................................................................... 15 
4.1 
Randomized Population ................................................................................................. 15 
4.2 
Safety Population ........................................................................................................... 15 
4.3 
Intent-to-Treat (ITT) Population .................................................................................... 15 
4.4 
Modified Intent-to-Treat (mITT) Population ................................................................. 15 
5. 
SUBJECT DISPOSITION ................................................................................................. 16 
6. 
 ............................................................................................. 17 
7. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ............................ 18 
8. 
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE .................................. 19 
8.1 
Extent of Treatment Exposure........................................................................................ 19 
8.2 
Measurement of Treatment Compliance ........................................................................ 19 
8.3 
Prior and Concomitant Medication ................................................................................ 19 
9. 
EFFICACY ANALYSES .................................................................................................. 20 
9.1 
Primary Efficacy Endpoint ............................................................................................. 21 
9.1.1 
Primary Efficacy Analysis ...................................................................................... 21 
9.1.2 
 ......................................................................... 23 
9.1.3 
......................................................................... 24 
9.1.4 
 ............................................................. 25 
9.2 
Key Secondary Efficacy Endpoint ................................................................................. 26 
9.2.1 
Key Secondary Analysis ......................................................................................... 26 
9.2.2 
 ...................................................................... 26 
9.3 
 ......................................................................................... 27 


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9.4 
 ................................................................................ 28 
10. 
SAFETY ANALYSES....................................................................................................... 29 
10.1 
Adverse Events ............................................................................................................... 29 
10.2 
Clinical Laboratory Parameters ...................................................................................... 30 
10.3 
Vital Signs ...................................................................................................................... 33 
10.4 
Electrocardiograms......................................................................................................... 34 
10.5 
Other Safety Parameters ................................................................................................. 35 
10.5.1 
Abnormal Involuntary Movement Scale (AIMS) ................................................... 35 
10.5.2 
Barnes Akathisia Rating Scale (BARS) .................................................................. 35 
10.5.3 
Simpson-Angus Rating Scale (SAS) ...................................................................... 35 
10.5.4 
Columbia–Suicide Severity Rating Scale (C–SSRS) ............................................. 35 
11. 
 ............................................................................... 37 
12. 
 ...................................................................................................... 38 
13. 
 ................................................................................. 39 
14. 
STATISTICAL SOFTWARE ............................................................................................ 40 
15. 
DATA HANDLING CONVENTIONS ............................................................................. 41 
15.1 
Visit Time Windows ...................................................................................................... 41 
15.2 
Repeated or Unscheduled Assessments of Safety Parameters ....................................... 43 
15.3 
Missing Date of Double-Blind Study Treatment ........................................................... 44 
15.4 
Missing Severity Assessment for Adverse Events ......................................................... 44 
15.5 
Missing Relationship to Investigational Product for Adverse Events............................ 44 
15.6 
Missing Date Information for Adverse Events .............................................................. 44 
15.7 
Missing Date Information for Prior or Concomitant Medications ................................. 45 
15.7.1 
Incomplete Start Date ............................................................................................. 45 
15.7.2 
Incomplete Stop Date .............................................................................................. 46 
15.8 
Character Values of Clinical Laboratory Parameters ..................................................... 47 
16. 
............................................ 48 
17. 
REFERENCES .................................................................................................................. 50 
18. 
................................................................................................................... 51 
 ..................................... 51 
 ...................................... 57 
 .... 62 


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1. 
LIST OF ABBREVIATIONS 
ADT 
antidepressant therapy 
AE 
adverse event 
AIMS 
Abnormal Involuntary Movement Scale 
ALT 
alanine aminotransferase  
ALP 
alkaline phosphatase 
ANC 
absolute neutrophil count 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
ATRQ 
Antidepressant Treatment Response Questionnaire 
BARS 
Barnes Akathisia Rating Scale 
BMI 
body mass index 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CGI-S 
Clinical Global Impression Scale-Severity 
CPK 
creatine phosphokinase 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ET 
Early Termination 
GAD-7 
Generalized Anxiety Disorder-7 item 
HbA1c 
hemoglobin A1c 
ICE 
intercurrent event 
LLN 
lower limit of normal 
MADRS 
Montgomery-Åsberg Depression Rating Scale 
MAR 
Missing at random 
MDD 
major depressive disorder 
MedDRA 
Medical Dictionary for Regulatory Activities 
MINI 
MINI International Neuropsychiatric Interview 
MMRM 
mixed-effects model for repeated measures 
MNAR 
Missing not at random 
OH 
orthostatic hypotension 
PCS 
potentially clinically significant 
PK 
pharmacokinetic 
QIDS-SR-16 
Quick Inventory of Depressive Symptomatology-Self- Report-16 item 
QTcB 
QT interval corrected for heart rate using the Bazett formula  


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QTcF 
QT interval corrected for heart rate using the Fridericia formula  
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
Simpson Angus Scale 
SFU 
Safety Follow-up 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
TSH 
thyroid-stimulating hormone 
ULN 
upper limit of normal 
WHO 
World Health Organization  
 
 


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2. 
INTRODUCTION 
This statistical analysis plan (SAP) provides the technical and detailed elaboration of the statistical 
analyses of the efficacy and safety data as outlined and/or specified in the Protocol Amendment 2 
(dated 20 Aug 2021) of Study ITI-007-501. Specifications of tables, figures, and data listings are 
contained in a separate document.
 
  
Study ITI-007-501 is a Phase 3, randomized, double-blind, placebo-controlled, multicenter study 
to evaluate the efficacy, safety, and tolerability of lumateperone as adjunctive therapy for the 
treatment of patients with major depressive disorder (MDD). This study will be performed at 
approximately 60 study centers in the United States and globally.  
The study design schematic is provided in Figure 2-1. The Schedule of Evaluations is presented in 
Table 2-1. Detailed descriptions of the procedures conducted at each study visit are provided in 
Section 8.5 of Protocol Amendment 2. 
Figure 2-1: Schematic of Study Design   
 
ADT = antidepressant treatment; ET = early termination; SFU = Safety Follow-up. 
a Eligible patients who complete 6 weeks of double-blind treatment and provide informed consent to rollover into 
the Open-label Safety Study will not enter the SFU Period. 
 
Screening Period (up to 2 Weeks)  
Potential patients will be evaluated during a Screening Period lasting up to 14 days. With approval 
from the Sponsor or designee, short extensions to the Screening Period may be granted in 
exceptional circumstances. After obtaining written informed consent, diagnostic interviews, 
determination of inadequate response to current antidepressant therapy (ADT), and physical 
examinations will be conducted, vital signs and ECGs will be assessed, and blood samples will be 


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collected for laboratory assessments. Patients considered potentially eligible will be required to 
continue their current ADT but will be required to discontinue other psychotropic drugs.  
Evaluation of diagnostic validity and eligibility of each patient will be undertaken by the Sponsor 
or designee. 
At Baseline (Visit 2), patients who continue to meet all eligibility criteria will be randomized to 
1 of 2 treatment arms, lumateperone 42 mg or matching placebo, and will enter the 6-week, double-
blind treatment period.  
Double-blind Treatment Period (6 Weeks)  
Patients will self-administer his/her first dose of study treatment on the evening of the Baseline 
visit (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. Antidepressant treatment will also 
continue as previously prescribed. The dose and frequency of ADT must not change during the 
Screening Period or for the duration of the Double-blind Treatment Period. 
Patients will attend outpatient study visits on Days 8, 15, 22, 29, 36, and 43. With approval from 
the Sponsor or designee, sites will be permitted to conduct remote visits if a site-based visit is not 
feasible. However, all Screening (Visit 1) and Baseline (Visit 2) assessments must be performed 
in person.  
A patient will be defined as a treatment completer if the patient completes the Double-blind 
Treatment Period (all scheduled visits up to and including Visit 8). Patients who withdraw 
prematurely should be seen for an Early Termination (ET) visit as soon as possible and will also 
be asked to return for a Safety Follow-up (SFU) Visit approximately one week after Visit 8/ET. 
Safety Follow-up Period (1 Week)  
All patients should return to the clinic for the SFU Visit approximately 1 week after Visit 8/ET. 
Any ongoing AEs at the SFU Visit must be followed until resolution, until the AE stabilizes, until 
it is determined to be not clinically significant, or until the patient is lost to follow-up. 
Patients who complete the 6-week Double-blind Treatment Period, who are considered to be 
appropriate by the Investigator, and who meet eligibility criteria may enroll in the 6-month 
Open-label Safety Study at the Visit 8/Week 6 visit. This rollover visit to the Open-label Safety 
Study at Visit 8/Week 6 must be in person. A patient who enters the Open-label Safety Study will 
not have a SFU visit (Visit 9/Week 7). 
 






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3. 
STUDY OBJECTIVES 
3.1 
Efficacy Objectives and Estimands 
3.1.1 Primary Objective 
The primary efficacy objective of this study is to evaluate the efficacy of lumateperone 42 mg 
administered once daily compared to placebo as adjunctive treatment to ADT in patients with 
MDD who have an inadequate response to ongoing ADT as measured by change from baseline to 
Day 43 in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score. 
The hypothetical estimand strategy is considered to address the primary objective and it is 
described as follows: 
• Target Population: Patients with MDD who have an inadequate response to ongoing ADT  
• Treatment: Lumateperone 42 mg vs placebo as adjunctive therapy to existing ADT 
• Variable (Endpoint): Change from baseline to Day 43 in the MADRS total score 
• Intercurrent events (ICE) and corresponding strategies (see Table 3-1) 
• Summary measure: Difference in treatment means between lumateperone 42 mg and 
placebo. 


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3.1.2 Key Secondary Efficacy Objective 
The key secondary efficacy objective of this study is to evaluate the efficacy of lumateperone 
42 mg administered once daily compared to placebo as adjunctive treatment to antidepressant 
therapy in patients with MDD who have an inadequate response to ongoing ADT as measured by 
change from baseline to day 43 in the Clinical Global Impression Scale-Severity (CGI-S). 
The proposed estimand strategy to address the secondary objective will be based on hypothetical 
strategy and will be similar as the proposed primary estimand based on the 5 attributes described 
in Section 3.1.1, except the variable and ICE will be based on CGI-S score instead of MADRS 
total score. 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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4. 
ANALYSIS POPULATIONS 
4.1 
Randomized Population 
The Randomized Population includes all patients who were randomly assigned to study 
treatment. 
4.2 
Safety Population 
The Safety Population includes all randomized patients who received at least 1 dose of 
study treatment.  
4.3 
Intent-to-Treat (ITT) Population 
The ITT Population includes all randomized patients who received at least 1 dose of study 
treatment and have a baseline MADRS total score. 
4.4 
Modified Intent-to-Treat (mITT) Population 
The mITT Population includes all randomized patients who received at least 1 dose of 
study treatment, have a baseline MADRS total score, and who have at least one 
on-treatment, postbaseline MADRS total score. On-treatment MADRS assessments are 
those performed no later than 3 days after the last dose of study treatment. 
 
 
 


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5. 
SUBJECT DISPOSITION 
The number of patients in each study analysis population will be summarized by treatment group 
and study center as follows: 
• The number of patients who were screened will be summarized overall by study center. 
• The number of patients in the Safety, ITT and mITT Populations will be summarized 
overall and by treatment group and study center. 
In addition, the number and percentage of patients who completed the Double-blind Treatment 
Period and who prematurely discontinue from the Double-blind Treatment Period will be 
summarized overall, by treatment group, and by reasons for premature discontinuation for the 
Safety, ITT, and mITT Populations, respectively. The number and percentage of patients with 
reasons for premature discontinuation from the Double-blind Treatment Period as recorded on the 
termination page of the eCRF will be provided by treatment group for the Safety, ITT, and mITT 
Populations respectively. 
  


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6. 
 
 
 
 
 
 


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7. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic parameters as allowed by local country legislation (eg, age, sex, race, and ethnicity) 
and other baseline characteristics (eg, weight and body mass index) will be summarized by 
treatment group for the Safety, ITT and mITT Populations. 
Prior medical and surgical history will be summarized by treatment group for the Safety 
Population. 
Baseline efficacy parameters including MADRS total score, CGI-S score, and GAD-7 total score 
will be summarized by treatment group for the mITT Populations. 


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8. 
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE 
8.1 
Extent of Treatment Exposure 
Exposure to study treatment for the Safety Population will be summarized using treatment 
duration, calculated as the number of days from the date of the first dose of double-blind study 
treatment taken to the date of the last dose taken, inclusive. The number and percentage of patients 
with treatment duration of ≥ 1 day, ≥ 7 days, ≥ 14 days, ≥ 21 days, ≥ 28 days, ≥ 35 days, and 
≥ 42 days will be also provided by treatment group, respectively. 
8.2 
Measurement of Treatment Compliance 
Dosing compliance for a specified period is defined as the total number of capsules of study 
treatment taken by a patient during the treatment period divided by the number of capsules of study 
treatment that were expected to be taken during the treatment period multiplied by 100. 
The total number of capsules taken during the treatment period will be calculated from the study 
treatment record. Descriptive statistics for study treatment dosing compliance together with 
compliance category will be summarized by treatment group for the Safety Population. 
8.3 
Prior and Concomitant Medication 
The latest version of the World Health Organization Drug Global (WHODG) will be used to code 
prior, prior concomitant, and concomitant medications. Prior medication is defined as any 
medication started and stopped before the date of the first dose of double-blind study treatment. A 
prior concomitant medication is any medication that started before the date of the first dose of 
double-blind study treatment and stopped or is ongoing after the date of the first dose of study 
treatment. Concomitant medication is defined as any medication taken on or after the date of the 
first dose of double-blind study treatment. Both prior and concomitant medications, including prior 
concomitant medication use, will be summarized as the number and proportion of patients in each 
treatment group who received each medication within each therapeutic class (ie, Anatomical 
Therapeutic Chemical code, Levels 2, 3 and 4) and preferred term for the Safety Population. 
Multiple medications used by a patient will only be counted once. 
Any concomitant medication started after the date of the last dose of double-blind study treatment 
will not be included in the summary but will be included in the patient data listings. 
 




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9.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the change from baseline to Day 43 in the MADRS total score. 
9.1.1 Primary Efficacy Analysis 
The primary efficacy analysis will be assessed for the hypothetical estimand and the data to be 
included in this primary analysis will be decided by the intercurrent events as described in 
Table 3-1. 
Based on the study primary hypothetical estimand strategy which assumes patients are on study 
treatment up to the primary time point, efficacy data collected after discontinuing study treatment 
(ie, performed more than 3 days after last dose of study treatment) or after starting new ADT will 
be set to missing and will not be included in the primary analysis. Instead, these missing data are 
assumed as missing at random (MAR).  
The hypothetical estimand strategy is being considered to address the primary and key secondary 
efficacy objectives for the proposed 6-week, double-blind, placebo-controlled study in patients 
with MDD with mixed features. 
 
 
 
 
 
 
 
 
 
 
The primary analysis to estimate and compare the treatment effects of lumateperone vs placebo as 
defined by the primary estimand will be performed using a mixed-effects model for repeated 
measures (MMRM) method. The model will include the change from baseline in MADRS total 
score at each study visit as the response variable, and treatment group, study visit, site (or pooled 
site) as factors and the baseline MADRS total score as covariate, and interaction terms for baseline 
MADRS total score-by-study visit and treatment group-by-study visit. An unstructured covariance 
matrix will be used to estimate the correlation among repeated measurements within patient. The 
Kenward-Roger approximation (Kenward and Roger, 1997) will be used to estimate the 
denominator degrees of freedom. The mean treatment difference for lumateperone vs placebo will 
be estimated via contrast based on treatment group and treatment group-by-study visit factors and 
will be reported along with the corresponding 95% CI and the p-value for superiority testing. 
 
 
 
 
 
 
 
 
 
 
 
 
 


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The mixed model with repeated measures (MMRM) is being considered as the statistical model 
for the estimation of the primary and key secondary estimands to compare the treatment effect 
between the lumateperone 42 mg group and the placebo group in combination with the fixed-
sequence testing procedure (first test for the primary efficacy endpoint and, if significant, then test 
for the key secondary efficacy endpoint) for the analyses of the primary and key secondary efficacy 
endpoints for the proposed 6-week double-blind, placebo-controlled studies in patients with MDD 
with mixed features.   
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 


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9.2 
Key Secondary Efficacy Endpoint 
The key secondary efficacy endpoint is the change from baseline to Day 43 in the CGI-S score. 
9.2.1 Key Secondary Analysis 
The key secondary efficacy endpoint will be tested using the same hypothetical estimand strategy 
as for the primary efficacy endpoint. 
The data to be included in the key secondary efficacy analysis will be decided by the intercurrent 
events as described in Table 9-3. 
 
 
 
 
 
 
 


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10. 
SAFETY ANALYSES 
Safety analyses will be performed using the Safety Population. The safety parameters will include 
AEs, clinical laboratory, vital signs, ECG, and EPS (AIMS, BARS, and SAS) and C-SSRS scales. 
The baseline for each safety endpoint is defined as the last measurement prior to the first dose of 
randomized treatment. 
10.1 
Adverse Events 
Adverse events will be coded by system organ class (SOC) and preferred term using the latest 
version of the Medical Dictionary for Regulatory Activities (MedDRA).  
An AE will be considered a treatment-emergent AE (TEAE) if it was not present before the first 
dose of double-blind study treatment or was present before the first dose of double-blind study 
treatment but increased in severity after the first dose. An AE that occurs more than 1 day after the 
date of the last dose of double-blind study treatment will not be counted as a TEAE. 
The number and percentage of patients reporting TEAEs in each treatment group will be tabulated 
by SOC and preferred term; by SOC, preferred term, and severity; and by SOC, preferred term, 
and relationship to study treatment. If more than one AE is coded to the same preferred term for 
the same patient, the patient will be counted only once for that preferred term using the most severe 
and most related occurrence for the summary by severity and by relationship to study treatment. 
The incidence of common (≥ 5% of patients in either treatment group) TEAEs will be summarized 
by preferred term and treatment group. 
The number and percentage of patients reporting serious AEs (SAEs) in each treatment group 
during double-blind treatment period will be tabulated by SOC and preferred term. Also, the 
number and percentage of patients reporting AEs leading to drug withdrawal in each treatment 
group will be tabulated by SOC and preferred term. Listings will be presented for patients with 
SAEs, patients with AEs leading to drug withdrawal, and patients who died (if any). 
The incidence of extrapyramidal symptom (EPS) TEAEs will be summarized by PT and treatment 
group and will be sorted by decreasing frequency for lumateperone 42 mg group. The PTs for EPS 
will be based on broad and narrow Standardised MedDRA Queries (SMQs) as listed in Table 10-1. 
The analysis for EPS TEAEs based on Broad SMQs will also include the preferred terms listed 
under Narrow SMQs. 


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Table 10-1: Preferred Terms for Extrapyramidal Symptoms 
Scope 
Preferred Terms  
Narrow  
 
Akathisia, Athetosis, Ballismus, Buccoglossal syndrome, Chorea, Choreoathetosis, 
Dopamine, dysregulation syndrome, Dyskinesia, Dyskinesia neonatal, Dyskinesia 
oesophageal, Grimacing, Oculogyric crisis, Pharyngeal dyskinesia, Protrusion tongue, 
Rabbit syndrome, Respiratory dyskinesia, Tardive Dopa-responsive dystonia, Dystonia, 
Dystonic tremor, Early onset primary dystonia, Emprosthotonus, Meige's syndrome, 
Oculogyric 
crisis, 
Opisthotonus, 
Oromandibular 
dystonia, 
Pharyngeal 
dystonia, 
Pleurothotonus, Spasmodic dysphonia, Torticollis, Trismus, Writer's cramp, Akinesia, 
Bradykinesia, Cogwheel rigidity, Freezing phenomenon, Hypertonia, Hypertonia neonatal, 
Hypokinetic dysarthria, Muscle rigidity, On and off phenomenon, Parkinsonian crisis, 
Parkinsonian gait, Parkinsonian rest tremor, Parkinsonism, Parkinsonism hyperpyrexia 
syndrome, Parkinson's disease, Parkinson's disease psychosis, Propulsive gait, Resting 
tremor. 
Broad  
 
All preferred terms listed under Narrow (above) plus the following:  
Extrapyramidal disorder, Hyperkinesia, Hyperkinesia neonatal, Motor dysfunction, 
Movement disorder, Psychomotor hyperactivity, Restlessness, Abnormal involuntary 
movement scale, Chronic tic disorder, Complex tic, Drooling, , Muscle twitching, 
Provisional tic disorder, Secondary tic, Tic, Blepharospasm, Facial spasm, Gait inability, 
Laryngospasm,, Muscle contractions involuntary, Muscle spasms, Muscle spasticity, Muscle 
tightness, Muscle tone disorder, Musculoskeletal stiffness, Oesophageal spasm, 
Oropharyngeal spasm, Posture abnormal, Posturing, Provisional tic disorder, Risus 
sardonicus, Tongue spasm, Torticollis psychogenic, Uvular spasm, Action tremor, 
Bradyphrenia, Dysphonia, Fine motor skill dysfunction, Gait disturbance, Hypokinesia, 
Hypokinesia neonatal, Laryngeal tremor, Micrographia, Mobility decreased, Postural reflex 
impairment, Postural tremor, Reduced facial expression, Tremor, Tremor neonatal, Walking 
disability. 
 
10.2 
Clinical Laboratory Parameters 
Descriptive statistics for clinical laboratory values (in International System of units [SI] and 
conventional units) and changes from baseline values at each assessment visit and at the end of 
double-blind treatment period will be summarized by treatment group for the following clinical 
laboratory parameters: 
• Hematology: hematocrit; hemoglobin; 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. 
• Chemistry: albumin; alkaline phosphatase; alanine aminotransferase (ALT); aspartate 
aminotransferase (AST); bilirubin (total, direct); blood urea nitrogen (BUN); calcium; 
chloride; cholesterol (high-density lipoprotein [HDL] and low-density lipoprotein [LDL] 
will be calculated and reported); creatinine; creatine phosphokinase; gamma-glutamyl 
transferase; glucose; insulin; lactate dehydrogenase; phosphate; potassium; prolactin; 
sodium; triglycerides; total protein; uric acid; HbA1c; and thyroid-stimulating hormone 
(TSH) (reflex free T3 and free T4). 
• Urinalysis: pH and specific gravity. 


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Clinical laboratory values are considered potentially clinically significant (PCS) values if they 
meet either the lower or upper criteria listed in Table 10-2. The number and percentage of patients 
with PCS postbaseline clinical laboratory values during double-blind treatment period will be 
tabulated by treatment group. The percentages will be calculated relative to the number of patients 
with available non-PCS baseline values and at least 1 postbaseline assessment. The numerator will 
be the total number of patients with available non-PCS baseline values and at least 1 PCS 
postbaseline value. A supportive listing of patients who have PCS values will be provided and will 
include the PID number and baseline and postbaseline values for each patient. A listing of all AEs 
for patients with PCS clinical laboratory values will also be provided. 
Table 10-2: Criteria for Potentially Clinically Significant Clinical Laboratory Tests 
Laboratory Parameter 
Conventional 
Unit 
PCS Criteriaa Low Values 
PCS Criteriaa High Values 
Hematology 
Hemoglobin 
g/dL 
< 0.9 × LLN 
— 
Hematocrit 
% 
< 0.9 × LLN 
— 
Absolute neutrophil count (ANC) 
103/µL 
< 1.0 
— 
Platelet count 
103/µL 
≤ 75 
≥ 700 
White blood cell (WBC) count 
103/µL 
≤ 2.5 
≥ 15 
Chemistry 
Albumin 
g/dL 
< 2.5 
— 
Alkaline phosphatase 
U/L 
— 
≥ 2 × ULN 
ALT 
U/L 
— 
≥ 3 × ULN 
AST  
U/L 
— 
≥ 3 × ULN 
BUN 
mg/dL 
— 
≥ 30 
Calcium 
mg/dL 
< 7 
> 12 
Chloride 
mEq/L 
< 90 
> 115 
Total Cholesterol 
mg/dL 
— 
≥ 300 
CPK 
U/L 
— 
≥ 5 × ULN 
Creatinine 
mg/dL 
— 
> 1.3 × ULN 
Glucose 
mg/dL 
< 45 
> 160 
LDL Cholesterol 
mg/dL 
— 
> 200 
Potassium 
mEq/L 
< 3 
> 5.5 
Prolactin 
ng/ml 
— 
> 200 
Sodium 
mEq/L 
< 130 
> 150 
Total bilirubin 
mg/dL 
— 
≥ 2 × ULN 
Total protein 
— 
< 0.9 × LLN 
> 1.1 × ULN 
Triglycerides 
mg/dL 
— 
≥ 300 
Uric Acid  
mg/dL 
— 
> 1.1 × ULN 


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Laboratory Parameter 
Conventional 
Unit 
PCS Criteriaa Low Values 
PCS Criteriaa High Values 
Urinalysis 
Protein 
— 
— 
At least 2 + 
Glucose 
— 
— 
At least 2 + 
Blood 
— 
— 
At least 2 + 
a 
Criteria refer to conventional units. 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; CPK=creatine 
phosphokinase; LLN = lower limit of normal of laboratory reference range; PCS = potentially clinically significant; 
ULN = upper limit of normal of laboratory reference range. 
The number and percentage of patients with shifts from baseline at the end of double-blind 
treatment period according to normal range and PCS criteria (PCS Low, Low, Normal, High, PCS 
High) will be provided if applicable.  
The criteria for elevated liver function-related laboratory values are specified in Table 10-3. The 
frequency and percentage of subjects with treatment-emergent elevated liver function values 
during the double-blind treatment period will be summarized for each treatment group for the 
Safety Population. 




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provided and will include the PID number and baseline and postbaseline values for each patient. 
A listing of all AEs for patients with PCS vital sign values will also be provided.  
Table 10-4: Criteria for Potentially Clinically Significant Vital Signs 
Vital Sign Parameter, unit 
Flag 
Criteriaa 
Observed Value 
Change From Baseline 
Supine Systolic blood pressure, mm Hg 
High 
≥ 180 
Increase of ≥ 20 
Low 
< 90 
Decrease of ≥ 20 
Supine Diastolic blood pressure, mm Hg 
High 
≥ 105 
Increase of ≥ 15 
Low 
< 50 
Decrease of ≥ 15 
Supine Pulse rate, bpm 
High 
≥ 120 
Increase of ≥ 15 
Low 
≤ 50  
Decrease of ≥ 15 
Weightb 
High 
— 
Increase of ≥ 7% 
Low 
— 
Decrease of ≥ 7% 
a A postbaseline value will be considered potentially clinically significant if it meets both criterion value and change 
from baseline. 
b Weight change is relative to baseline. 
bpm = beats per minute. 
The number and percentage of patients with post-baseline orthostatic hypotension (OH) will be 
provided by treatment group for the Safety Population. OH is defined as a reduction of 
≥ 20 mm Hg in SBP or a reduction of ≥ 10 mm Hg in DBP while changing from the supine to 
standing position. A supportive listing of patients with OH will be provided. A listing of all AEs 
occurring in patients who experienced OH will also be provided. 
10.4 
Electrocardiograms 
Descriptive statistics for ECG parameters (eg, ventricular heart rate, QTc interval, QRS interval) 
at baseline and changes from baseline values at each assessment visit, and at the end of the double-
blind treatment period will be summarized by treatment group.  
ECG parameter values will be considered PCS if they meet the criteria listed in Table 10-5. The 
number and percentage of patients with PCS postbaseline values during double-blind treatment 
period will be tabulated by treatment group for the Safety Population. The percentages will be 
calculated relative to the number of patients with baseline value (for criteria involving change from 
baseline) or non-PCS baseline value (for criteria not involving change from baseline), and at least 
1 assessment during the double-blind treatment period. The numerator will be the total number of 
patients out of those included in the denominator and with at least 1 PCS value during the double-
blind treatment period. A supportive listing for all patients with PCS values will be provided, 
which will include the PID number and baseline and postbaseline ECG values for each patient. A 
listing of all AEs for patients with PCS ECG values will also be provided. 


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Table 10-5. Criteria for Potentially Clinically Significant Electrocardiographic Values 
Parameter, unit 
Criteriaa 
Value 
Change from Baseline 
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; 
QTc = corrected 
QT 
interval; 
QTcB = QT 
interval/(RR)½; 
QTcF = QT interval/(RR)⅓. 
10.5 
Other Safety Parameters 
10.5.1 Abnormal Involuntary Movement Scale (AIMS) 
Descriptive statistics for AIMS total score at baseline and changes from baseline at each 
assessment visit (including the end of the double-blind treatment period) will be presented by 
treatment group for the Safety Population. 
10.5.2 Barnes Akathisia Rating Scale (BARS) 
Descriptive statistics for BARS total score at baseline and changes from baseline at each 
assessment visit (including the end of the double-blind treatment period) will be presented by 
treatment group for the Safety Population. 
10.5.3 Simpson-Angus Rating Scale (SAS) 
Descriptive statistics for SAS total score at baseline and changes from baseline at each assessment 
visit (including the end of the double-blind treatment period) will be presented by treatment group 
for the Safety Population. 
10.5.4 Columbia–Suicide Severity Rating Scale (C–SSRS) 
The number and percentage of patients with suicidal ideation or suicidal behavior as recorded on 
the C-SSRS will be tabulated by treatment group for lifetime history (at the Screening Visit), 
baseline, double-blind treatment period, and SFU Period for the Safety Population. Baseline of C–
SSRS for each patient is defined as the last non-missing pre-treatment ‘since last visit’ assessment. 


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The distribution of responses for the most severe suicidal ideation and most severe suicidal 
behavior will be presented by treatment group.  
The severity of suicidal ideation will be presented in a decreasing order: 
• 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 be presented in a decreasing order: 
• Completed Suicide (for double-blind treatment period and for SFU period only) 
• Actual attempt 
• Interrupted attempt 
• Aborted attempt 
• Preparatory acts or behavior 
For each analysis period (lifetime, baseline, double-blind treatment period, and SFU Period), each 
patient will be counted only once for suicidal ideation and for suicidal behavior, based on the most 
severe suicidal ideation and the most severe suicidal behavior reported during each specific period. 
A listing of patients with suicidal ideation or suicidal behavior will be provided. 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 treatment period will be tabulated by treatment group 
for the Safety Population: 
• 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) 


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11. 
 
 


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12. 
 
 


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13. 
 
 
 
 
 
 
 
 


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14. 
STATISTICAL SOFTWARE 
Statistical analyses of efficacy and safety parameters will be performed using version 9.4 (or 
newer) of SAS®.  
 


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15. 
DATA HANDLING CONVENTIONS 
15.1 
Visit Time Windows 
Table 15-1 presents the visits assigned for the analyses of MADRS (primary efficacy assessment) 
and CGI-S (key secondary assessment) corresponding to the range of treatment days (window) 
during which an actual visit may have occurred. 
Table 15-1: Visit Time Windows for the Double-blind Treatment Period for MDARS and CGI-S 
Derived Visit 
Scheduled Visit (Daya) 
Windowb 
Target Day 
Baseline 
Week 0 (Day 1) 
Days ≤ 1 
Day 1 
Week 1 
Week 1 (Day 8) 
Days [2, 11] 
Day 8 
Week 2 
Week 2 (Day 15) 
Days [12, 18] 
Day 15 
Week 3 
Week 3 (Day 22) 
Days [19, 25] 
Day 22 
Week 4 
Week 4 (Day 29) 
Days [26, 32] 
Day 29 
Week 5 
Week 5 (Day 36) 
Days [33, 39] 
Day 36 
Week 6 
Week 6 (Day 43) 
Days ≥ 40 
Day 43 
a 
Relative to the date of the first dose of double-blind study treatment.  
b 
Visit day is calculated as visit date − date of the first dose of double-blind study treatment, + 1 day if the visit 
date is on or after the date of the first dose of double-blind study treatment. 
The analysis window will be applied to the MADRS and CGI-S assessments based on the 
considerations of the ICEs: 
• For Primary Efficacy Analysis (Section 9.1.1), 
, and Key 
Secondary Efficacy Analysis (Section 9.2.1), the visit time window will be applied to the 
assessments made before last dose plus 3 days and before starting new ADT (Table 3-1); 
 
 
 
 
  
 
 
 
 
 
If more than one assessment is available in the same analysis window for MADRS or for CGI-S, 
the assessment closest to the scheduled target day will be selected and assigned to the derived visit. 
If two or more assessments of MADRS or of CGI-S are available in the same window and are 
equidistant from the scheduled target day, the earliest assessment will be selected. 
 
  


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Table 15-3 presents the visits assigned for vital signs parameters to the range of treatment days 
(window) during which an actual visit may have occurred. 
Table 15-3: Visit Time Windows for the Double-blind Treatment Period for Vital Sign Parameters 
Derived Visit 
Scheduled Visit (Daya) 
Windowb 
Target Day 
Baseline 
Week 0 (Day 1) 
Days ≤ 1 
Day 1 
Week 1 
Week 1 (Day 8) 
Days [2, 11] 
Day 8 
Week 2 
Week 2 (Day 15) 
Days [12, 18] 
Day 15 
Week 3 
Week 3 (Day 22) 
Days [19, 25] 
Day 22 
Week 4 
Week 4 (Day 29) 
Days [26, 32] 
Day 29 
Week 5 
Week 5 (Day 36) 
Days [33, 39] 
Day 36 
Week 6 
Week 6 (Day 43) 
Days ≥ 40 and within double-blind treatment period 
Day 43 
End of double-
blind treatment 
period 
Final or termination visit during the double-blind treatment period 
a 
Relative to the date of the first dose of double-blind study treatment.  
b 
Visit day is calculated as visit date − date of the first dose of double-blind study treatment, + 1 day if the visit 
date is on or after the date of the first dose of double-blind study treatment.  
Table 15-4 presents the visits assigned for laboratory and ECG parameters to the range of treatment 
days (window) during which an actual visit may have occurred. 


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Table 15-4: Visit Time Windows for the Double-blind Treatment Period for Lab and ECG Parameters 
Derived Visit 
Scheduled Visit (Daya) 
Windowb 
Target Day 
Baseline 
Week 0 (Day 1) 
Days ≤ 1 
Day 1 
Week 3 
Week 3 (Day 22) 
Days [2, 32] 
Day 22 
Week 6 
Week 6 (Day 43) 
Days ≥ 33 and within double-blind treatment period 
Day 43 
End of double-
blind treatment 
period 
Final or termination visit during the double-blind treatment period 
a 
Relative to the date of the first dose of double-blind study treatment.  
b 
Visit day is calculated as visit date − date of the first dose of double-blind study treatment, + 1 day if the visit 
date is on or after the date of the first dose of double-blind study treatment. 
Table 15-5 presents the visits assigned for AIMS, BARS, and SAS parameters to the range of 
treatment days (window) during which an actual visit may have occurred. 
Table 15-5: Visit Time Windows for the Double-blind Treatment Period for AIMS, BARS and SAS Parameters 
Derived Visit 
Scheduled Visit (Daya) 
Windowb 
Target Day 
Baseline 
Week 0 (Day 1) 
Days ≤ 1 
Day 1 
Week 2 
Week 2 (Day 15) 
Days [2, 22] 
Day 15 
Week 4 
Week 4 (Day 29) 
Days [23, 36] 
Day 29 
Week 6 
Week 6 (Day 43) 
Days ≥ 37 and within double-blind treatment period 
Day 43 
End of double-
blind treatment 
period 
Final or termination visit during the double-blind treatment period 
a 
Relative to the date of the first dose of double-blind study treatment.  
b 
Visit day is calculated as visit date − date of the first dose of double-blind study treatment, + 1 day if the visit date is on or 
after the date of the first dose of double-blind study treatment. 
Handling of multiple records of safety assessments within the same analysis window is provided 
in Section 15.2. 
15.2 
Repeated or Unscheduled Assessments of Safety Parameters 
If a patient has repeated assessments on or before the start of double-blind study treatment, then 
the results from the last assessment made before the start of double-blind study treatment will be 
used as baseline. For visits with postbaseline repeated or unscheduled assessments of laboratory 
parameters, the non-missing values of the scheduled assessment will be used for summary 
statistics. If the scheduled assessments are missing, the last value from repeated or unscheduled 
assessments within the analysis window will be used. If postbaseline repeated or unscheduled vital 
signs and/or ECGs occur, apply the time-window rule and select the last non-missing values for 
each visit or endpoint. All postbaseline assessments will be used for PCS value determination and 
will be presented in the data listings. 


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15.3 
Missing Date of Double-Blind Study Treatment  
When the date of the last dose of double-blind study treatment taken during the double-blind 
treatment period is missing for a patient in the Safety Population, all efforts should be made to 
obtain the date from the Investigator. If it is still missing after all efforts, then the last known dose 
date will be set as the date of the last dose of double-blind study treatment. 
15.4 
Missing Severity Assessment for Adverse Events 
If severity is missing for an AE that started before the date of the first dose of double-blind study 
treatment, then a severity of mild will be assigned. If the severity is missing for an AE that started 
on or after the date of the first dose of double-blind study treatment, then a severity of severe will 
be assigned. The imputed values for severity assessment will be used for the incidence summary; 
while the actual values will be presented in the data listings. 
15.5 
Missing Relationship to Investigational Product for Adverse Events 
If the relationship to double-blind study treatment is missing for an AE that started on or after the 
first dose date of double-blind study treatment, a causality of yes will be assigned. The imputed 
values for relationship to double-blind study treatment will be used for the incidence summary, 
while the actual values will be presented in the data listings. 
15.6 
Missing Date Information for Adverse Events 
The following imputation rules apply only to cases in which the start date is incomplete (ie, 
partially missing) for AEs. 
Missing month and day 
• If the year of the incomplete start date is the same as the year of the date of the first dose 
of double-blind study treatment, then the day and month of the date of the first dose of 
double-blind study treatment will be assigned to the missing fields; 
• If the year of the incomplete start date is before the year of the date of the first dose of 
double-blind study treatment, then December 31 will be assigned to the missing fields; 
• If the year of the incomplete start date is after the year of the date of the first dose of double-
blind study treatment, then January 1 will be assigned to the missing fields. 
Missing month only 
• If only the month of the incomplete start date is missing, the day will also be treated as 
missing, and both the month and day will be replaced according to the procedure described 
above. 
Missing day only 
• If the month and year of the incomplete start date are the same as the month and year of 
the date of the first dose of double-blind study treatment, then the day of the date of the 
first dose of double-blind study treatment will be assigned to the missing field; 


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• If either the year of the incomplete start date is before the year of the date of the first dose 
of double-blind study treatment or if the 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 treatment, 
then the last day of the month will be assigned to the missing field; 
• If either the year of the incomplete start date is after the year of the date of the first dose of 
double-blind study treatment or if the 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 treatment, 
then the first day of the month will be assigned to the missing field. 
If the stop date is complete and the imputed start date, when imputed as instructed above, is after 
the stop date, then the start date will be imputed to equal the stop date. 
If the start date is completely missing and the stop date is complete, then use the following 
algorithm to impute the start date: 
• If the stop date is on or after the date of the first dose of double-blind study treatment, the 
date of the first dose of double-blind study treatment will be assigned to the missing start 
date; 
• If the stop date is before the date of the first dose of double-blind study treatment, the stop 
date will be assigned to the missing start date. 
15.7 
Missing Date Information for Prior or Concomitant Medications 
For prior or concomitant medications, including psychotropic medications, incomplete (ie, 
partially missing) start dates and/or stop dates will be imputed. If the start date and the stop date 
for a patient are both incomplete, the start date will be imputed first. 
15.7.1 Incomplete Start Date 
The following rules will be applied to impute the missing numeric fields. If the stop date is 
complete and the imputed start date is after the stop date, then 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 date of the first dose 
of double-blind study treatment, then the month and day of the date of the first dose of 
double-blind study treatment will be assigned to the missing fields; 
• If the year of the incomplete start date is before the year of the date of the first dose of 
double-blind study treatment, then December 31 will be assigned to the missing fields; 
• If the year of the incomplete start date is after the year of the date of the first dose of double-
blind study treatment, then January 1 will be assigned to the missing fields. 


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Missing month only 
• If only the month of the incomplete start date is missing, the day will also be treated as 
missing, and both month and day will be replaced according to the procedure described 
above. 
Missing day only  
• If the month and year of the incomplete start date are the same as the month and year of 
the date of the first dose of double-blind study treatment, then the day of the date of the 
first dose of study treatment will be assigned to the missing field; 
• If either the year of the incomplete start date is before the year of the date of the first dose 
of double-blind study treatment or if the 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 treatment, 
then the last day of the month will be assigned to the missing field; 
• If either the year of the incomplete start date is after the year of the date of the first dose of 
double-blind study treatment or if the 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 treatment, 
then the first day of the month will be assigned to the missing field. 
15.7.2 Incomplete Stop Date 
The following rules will be applied to impute the missing numeric fields. If the date of the last 
dose of double-blind study treatment is missing, it will be replaced with the last visit date. If the 
imputed stop date is before the start date (imputed or non-imputed), then 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 date of the last dose of 
double-blind study treatment, then the month and day of the date of the last dose of study 
treatment will be assigned to the missing fields; 
• If the year of the incomplete stop date is before the year of the date of the last dose of 
double-blind study treatment, then December 31 will be assigned to the missing fields; 
• If the year of the incomplete stop date is after the year of the date of the last dose of double-
blind study treatment, then January 1 will be assigned to the missing fields. 
Missing month only 
• If only the month of the incomplete stop date is missing, the day will also be treated as 
missing, and both month and day will be replaced according to the procedure described 
above. 
Missing day only 
• If the month and year of the incomplete stop date are the same as the month and year of 
the date of the last dose of double-blind study treatment, then the day of the date of the last 
dose will be assigned to the missing field; 


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• If either the year of the incomplete stop date is before the year of the date of the last dose 
of double-blind study treatment or if the 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 treatment, 
then the last day of the month will be assigned to the missing field; 
• If either the year of the incomplete stop date is after the year of the date of the last dose of 
double-blind study treatment or if the 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 treatment, 
then the first day of the month will be assigned to the missing field. 
15.8 
Character Values of Clinical Laboratory Parameters 
If the reported value of a clinical laboratory parameter cannot be used in a statistical summary 
table because, for example, a character string is reported for a parameter of the numeric type, the 
coded value will need to be appropriately determined for use in the statistical analysis. However, 
the actual values as reported in the database will be presented in the data listings. 
Table 15-6: Example for Coding of Special Character Values for Clinical Laboratory Parameters 
Laboratory Test 
Possible Laboratory Results, SI Units 
Coded Value for Analysis 
Chemistry: ALT 
< 5 
5 
Chemistry: AST 
< 5 
5 
Chemistry: bilirubin, total 
< 2 
2 
Urinalysis: ketones 
= OR > 8.0, ≥ 8.0, > 0 
Positive 
≤ 0, negative 
Negative 
Urinalysis: pH 
> 8.0, ≥ 8.0 
8.0 
≥ 8.5 
8.5 
Urinalysis: glucose 
≤ 50 
0 
(50, 100] 
1+ 
(100, 250] 
2+ 
(250, 500] 
3+ 
(500, 1000] 
4+ 
> 1000 
5+ 
Urinalysis: protein 
≤ 0 
Negative 
(0, 15] 
0 
(15,30] 
1+ 
(30,100] 
2+ 
(100,500] 
3+ 
> 500 
4+ 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; SI = Le Système International d'Unités 
(International System of Units). 
 


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16. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  


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17. 
REFERENCES 
Kenward MG, Roger JH. Small sample inference for fixed effects from restricted maximum 
likelihood. Biometrics. 1997;53(3):983-97. 
Koch GG, Wienner LE. Commentary for the Missing Data Working Group’s Perspective for 
Regulatory Clinical Trials, Estimands, and Sensitivity analyses. Stat Med. 2016; 
35(17):2887-2893. 
Lu K. Sample size calculations with multiplicity adjustment for longitudinal clinical trials with 
missing data. Stat Med. 2012; 31(1):19-28. 
Lu K, Mehrotra DV. Specification of covariance structure in longitudinal data analysis for 
randomized clinical trials. Stat Med. 2010; 29(4):474-488. 
Permutt T. Sensitivity analysis for missing data in regulatory submissions. Stat. Med. 2016; 
35(17):2876-2879. 
Rubin DB. Multiple Imputation for Nonresponse in Surveys. New York: John Wiley & Sons, 1987. 
 


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18. 
APPENDICES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
   
  
   
 
   
 
 
  
   
 
   


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