Clinical trial NCT01914393
Conditions: Schizophrenia Autism Bipolar Depression
Keywords: Schizophrenia Autism Lurasidone Latuda
Sponsor: Sumitomo Pharma America, Inc.
Start date: 2013-09-30; Completion date: 2018-10-17
Enrollment: 702 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is an open-label, 104-week, multicenter, extension study designed to evaluate the long-term safety, tolerability and effectiveness of flexibly dosed lurasidone (20, 40, 60 or 80 mg/day) in pediatric subjects who have completed the 6-week treatment period in the preceding studies, D1050301, D1050325, and D1050326

Detailed description:

Arms: arm 1: Lurasidone 20, 40, 60, 80 mg, flexibly dosed, once daily
Interventions: intervention 1: Lurasidone 20, 40, 60, 80 mg, flexibly dosed
Intervention descriptions: intervention 1: Lurasidone 20, 40, 60, 80 mg once daily, flexibly dosed

Protocol documents:
Prot_000.pdf: 
Title page
 
LURASIDONE 
D1050302 
A 104-WEEK, FLEXIBLE-DOSE, OPEN-LABEL, 
MULTICENTER, EXTENSION STUDY TO EVALUATE 
THE LONG-TERM SAFETY AND EFFECTIVENESS OF 
LURASIDONE IN PEDIATRIC SUBJECTS  
IND Nos. 61,292 and 103,427 
EudraCT No. 2013-001694-24 
Version 4.0 
30 June 2017 
Incorporates Amendment 3 and Non-substantial Protocol Amendment 1.00 
SUNOVION PHARMACEUTICALS INC. 
One Bridge Plaza Suite 510 
Fort Lee, NJ 07024 
USA 
(201) 592-2050 


Protocol D1050302 Version 4.0 
 
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RESTRICTED DISTRIBUTION OF PROTOCOLS 
This document contains information confidential and/or of proprietary interest to Sumitomo 
Dainippon Pharma Co. Ltd. and/or Sunovion Pharmaceuticals Inc. (including their 
The information cannot be disclosed to any third party or 
predecessors, subsidiaries or affiliates). 
used for any purpose other than the purpose for which it is being submitted without the prior 
written consent of the appropriate Sumitomo Dainippon Pharma company. 
This information is being provided to you for the purpose of conducting a clinical study for 
. (hereafter referred to as Sunovion, or Sponsor). You may 
Sunovion Pharmaceuticals Inc
disclose the contents of this protocol to the study personnel under your supervision and to your 
Institutional Review Board or Independent Ethics Committee for the above purpose. You may 
not disclose the contents of this protocol to any other parties, unless such disclosure is required 
by government regulations or laws, without the prior written permission of Sunovion. 
Any data gathered during the conduct of this protocol and supplemental information (eg, a 
 
protocol amendment) that may be added to this document is also proprietary to Sunovion, and 
should be handled consistently with that stated above. 
 


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EMERGENCY CONTACTS 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Contact Information 
Clinical Study Leader 
 
Head of Global Clinical Research, 
Psychiatry 
Sunovion Pharmaceuticals Inc. 
Medical Monitor 
 
Executive Director, Medical and 
Scientific Services 
Quintiles 
SAE Reporting 
SunovionSafety@druginfo.com   
SAE Reporting in EU 
and Africa 
 
Principal Drug Safety Scientist 
Sunovion Pharmaceuticals Europe, 
Ltd. 
 


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1.
SYNOPSIS
Name of Sponsor/Company: Sunovion Pharmaceuticals Inc. 
Name of Investigational Product: Lurasidone (lurasidone HCl) 
Title of Study: A 104-Week, Flexible-Dose, Open-Label, Multicenter, Extension Study to Evaluate the 
Long-Term Safety and Effectiveness of Lurasidone in Pediatric Subjects  
Study Centers: Multicenter study in the United States and Worldwide 
Phase of Development: 3 
Study Objectives:  
Primary: To evaluate the long-term safety, tolerability, and effectiveness of lurasidone (20, 40, 60 or 
80 mg/day, flexibly dosed) in pediatric subjects who have completed a prior lurasidone study. 
Secondary: 
For all subjects, the following will be assessed: 
•
Proportions of subjects with adverse events (AEs), discontinuations due to AEs, and serious
AEs (SAEs). 
For subjects continued from Study D1050301, the following will be assessed: 
•
Change in Positive and Negative Syndrome Scale (PANSS) total, positive, negative, general
psychopathology, and excitability subscale scores; 
•
Change in the Clinical Global Impression – Severity (CGI-S);
•
Change in the Clinician-rated Children’s Global Assessment Scale (CGAS);
•
Change in the Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire
(PQ-LES-Q).
For subjects continued from Study D1050325, the following will be assessed: 
•
Change in Aberrant Behavior Checklist (ABC) irritability subscale, and the following subscale
scores (hyperactivity, stereotypy, inappropriate speech, and lethargy/social withdrawal); 
•
Change in the Clinical Global Impression – Severity (CGI-S);
•
Change in Children's Yale-Brown Obsessive Compulsive Scales (CY-BOCS) modified for
pervasive developmental disorders (PDDs);
•
Change in the Caregiver Strain Questionnaire (CGSQ).
For subjects continued from Study D1050326, the following will be assessed: 
•
Change in the Children's Depression Rating Scale, Revised (CDRS-R);
•
Change in the Clinical Global Impression Bipolar Version – Severity (CGI-BP-S);
•
Change in the Clinician-rated Children’s Global Assessment Scale (CGAS);
•
Change in the Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire
(PQ-LES-Q);
•
Change in anxiety symptoms as measured by the Pediatric Anxiety Rating Scale (PARS);
•
Change in attention-deficit/hyperactivity symptoms as measured by the Attention-Deficit/
Hyperactivity Disorder Rating Scale (ADHD-RS) total score.
Study Design:  
This is an open-label, 104-week, multicenter, extension study designed to evaluate the long-term 
safety, tolerability and effectiveness of flexibly dosed lurasidone (20, 40, 60 or 80 mg/day) in pediatric 


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Name of Sponsor/Company: Sunovion Pharmaceuticals Inc. 
Name of Investigational Product: Lurasidone (lurasidone HCl) 
subjects who have completed the 6-week treatment period in the preceding studies, D1050301, 
D1050325, or D1050326.   
Subjects who complete participation in the preceding studies, D1050301, D1050325, or D1050326 will 
be eligible for enrollment in this study. Informed consent/assent will be obtained from all subjects 
(where developmentally appropriate) before any study procedures are performed. Subjects who meet 
entry criteria will transition to this study directly from Study D1050301, D1050325, or D1050326. All 
subjects will be treated with flexibly dosed lurasidone during the trial. 
A reliable informant (eg, parent, legal guardian, or caregiver) of the subject must accompany the 
subject at each visit. For subjects entering from Study D1050325, the reliable caregiver will also 
oversee the administration of the study drug throughout the study. 
All eligible subjects will be treated with lurasidone 40 mg/day for Days 1-7. Beginning with Day 8, 
dose adjustments (20, 40, 60 or 80 mg/day) will be permitted, based on investigator judgment, to 
optimize tolerability and effectiveness.  
Dose adjustment of study drug should occur at the regularly scheduled visits and in increments or 
decrements of 1 dose level. However, dose reductions for tolerability or safety purposes may occur 
beginning on Day 2, based on investigator judgment. These dose reductions may be between study 
visits and at more than 1 dose level at a time (maximum of 2 dose levels at a time). If dose reductions 
are required between regular study visits, the subject must return to the study site for an unscheduled 
visit to receive new medication kits and return all used/unused medication kits at the time of dose 
adjustment. 
Safety and effectiveness assessments will be conducted at scheduled visits during the study. 
A follow-up visit will occur 1 week post last dose of study drug. 
A Data and Safety Monitoring Board (DSMB) will review safety and clinical outcome data including 
data on adverse events (AEs) and serious adverse events (SAEs) at regular intervals until the 
D1050301, D1050325, and D1050326 studies are complete and as long as necessary for the D1050302 
study, as determined by the Sponsor. The DSMB will be independent of the Sponsor, contract research 
organization (CRO), and the investigators and will be empowered to recommend stopping the study 
due to safety concerns, but not for efficacy or futility. The membership of the DSMB and its mandate is 
denoted in the DSMB charter. 
Number of Subjects (planned): The estimated number of subjects eligible for enrollment is 
approximately 702 subjects. 
Diagnosis and Main Criteria for Inclusion: 
Subject has completed Study D1050301 (Visit 9), Study D1050325 (Visit 9), or Study D1050326 
(Visit 8); is judged to be appropriate for long-term treatment with lurasidone; has provided informed 
assent/consent (where developmentally appropriate); and has met all other entry criteria. 
Investigational Product, Dosage and Mode of Administration: Subjects will receive lurasidone 
(lurasidone HCl) administered orally, 20, 40, 60 or 80 mg (flexibly dosed), once daily in the evening 
with food (at least 350 calories) or within 30 minutes after eating. 
Duration of Treatment: 24 months (104 weeks) 
Reference Therapy, Dosage and Mode of Administration: Not applicable 
Criteria for Evaluation: 
Safety Assessments:  


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Name of Sponsor/Company: Sunovion Pharmaceuticals Inc. 
Name of Investigational Product: Lurasidone (lurasidone HCl) 
All Subjects: 
•
Treatment-emergent adverse events (TEAEs), TEAEs leading to discontinuation and serious
AEs (SAEs); 
•
Laboratory tests, vital signs, body weight and body mass index (BMI), waist circumference,
physical examination, height (as measured by stadiometer), electrocardiogram (ECG), 
hormonal parameters; 
•
Movement disorders as assessed by Abnormal Involuntary Movement Scale (AIMS), Barnes
Akathisia Rating Scale (BARS), and the Simpson-Angus Scale (SAS); 
•
Tanner staging, and menstrual cyclicity (female subjects).
For subjects continued from Study D1050301 and D1050326: 
•
Columbia Suicide Severity Rating Scale (C-SSRS);
•
CogState Computerized Cognitive Test Battery;
•
Udvalg for Kliniske Undersogelser Side Effect Rating Scale (UKU).
For subjects continued from Study D1050326: 
•
Young Mania Rating Scale (YMRS) score.
Effectiveness Assessments: 
For subjects continued from Study D1050301: 
•
Positive and Negative Syndrome Scale (PANSS);
•
Clinical Global Impression-Severity (CGI-S) scale;
•
Clinician-rated Children’s Global Assessment Scale (CGAS);
•
Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q).
For subjects continued from Study D1050325: 
•
Aberrant Behavior Checklist (ABC);
•
Clinical Global Impression-Severity (CGI-S) scale.
•
Children's Yale-Brown Obsessive Compulsive Scales (CY-BOCS) modified for pervasive
developmental disorders (PDDs);
•
Caregiver Strain Questionnaire (CGSQ).
For subjects continued from Study D1050326: 
•
Children's Depression Rating Scale, Revised (CDRS-R);
•
Clinical Global Impression Bipolar Version -Severity (CGI-BP-S) scale;
•
Clinician-rated Children’s Global Assessment Scale (CGAS);
•
Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q);
•
Pediatric Anxiety Rating Scale (PARS);
•
Attention-Deficit/Hyperactivity Disorder Rating Scale (ADHD-RS).
Statistical Methods: 
The safety population will include all subjects who receive at least one dose of study medication. A 
total of three analysis groups will be formed based on a subject’s previous participation status in 
double-blind studies D1050301, D1050325, or D1050326. Safety and efficacy analyses will be 


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Name of Sponsor/Company: Sunovion Pharmaceuticals Inc. 
Name of Investigational Product: Lurasidone (lurasidone HCl) 
presented by the above analysis groups, respectively. In efficacy and safety analyses, the pre-treatment 
baseline from studies D1050301, D1050325, or D1050326 will be referred to as the double-blind study 
baseline or "DB baseline," and the last assessment prior to the first dose in the open-label study 
D1050302 will be referred to as the open label study baseline or "OL baseline." No statistical 
comparisons will be conducted for treatment groups. 
Safety Analyses: 
For all subjects: 
The incidence of AEs, SAEs, and discontinuations due to AEs. AEs (or SAEs) will be summarized by 
presenting the number and percentage of subjects having each individual AE (or SAE) by analysis 
group. Discontinuations due to AEs and SAEs will be summarized by presenting number and 
percentage of subjects terminated prematurely due to AEs or SAEs by analysis group. 
Descriptive statistics will also be provided for the following safety variables and the corresponding 
changes from baseline: body weight, height, body mass index (BMI), waist circumference, vital signs, 
electrocardiogram (ECG) parameters, movement disorders as assessed by Abnormal Involuntary 
Movement Scale (AIMS), Barnes Akathisia Rating Scale (BARS), and the Simpson-Angus Scale 
(SAS), Tanner staging, and menstrual cyclicity (female subjects), physical examination results, and 
standard laboratory tests covering hematology, chemistry, hormonal parameters, and urinalysis. 
For subjects continued from Study D1050301 and D1050326: 
Descriptive statistics will also be provided for the CogState Computerized Cognitive Test Battery, and 
Udvalg for Kliniske Undersogelser Side Effect Rating Scale (UKU) by visit for each analysis group. 
For C-SSRS data, number and percentage of subjects with suicidal ideations and behaviors will be 
summarized. 
For subjects continued from Study D1050326: 
Descriptive statistics will be presented for YMRS result by analysis group and study visit. 
For above safety analyses, continuous variables will be summarized using descriptive statistics of 
number of subjects, mean, standard deviation, median, minimum and maximum values. Categorical 
variables will be reported as frequencies and percentages. 
Effectiveness Analyses 
This open-label study includes subjects coming from three different studies (D1050301, D1050325, 
and D1050326). Efficacy variables to be summarized for this study will include: 
For subjects continued from Study D1050301: 
Descriptive statistics of observed value and change from DB baseline and OL baseline in PANSS total 
score and positive, negative, general psychopathology, and excitability subscale scores, CGI-S, CGAS, 
and PQ-LES-Q scores will be provided by visit and by analysis group.  
For subjects continued from Study D1050325: 
Descriptive statistics of observed value and change from DB baseline and OL baseline in ABC 
subscale scores (irritability, hyperactivity, stereotypy, inappropriate speech, and lethargy/social 
withdrawal), CGI-S, CY-BOCS, and CGSQ scores will be provided by visit and by analysis group. 
For subjects continued from Study D1050326: 
Descriptive statistics of observed value and change from DB baseline and OL baseline in CDRS-R, 
CGI-BP-S, CGAS, PQ-LES-Q, PARS, and ADHD-RS scores will be provided by visit and by analysis 
group. 
For above effectiveness analyses, descriptive statistics, including number of subjects, mean, standard 


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Name of Sponsor/Company: Sunovion Pharmaceuticals Inc. 
Name of Investigational Product: Lurasidone (lurasidone HCl) 
deviation, median, minimum, maximum, and a 95% confidence interval, will be provided. Since this is 
an uncontrolled open-label extension of studies D1050301, D1050325, or D1050326, no inferential 
statistics on effectiveness will be presented. 
Sample Size:  
Subjects who complete the respective double-blind studies D1050301, D1050325 or D1050326, sign 
the consent, and meet all entry criteria will be included in this study. Studies D1050301, D1050325, 
and D1050326 have finished, with a total of 271 subjects from D1050301, 125 subjects from 
D1050325, and 306 subjects from D1050326 enrolling into D1050302. Based on an estimated attrition 
rate of approximately 30% of subjects over six months, it is expected that at least 100 subjects will be 
exposed to lurasidone for a minimum of 6 months for subjects continued from Studies D1050301 and 
D1050325 in Study D1050302. 
Data Analyses of Interim Data for FDA Filing 
After studies D1050301 and D1050325 are completed, when at least 100 subjects previously from 
these two studies complete the Week 28 visit (ie, exposed to study drug for at least 6 months), data 
analyses based on these interim data will be done to prepare a safety/effectiveness report in support of 
the initial health authority filing for US regulatory submission for the lurasidone pediatric program. A 
subsequent final analysis of study D1050302 will be performed after every subject previously enrolled 
from study D1050301, D1050325, and D1050326 complete the study. 
 


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2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
SYNOPSIS ...................................................................................................................4 
2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES .................9 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................15 
4. 
INTRODUCTION ......................................................................................................18 
4.1. 
Previous Human Experience in Pediatric Subjects .....................................................18 
4.2. 
Study Rationale ...........................................................................................................18 
4.3. 
Dose Justification ........................................................................................................18 
5. 
STUDY OBJECTIVES ..............................................................................................19 
5.1. 
Primary Objective .......................................................................................................19 
5.2. 
Secondary Objectives .................................................................................................19 
6. 
STUDY ENDPOINTS ................................................................................................20 
6.1. 
Safety Assessments .....................................................................................................20 
6.2. 
Effectiveness Assessments .........................................................................................20 
7. 
INVESTIGATIONAL PLAN .....................................................................................22 
7.1. 
Overall Study Design ..................................................................................................22 
7.2. 
Study Termination Criteria .........................................................................................23 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................33 
8.1. 
Subject Inclusion Criteria ...........................................................................................33 
8.2. 
Subject Exclusion Criteria ..........................................................................................34 
9. 
TREATMENT OF SUBJECTS ..................................................................................35 
9.1. 
Concomitant Medications ...........................................................................................35 
9.1.1. 
Concomitant Non-psychotropic Medications .............................................................35 
9.1.2. 
Concomitant Psychotropic Medications .....................................................................35 
9.2. 
Treatment Compliance ................................................................................................36 
9.3. 
Hospitalization ............................................................................................................36 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................38 
10.1. 
Description of Study Drug ..........................................................................................38 
10.2. 
Study Drug Packaging and Labeling ..........................................................................38 
10.2.1. 
Blister Cards ...............................................................................................................38 


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10.3. 
Study Drug Storage .....................................................................................................39 
10.4. 
Study Drug Dispensation and Handling .....................................................................39 
10.5. 
Interactive Voice Response/Web Response System (IXRS) ......................................40 
10.6. 
Administration ............................................................................................................40 
10.7. 
Study Drug Accountability .........................................................................................40 
11. 
TREATMENT PLAN .................................................................................................41 
11.1. 
Study Assessments ......................................................................................................41 
11.1.1. 
Effectiveness ...............................................................................................................41 
11.1.2. 
Safety ..........................................................................................................................43 
11.2. 
Standardization of Data Capture .................................................................................46 
11.3. 
Electronic Data Capture (EDC) ..................................................................................46 
11.4. 
Study Visits and Assessments ....................................................................................46 
11.4.1. 
Visit 1E (Day 1) ..........................................................................................................46 
11.4.2. 
Visit 2E (Week 2) .......................................................................................................47 
11.4.3. 
Visit 3E (Week 4) .......................................................................................................47 
11.4.4. 
Visit 4E (Week 6) .......................................................................................................48 
11.4.5. 
Visit 5E (Week 8) .......................................................................................................49 
11.4.6. 
Visit 6E (Week 12) .....................................................................................................50 
11.4.7. 
Visit 7E (Week 16) .....................................................................................................51 
11.4.8. 
Visit 8E (Week 20) .....................................................................................................52 
11.4.9. 
Visit 9E (Week 24) .....................................................................................................53 
11.4.10. 
Visit 10E (Week 28) ...................................................................................................54 
11.4.11. 
Visit 11E (Week 32) ...................................................................................................55 
11.4.12. 
Visit 12E (Week 36) ...................................................................................................56 
11.4.13. 
Visit 13E (Week 40) ...................................................................................................57 
11.4.14. 
Visit 14E (Week 44) ...................................................................................................58 
11.4.15. 
Visit 15E (Week 48) ...................................................................................................59 
11.4.16. 
Visit 16E (Week 52) ...................................................................................................59 
11.4.17. 
Visit 17E (Week 56) ...................................................................................................61 
11.4.18. 
Visit 18E (Week 60) ...................................................................................................62 
11.4.19. 
Visit 19E (Week 64) ...................................................................................................63 
11.4.20. 
Visit 20E (Week 68) ...................................................................................................64 
11.4.21. 
Visit 21E (Week 72) ...................................................................................................65 


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11.4.22. 
Visit 22E (Week 76) ...................................................................................................65 
11.4.23. 
Visit 23E (Week 80) ...................................................................................................67 
11.4.24. 
Visit 24E (Week 84) ...................................................................................................68 
11.4.25. 
Visit 25E (Week 88) ...................................................................................................68 
11.4.26. 
Visit 26E (Week 92) ...................................................................................................70 
11.4.27. 
Visit 27E (Week 96) ...................................................................................................70 
11.4.28. 
Visit 28E (Week 100) .................................................................................................71 
11.4.29. 
Visit 29E EOS/ET (Week 104) ...................................................................................72 
11.4.30. 
Visit 30E (Week 105) .................................................................................................73 
12. 
DISCONTINUATION AND REPLACEMENT OF SUBJECTS/ 
CLINICAL ASSESSMENTS AFTER STUDY MEDICATION 
DISCONTINUATION ...............................................................................................75 
12.1. 
Study Participation Termination Criteria ....................................................................75 
12.2. 
Follow-up Procedures Upon Discontinuation/Withdrawal ........................................75 
13. 
ADVERSE EXPERIENCE REPORTING .................................................................76 
13.1. 
Adverse Events ...........................................................................................................76 
13.2. 
Objective Findings ......................................................................................................76 
13.3. 
Immediately Reportable Events ..................................................................................77 
13.3.1. 
Bone Fractures ............................................................................................................78 
13.4. 
Preplanned Hospitalizations or Procedures ................................................................78 
13.5. 
Data and Safety Monitoring Board .............................................................................78 
14. 
STATISTICS ..............................................................................................................79 
14.1. 
Randomization and Blinding ......................................................................................79 
14.2. 
Unblinding Procedures ...............................................................................................79 
14.3. 
Hypotheses ..................................................................................................................79 
14.4. 
Variables and Timepoints ...........................................................................................79 
14.4.1. 
Primary Safety Variables ............................................................................................79 
14.4.2. 
Other Safety Variables ................................................................................................79 
14.5. 
Sample Size Considerations .......................................................................................79 
14.6. 
Data Analyses of Interim Data for FDA Filing ..........................................................79 
14.7. 
Data Analyses .............................................................................................................80 
14.7.1. 
Analysis Population ....................................................................................................80 
14.7.2. 
Definitions of Assessments .........................................................................................80 


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14.7.3. 
Analysis Group ...........................................................................................................81 
14.7.4. 
Statistical Methods ......................................................................................................81 
14.7.4.1. 
Efficacy Evaluation ....................................................................................................81 
14.7.4.2. 
Safety Evaluation ........................................................................................................82 
15. 
COMPUTERIZED SYSTEMS USED FOR SOURCE DATA .................................84 
16. 
ETHICAL AND REGULATORY OBLIGATIONS ..................................................86 
16.1. 
Study Conduct ............................................................................................................86 
16.2. 
Institutional Review Board or Independent Ethics Committee ..................................86 
16.3. 
Informed Consent .......................................................................................................87 
16.4. 
Subject Privacy ...........................................................................................................88 
16.5. 
Protocol Amendments and Emergency Deviations ....................................................88 
16.6. 
Monitoring and Auditing of the Study ........................................................................88 
16.7. 
Study Documentation .................................................................................................89 
16.8. 
Laboratory Certification and Normal Values .............................................................89 
16.9. 
Records Retention .......................................................................................................89 
16.10. 
Inspection of Records .................................................................................................90 
16.11. 
Financial Disclosure ...................................................................................................90 
17. 
STUDY ACKNOWLEDGMENT ..............................................................................91 
18. 
REFERENCES ...........................................................................................................92 
APPENDIX A. CLINICAL LABORATORY TESTS ...............................................................93 
APPENDIX B. POTENT INHIBITORS AND INDUCERS OF THE 
CYP3A4 ENZYME SYSTEM ...................................................................................95 
APPENDIX C. DEFINITIONS FOR REPORTING ADVERSE EVENTS ..............................96 
 


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LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................3 
Table 2: 
Abbreviations and Specialist Terms ...........................................................................15 
Table 3: 
Schedule of Assessments Enrollment to Week 40 .....................................................24 
Table 4: 
Schedule of Assessments - Week 44 to 92 .................................................................27 
Table 5: 
Schedule of Assessments - Week 96 to 105 ...............................................................30 
Table 6: 
Investigational Product ...............................................................................................38 
Table 7: 
Blister Card and Carton Label Example .....................................................................39 
Table 8: 
Computerized Systems Used for Source Data ............................................................84 
Table 9: 
Total Blood Drawn For Laboratory Tests ..................................................................94 
 


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LIST OF FIGURES 
Figure 1: 
Study Schematic .........................................................................................................23 
 
  


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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Table 2: 
Abbreviations and Specialist Terms  
For the purposes of standardization, the following definitions will be used:  
Abbreviation  
Term 
5-HT 
5-hydroxytryptamine 
ABC 
Aberrant Behavior Checklist 
ADHD-RS 
Attention-Deficit/ Hyperactivity Disorder Rating Scale 
AE 
adverse event 
AIMS 
Abnormal Involuntary Movement Scale 
ATC 
Anatomic Therapeutic Chemical 
BARS 
Barnes Akathisia Rating Scale  
β-hCG 
beta-subunit of human chorionic gonadotropin 
BMI 
Body Mass Index 
CDRS-R 
Children's Depression Rating Scale, Revised 
CFR 
Code of Federal Regulations 
CGAS 
Clinician-rated Children’s Global Assessment Scale 
CGI-BP-S 
Clinical Global Impression Bipolar Version – Severity 
CGI-S 
Clinical Global Impression-Severity Scale 
CGSQ 
Caregiver Strain Questionnaire 
CNS 
central nervous system 
CRA 
clinical research associate 
CRO 
contract research organization 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CY-BOCS 
Children's Yale-Brown Obsessive Compulsive Scales 
CYP 
cytochrome P 
DSMB 
Data and Safety Monitoring Board 
DSM-IV-TR 
Diagnostic and Statistical Manual of Mental Disorders, 4th 
Edition, Text Revision 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
Electronic data capture 
EPS 
extrapyramidal symptoms  


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Abbreviation  
Term 
FSH 
Follicle stimulating hormone 
GCP 
Good Clinical Practice 
HbA1c 
Hemoglobin A1c 
HIV 
human immunodeficiency virus 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IXRS 
Interactive Voice/Web Response System 
MAO 
monoamine oxidase 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
PANSS 
Positive and Negative Syndrome Scale 
PARS 
Pediatric Anxiety Rating Scale 
PDD 
Pervasive developmental disorders 
PQ-LES-Q 
Pediatric Quality of Life Enjoyment and Satisfaction 
Questionnaire 
QD 
once-daily 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
Simpson-Angus Scale 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
treatment-emergent adverse event 
UKU 
Udvalg for Kliniske Undersogelser Side Effect Rating Scale 
WHO 
World Health Organization  
YMRS 
Young Mania Rating Scale 
• CRF: A printed, optical, or electronic document designed to record all of the protocol 
required information to report to the sponsor for each study subject. 
• Screened Subject: Any subject who signed the study specific informed consent. 
• Screen Failures: Any subject who signed the study specific informed consent but 
either failed to meet study requirements during screening or met study requirements 
at screening but was not enrolled. 


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• Study Drug (or study medication): Term to cover investigational drug.  
• Treatment Phase: The period of the study in which the study drug is administered. 
• Enrolled Subject: Any subject who was successfully screened and enter the treatment 
phase of the study. 
• Completed Subject: Any subject who participated throughout the duration of the 
study, up to and including the end of study visit. 
• Early Termination Subject: Any subject who was successfully screened and enrolled 
into the treatment phase of the study, but did not complete the study. 


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4. 
INTRODUCTION 
4.1. 
Previous Human Experience in Pediatric Subjects 
There has been 1 completed pediatric clinical study evaluating the safety, tolerability, and 
pharmacokinetics of single and multiple doses of lurasidone in adolescents (12-17 years of age) 
and children (6-11 years of age) with schizophrenia spectrum, bipolar spectrum, autistic 
spectrum disorder, or other psychiatric disorders (Study D1050300). 
Preliminary results from this study revealed that exposure in the pediatric population (6-17 years 
of age) are similar to observed exposure in adults across the dose range (20-160 mg). The most 
frequently observed AEs (≥10%) across the dose range in this population were somnolence 
(42%), sedation (18%), nausea (17%), and vomiting (15%). 
4.2. 
Study Rationale 
Lurasidone is a novel compound being developed by Sunovion Pharmaceuticals Inc, and is an 
approved agent for the treatment of adult patients with schizophrenia. Lurasidone has a unique 
chemical structure that differs from conventional and atypical antipsychotic agents. Lurasidone is 
a novel compound with high affinities for dopamine D2, serotonin 5-HT2A and 5-HT7 receptors, 
moderate affinity for serotonin 5-HT1A and noradrenaline α2C and α2A receptors, and little or no 
affinity for histamine H1 and muscarinic M1 receptors which are thought to be responsible for 
some important side effects (weight gain, sedation) and worsening of the cognitive function. 
Clinical studies in adults with schizophrenia treated with lurasidone have shown significant 
beneficial effects on the amelioration of positive and negative symptoms with a minimal effect 
on weight gain, glucose metabolism, and lipid parameters. 
Based on its pharmacologic profile as well as clinical studies in adult subjects with schizophrenia 
and bipolar depression, lurasidone is expected to be associated with few extrapyramidal 
symptoms (EPS) and to be effective in ameliorating a broad range of symptoms in adolescents 
with schizophrenia, autistic disorder, and bipolar depression. 
This open-label extension study is designed to evaluate the longer-term safety, tolerability, and 
effectiveness of lurasidone over 104 weeks for the treatment of pediatric patients that have 
completed a previous lurasidone study. The 104-week study duration will provide an adequate 
timeframe within which to evaluate the longer-term effects of lurasidone in this patient 
population. 
4.3. 
Dose Justification 
Based on the therapeutic dose ranges evaluated in prior lurasidone clinical studies, doses of 
20, 40, 60 or 80 mg/day will be used in this study. Lurasidone will be taken with food for 
optimal exposure to the administered dose. The dose of lurasidone may be adjusted to optimize 
efficacy and tolerability, as deemed clinically appropriate. 


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5. 
STUDY OBJECTIVES  
5.1. 
Primary Objective 
To evaluate the long-term safety, tolerability, and effectiveness of lurasidone (20, 40, 60 or 
80 mg/day, flexibly dosed) in pediatric subjects who have completed a prior lurasidone study. 
5.2. 
Secondary Objectives 
For all subjects: 
• Proportions of subjects with adverse events (AEs), discontinuations due to AEs, and 
serious AEs (SAEs).  
For subjects continued from Study D1050301, the following will be assessed: 
• Change in Positive and Negative Syndrome Scale (PANSS) total, positive, negative, 
general psychopathology, and excitability subscale scores;  
• Change in the Clinical Global Impression – Severity (CGI-S); 
• Change in the Clinician-rated Children’s Global Assessment Scale (CGAS);  
• Change in the Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire 
(PQ-LES-Q). 
For subjects continued from Study D1050325, the following will be assessed: 
• Change in Aberrant Behavior Checklist (ABC) irritability subscale, and the following 
subscale scores (hyperactivity, stereotypy, inappropriate speech, and lethargy/social 
withdrawal); 
• Change in the Clinical Global Impression – Severity (CGI-S);  
• Change in Children's Yale-Brown Obsessive Compulsive Scales (CY-BOCS) 
modified for pervasive developmental disorders (PDDs); 
• Change in the Caregiver Strain Questionnaire (CGSQ). 
For subjects continued from Study D1050326, the following will be assessed: 
• Change in the Children's Depression Rating Scale, Revised (CDRS-R); 
• Change in the Clinical Global Impression Bipolar Version – Severity (CGI-BP-S); 
• Change in the Clinician-rated Children’s Global Assessment Scale (CGAS);  
• Change in the Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire 
(PQ-LES-Q); 
• Change in anxiety symptoms as measured by the Pediatric Anxiety Rating Scale 
(PARS); 
• Change in attention-deficit/hyperactivity symptoms as measured by the Attention-
Deficit/ Hyperactivity Disorder Rating Scale (ADHD-RS) total score. 


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6. 
STUDY ENDPOINTS 
6.1. 
Safety Assessments 
All Subjects: 
• Treatment-emergent adverse events (TEAEs), TEAEs leading to discontinuation and 
serious AEs (SAEs); 
• Laboratory tests, vital signs, body weight and body mass index (BMI), waist 
circumference, physical examination, height (as measured by stadiometer), 
electrocardiogram (ECG), hormonal parameters; 
• Movement disorders as assessed by Abnormal Involuntary Movement Scale (AIMS), 
Barnes Akathisia Rating Scale (BARS), and the Simpson-Angus Scale (SAS); 
• Tanner staging, and menstrual cyclicity (female subjects). 
For subjects continued from Study D1050301 and D1050326: 
• Columbia Suicide Severity Rating Scale (C-SSRS); 
• Composite Score of the CogState Computerized Cognitive Test Battery; 
• Udvalg for Kliniske Undersogelser Side Effect Rating Scale (UKU). 
For subjects continued from Study D1050326: 
• Young Mania Rating Scale (YMRS) score. 
6.2. 
Effectiveness Assessments 
For subjects continued from Study D1050301: 
• Positive and Negative Syndrome Scale (PANSS); 
• Clinical Global Impression-Severity (CGI-S) scale; 
• Clinician-rated Children’s Global Assessment Scale (CGAS); 
• Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q). 
For subjects continued from Study D1050325: 
• Aberrant Behavior Checklist (ABC); 
• Clinical Global Impression-Severity (CGI-S) scale; 
• Children's Yale-Brown Obsessive Compulsive Scales (CY-BOCS) modified for 
pervasive developmental disorders (PDDs); 
• Caregiver Strain Questionnaire (CGSQ). 
For subjects continued from Study D1050326: 
• Children's Depression Rating Scale, Revised (CDRS-R); 
• Clinical Global Impression Bipolar Version -Severity (CGI-BP-S) scale; 


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• Clinician-rated Children’s Global Assessment Scale (CGAS); 
• Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q); 
• Pediatric Anxiety Rating Scale (PARS); 
• Attention-Deficit/Hyperactivity Disorder Rating Scale (ADHD-RS). 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is an open-label, 104-week, multicenter, extension study designed to evaluate the long-term 
safety, tolerability and effectiveness of flexibly dosed lurasidone (20, 40, 60 or 80 mg/day) in 
pediatric subjects who have completed a 6-week treatment period in one of the preceding studies, 
D1050301, D1050325, or D1050326.   
Subjects who complete participation in one of the preceding studies, D1050301, D1050325 or 
D1050326, will be eligible for enrollment in this study. Informed consent/assent will be obtained 
from all subjects (where developmentally appropriate) before any study procedures are 
performed. Subjects who meet entry criteria will transition to this study directly from Study 
D1050301, D1050325 or D1050326. All subjects will be treated with flexibly dosed lurasidone 
during the trial. 
A reliable informant (eg, parent, legal guardian, or caregiver) of the subject must accompany the 
subject at each visit. For subjects entering from Study D1050325, the reliable caregiver will also 
oversee the administration of the study drug throughout the study. 
All eligible subjects will be treated with lurasidone 40 mg/day for Days 1-7. Beginning with 
Day 8, dose adjustments (20, 40, 60 or 80 mg/day) will be permitted, based on investigator 
judgment, to optimize tolerability and effectiveness.  
Dose adjustment of study drug should occur at the regularly scheduled visits and in increments 
or decrements of 1 dose level. However, dose reductions for tolerability or safety purposes may 
occur beginning on Day 2, based on investigator judgment. These dose reductions may be 
between study visits and at more than 1 dose level at a time (maximum of 2 dose levels at a 
time). If dose reductions are required between regular study visits, the subject must return to the 
study site for an unscheduled visit to receive new medication kits and return all used/unused 
medication kits at the time of dose adjustment.  
Safety and effectiveness assessments will be conducted at scheduled visits during the study. 
A follow-up visit will occur 1 week post last dose of study drug. 
A DSMB will review safety and clinical outcome data including data on AEs and SAEs at 
regular intervals until the D1050301, D1050325, and D1050326 studies are complete and as long 
as necessary for the D1050302 study, as determined by the Sponsor. The DSMB will be 
independent of the Sponsor, contract research organization (CRO), and the investigators and will 
be empowered to recommend stopping the study due to safety concerns, but not for efficacy or 
futility. The membership of the DSMB and its mandate is denoted in the DSMB charter. 
A study schematic is presented below in Figure 1. Details of study assessments and other 
procedures to be performed at each visit are presented in Table 3, Schedule of Assessments, and 
Section 11, Treatment Plan. 


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Figure 1: 
Study Schematic 
D1050301 Adolescent 
Schizophrenia Study
D1050325 Children and 
Adolescent Autistic 
Disorder Study
Lurasidone flexibly dosed
20, 40, 60, or 80 mg/day
Enrollment into the 
D1050302 
Extension Study
Follow-up
24 Months
1 Week post last dose
D1050326 Children and 
Adolescent Bipolar 
Depression Study
 
 
7.2. 
Study Termination Criteria 
The study may be terminated at any time by the sponsor for any reason. 
 


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Table 3: 
Schedule of Assessments Enrollment to Week 40 
Study Visit Number 
Study Visit Week (±3 days) 
V 1E 
V 2E 
V 3E 
V 4E 
V 5E 
V 6E 
V 7E 
V 8E 
V 9E 
V 10E 
V 11E 
V 12E 
V 13E 
Day 1 
W2 
W4 
W6 
W8 
W12 
W16 
W20 
W24 
W28 
W32 
W36 
W40 
Obtain informed consent/assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Interactive Voice/Web Response System 
(IXRS) subject registry/visit 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense study medication  
X 
Xa 
X 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug accountability/assess compliance 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical and Laboratory Evaluations: ALL 
SUBJECTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant medication review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse event (AE) monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
These 
clinical 
evaluations 
were to 
have been 
performed 
at Study 
Visit 
Number 9 
in study 
D1050301 
or 
D1050325 
or at Study 
Visit 
Number 8 
in study 
D1050326 
and will 
serve as the 
baseline 
evaluations 
for this 
study. 
 
 
 
 
 
 
 
 
X 
 
 
X 
Height as measured by stadiometer 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
Tanner staging 
 
 
 
 
 
 
 
 
X 
 
 
X 
Menstrual cyclicity (female subjects) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signsb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight  
 
 
X 
 
X 
 
 
 
X 
 
 
X 
Waist circumference measurement 
 
 
 
 
X 
 
 
 
X 
 
 
X 
Electrocardiogram (ECG) 
 
 
 
 
 
 
 
 
X 
 
 
 
Hematology, chemistry, and urinalysis 
 
 
 
 
X 
 
 
 
X 
 
 
 
Hormonal Parametersc 
 
 
 
 
X 
 
 
 
X 
 
 
 
Serum prolactin 
 
 
 
 
X 
 
 
 
X 
 
 
 
Glycosylated hemoglobin (HbA1c) 
 
 
 
 
X 
 
 
 
X 
 
 
 
Glucose and lipid paneld 
 
 
 
 
X 
 
 
 
X 
 
 
 
Serum insulin and C-reactive protein 
 
 
 
 
X 
 
 
 
X 
 
 
 


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Study Visit Number 
Study Visit Week (±3 days) 
V 1E 
V 2E 
V 3E 
V 4E 
V 5E 
V 6E 
V 7E 
V 8E 
V 9E 
V 10E 
V 11E 
V 12E 
V 13E 
Day 1 
W2 
W4 
W6 
W8 
W12 
W16 
W20 
W24 
W28 
W32 
W36 
W40 
Urine drug screen 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine β-hCGe, f 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Simpson-Angus Scale (SAS) 
These 
clinical 
evaluations 
were to 
have been 
performed 
at Study 
Visit 
Number 9 
in study 
D1050301 
or 
D1050325 
or at Study 
Visit 
Number 8 
in study 
D1050326 
and will 
serve as the 
baseline 
evaluations 
for this 
study. 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Barnes Akathisia Rating Scale (BARS) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abnormal Involuntary Movement Scale 
(AIMS) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Evaluations:  
SUBJECTS from D1050301 ONLY 
 
 
 
 
 
 
 
 
 
 
 
 
Children’s Global Assessment Scale (CGAS) 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
Clinical Global Impression – Severity (CGI-S) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pediatric Quality of Life Enjoyment and 
Satisfaction Questionnaire (PQ-LES-Q) 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
Udvalg for Kliniske Undersogelser Side Effect 
Rating Scale (UKU) 
X 
 
X 
 
X 
 
 
 
X 
 
 
X 
Columbia Suicide Severity Rating Scale  
(C-SSRS) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Positive and Negative Syndrome Scale 
(PANSS) 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
CogState Computerized Cognitive Test Battery 
 
 
 
 
X 
 
 
 
X 
 
 
 
Clinical Evaluations:  
SUBJECTS from D1050325 ONLY 
 
 
 
 
 
 
 
 
 
 
 
 
Aberrant Behavior Checklist (ABC) 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
Clinical Global Impression – Severity (CGI-S) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Children's Yale-Brown Obsessive Compulsive 
Scales (CY-BOCS) modified for pervasive 
developmental disorders (PDDs) 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
Caregiver Strain Questionnaire (CGSQ) 
 
 
X 
 
X 
 
 
 
X 
 
 
X 


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Study Visit Number 
Study Visit Week (±3 days) 
V 1E 
V 2E 
V 3E 
V 4E 
V 5E 
V 6E 
V 7E 
V 8E 
V 9E 
V 10E 
V 11E 
V 12E 
V 13E 
Day 1 
W2 
W4 
W6 
W8 
W12 
W16 
W20 
W24 
W28 
W32 
W36 
W40 
Clinical Evaluations:  
SUBJECTS from D1050326 ONLY 
These 
clinical 
evaluations 
were to 
have been 
performed 
at Study 
Visit 
Number 9 
in study 
D1050301 
or 
D1050325 
or at Study 
Visit 
Number 8 
in study 
D1050326 
and will 
serve as the 
baseline 
evaluations 
for this 
study. 
 
 
 
 
 
 
 
 
 
 
 
 
Children’s Depression Rating Scale, Revised 
(CDRS-R) 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
Clinical Global Impression-Bipolar Version, 
Severity of Illness (CGI BP-S) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Children’s Global Assessment Scale (CGAS) 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
Young Mania Rating Scale (YMRS) 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
Pediatric Quality of Life Enjoyment and 
Satisfaction Questionnaire (PQ-LES-Q) 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
Columbia Suicide Severity Rating Scale  
(C-SSRS) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Udvalg for Kliniske Undersogelser Side Effect 
Rating Scale (UKU) 
X 
 
X 
 
X 
 
 
 
X 
 
 
X 
Pediatric Anxiety Rating Scale (PARS) 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
Attention-Deficit/Hyperactivity Disorder Rating 
Scale (ADHD-RS) 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
CogState Computerized Cognitive Test Battery 
 
 
 
 
X 
 
 
 
X 
 
 
 
Abbreviations: V = Visit; Wk = Week 
a Study drug will be dispensed only if a dose change is required. 
b Vital sign measurements to include orthostatic changes in blood pressure and heart rate. 
c Hormonal Parameters include the following measures: follicle stimulating hormone; luteinizing hormone; testosterone (male subjects only); estradiol (female subjects only). 
d Subjects will fast for laboratory tests.  
e Any positive urine β-hCG test will be confirmed by serum β-hCG. 
f Females subjects ≥ 11 years of age only. 
If a subject discontinues from the study, all Visit 29E procedures will be performed at the discontinuation visit, within 48 hours of the last dose of study medication.  


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Table 4: 
Schedule of Assessments - Week 44 to 92 
Study Visit Number 
Study Visit Week (±3 days) 
V 14E 
V 15E 
V 16E 
V 17E 
V 18E 
V 19E 
V 20E 
V 21E 
V 22E 
V 23E 
V 24E 
V 25E 
V 26E 
W44  
W48  
W52  
W56 
W60  
W64  
W68 
W72 
W76 
W80 
W84 
W88 
W92 
Interactive Voice/Web Response System (IXRS) 
subject registry/visit 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense study medication  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug accountability/assess compliance 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical and Laboratory Evaluations: ALL 
SUBJECTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant medication review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse event monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Height as measured by stadiometer 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Tanner staging 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Menstrual cyclicity (female subjects) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signsa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight  
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Waist circumference measurement 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Electrocardiogram (ECG) 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Hematology, chemistry, and urinalysis 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Hormonal Parametersb 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Serum prolactin 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Glycosylated hemoglobin (HbA1c) 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Glucose and lipid panelc 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Serum insulin and C-reactive protein 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Urine drug screen 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine β-hCGd, e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Study Visit Number 
Study Visit Week (±3 days) 
V 14E 
V 15E 
V 16E 
V 17E 
V 18E 
V 19E 
V 20E 
V 21E 
V 22E 
V 23E 
V 24E 
V 25E 
V 26E 
W44  
W48  
W52  
W56 
W60  
W64  
W68 
W72 
W76 
W80 
W84 
W88 
W92 
Simpson-Angus Scale (SAS) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Barnes Akathisia Rating Scale (BARS) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abnormal Involuntary Movement Scale (AIMS) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Evaluations:  
SUBJECTS from D1050301 ONLY 
 
 
 
 
 
 
 
 
 
 
 
 
 
Children’s Global Assessment Scale (CGAS) 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Clinical Global Impression – Severity Scale 
(CGI-S) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pediatric Quality of Life Enjoyment and 
Satisfaction Questionnaire (PQ-LES-Q) 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Udvalg for Kliniske Undersogelser Side Effect 
Rating Scale (UKU) 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Columbia Suicide Severity Rating Scale  
(C-SSRS) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Positive and Negative Syndrome Scale (PANSS) 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
CogState Computerized Cognitive Test Battery 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Clinical Evaluations:  
SUBJECTS from D1050325 ONLY 
 
 
 
 
 
 
 
 
 
 
 
 
 
Aberrant Behavior Checklist (ABC) 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Clinical Global Impression – Severity Scale 
(CGI-S) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Children's Yale-Brown Obsessive Compulsive 
Scales (CY-BOCS) modified for pervasive 
developmental disorders (PDDs) 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Caregiver Strain Questionnaire (CGSQ) 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Clinical Evaluations:  
SUBJECTS from D1050326 ONLY 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Study Visit Number 
Study Visit Week (±3 days) 
V 14E 
V 15E 
V 16E 
V 17E 
V 18E 
V 19E 
V 20E 
V 21E 
V 22E 
V 23E 
V 24E 
V 25E 
V 26E 
W44  
W48  
W52  
W56 
W60  
W64  
W68 
W72 
W76 
W80 
W84 
W88 
W92 
Children’s Depression Rating Scale, Revised 
(CDRS-R) 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Clinical Global Impression-Bipolar Version, 
Severity of Illness (CGI BP-S) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Children’s Global Assessment Scale (CGAS) 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Young Mania Rating Scale (YMRS) 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Pediatric Quality of Life Enjoyment and 
Satisfaction Questionnaire (PQ-LES-Q) 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Columbia Suicide Severity Rating Scale  
(C-SSRS) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Udvalg for Kliniske Undersogelser Side Effect 
Rating Scale (UKU) 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Pediatric Anxiety Rating Scale (PARS) 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Attention-Deficit/Hyperactivity Disorder Rating 
Scale (ADHD-RS) 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
CogState Computerized Cognitive Test Battery 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Abbreviations: V = Visit; Wk = Week 
a Vital sign measurements to include orthostatic changes in blood pressure and heart rate. 
b Hormonal Parameters include the following measures: follicle stimulating hormone; luteinizing hormone; testosterone (male subjects only); estradiol (female subjects only). 
c Subjects will fast for laboratory tests.  
d Any positive urine β-hCG test will be confirmed by serum β-hCG. 
e Females subjects ≥ 11 years of age only. 
If a subject discontinues from the study, all Visit 29E procedures will be performed at the discontinuation visit, within 48 hours of the last dose of study medication.  


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Table 5: 
Schedule of Assessments - Week 96 to 105 
Study Visit Number 
Study Visit Week (±3 days) 
V 27E 
V 28E 
EOS/ET 
V 29E a 
F/U 
V 30E 
Wk96  
Wk100  
Wk104  
Wk105 
Interactive Voice/Web Response System (IXRS) subject 
registry/visit 
X 
X 
X 
X 
Dispense study medication  
X 
X 
 
 
Study drug accountability/assess compliance 
X 
X 
X 
 
Clinical and Laboratory Evaluations: ALL SUBJECTS 
 
 
 
 
Prior/concomitant medication review 
X 
X 
X 
X 
Adverse event monitoring 
X 
X 
X 
X 
Physical examination 
 
 
X 
 
Height as measured by stadiometer 
 
 
X 
 
Tanner staging 
 
 
X 
 
Menstrual cyclicity (female subjects) 
X 
X 
X 
X 
Vital signsb 
X 
X 
X 
X 
Weight  
 
 
X 
 
Waist circumference measurement 
 
 
X 
 
Electrocardiogram (ECG) 
 
 
X 
 
Hematology, chemistry, and urinalysis 
 
 
X 
 
Hormonal Parametersc 
 
 
X 
 
Serum prolactin 
 
 
X 
 
Glycosylated hemoglobin (HbA1c) 
 
 
X 
 
Glucose and lipid paneld 
 
 
X 
 
Serum insulin and C-reactive protein 
 
 
X 
 
Urine drug screen 
X 
X 
X 
 
Urine β-hCGe, f 
X 
X 
X 
X 


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Study Visit Number 
Study Visit Week (±3 days) 
V 27E 
V 28E 
EOS/ET 
V 29E a 
F/U 
V 30E 
Wk96  
Wk100  
Wk104  
Wk105 
Simpson-Angus Scale (SAS) 
X 
X 
X 
X 
Barnes Akathisia Rating Scale (BARS) 
X 
X 
X 
X 
Abnormal Involuntary Movement Scale (AIMS) 
X 
X 
X 
X 
Clinical Evaluations:  
SUBJECTS from D1050301 ONLY 
 
 
 
 
Children’s Global Assessment Scale (CGAS) 
 
 
X 
 
Clinical Global Impression – Severity Scale (CGI-S) 
X 
X 
X 
 
Pediatric Quality of Life Enjoyment and Satisfaction 
Questionnaire (PQ-LES-Q) 
 
 
X 
 
Udvalg for Kliniske Undersogelser Side Effect Rating 
Scale (UKU) 
 
 
X 
 
Columbia Suicide Severity Rating Scale  
(C-SSRS) 
X 
X 
X 
X 
Positive and Negative Syndrome Scale (PANSS) 
 
 
X 
 
CogState Computerized Cognitive Test Battery 
 
 
X 
 
Clinical Evaluations:  
SUBJECTS from D1050325 ONLY 
 
 
 
 
Aberrant Behavior Checklist (ABC) 
 
 
X 
 
Clinical Global Impression – Severity Scale (CGI-S) 
X 
X 
X 
 
Children's Yale-Brown Obsessive Compulsive Scales (CY-
BOCS) modified for pervasive developmental disorders 
(PDDs) 
 
 
X 
 
Caregiver Strain Questionnaire (CGSQ) 
 
 
X 
 
Clinical Evaluations:  
SUBJECTS from D1050326 ONLY 
 
 
 
 
Children’s Depression Rating Scale, Revised (CDRS-R) 
 
 
X 
 
Clinical Global Impression-Bipolar Version, Severity of 
X 
X 
X 
 


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Study Visit Number 
Study Visit Week (±3 days) 
V 27E 
V 28E 
EOS/ET 
V 29E a 
F/U 
V 30E 
Wk96  
Wk100  
Wk104  
Wk105 
Illness (CGI BP-S) 
Children’s Global Assessment Scale (CGAS) 
 
 
X 
 
Young Mania Rating Scale (YMRS) 
 
 
X 
 
Pediatric Quality of Life Enjoyment and Satisfaction 
Questionnaire (PQ-LES-Q) 
 
 
X 
 
Columbia Suicide Severity Rating Scale  
(C-SSRS) 
X 
X 
X 
X 
Udvalg for Kliniske Undersogelser Side Effect Rating 
Scale (UKU) 
 
 
X 
 
Pediatric Anxiety Rating Scale (PARS) 
 
 
X 
 
Attention-Deficit/Hyperactivity Disorder Rating Scale 
(ADHD-RS) 
 
 
X 
 
CogState Computerized Cognitive Test Battery 
 
 
X 
 
Abbreviations: V = Visit; Wk = Week; F/U = follow-up 
a If a subject discontinues from the study, all Visit 29E procedures will be performed at the discontinuation visit, within 48 hours of the last dose of study medication.  
b Vital sign measurements to include orthostatic changes in blood pressure and heart rate. 
c Hormonal Parameters include the following measures: follicle stimulating hormone; luteinizing hormone; testosterone (male subjects only); estradiol (female subjects only). 
d Subjects will fast for laboratory tests.  
e Any positive urine β-hCG test will be confirmed by serum β-hCG. 
f Females subjects ≥ 11 years of age only. 


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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
The following inclusion/exclusion criteria must be met prior to enrolling the subject into the 
study. 
8.1. 
Subject Inclusion Criteria 
1. Written informed consent from parent(s) or legal guardian(s) with sufficient intellectual 
capacity to understand the study and support subjects’ participation in the study 
procedures must be obtained for subjects who are not emancipated. In accordance with 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) requirements, 
the subject will complete an informed assent when developmentally appropriate, to 
participate in the study before conduct of any study-specific procedures. 
2. Subject has completed Study D1050301 (Visit 9); 
OR 
Subject has completed Study D1050325 (Visit 9); 
OR 
Subject has completed Study D1050326 (Visit 8). 
 
3. Subject is judged by the investigator to be appropriate for participation in a 104-week 
clinical trial in an outpatient setting involving open-label lurasidone treatment, and is able 
to comply with the protocol. 
4. A reliable informant (eg, parent, legal guardian, or caregiver) must be available to 
accompany the subject at each visit. For subjects entering from Study D1050325, the 
reliable caregiver must also oversee the administration of the study drug throughout the 
study. 
5. Females who participate in this study: 
• are unable to become pregnant (eg, premenarchal, surgically sterile, etc.) 
-OR- 
• practices true abstinence (consistent with lifestyle) and must agree to remain abstinent 
from signing informed consent to at least 7 days after the last dose of study drug has 
been taken; 
-OR- 
• are sexually active and willing to use a medically effective method of birth control 
(eg, male using condom and female using condom, diaphragm, contraceptive sponge, 
spermicide, contraceptive pill, or intrauterine device) from signing informed consent 
to at least 7 days after the last dose of study drug has been taken. 
6. Males must be willing to remain sexually abstinent (consistent with lifestyle) or use an 
effective method of birth control (eg, male using condom and female using condom, 
diaphragm, contraceptive sponge, spermicide, contraceptive pill, or intrauterine device) 


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from signing informed consent to at least 7 days after the last dose of study drug has been 
taken.  
8.2. 
Subject Exclusion Criteria 
1. Subject is considered by the investigator to be at imminent risk of suicide. 
2. Exhibits evidence of moderate or severe extrapyramidal symptoms, dystonia, tardive 
dyskinesia, or any other moderate or severe movement disorder. Severity to be 
determined by the investigator. 


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9. 
TREATMENT OF SUBJECTS 
9.1. 
Concomitant Medications 
Any medication or non-pharmacological therapy that is taken by or administered to the subject at 
any point during the course of this study must be recorded in the electronic case report form 
(eCRF). The entry must include the dose, regimen, route, indication, and dates of use. 
Potent inducers or inhibitors of the CYP3A4 enzyme system (Appendix B) and any medications 
that consistently prolong the QTc interval are prohibited. In addition, the use of herbal 
supplements (for psychotropic reasons, eg, Gingko Biloba, Kava Kava, St. John’s Wort, etc.) or 
other complementary or alternative medications except melatonin during the study are not 
permitted. 
Initiation of new non-pharmacologic therapy (eg, a new course of psychotherapy or behavior 
modification) is permitted during the study. Subjects who have participated in ongoing 
psychotherapy or other non-pharmacological treatment during Study D1050301, D1050325, or 
D1050326 will be permitted to continue this treatment during the study. 
9.1.1. 
Concomitant Non-psychotropic Medications 
Non-psychotropic medications may be used to treat mild, chronic medical conditions if the dose 
and regimen have been stable (± 25%) during Study D1050301, D1050325, or D1050326. 
β-adrenergic antagonists used to treat stable hypertension can be continued throughout the study. 
In addition, use of non-prescription pain medications (eg, acetaminophen or ibuprofen) are 
allowed provided these medications do not have a propensity for psychotropic effects and do not 
interfere with the evaluation of study drug. Medications for short-term treatment of a medical 
condition (no more than 14 days) are allowed provided that the medications are not CYP3A4 
inhibitors/inducers and do not consistently prolong the QTc interval. 
9.1.2. 
Concomitant Psychotropic Medications  
Subjects may be treated with any approved benzodiazepines or antidepressants provided that the 
medications are not potent CYP3A4 inhibitors/inducers (Appendix B), during the course of the 
study, at the discretion of the investigator in a manner consistent with labeling recommendations 
and conventional medical practice. Monoamine oxidase inhibitors (MAOI) and additional 
antipsychotic medications (with the exception of lurasidone) will be prohibited.  
Treatment with stimulants (provided that the medications are not potent CYP3A4 
inhibitors/inducers), guanfacine or atomoxetine will be permitted during the course of the study 
for treatment of attentional deficits, at the discretion of the investigator in a manner consistent 
with labeling recommendations and conventional medical practice. 
Treatment with benztropine (≤ 6 mg/day) will be permitted as needed for movement disorders. In 
cases where benztropine is not available, or a subject has had an inadequate response or 
intolerability to benztropine treatment, the following medications may be used to treat acute 
EPS: biperiden (≤ 16 mg/day) or trihexyphenidyl (≤ 15 mg/day) or diphenhydramine 
(≤ 100 mg/day for subjects entering from Study D1050301 or Study D1050326; ≤ 50 mg/day for 
subjects entering from Study D1050325). Treatment with propranolol (≤ 120 mg/day) will be 


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permitted as needed for akathisia. Medications used to treat movement disorders should not be 
given prophylactically. 
Concomitant use of lorazepam, or equivalent benzodiazepine, is permitted at the discretion of the 
investigator (≤ 6 mg/day or equivalent dose) for intolerable anxiety/agitation, as clinically 
indicated. In regions where lorazepam or other specified medications are not available, another 
similar agent at equivalent doses will be permitted as specified by the Medical Monitor and/or 
the Operations Manual. Benzodiazepines administered orally or as a rapid acting IM injection 
should be used sparingly, and only when clinically required per investigator judgment. The date 
and time of last dose of lorazepam (or equivalent benzodiazepine) must be recorded at each visit. 
Subjects should be encouraged to avoid taking these medications within 8 hours prior to 
scheduled study assessments. 
Temazepam (≤ 30 mg/day), eszopiclone (≤ 3 mg/day), zaleplon (≤ 20mg/day), zolpidem 
(≤ 10 mg/day for males; ≤ 5 mg/day for females), zolpidem CR (≤ 12.5 mg/day for males; 
≤ 6.25 mg/day for females), diphenhydramine (≤ 100 mg/day for subjects entering from Study 
D1050301 or D1050326; ≤ 50 mg/day for subjects entering from Study D1050325), melatonin 
(≤ 5 mg/day), or clonidine immediate release (≤ 0.1 mg/day) may be administered at bedtime for 
insomnia, as needed. For those subjects taking melatonin, over the counter melatonin should be 
used; combination melatonin products are not allowed. Sedative-hypnotic agents should be 
administered no more than once nightly and should not be used in combination. 
Since the list of prohibited potent CYP3A4 inhibitors and inducers (Appendix B) is not 
comprehensive, investigators should use medical judgment when a subject presents with a 
medication not on the list or consult with the Medical Monitor for clarification. 
9.2. 
Treatment Compliance 
All subjects and caregivers will be reminded at each study visit of the importance of strict 
compliance with taking study medication as directed, with food. Compliance with study 
medication must be monitored closely at each visit. Subjects will be instructed to bring all 
unused study medication with them to each visit. Subjects missing more than 25% or taking 
more than 125% of scheduled doses between visits must be immediately reported to and 
discussed with the Medical Monitor. 
9.3. 
Hospitalization 
Subjects who were hospitalized at the conclusion of the previous core study (either D1050301 or 
D1050326) can continue to be hospitalized for up to 14 days in this study at the discretion of the 
investigator. The investigator must evaluate the subject to determine the length of hospitalization 
based on his/her clinical judgment. After these initial 14 days, subjects must be transitioned to an 
outpatient setting for the remainder of the study. If the subject cannot be transitioned to an 
outpatient setting, they must be discontinued from the study.  
If a subject discontinues and is clinically unstable, additional hospitalization (beyond the original 
14 days allowed) may be allowed on a case-by-case basis with pre-approval of the Medical 
Monitor. 
For hospitalized subjects, they must be clinically stable, in the judgment of the investigator, to 
warrant discharge to the appropriate living environment. In making a discharge determination, 
investigators should also consider the following additional factors: appropriateness for outpatient 


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treatment; a stable residence with adequate caregiver support; and the ability of the subject to be 
compliant with study medications and study visits. 


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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Description of Study Drug 
The study drug is lurasidone 20 mg tablets and lurasidone 40 mg tablets. 
Table 6: 
Investigational Product 
Investigational Drug: 
Lurasidone  
Active Ingredient: 
Lurasidone hydrochloride (HCl) 
Formulation: 
Film-coated lurasidone 20 mg active tablets and film-coated 
lurasidone 40 mg active tablets. 
Frequency: 
20 mg, 40 mg, 60 mg, or 80 mg once daily (QD)  
Packaged as: 
20 mg or 40 mg tablets in Aluminum-Aluminum blister package 
Manufactured by: 
Dainippon Sumitomo Pharma Co., Ltd. 
Storage Conditions: 
Store between 15-25ºC (59-77ºF). Protect from light and moisture 
Packaging Description: 
Aluminum-Aluminum blister package. 
10.2. 
Study Drug Packaging and Labeling 
Supplies will be packaged in blister cards as described below. Study medication will be labeled 
with the clinical trial number and all appropriate investigational labeling requirements. 
10.2.1. 
Blister Cards 
All study medication will be packaged in uniquely identifiable 7-day supply (plus 2 days) blister 
cards. At each dispensing visit a subject will receive a 4-week carton which contains four blister 
cards. The 20 mg per day and 40 mg per day blister cards will contain one column and 9 rows. 
The 60 mg per day and 80 mg per day blister cards will contain two columns and 9 rows. 
Subjects assigned to the 20 mg per day or 40 mg per day dose will be requested to take 1 tablet 
(one row) each day, according to dosing instructions. Subjects assigned to the 60 mg per day or 
80 mg per day dose will be requested to take 2 tablets (one row), each day according to dosing 
instructions.  
The labeling and packaging of the study medication will be based on the guidance described in 
US Code of Federal Regulations, CFR 21, Part 312.6, Annex 13 and any other local applicable 
regulatory requirements. Container label text for study medication blister cards may include the 
following information listed in Table 7 below: 
 


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Table 7: 
Blister Card and Carton Label Example 
1) 
Med ID #: XXXXXX 
 
(IXRS identifying number)  
2) 
Protocol # D1050302 
3) 
Space for subject number (assigned by IXRS)  
4) 
Fill Count & Dosage Form  
5) 
Visit #   ___________ 
6) 
Packaging batch number XXXXXXXX-XX 
7) 
Expiry Date: MM/YYYY 
8) 
Investigator Information (contact information 
–if applicable) 
9) 
Sponsor Address:  
Sunovion Pharmaceuticals Inc.  
         One Bridge Plaza, Suite 510 
Fort Lee, NJ 07024, USA 
10) 
Directions for Use 
11) 
“Keep out of reach of children” 
statement  
12) 
For Oral Use 
13) 
Storage Conditions: Store 
between 15- 25°C (59-77°F). 
Protect from light and moisture. 
14) 
Caution: New Drug–Limited By 
Federal (or United States) Law to 
Investigational Use. 
15) 
For Clinical Trial Use Only and 
other Country Regulatory 
Requirements 
NOTE: Item 7, Expiration will not be on the US and Puerto Rico ONLY label 
10.3. 
Study Drug Storage 
The clinical study drug lurasidone should be stored between 15-25°C (59-77°F) and protected 
from light and moisture. The subject will be instructed to store the medication at room 
temperature. 
The study drug storage area will be monitored for temperature. A monitoring system recording 
temperature 24 hours a day, 7 days a week will be employed. Appropriate temperature records 
will be maintained. If the storage conditions fall outside of the indicated range, 15-25°C 
(59-77°F), the sponsor must be contacted to discuss the potential implications and any actions(s), 
if necessary. 
The investigator is responsible for the proper storage of the study drug according to the sponsor’s 
recommendations and all applicable federal and state regulatory guidelines. The investigator 
agrees not to dispense or store the study drug at any location other than that listed on Form FDA 
1572. 
10.4. 
Study Drug Dispensation and Handling 
A 4-week supply of study drug will be dispensed according to the visit schedule. The subject (or 
caregiver as appropriate) will be instructed to use the 2-day reserve if they miss their regularly 
scheduled visit. The subject (or caregiver as appropriate) will be instructed to return all unused 
study medication and empty blister cards to the clinical trial site at each visit. 


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10.5. 
Interactive Voice Response/Web Response System (IXRS) 
IXRS is an integrated phone and web, subject and drug management system. The interactive 
system that will assign unique subject numbers and medication identification numbers 
(Med ID #) corresponding to the appropriate cartons and blister cards. 
10.6. 
Administration 
The study drug will be dispensed by appropriately qualified site study staff. Under the 
supervision from the subject's caregiver, as appropriate, subjects will take the study drug 
following the directions given to them in the clinic. 
All study medication will be taken once daily in the evening by mouth with food (at least 
350 calories; eg, dinner) or within 30 minutes after eating. Subjects who, in the judgment of the 
investigator, are intolerant to evening dosing may be allowed for take study medication in the 
morning. Exceptions to the evening dosing of study medication are acceptable on a case-by case 
basis, and must be recorded appropriately in the eCRF. Subjects who change to morning dosing 
should continue morning dosing for the duration of the study. 
10.7. 
Study Drug Accountability 
Study drug must be received by the investigator or a designated person at the study site, handled 
and stored safely and properly, and kept in a secured location to which only the investigator 
and/or designated assistants have access. Study medication is to be dispensed only in accordance 
with the protocol. 
The investigator (or qualified designee) is responsible for maintaining accurate records of the 
study drug received from the Sponsor, the amount dispensed to and returned by the subjects, and 
the amount remaining at the conclusion of the study. At the end of the study, all study 
medication including unused, partially used, and empty blister cards must be returned to the 
Sponsor, or designee, after confirmation with the CRA. The investigator will be provided with 
instructions on the return of all study drug. The following information is to be included in the 
eCRF: visit medication dispensed, blister card number, time of dose, dosing start/stop dates, 
number of tablets dispensed, blister card return status and number of tablets returned. 
If the investigation is terminated, discontinued, suspended, or completed, all unused study drug 
will be returned to the Sponsor’s designee, unless other instructions are provided in writing by 
CRO/Sponsor. 
 


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11. 
TREATMENT PLAN 
11.1. 
Study Assessments 
11.1.1. 
Effectiveness 
Aberrant Behavior Checklist (ABC): The ABC is a symptom checklist for assessing problem 
behaviors of children and adults with intellectual disability and developmental disorders at home, 
in residential facilities, intermediate care facilities for individuals with intellectual disability, and 
work training center. It is also useful for classifying problem behaviors of these children and 
adolescent in educational settings, residential and community-based facilities, and developmental 
centers. The 58 items resolve into five subscales: (1) irritability and agitation, (2) lethargy and 
social withdrawal, (3) stereotypic behavior, (4) hyperactivity and noncompliance, and 
(5) inappropriate speech. The ABC irritability subscale contains 15 items that rate symptoms 
such as “injures self”, “aggressive to other children and adults”, “irritable”, “temper  outbursts”, 
“depressed mood”, “mood changes”, and “yells or screams inappropriately” on a scale ranging 
from 0 (not at all a problem) to 3 (severe). The checklist is completed by the subject’s 
parent/caregiver and the same parent/caregiver should complete all ABC assessments for a given 
subject whenever possible. The ABC-C (community) version will be used. 
Clinical Global Impression – Severity Scale (CGI-S): The CGI-S is a clinician-rated 
assessment of the subject’s current illness state on a 7 point scale, where a higher score is 
associated with greater illness severity (eg, schizophrenia or irritability associated with autism). 
Following a clinical interview, the CGI-S can be completed in 1-2 minutes (Guy 1976; Williams 
2000). The CGI-S will be administered by a qualified rater at the site and the same study site 
rater should perform all CGI-S assessments for a given subject whenever possible. 
Children's Yale-Brown Obsessive Compulsive Scales (CY-BOCS) modified for pervasive 
developmental disorders (PDDs): The Children's Yale-Brown Obsessive Compulsive Scale 
(CY-BOCS) modified for pervasive developmental disorders (PDDs) (Scahill, 2006) is a 
clinical-administered semistructured clinician rating that measures to measure the severity of 
obsessive-compulsive disorder. The modification for PDDs eliminates the obsessions checklist 
and severity scales of the CY-BOCS, while expanding the compulsions checklist to include 
repetitive behaviors more commonly seen in children with PDD. In addition, the modified for 
PDDs version relies more on parental input than on the child's input. The CY-BOCS will be 
administered by a qualified rater at the site and the same study site rater should perform all CY-
BOCS assessments for a given subject whenever possible. 
Children's Global Assessment Scale (CGAS): The CGAS is a clinician-rated assessment of the 
overall severity of disturbance in children, with a range of scores from 1 to 100. It anchors at 
10-point intervals include descriptors of functioning and psychopathology for each interval. A 
second version of the CGAS, designed for nonclinicians who have conducted a standardized 
diagnostic assessment of the child (usually in community surveys), was constructed similarly, 
except that the descriptors of psychopathology and functioning are written in lay terminology. 
The single numerical score representing severity of disturbance ranges from 1 (most impaired) to 
100 (healthiest). On the basis of the descriptors, raters are expected to synthesize their 
knowledge about the child’s social and symptomatic functioning and condense this information 


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into a score. For example, a score of 61–70 indicates that the child has some difficulty in a single 
area but is generally functioning pretty well. Scores above 70 are considered to be in the normal 
range, whereas scores on the low end of the continuum indicate a need for constant supervision 
(1–10) or considerable supervision (11–20). The CGAS will be administered by a qualified rater 
at the site and the same study site rater should perform all CGAS assessments for a given subject 
whenever possible. 
Caregiver Strain Questionnaire (CGSQ): The CGSQ is a caregiver reported assessment that 
assesses the extent to which caregivers are affected by the special demands associated with 
caring for a child with emotional and behavioral problems. The CGSQ is comprised of three 
subscales which range in severity from 1 to 5. Objective Strain refers to observable disruptions in 
family and community life (eg, interruption of personal time, lost work time, financial strain). 
Subjective Externalized Strain refers to negative feelings about the child such as anger, 
resentment, or embarrassment. Subjective Internalized Strain refers to the negative feelings that 
the caregiver experiences such as worry, guilt, or fatigue. Higher scores on each of these scales 
indicate greater strain. A Global Strain score is calculated by summing the three subscales (ie, 
Objective Strain, Subjective Externalized Strain, and Subjective Internalized Strain) to provide 
an indication of the total impact of the special demands on the family. Global Strain scores range 
from 3 to 15. As with the individual subscales, higher scores indicate greater strain. 
Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q): The 
Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q) is a 15-item 
measure that assesses the quality of life in children and adolescents. This scale focuses on the 
child’s or adolescent’s views about general health, well-being, and feelings about the medical 
condition. Response categories range from “very poor” to “very good”. The PQ-LES-Q is a 
subject self-reported assessment. 
Positive and Negative Syndrome Scale (PANSS): The PANSS is an interview-based measure 
of the severity of psychopathology in adults with psychotic disorders. The measure is comprised 
of 30 items and 3 scales: the Positive scale assesses hallucinations, delusions, and related 
symptoms; the Negative scale assesses emotional withdrawal, lack of motivation, and similar 
symptoms; and the General Psychopathology scale addresses other symptoms such as anxiety, 
somatic concern, and disorientation. An anchored Likert scale from 1-7, where values of 2 and 
above indicate the presence of progressively more severe symptoms, is used to score each item. 
Individual items are then summed to determine scores for the 3 scales, as well as a total score. A 
Composite scale score (Positive scale score minus Negative scale score) can also be calculated to 
show the relative valence of positive and negative symptoms. Total time required for the PANSS 
interview and scoring is approximately 30-40 minutes (Kay, 1994; Perkins, 2000; Opler, 1992). 
PANSS raters will be required to meet specific training and education criteria before they are 
certified to rate for this study. In addition, raters will receive specific training and education 
regarding all of the assessments prior to study initiation. The PANSS will be administered by a 
qualified rater at the site and the same study site rater should perform all PANSS assessments for 
a given subject whenever possible. 
Children's Depression Rating Scale, Revised (CDRS-R): The CDRS-R is a semi-structured, 
clinician-rated instrument designed for use with children and adolescents between the ages of 
6-17 years. It contains 17 ordinally-scaled items that evaluate the presence and severity of 
symptoms commonly associated with depression in childhood.  The CDRS-R score ranges from 


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17-113. The CDRS-R will be administered separately to the patient and to the caregiver. For 
each item, the rating that provides the best description of the patient will be selected by the 
clinician administering the interviews. The CDRS-R will be administered by a qualified rater at 
the site and the same study site rater should perform all CDRS-R assessments for a given subject 
whenever possible. 
Clinical Global Impression-Bipolar Version, Severity of Illness (CGI-BP-S): The CGI-BP-S 
is a three-part clinician-rated assessment of the subject’s current illness state (depression, mania, 
and overall) using a 7-point scale for each part, where a higher score is associated with greater 
illness severity. Following a clinical interview, the CGI-BP-S can be completed in 1-2 minutes. 
The CGI-BP-S will be administered by a qualified rater at the site and the same study site rater 
should perform all CGI-BP-S assessments for a given subject whenever possible. 
Pediatric Anxiety Rating Scale (PARS):  The PARS is a clinician-rated instrument for 
assessing over time the severity of anxiety symptoms associated with common DSM-IV anxiety 
disorders (generalized anxiety disorder, separation anxiety, and social phobia) in children ages 
6-17 years. The PARS will be administered separately to the subject and to the caregiver. The 
instrument has 2 sections.  The first section includes a 50-item symptom checklist, which the 
clinician rates as present or absent during the past week. The second section is comprised of 7 
severity impairment items that are rated on a 6 point Likert scale. The 7 severity impairment 
items reflect the severity/impairment of all symptoms endorsed in Section 1 of the PARS (during 
the past week). The PARS will be administered by a qualified rater at the site and the same study 
site rater should perform all PARS assessments for a given subject whenever possible. 
Attention-Deficit/ Hyperactivity Disorder Rating Scale (ADHD-RS): The ADHD-RS IV was 
developed to measure the behaviors of children with ADHD. The ADHD-RS IV is a validated 
scale that consists of 18 items designed to reflect current symptomatology of ADHD based on 
DSM-IV-TR criteria. Each item is scored from a range of zero (reflecting no symptoms) to three 
(reflecting severe symptoms) with total scores ranging from zero to 54. The 18 items may be 
grouped into two sub-scales: hyperactivity/impulsivity (even number items 2 through 18) and 
inattentiveness (odd number items 1 through 17). The ADHD-RS will be administered to the 
caregiver by a qualified rater at the site and the same study site rater should perform all ADHD-
RS assessments for a given subject whenever possible. 
11.1.2. 
Safety 
Vital Signs: Vital signs following 5 minutes of seated rest will consist of supine systolic and 
diastolic blood pressures, respiration rate, heart rate, and oral body temperature.  
Blood pressure and heart rate should first be taken with the subject in the supine position after 
resting for ≥ 5 minutes. Blood pressure and heart rate will be taken again after standing for 2 to 
4 minutes. The same arm should be used during each assessment of blood pressure and heart rate 
throughout the study. If a subject develops symptoms consistent with orthostatic hypotension 
(light-headedness, dizziness, or changes in sensorium upon standing) at any point, his or her 
supine and standing blood pressure and heart rate should be collected at that time in the manner 
described above. Vital signs will be obtained prior to clinical laboratory collection and 
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Orthostatic effects: Orthostatic changes with clinically significant symptoms should be 
recorded as AEs. The categorization of orthostatic effects is intended for the data analysis and 
reporting of group effects and does not constitute guidance as to whether individual assessments 
reflect clinically meaningful changes. 
Physical Examination Assessments: A full physical examination will be performed. The 
physical examination includes an assessment of general appearance and a review of systems 
(dermatologic, head, eyes, ears, nose, mouth/throat/neck, thyroid, lymph nodes, respiratory, 
cardiovascular, gastrointestinal, extremities, musculoskeletal, neurologic, and psychiatric 
systems).  
Weight, height, and waist circumference: Weight and height should be measured in street 
clothing with no shoes. Waist circumference measurement should be taken around the body at 
the level of the abdomen and just above the hip bone. The waist circumference measurement is 
usually taken immediately after exhalation. 
Centrally-read ECG: All ECGs will be obtained in the supine position, after the subject has 
been resting supine for at least 10 minutes. ECGs will be 12-lead with a 10-second rhythm strip. 
ECGs should be obtained prior to drawing blood samples. All attempts should be made to use the 
same ECG recorder for all visits within individual subjects. ECGs will be centrally read at a core 
lab according to established quality assurance procedures for inter/intra reader variability.  
Clinical Laboratory: For detailed instructions regarding laboratory procedures, sampling, and 
shipping guidelines refer to the Central Laboratory Instructions Manual. Samples will be 
processed at a central laboratory to ensure consistency. All laboratories will be College of 
American Pathologists (CAP) and Clinical Laboratory Improvement Amendments (CLIA) (or 
equivalent) certified. See Appendix A for a list of required clinical laboratory tests. 
Hyperglycemia will be defined as any glucose result of ≥ 126 mg/dL; dyslipidemia will be 
defined as any result of total cholesterol ≥ 240 mg/dL or triglycerides ≥ 200 mg/dL. 
Adverse Events: As a discussion guide, subjects should be queried in a non-leading manner, 
without specific prompting (eg, “Has there been any change in your health status since your last 
visit?”). See Appendix C.  
Concomitant Medications and Medical History: Subject and caregiver self-report will be 
acceptable for listing all concomitant medication use, medical history, psychiatric history, and 
evaluation for inclusion/exclusion except where specific protocol procedures are mandated to 
ensure appropriate enrollment (eg, certain baseline lab values). 
Simpson-Angus Scale (SAS): The SAS is a clinician-rated assessment of neuroleptic-induced 
parkinsonism consisting of 10 items. Items are anchor-based, rated on a 5-point scale, and 
address rigidity, gait (bradykinesia), tremor, glabellar tap, and salivation (Simpson, 1970). SAS 
raters will be required to meet specific credential and educational criteria before they are 
certified to rate for this study. The same study site rater should perform all SAS assessments for 
a given subject whenever possible. 
Barnes Akathisia Rating Scale (BARS): The BARS (Barnes, 1989, Barnes, 2003, 
Schooler, 2000) is a rating scale geared toward assessment of neuroleptic-induced akathisia, 
though it can be used to measure akathisia associated with other drugs as well. The BARS 
consists of 4 items, including one item assessing objective restlessness, 2 items targeting 


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subjective restlessness (awareness and related distress), and one global clinical assessment item. 
All items are anchored and utilize a 4-point scale, except for the global rating which has a 6-
point scale (from absence of akathisia through severe akathisia). The subjective and objective 
items are summed to yield a total score. The BARS can be administered in about 10 minutes. 
The BARS will be administered by a qualified rater at the site. The same study site rater should 
perform all BARS assessments for a given subject whenever possible. 
Abnormal Involuntary Movement Scale (AIMS): The AIMS is a clinician-rated assessment of 
abnormal movements consisting of unobtrusive observation of the subject at rest (with shoes 
removed) and several questions or instructions directed toward the subject. Using a severity scale 
ranging from 0 (none) to 4 (severe), clinicians rate dyskinesia in several body regions, including 
the facial area, extremities, and trunk. There are 2 items related to dental status, as well as 
3 global impression items assessing overall severity, incapacitation, and the subject’s awareness 
of abnormal movements (Guy, 1976; Munetz, 1988). AIMS raters will be required to meet 
specific credential and educational criteria before they are certified to rate for this study. The 
same study site rater should perform all AIMS assessments for a given subject whenever 
possible. 
Udvalg for Kliniske Undersogelser Side Effect Rating Scale (UKU): The Udvalg for Kliniske 
Undersøgelser (UKU) Side Effect Rating Scale (Lingiaerde, 1987) is a comprehensive, clinician-
rated scale, designed to assess the side effects in patients treated with psychotropic medications. 
The UKU contains information obtained via interviews with the patient, as well as observations 
made by the clinician. The UKU consists of 48 questions. A rating can typically be assessed 
within 30 minutes. Each point on the UKU is assigned a degree of zero, one, two or three. 
Zero indicates normal; one indicates mild symptoms; two indicates moderate symptoms; and 
three indicates severe symptoms. The same study site rater should perform all UKU assessments 
for a given subject whenever possible. 
Columbia Suicide Severity Rating Scale (C-SSRS): The C-SSRS is a tool designed to 
systematically assess and track suicidal adverse events (suicidal behavior and suicidal ideation) 
throughout the trial. The strength of this suicide classification system is in its ability to 
comprehensively identify suicidal events while limiting the over-identification of suicidal 
behavior. The scale takes approximately 5 minutes to administer. The C-SSRS will be 
administered by a trained rater at the site. Subjects with Type 4 (active suicidal ideation with 
some intent to act, without specific plan) or Type 5 (active suicidal ideation with specific plan 
and intent) suicidal ideation during the study will be discontinued from the study and referred to 
a mental health professional. The same study site rater should perform all C-SSRS assessments 
for a given subject whenever possible. 
Young Mania Rating Scale (YMRS): The YMRS is an 11-item instrument used to assess the 
severity of mania in patients with a diagnosis of bipolar disorder. The 11 items are: Elevated 
Mood, Increased Motor Activity Energy, Sexual Interest, Sleep, Irritability, Speech (Rate and 
Amount), Language-Thought Disorder, Content, Disruptive-Aggressive Behaviour, Appearance 
and Insight. The YMRS is a clinician-rated assessment and uses operationally-defined anchor 
points. Ratings are based on patient self-reporting, combined with clinician observation 
(accorded greater score). The YMRS will be administered separately to the subject and to the 
caregiver by a qualified rater at the site and the same study site rater should perform all YMRS 
assessments for a given subject whenever possible. 


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CogState Computerized Cognitive Test Battery: The CogState Computerized Cognitive Test 
Battery is a computerized testing platform designed to provide brief, standardized, and easily 
administered assessment of a range of cognitive functions. The CogState test battery to be used 
in this study consists of four tasks each designed to specifically assess functioning in the 
following cognitive domains: psychomotor speed (detection task); attention (identification task); 
learning/memory (one card learning task); and working memory (one back task). The 
computerized test will be administered to each subject using the computer interface at the study 
site. 
Tanner Staging: a scale of physical development in children, adolescents and adults. The scale 
defines physical measurements of development based on external primary and secondary sex 
characteristics, such as the size of the breasts, genitalia, testicular volume and development of 
pubic and axillary hair. 
Menstrual cyclicity (female subjects only): Menstrual cyclicity will be monitored in female 
subjects who have begun menses. Female subjects will be given a calendar to mark the beginning 
and end of each menses. This calendar will be reviewed at each visit. 
11.2. 
Standardization of Data Capture 
Study Schematic and Schedule of Assessments: A schematic of the study design and summary 
of assessments to be conducted at each visit are presented in Figure 1 and Table 3, Table 4, and 
Table 5, respectively. 
Assessment Windows: Assessments will be conducted within the time frames specified 
(ie ± 3 days). All times are relative to the time of dosing for individual subjects 
11.3. 
Electronic Data Capture (EDC)  
The study sites will use a validated EDC system to enter subject data onto CRFs. Medidata 
RAVE will be used for this clinical study. Password protected access to the EDC system will be 
via a secure website. Data queries and data corrections will be handled through the same system. 
All transactions within the EDC system are fully documented within an electronic audit trail. 
Each set of completed CRFs must be reviewed and electronically signed and dated by the 
investigator.  
11.4. 
Study Visits and Assessments 
11.4.1. 
Visit 1E (Day 1) 
Visit 1E (Day 1) – this visit will occur on the same day as Study Visit Number 9 in 
Study D1050301 and Study D1050325 and Study Visit Number 8 in Study D1050326. 
Note:  Assessments specific to this study are listed below; all other assessments will be 
carried over from Study Visit Number 9 in Study D1050301 and Study D1050325 and 
Study Visit Number 8 in Study D1050326. 
• Obtain informed consent/assent 
• Inclusion/exclusion criteria 


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• Interactive Voice/Web Response System (IXRS) subject registry/visit 
• Dispense study medication  
Clinical and Laboratory Evaluations: ALL SUBJECTS 
• Prior/concomitant medication review 
• Adverse event (AE) monitoring 
11.4.2. 
Visit 2E (Week 2) 
• Interactive Voice/Web Response System (IXRS) subject registry/visit 
• Study drug accountability/assess compliance 
Clinical and Laboratory Evaluations: ALL SUBJECTS 
• Prior/concomitant medication review 
• Adverse event (AE) monitoring 
• Menstrual cyclicity (female subjects) 
• Vital signs 
• Simpson-Angus Scale (SAS) 
• Barnes Akathisia Rating Scale (BARS) 
• Abnormal Involuntary Movement Scale (AIMS) 
Clinical Evaluations: SUBJECTS from D1050301 ONLY 
• Clinical Global Impression – Severity Scale (CGI-S) 
• Udvalg for Kliniske Undersogelser Side Effect Rating Scale (UKU) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
Clinical Evaluations: SUBJECTS from D1050325 ONLY 
• Clinical Global Impression – Severity Scale (CGI-S) 
Clinical Evaluations: SUBJECTS from D1050326 ONLY 
• Clinical Global Impression-Bipolar Version, Severity of Illness (CGI BP-S) 
• Udvalg for Kliniske Undersogelser Side Effect Rating Scale (UKU) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
11.4.3. 
Visit 3E (Week 4) 
• Interactive Voice/Web Response System (IXRS) subject registry/visit 
• Dispense study medication 
• Study drug accountability/assess compliance 
Clinical and Laboratory Evaluations: ALL SUBJECTS 


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• Prior/concomitant medication review 
• Adverse event (AE) monitoring 
• Menstrual cyclicity (female subjects) 
• Vital signs 
• Urine drug screen  
• Urine β-hCG (female subjects ≥ 11 years of age only) 
• Simpson-Angus Scale (SAS) 
• Barnes Akathisia Rating Scale (BARS) 
• Abnormal Involuntary Movement Scale (AIMS) 
Clinical Evaluations: SUBJECTS from D1050301 ONLY 
• Clinical Global Impression – Severity Scale (CGI-S) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
Clinical Evaluations: SUBJECTS from D1050325 ONLY 
• Clinical Global Impression – Severity Scale (CGI-S) 
Clinical Evaluations: SUBJECTS from D1050326 ONLY 
• Clinical Global Impression-Bipolar Version, Severity of Illness (CGI BP-S) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
11.4.4. 
Visit 4E (Week 6) 
• Interactive Voice/Web Response System (IXRS) subject registry/visit 
• Study drug accountability/assess compliance 
Clinical and Laboratory Evaluations: ALL SUBJECTS 
• Prior/concomitant medication review 
• Adverse event (AE) monitoring 
• Height as measured by stadiometer 
• Menstrual cyclicity (female subjects) 
• Vital signs 
• Weight  
• Simpson-Angus Scale (SAS) 
• Barnes Akathisia Rating Scale (BARS) 
• Abnormal Involuntary Movement Scale (AIMS) 
Clinical Evaluations: SUBJECTS from D1050301 ONLY 


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• Children’s Global Assessment Scale (CGAS) 
• Clinical Global Impression – Severity Scale (CGI-S) 
• Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q) 
• Udvalg for Kliniske Undersogelser Side Effect Rating Scale (UKU) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
• Positive and Negative Syndrome Scale (PANSS) 
Clinical Evaluations: SUBJECTS from D1050325 ONLY 
• Aberrant Behavior Checklist (ABC) 
• Clinical Global Impression – Severity Scale (CGI-S) 
• Children's Yale-Brown Obsessive Compulsive Scales (CY-BOCS) modified for 
pervasive developmental disorders (PDDs) 
• Caregiver Strain Questionnaire (CGSQ) 
Clinical Evaluations: SUBJECTS from D1050326 ONLY 
• Children’s Depression Rating Scale, Revised (CDRS-R) 
• Clinical Global Impression-Bipolar Version, Severity of Illness (CGI BP-S) 
• Young Mania Rating Scale (YMRS) 
• Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
• Udvalg for Kliniske Undersogelser Side Effect Rating Scale (UKU) 
• Pediatric Anxiety Rating Scale (PARS) 
• Attention-Deficit/Hyperactivity Disorder Rating Scale (ADHD-RS) 
11.4.5. 
Visit 5E (Week 8) 
• Interactive Voice/Web Response System (IXRS) subject registry/visit 
• Dispense study medication 
• Study drug accountability/assess compliance 
Clinical and Laboratory Evaluations: ALL SUBJECTS 
• Prior/concomitant medication review 
• Adverse event (AE) monitoring 
• Menstrual cyclicity (female subjects) 
• Vital signs 
• Urine drug screen  


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• Urine β-hCG (female subjects ≥ 11 years of age only) 
• Simpson-Angus Scale (SAS) 
• Barnes Akathisia Rating Scale (BARS) 
• Abnormal Involuntary Movement Scale (AIMS) 
Clinical Evaluations: SUBJECTS from D1050301 ONLY 
• Clinical Global Impression – Severity Scale (CGI-S) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
Clinical Evaluations: SUBJECTS from D1050325 ONLY 
• Clinical Global Impression – Severity Scale (CGI-S) 
Clinical Evaluations: SUBJECTS from D1050326 ONLY 
• Clinical Global Impression-Bipolar Version, Severity of Illness (CGI BP-S) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
11.4.6. 
Visit 6E (Week 12) 
• Interactive Voice/Web Response System (IXRS) subject registry/visit 
• Dispense study medication 
• Study drug accountability/assess compliance 
Clinical and Laboratory Evaluations: ALL SUBJECTS 
• Prior/concomitant medication review 
• Adverse event (AE) monitoring 
• Height as measured by stadiometer 
• Menstrual cyclicity (female subjects) 
• Vital signs 
• Weight  
• Waist circumference measurement 
• Hematology, chemistry, and urinalysis 
• Hormonal Parameters 
• Serum prolactin 
• Glycosylated hemoglobin (HbA1c) 
• Glucose and lipid panel 
• Serum insulin and C-reactive protein 
• Urine drug screen  


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• Urine β-hCG (female subjects ≥ 11 years of age only) 
• Simpson-Angus Scale (SAS) 
• Barnes Akathisia Rating Scale (BARS) 
• Abnormal Involuntary Movement Scale (AIMS) 
Clinical Evaluations: SUBJECTS from D1050301 ONLY 
• Children’s Global Assessment Scale (CGAS) 
• Clinical Global Impression – Severity Scale (CGI-S) 
• Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q) 
• Udvalg for Kliniske Undersogelser Side Effect Rating Scale (UKU) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
• Positive and Negative Syndrome Scale (PANSS) 
• CogState Cognitive Test Battery  
Clinical Evaluations: SUBJECTS from D1050325 ONLY 
• Aberrant Behavior Checklist (ABC) 
• Clinical Global Impression – Severity Scale (CGI-S) 
• Children's Yale-Brown Obsessive Compulsive Scales (CY-BOCS) modified for 
pervasive developmental disorders (PDDs) 
• Caregiver Strain Questionnaire (CGSQ) 
Clinical Evaluations: SUBJECTS from D1050326 ONLY 
• Children’s Depression Rating Scale, Revised (CDRS-R) 
• Clinical Global Impression-Bipolar Version, Severity of Illness (CGI BP-S) 
• Children’s Global Assessment Scale (CGAS) 
• Young Mania Rating Scale (YMRS) 
• Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
• Udvalg for Kliniske Undersogelser Side Effect Rating Scale (UKU) 
• Pediatric Anxiety Rating Scale (PARS) 
• Attention-Deficit/Hyperactivity Disorder Rating Scale (ADHD-RS) 
• CogState Cognitive Test Battery  
11.4.7. 
Visit 7E (Week 16) 
• Interactive Voice/Web Response System (IXRS) subject registry/visit 


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• Dispense study medication 
• Study drug accountability/assess compliance 
Clinical and Laboratory Evaluations: ALL SUBJECTS 
• Prior/concomitant medication review 
• Adverse event (AE) monitoring 
• Menstrual cyclicity (female subjects) 
• Vital signs 
• Urine drug screen  
• Urine β-hCG (female subjects ≥ 11 years of age only) 
• Simpson-Angus Scale (SAS) 
• Barnes Akathisia Rating Scale (BARS) 
• Abnormal Involuntary Movement Scale (AIMS) 
Clinical Evaluations: SUBJECTS from D1050301 ONLY 
• Clinical Global Impression – Severity Scale (CGI-S) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
Clinical Evaluations: SUBJECTS from D1050325 ONLY 
• Clinical Global Impression – Severity Scale (CGI-S) 
Clinical Evaluations: SUBJECTS from D1050326 ONLY 
• Clinical Global Impression-Bipolar Version, Severity of Illness (CGI BP-S) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
11.4.8. 
Visit 8E (Week 20) 
• Interactive Voice/Web Response System (IXRS) subject registry/visit 
• Dispense study medication 
• Study drug accountability/assess compliance 
Clinical and Laboratory Evaluations: ALL SUBJECTS 
• Prior/concomitant medication review 
• Adverse event (AE) monitoring 
• Menstrual cyclicity (female subjects) 
• Vital signs 
• Urine drug screen  
• Urine β-hCG (female subjects ≥ 11 years of age only) 


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• Simpson-Angus Scale (SAS) 
• Barnes Akathisia Rating Scale (BARS) 
• Abnormal Involuntary Movement Scale (AIMS) 
Clinical Evaluations: SUBJECTS from D1050301 ONLY 
• Clinical Global Impression – Severity Scale (CGI-S) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
Clinical Evaluations: SUBJECTS from D1050325 ONLY 
• Clinical Global Impression – Severity Scale (CGI-S) 
Clinical Evaluations: SUBJECTS from D1050326 ONLY 
• Clinical Global Impression-Bipolar Version, Severity of Illness (CGI BP-S) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
11.4.9. 
Visit 9E (Week 24) 
• Interactive Voice/Web Response System (IXRS) subject registry/visit 
• Dispense study medication 
• Study drug accountability/assess compliance 
Clinical and Laboratory Evaluations: ALL SUBJECTS 
• Prior/concomitant medication review 
• Adverse event (AE) monitoring 
• Menstrual cyclicity (female subjects) 
• Vital signs 
• Urine drug screen  
• Urine β-hCG (female subjects ≥ 11 years of age only) 
• Simpson-Angus Scale (SAS) 
• Barnes Akathisia Rating Scale (BARS) 
• Abnormal Involuntary Movement Scale (AIMS) 
Clinical Evaluations: SUBJECTS from D1050301 ONLY 
• Clinical Global Impression – Severity Scale (CGI-S) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
Clinical Evaluations: SUBJECTS from D1050325 ONLY 
• Clinical Global Impression – Severity Scale (CGI-S) 
Clinical Evaluations: SUBJECTS from D1050326 ONLY 


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• Clinical Global Impression-Bipolar Version, Severity of Illness (CGI BP-S) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
11.4.10. 
Visit 10E (Week 28) 
• Interactive Voice/Web Response System (IXRS) subject registry/visit 
• Dispense study medication 
• Study drug accountability/assess compliance 
Clinical and Laboratory Evaluations: ALL SUBJECTS 
• Prior/concomitant medication review 
• Adverse event (AE) monitoring 
• Physical examination 
• Height as measured by stadiometer 
• Tanner staging 
• Menstrual cyclicity (female subjects) 
• Vital signs 
• Weight  
• Waist circumference measurement 
• Electrocardiogram (ECG) 
• Hematology, chemistry, and urinalysis 
• Hormonal Parameters 
• Serum prolactin 
• Glycosylated hemoglobin (HbA1c) 
• Glucose and lipid panel 
• Serum insulin and C-reactive protein 
• Urine drug screen  
• Urine β-hCG (female subjects ≥ 11 years of age only) 
• Simpson-Angus Scale (SAS) 
• Barnes Akathisia Rating Scale (BARS) 
• Abnormal Involuntary Movement Scale (AIMS) 
Clinical Evaluations: SUBJECTS from D1050301 ONLY 
• Clinical Global Impression – Severity Scale (CGI-S) 
• Children’s Global Assessment Scale (CGAS) 


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• Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q) 
• Udvalg for Kliniske Undersogelser Side Effect Rating Scale (UKU) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
• Positive and Negative Syndrome Scale (PANSS) 
• CogState Cognitive Test Battery 
Clinical Evaluations: SUBJECTS from D1050325 ONLY 
• Aberrant Behavior Checklist (ABC) 
• Clinical Global Impression – Severity Scale (CGI-S) 
• Children's Yale-Brown Obsessive Compulsive Scales (CY-BOCS) modified for 
pervasive developmental disorders (PDDs) 
• Caregiver Strain Questionnaire (CGSQ) 
Clinical Evaluations: SUBJECTS from D1050326 ONLY 
• Children’s Depression Rating Scale, Revised (CDRS-R) 
• Clinical Global Impression-Bipolar Version, Severity of Illness (CGI BP-S) 
• Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q) 
• Children’s Global Assessment Scale (CGAS) 
• Young Mania Rating Scale (YMRS) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
• Udvalg for Kliniske Undersogelser Side Effect Rating Scale (UKU) 
• Pediatric Anxiety Rating Scale (PARS) 
• Attention-Deficit/Hyperactivity Disorder Rating Scale (ADHD-RS) 
• CogState Cognitive Test Battery  
11.4.11. 
Visit 11E (Week 32) 
• Interactive Voice/Web Response System (IXRS) subject registry/visit 
• Dispense study medication 
• Study drug accountability/assess compliance 
Clinical and Laboratory Evaluations: ALL SUBJECTS 
• Prior/concomitant medication review 
• Adverse event (AE) monitoring 
• Menstrual cyclicity (female subjects) 
• Vital signs 


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• Urine drug screen  
• Urine β-hCG (female subjects ≥ 11 years of age only) 
• Simpson-Angus Scale (SAS) 
• Barnes Akathisia Rating Scale (BARS) 
• Abnormal Involuntary Movement Scale (AIMS) 
Clinical Evaluations: SUBJECTS from D1050301 ONLY 
• Clinical Global Impression – Severity Scale (CGI-S) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
Clinical Evaluations: SUBJECTS from D1050325 ONLY 
• Clinical Global Impression – Severity Scale (CGI-S) 
Clinical Evaluations: SUBJECTS from D1050326 ONLY 
• Clinical Global Impression-Bipolar Version, Severity of Illness (CGI BP-S) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
11.4.12. 
Visit 12E (Week 36) 
• Interactive Voice/Web Response System (IXRS) subject registry/visit 
• Dispense study medication 
• Study drug accountability/assess compliance 
Clinical and Laboratory Evaluations: ALL SUBJECTS 
• Prior/concomitant medication review 
• Adverse event (AE) monitoring 
• Menstrual cyclicity (female subjects) 
• Vital signs 
• Urine drug screen  
• Urine β-hCG (female subjects ≥ 11 years of age only) 
• Simpson-Angus Scale (SAS) 
• Barnes Akathisia Rating Scale (BARS) 
• Abnormal Involuntary Movement Scale (AIMS) 
Clinical Evaluations: SUBJECTS from D1050301 ONLY 
• Clinical Global Impression – Severity Scale (CGI-S) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
Clinical Evaluations: SUBJECTS from D1050325 ONLY 


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• Clinical Global Impression – Severity Scale (CGI-S) 
Clinical Evaluations: SUBJECTS from D1050326 ONLY 
• Clinical Global Impression-Bipolar Version, Severity of Illness (CGI BP-S) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
11.4.13. 
Visit 13E (Week 40) 
• Interactive Voice/Web Response System (IXRS) subject registry/visit 
• Dispense study medication 
• Study drug accountability/assess compliance 
Clinical and Laboratory Evaluations: ALL SUBJECTS 
• Prior/concomitant medication review 
• Adverse event (AE) monitoring 
• Physical examination 
• Height as measured by stadiometer 
• Tanner staging 
• Menstrual cyclicity (female subjects) 
• Vital signs 
• Weight  
• Waist circumference measurement 
• Urine drug screen  
• Urine β-hCG (female subjects ≥ 11 years of age only) 
• Simpson-Angus Scale (SAS) 
• Barnes Akathisia Rating Scale (BARS) 
• Abnormal Involuntary Movement Scale (AIMS) 
Clinical Evaluations: SUBJECTS from D1050301 ONLY 
• Clinical Global Impression – Severity Scale (CGI-S) 
• Children’s Global Assessment Scale (CGAS) 
• Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q) 
• Udvalg for Kliniske Undersogelser Side Effect Rating Scale (UKU) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
• Positive and Negative Syndrome Scale (PANSS) 
Clinical Evaluations: SUBJECTS from D1050325 ONLY 


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58 
30 Jun 2017 
• Aberrant Behavior Checklist (ABC) 
• Clinical Global Impression – Severity Scale (CGI-S) 
• Children's Yale-Brown Obsessive Compulsive Scales (CY-BOCS) modified for 
pervasive developmental disorders (PDDs) 
• Caregiver Strain Questionnaire (CGSQ) 
Clinical Evaluations: SUBJECTS from D1050326 ONLY 
• Children’s Depression Rating Scale, Revised (CDRS-R) 
• Clinical Global Impression-Bipolar Version, Severity of Illness (CGI BP-S) 
• Children’s Global Assessment Scale (CGAS) 
• Young Mania Rating Scale (YMRS) 
• Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
• Udvalg for Kliniske Undersogelser Side Effect Rating Scale (UKU) 
• Pediatric Anxiety Rating Scale (PARS) 
• Attention-Deficit/Hyperactivity Disorder Rating Scale (ADHD-RS) 
11.4.14. 
Visit 14E (Week 44) 
• Interactive Voice/Web Response System (IXRS) subject registry/visit 
• Dispense study medication 
• Study drug accountability/assess compliance 
Clinical and Laboratory Evaluations: ALL SUBJECTS 
• Prior/concomitant medication review 
• Adverse event (AE) monitoring 
• Menstrual cyclicity (female subjects) 
• Vital signs 
• Urine drug screen  
• Urine β-hCG (female subjects ≥ 11 years of age only) 
• Simpson-Angus Scale (SAS) 
• Barnes Akathisia Rating Scale (BARS) 
• Abnormal Involuntary Movement Scale (AIMS) 
Clinical Evaluations: SUBJECTS from D1050301 ONLY 
• Clinical Global Impression – Severity Scale (CGI-S) 


Protocol D1050302 Version 4.0 
 
Lurasidone 
 
Confidential and Proprietary 
59 
30 Jun 2017 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
Clinical Evaluations: SUBJECTS from D1050325 ONLY 
• Clinical Global Impression – Severity Scale (CGI-S) 
Clinical Evaluations: SUBJECTS from D1050326 ONLY 
• Clinical Global Impression-Bipolar Version, Severity of Illness (CGI BP-S) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
11.4.15. 
Visit 15E (Week 48) 
• Interactive Voice/Web Response System (IXRS) subject registry/visit 
• Dispense study medication 
• Study drug accountability/assess compliance 
Clinical and Laboratory Evaluations: ALL SUBJECTS 
• Prior/concomitant medication review 
• Adverse event (AE) monitoring 
• Menstrual cyclicity (female subjects) 
• Vital signs 
• Urine drug screen  
• Urine β-hCG (female subjects ≥ 11 years of age only) 
• Simpson-Angus Scale (SAS) 
• Barnes Akathisia Rating Scale (BARS) 
• Abnormal Involuntary Movement Scale (AIMS) 
Clinical Evaluations: SUBJECTS from D1050301 ONLY 
• Clinical Global Impression – Severity Scale (CGI-S) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
Clinical Evaluations: SUBJECTS from D1050325 ONLY 
• Clinical Global Impression – Severity Scale (CGI-S) 
Clinical Evaluations: SUBJECTS from D1050326 ONLY 
• Clinical Global Impression-Bipolar Version, Severity of Illness (CGI BP-S) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
11.4.16. 
Visit 16E (Week 52) 
• Interactive Voice/Web Response System (IXRS) subject registry/visit 
• Dispense study medication 


Protocol D1050302 Version 4.0 
 
Lurasidone 
 
Confidential and Proprietary 
60 
30 Jun 2017 
• Study drug accountability/assess compliance 
Clinical and Laboratory Evaluations: ALL SUBJECTS 
• Prior/concomitant medication review 
• Adverse event (AE) monitoring 
• Physical examination 
• Height as measured by stadiometer 
• Tanner staging 
• Menstrual cyclicity (female subjects) 
• Vital signs 
• Weight  
• Waist circumference measurement 
• Electrocardiogram (ECG) 
• Hematology, chemistry, and urinalysis 
• Hormonal Parameters 
• Serum prolactin 
• Glycosylated hemoglobin (HbA1c) 
• Glucose and lipid panel 
• Serum insulin and C-reactive protein 
• Urine drug screen  
• Urine β-hCG (female subjects ≥ 11 years of age only) 
• Simpson-Angus Scale (SAS) 
• Barnes Akathisia Rating Scale (BARS) 
• Abnormal Involuntary Movement Scale (AIMS) 
Clinical Evaluations: SUBJECTS from D1050301 ONLY 
• Clinical Global Impression – Severity Scale (CGI-S) 
• Children’s Global Assessment Scale (CGAS) 
• Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q) 
• Udvalg for Kliniske Undersogelser Side Effect Rating Scale (UKU) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
• Positive and Negative Syndrome Scale (PANSS) 
• CogState Cognitive Test Battery 


Protocol D1050302 Version 4.0 
 
Lurasidone 
 
Confidential and Proprietary 
61 
30 Jun 2017 
Clinical Evaluations: SUBJECTS from D1050325 ONLY 
• Aberrant Behavior Checklist (ABC) 
• Clinical Global Impression – Severity Scale (CGI-S) 
• Children's Yale-Brown Obsessive Compulsive Scales (CY-BOCS) modified for 
pervasive developmental disorders (PDDs) 
• Caregiver Strain Questionnaire (CGSQ) 
Clinical Evaluations: SUBJECTS from D1050326 ONLY 
• Children’s Depression Rating Scale, Revised (CDRS-R) 
• Clinical Global Impression-Bipolar Version, Severity of Illness (CGI BP-S) 
• Children’s Global Assessment Scale (CGAS) 
• Young Mania Rating Scale (YMRS) 
• Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
• Udvalg for Kliniske Undersogelser Side Effect Rating Scale (UKU) 
• Pediatric Anxiety Rating Scale (PARS) 
• Attention-Deficit/Hyperactivity Disorder Rating Scale (ADHD-RS) 
• CogState Computerized Cognitive Test Battery 
11.4.17. 
Visit 17E (Week 56) 
• Interactive Voice/Web Response System (IXRS) subject registry/visit 
• Dispense study medication 
• Study drug accountability/assess compliance 
Clinical and Laboratory Evaluations: ALL SUBJECTS 
• Prior/concomitant medication review 
• Adverse event (AE) monitoring 
• Menstrual cyclicity (female subjects) 
• Vital signs 
• Urine drug screen  
• Urine β-hCG (female subjects ≥ 11 years of age only) 
• Simpson-Angus Scale (SAS) 
• Barnes Akathisia Rating Scale (BARS) 
• Abnormal Involuntary Movement Scale (AIMS) 


Protocol D1050302 Version 4.0 
 
Lurasidone 
 
Confidential and Proprietary 
62 
30 Jun 2017 
Clinical Evaluations: SUBJECTS from D1050301 ONLY 
• Clinical Global Impression – Severity Scale (CGI-S) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
Clinical Evaluations: SUBJECTS from D1050325 ONLY 
• Clinical Global Impression – Severity Scale (CGI-S) 
Clinical Evaluations: SUBJECTS from D1050326 ONLY 
• Clinical Global Impression-Bipolar Version, Severity of Illness (CGI BP-S) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
11.4.18. 
Visit 18E (Week 60) 
• Interactive Voice/Web Response System (IXRS) subject registry/visit 
• Dispense study medication 
• Study drug accountability/assess compliance 
Clinical and Laboratory Evaluations: ALL SUBJECTS 
• Prior/concomitant medication review 
• Adverse event (AE) monitoring 
• Menstrual cyclicity (female subjects) 
• Vital signs 
• Urine drug screen  
• Urine β-hCG (female subjects ≥ 11 years of age only) 
• Simpson-Angus Scale (SAS) 
• Barnes Akathisia Rating Scale (BARS) 
• Abnormal Involuntary Movement Scale (AIMS) 
Clinical Evaluations: SUBJECTS from D1050301 ONLY 
• Clinical Global Impression – Severity Scale (CGI-S) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
Clinical Evaluations: SUBJECTS from D1050325 ONLY 
• Clinical Global Impression – Severity Scale (CGI-S) 
Clinical Evaluations: SUBJECTS from D1050326 ONLY 
• Clinical Global Impression-Bipolar Version, Severity of Illness (CGI BP-S) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 


Protocol D1050302 Version 4.0 
 
Lurasidone 
 
Confidential and Proprietary 
63 
30 Jun 2017 
11.4.19. 
Visit 19E (Week 64) 
• Interactive Voice/Web Response System (IXRS) subject registry/visit 
• Dispense study medication 
• Study drug accountability/assess compliance 
Clinical and Laboratory Evaluations: ALL SUBJECTS 
• Prior/concomitant medication review 
• Adverse event (AE) monitoring 
• Height as measured by stadiometer 
• Menstrual cyclicity (female subjects) 
• Vital signs 
• Weight  
• Waist circumference measurement 
• Urine drug screen  
• Urine β-hCG (female subjects ≥ 11 years of age only) 
• Simpson-Angus Scale (SAS) 
• Barnes Akathisia Rating Scale (BARS) 
• Abnormal Involuntary Movement Scale (AIMS) 
Clinical Evaluations: SUBJECTS from D1050301 ONLY 
• Clinical Global Impression – Severity Scale (CGI-S) 
• Children’s Global Assessment Scale (CGAS) 
• Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q) 
• Udvalg for Kliniske Undersogelser Side Effect Rating Scale (UKU) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
• Positive and Negative Syndrome Scale (PANSS) 
Clinical Evaluations: SUBJECTS from D1050325 ONLY 
• Aberrant Behavior Checklist (ABC) 
• Clinical Global Impression – Severity Scale (CGI-S) 
• Children's Yale-Brown Obsessive Compulsive Scales (CY-BOCS) modified for 
pervasive developmental disorders (PDDs) 
• Caregiver Strain Questionnaire (CGSQ) 
Clinical Evaluations: SUBJECTS from D1050326 ONLY 
• Children’s Depression Rating Scale, Revised (CDRS-R) 


Protocol D1050302 Version 4.0 
 
Lurasidone 
 
Confidential and Proprietary 
64 
30 Jun 2017 
• Clinical Global Impression-Bipolar Version, Severity of Illness (CGI BP-S) 
• Children’s Global Assessment Scale (CGAS) 
• Young Mania Rating Scale (YMRS) 
• Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
• Udvalg for Kliniske Undersogelser Side Effect Rating Scale (UKU) 
• Pediatric Anxiety Rating Scale (PARS) 
• Attention-Deficit/Hyperactivity Disorder Rating Scale (ADHD-RS) 
11.4.20. 
Visit 20E (Week 68) 
• Interactive Voice/Web Response System (IXRS) subject registry/visit 
• Dispense study medication 
• Study drug accountability/assess compliance 
Clinical and Laboratory Evaluations: ALL SUBJECTS 
• Prior/concomitant medication review 
• Adverse event (AE) monitoring 
• Menstrual cyclicity (female subjects) 
• Vital signs 
• Urine drug screen  
• Urine β-hCG (female subjects ≥ 11 years of age only) 
• Simpson-Angus Scale (SAS) 
• Barnes Akathisia Rating Scale (BARS) 
• Abnormal Involuntary Movement Scale (AIMS) 
Clinical Evaluations: SUBJECTS from D1050301 ONLY 
• Clinical Global Impression – Severity Scale (CGI-S) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
Clinical Evaluations: SUBJECTS from D1050325 ONLY 
• Clinical Global Impression – Severity Scale (CGI-S) 
Clinical Evaluations: SUBJECTS from D1050326 ONLY 
• Clinical Global Impression-Bipolar Version, Severity of Illness (CGI BP-S) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 


Protocol D1050302 Version 4.0 
 
Lurasidone 
 
Confidential and Proprietary 
65 
30 Jun 2017 
11.4.21. 
Visit 21E (Week 72) 
• Interactive Voice/Web Response System (IXRS) subject registry/visit 
• Dispense study medication 
• Study drug accountability/assess compliance 
Clinical and Laboratory Evaluations: ALL SUBJECTS 
• Prior/concomitant medication review 
• Adverse event (AE) monitoring 
• Menstrual cyclicity (female subjects) 
• Vital signs 
• Urine drug screen  
• Urine β-hCG (female subjects ≥ 11 years of age only) 
• Simpson-Angus Scale (SAS) 
• Barnes Akathisia Rating Scale (BARS) 
• Abnormal Involuntary Movement Scale (AIMS) 
Clinical Evaluations: SUBJECTS from D1050301 ONLY 
• Clinical Global Impression – Severity Scale (CGI-S) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
Clinical Evaluations: SUBJECTS from D1050325 ONLY 
• Clinical Global Impression – Severity Scale (CGI-S) 
Clinical Evaluations: SUBJECTS from D1050326 ONLY 
• Clinical Global Impression-Bipolar Version, Severity of Illness (CGI BP-S) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
11.4.22. 
Visit 22E (Week 76) 
• Interactive Voice/Web Response System (IXRS) subject registry/visit 
• Dispense study medication 
• Study drug accountability/assess compliance 
Clinical and Laboratory Evaluations: ALL SUBJECTS 
• Prior/concomitant medication review 
• Adverse event (AE) monitoring 
• Physical examination 
• Height as measured by stadiometer 


Protocol D1050302 Version 4.0 
 
Lurasidone 
 
Confidential and Proprietary 
66 
30 Jun 2017 
• Tanner staging 
• Menstrual cyclicity (female subjects) 
• Vital signs 
• Weight  
• Waist circumference measurement 
• Electrocardiogram (ECG) 
• Hematology, chemistry, and urinalysis 
• Hormonal Parameters 
• Serum prolactin 
• Glycosylated hemoglobin (HbA1c) 
• Glucose and lipid panel 
• Serum insulin and C-reactive protein 
• Urine drug screen  
• Urine β-hCG (female subjects ≥ 11 years of age only) 
• Simpson-Angus Scale (SAS) 
• Barnes Akathisia Rating Scale (BARS) 
• Abnormal Involuntary Movement Scale (AIMS) 
Clinical Evaluations: SUBJECTS from D1050301 ONLY 
• Clinical Global Impression – Severity Scale (CGI-S) 
• Children’s Global Assessment Scale (CGAS) 
• Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q) 
• Udvalg for Kliniske Undersogelser Side Effect Rating Scale (UKU) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
• Positive and Negative Syndrome Scale (PANSS) 
• CogState Cognitive Test Battery 
Clinical Evaluations: SUBJECTS from D1050325 ONLY 
• Aberrant Behavior Checklist (ABC) 
• Clinical Global Impression – Severity Scale (CGI-S) 
• Children's Yale-Brown Obsessive Compulsive Scales (CY-BOCS) modified for 
pervasive developmental disorders (PDDs) 
• Caregiver Strain Questionnaire (CGSQ) 
Clinical Evaluations: SUBJECTS from D1050326 ONLY 


Protocol D1050302 Version 4.0 
 
Lurasidone 
 
Confidential and Proprietary 
67 
30 Jun 2017 
• Children’s Depression Rating Scale, Revised (CDRS-R) 
• Clinical Global Impression-Bipolar Version, Severity of Illness (CGI BP-S) 
• Children’s Global Assessment Scale (CGAS) 
• Young Mania Rating Scale (YMRS) 
• Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
• Udvalg for Kliniske Undersogelser Side Effect Rating Scale (UKU) 
• Pediatric Anxiety Rating Scale (PARS) 
• Attention-Deficit/Hyperactivity Disorder Rating Scale (ADHD-RS) 
• CogState Computerized Cognitive Test Battery 
11.4.23. 
Visit 23E (Week 80) 
• Interactive Voice/Web Response System (IXRS) subject registry/visit 
• Dispense study medication 
• Study drug accountability/assess compliance 
Clinical and Laboratory Evaluations: ALL SUBJECTS 
• Prior/concomitant medication review 
• Adverse event (AE) monitoring 
• Menstrual cyclicity (female subjects) 
• Vital signs 
• Urine drug screen  
• Urine β-hCG (female subjects ≥ 11 years of age only) 
• Simpson-Angus Scale (SAS) 
• Barnes Akathisia Rating Scale (BARS) 
• Abnormal Involuntary Movement Scale (AIMS) 
Clinical Evaluations: SUBJECTS from D1050301 ONLY 
• Clinical Global Impression – Severity Scale (CGI-S) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
Clinical Evaluations: SUBJECTS from D1050325 ONLY 
• Clinical Global Impression – Severity Scale (CGI-S) 
Clinical Evaluations: SUBJECTS from D1050326 ONLY 
• Clinical Global Impression-Bipolar Version, Severity of Illness (CGI BP-S) 


Protocol D1050302 Version 4.0 
 
Lurasidone 
 
Confidential and Proprietary 
68 
30 Jun 2017 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
11.4.24. 
Visit 24E (Week 84) 
• Interactive Voice/Web Response System (IXRS) subject registry/visit 
• Dispense study medication 
• Study drug accountability/assess compliance 
Clinical and Laboratory Evaluations: ALL SUBJECTS 
• Prior/concomitant medication review 
• Adverse event (AE) monitoring 
• Menstrual cyclicity (female subjects) 
• Vital signs 
• Urine drug screen  
• Urine β-hCG (female subjects ≥ 11 years of age only) 
• Simpson-Angus Scale (SAS) 
• Barnes Akathisia Rating Scale (BARS) 
• Abnormal Involuntary Movement Scale (AIMS) 
Clinical Evaluations: SUBJECTS from D1050301 ONLY 
• Clinical Global Impression – Severity Scale (CGI-S) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
Clinical Evaluations: SUBJECTS from D1050325 ONLY 
• Clinical Global Impression – Severity Scale (CGI-S) 
Clinical Evaluations: SUBJECTS from D1050326 ONLY 
• Clinical Global Impression-Bipolar Version, Severity of Illness (CGI BP-S) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
11.4.25. 
Visit 25E (Week 88) 
• Interactive Voice/Web Response System (IXRS) subject registry/visit 
• Dispense study medication 
• Study drug accountability/assess compliance 
Clinical and Laboratory Evaluations: ALL SUBJECTS 
• Prior/concomitant medication review 
• Adverse event (AE) monitoring 
• Height as measured by stadiometer 


Protocol D1050302 Version 4.0 
 
Lurasidone 
 
Confidential and Proprietary 
69 
30 Jun 2017 
• Menstrual cyclicity (female subjects) 
• Vital signs 
• Weight  
• Waist circumference measurement 
• Urine drug screen  
• Urine β-hCG (female subjects ≥ 11 years of age only) 
• Simpson-Angus Scale (SAS) 
• Barnes Akathisia Rating Scale (BARS) 
• Abnormal Involuntary Movement Scale (AIMS) 
Clinical Evaluations: SUBJECTS from D1050301 ONLY 
• Clinical Global Impression – Severity Scale (CGI-S) 
• Children’s Global Assessment Scale (CGAS) 
• Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q) 
• Udvalg for Kliniske Undersogelser Side Effect Rating Scale (UKU) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
• Positive and Negative Syndrome Scale (PANSS) 
Clinical Evaluations: SUBJECTS from D1050325 ONLY 
• Aberrant Behavior Checklist (ABC) 
• Clinical Global Impression – Severity Scale (CGI-S) 
• Children's Yale-Brown Obsessive Compulsive Scales (CY-BOCS) modified for 
pervasive developmental disorders (PDDs) 
• Caregiver Strain Questionnaire (CGSQ) 
Clinical Evaluations: SUBJECTS from D1050326 ONLY 
• Children’s Depression Rating Scale, Revised (CDRS-R) 
• Clinical Global Impression-Bipolar Version, Severity of Illness (CGI BP-S) 
• Children’s Global Assessment Scale (CGAS) 
• Young Mania Rating Scale (YMRS) 
• Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
• Udvalg for Kliniske Undersogelser Side Effect Rating Scale (UKU) 
• Pediatric Anxiety Rating Scale (PARS) 
• Attention-Deficit/Hyperactivity Disorder Rating Scale (ADHD-RS) 


Protocol D1050302 Version 4.0 
 
Lurasidone 
 
Confidential and Proprietary 
70 
30 Jun 2017 
11.4.26. 
Visit 26E (Week 92) 
• Interactive Voice/Web Response System (IXRS) subject registry/visit 
• Dispense study medication 
• Study drug accountability/assess compliance 
Clinical and Laboratory Evaluations: ALL SUBJECTS 
• Prior/concomitant medication review 
• Adverse event (AE) monitoring 
• Menstrual cyclicity (female subjects) 
• Vital signs 
• Urine drug screen  
• Urine β-hCG (female subjects ≥ 11 years of age only) 
• Simpson-Angus Scale (SAS) 
• Barnes Akathisia Rating Scale (BARS) 
• Abnormal Involuntary Movement Scale (AIMS) 
Clinical Evaluations: SUBJECTS from D1050301 ONLY 
• Clinical Global Impression – Severity Scale (CGI-S) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
Clinical Evaluations: SUBJECTS from D1050325 ONLY 
• Clinical Global Impression – Severity Scale (CGI-S) 
Clinical Evaluations: SUBJECTS from D1050326 ONLY 
• Clinical Global Impression-Bipolar Version, Severity of Illness (CGI BP-S) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
11.4.27. 
Visit 27E (Week 96) 
• Interactive Voice/Web Response System (IXRS) subject registry/visit 
• Dispense study medication 
• Study drug accountability/assess compliance 
Clinical and Laboratory Evaluations: ALL SUBJECTS 
• Prior/concomitant medication review 
• Adverse event (AE) monitoring 
• Menstrual cyclicity (female subjects) 
• Vital signs 


Protocol D1050302 Version 4.0 
 
Lurasidone 
 
Confidential and Proprietary 
71 
30 Jun 2017 
• Urine drug screen  
• Urine β-hCG (female subjects ≥ 11 years of age only) 
• Simpson-Angus Scale (SAS) 
• Barnes Akathisia Rating Scale (BARS) 
• Abnormal Involuntary Movement Scale (AIMS) 
Clinical Evaluations: SUBJECTS from D1050301 ONLY 
• Clinical Global Impression – Severity Scale (CGI-S) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
Clinical Evaluations: SUBJECTS from D1050325 ONLY 
• Clinical Global Impression – Severity Scale (CGI-S) 
Clinical Evaluations: SUBJECTS from D1050326 ONLY 
• Clinical Global Impression-Bipolar Version, Severity of Illness (CGI BP-S) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
11.4.28. 
Visit 28E (Week 100) 
• Interactive Voice/Web Response System (IXRS) subject registry/visit 
• Dispense study medication 
• Study drug accountability/assess compliance 
Clinical and Laboratory Evaluations: ALL SUBJECTS 
• Prior/concomitant medication review 
• Adverse event (AE) monitoring 
• Menstrual cyclicity (female subjects) 
• Vital signs 
• Urine drug screen  
• Urine β-hCG (female subjects ≥ 11 years of age only) 
• Simpson-Angus Scale (SAS) 
• Barnes Akathisia Rating Scale (BARS) 
• Abnormal Involuntary Movement Scale (AIMS) 
Clinical Evaluations: SUBJECTS from D1050301 ONLY 
• Clinical Global Impression – Severity Scale (CGI-S) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
Clinical Evaluations: SUBJECTS from D1050325 ONLY 


Protocol D1050302 Version 4.0 
 
Lurasidone 
 
Confidential and Proprietary 
72 
30 Jun 2017 
• Clinical Global Impression – Severity Scale (CGI-S) 
Clinical Evaluations: SUBJECTS from D1050326 ONLY 
• Clinical Global Impression-Bipolar Version, Severity of Illness (CGI BP-S) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
11.4.29. 
Visit 29E EOS/ET (Week 104) 
• Interactive Voice/Web Response System (IXRS) subject registry/visit 
• Study drug accountability/assess compliance 
Clinical and Laboratory Evaluations: ALL SUBJECTS 
• Prior/concomitant medication review 
• Adverse event (AE) monitoring 
• Physical examination 
• Height as measured by stadiometer 
• Tanner staging 
• Menstrual cyclicity (female subjects) 
• Vital signs 
• Weight  
• Waist circumference measurement 
• Electrocardiogram (ECG) 
• Hematology, chemistry, and urinalysis 
• Hormonal Parameters 
• Serum prolactin 
• Glycosylated hemoglobin (HbA1c) 
• Glucose and lipid panel 
• Serum insulin and C-reactive protein 
• Urine drug screen  
• Urine β-hCG (female subjects ≥ 11 years of age only) 
• Simpson-Angus Scale (SAS) 
• Barnes Akathisia Rating Scale (BARS) 
• Abnormal Involuntary Movement Scale (AIMS) 
Clinical Evaluations: SUBJECTS from D1050301 ONLY 
• Clinical Global Impression – Severity Scale (CGI-S) 


Protocol D1050302 Version 4.0 
 
Lurasidone 
 
Confidential and Proprietary 
73 
30 Jun 2017 
• Children’s Global Assessment Scale (CGAS) 
• Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q) 
• Udvalg for Kliniske Undersogelser Side Effect Rating Scale (UKU) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
• Positive and Negative Syndrome Scale (PANSS) 
• CogState Cognitive Test Battery 
Clinical Evaluations: SUBJECTS from D1050325 ONLY 
• Aberrant Behavior Checklist (ABC) 
• Clinical Global Impression – Severity Scale (CGI-S) 
• Children's Yale-Brown Obsessive Compulsive Scales (CY-BOCS) modified for 
pervasive developmental disorders (PDDs) 
• Caregiver Strain Questionnaire (CGSQ) 
Clinical Evaluations: SUBJECTS from D1050326 ONLY 
• Children’s Depression Rating Scale, Revised (CDRS-R) 
• Clinical Global Impression-Bipolar Version, Severity of Illness (CGI BP-S) 
• Children’s Global Assessment Scale (CGAS) 
• Young Mania Rating Scale (YMRS) 
• Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
• Udvalg for Kliniske Undersogelser Side Effect Rating Scale (UKU) 
• Pediatric Anxiety Rating Scale (PARS) 
• Attention-Deficit/Hyperactivity Disorder Rating Scale (ADHD-RS) 
• CogState Computerized Cognitive Test Battery 
11.4.30. 
Visit 30E (Week 105) 
• Interactive Voice/Web Response System (IXRS) subject registry/visit 
Clinical and Laboratory Evaluations: ALL SUBJECTS 
• Prior/concomitant medication review 
• Adverse event (AE) monitoring 
• Menstrual cyclicity (female subjects) 
• Vital signs 
• Urine β-hCG (female subjects ≥ 11 years of age only) 


Protocol D1050302 Version 4.0 
 
Lurasidone 
 
Confidential and Proprietary 
74 
30 Jun 2017 
• Simpson-Angus Scale (SAS) 
• Barnes Akathisia Rating Scale (BARS) 
• Abnormal Involuntary Movement Scale (AIMS) 
Clinical Evaluations: SUBJECTS from D1050301 ONLY 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
Clinical Evaluations: SUBJECTS from D1050326 ONLY 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
 
 
 


Protocol D1050302 Version 4.0 
 
Lurasidone 
 
Confidential and Proprietary 
75 
30 Jun 2017 
12. 
DISCONTINUATION AND REPLACEMENT OF SUBJECTS/ 
CLINICAL ASSESSMENTS AFTER STUDY MEDICATION 
DISCONTINUATION  
Subjects may withdraw from the study at any time for any reason. 
12.1. 
Study Participation Termination Criteria 
The reason for early discontinuation from study participation is to be recorded as one of the 
following: 
• Adverse event (specify) 
• Lack of efficacy (specify) 
• Lost to follow-up (specify) 
• Other (specify) 
• Protocol violation (specify) 
• Withdrawal by subject (specify) 
Discontinuations due to an adverse event may include laboratory, vital signs, or other test 
abnormalities that result in early discontinuation. Please note that all AEs are to be recorded on 
the AE page. Serious adverse events that result in discontinuation or that result in death (an 
outcome resulting from an AE) are to be recorded on the AE page. The investigator or study 
coordinator must notify the Sponsor or Sponsor designee as soon as possible when a subject has 
been discontinued/withdrawn due to an AE (telephone or fax). 
Subjects whose study participation is prematurely terminated will not be replaced.  
12.2. 
Follow-up Procedures Upon Discontinuation/Withdrawal 
If a subject discontinues study medication treatment due to an AE, then the subject should be 
evaluated until resolution or stabilization of the adverse event. When a subject 
discontinues/withdraws prior to study completion, all applicable activities scheduled for the final 
study visit should be performed at the time of discontinuation. A termination eCRF page should 
be completed for every subject who received study medication whether or not the subject 
completed the study. The reason for discontinuation should be indicated on the eCRF. Any AEs 
that are present at the time of discontinuation/withdrawal should be followed in accordance with 
the safety requirements outlined in Section 13. Subjects who discontinue from the study will not 
be replaced. Subjects who discontinue from the study must be referred by the Investigator for 
appropriate follow-up care. 
For all subjects a follow-up visit will be scheduled for 7 (± 3) days after the last dose of study 
medication to monitor AEs and SAEs. If an in-person visit is not possible, telephone contact will 
be made with the subject to assess any post study discontinuation adverse effects.  


Protocol D1050302 Version 4.0 
 
Lurasidone 
 
Confidential and Proprietary 
76 
30 Jun 2017 
13. 
ADVERSE EXPERIENCE REPORTING 
13.1. 
Adverse Events  
An adverse event (AE) is any new, untoward medical occurrence or worsening of a pre-existing 
medical condition that occurs during study participation, whether or not the event is considered 
drug related.  
AEs will be collected from the time the informed consent is signed to the end of the study. 
Serious adverse events (SAEs) will be collected and reported on the SAE form, from the time of 
informed consent to 14 days post last dose and will be followed until resolution or lost to follow 
up. SAEs occurring from the time of informed consent to the end of study must be recorded on 
the CRF and the data recorded should match that on the SAE form. 
Non-leading questions will be used to ask subjects about the possible occurrence of AEs. The 
investigator should attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. In such cases, the diagnosis should be documented as the AE 
and not the individual signs/symptoms. 
Following questioning and evaluation, all AEs, whether believed by the investigator to be related 
or unrelated to the study medication, must be documented in the subject’s study records/source 
documents, in accordance with the investigator’s normal clinical practice, and on the AE page of 
the CRF. Each AE is to be evaluated for duration, intensity, seriousness, and causal relationship 
to the study medication. Appendix C (Definitions for Reporting Adverse Events) provides 
definitions for severity of an adverse event, relationship to study medication, frequency, and 
action taken. An AE is deemed associated with the use of the study drug “if there is a reasonable 
possibility that the experience may have been caused by the drug” (21 CFR 312.32 [a]).  
The Medical Monitor is the initial contact person for protocol related questions or discussion of 
AEs. The contact information for the Medical Monitor as well as other emergency contact 
information can be found in Table 1 of this protocol. 
13.2. 
Objective Findings 
New and worsening signs and symptoms of underlying or emerging disease must be recorded as 
AEs. Clinically significant abnormal objective findings (eg, clinical laboratory value, ECG 
value, and physical examination observation) will also be recorded on the Adverse Event page of 
the CRF from signing of the informed consent onwards. When a clear diagnosis is available that 
explains the objective findings, this diagnosis will be recorded as the AE, and not the abnormal 
objective finding (eg, viral hepatitis will be recorded as the AE, not transaminase elevation). If a 
definite diagnosis is not available, then record the sign (eg, clinically significant elevation of 
transaminase levels) or symptom (eg, abdominal pain) as the AE. 
Clinical laboratory test results will be reviewed by an investigator as they become available. The 
investigator must determine the clinical significance of all out of range values. Possibly 
drug-related or clinically relevant abnormal values of uncertain causality must be repeated. Any 
abnormal values that persist should be followed at the discretion of the investigator. Laboratory 
reports will be initialed and dated on all pages by a Form FDA 1572-listed investigator. 


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All on site ECG tracings and ECG over-read reports will be reviewed by an investigator as they 
become available. The investigator must determine the clinical significance of all abnormal ECG 
interpretations on the machine read tracing. Possibly drug-related or clinically relevant abnormal 
ECGs of uncertain causality must be repeated. Any abnormal ECGs that persist should be 
followed at the discretion of the investigator. ECG tracings will be initialed and dated on all 
pages by a Form FDA 1572-listed investigator. 
13.3. 
Immediately Reportable Events 
There are two categories of medical events that could occur during participation in a clinical 
study that must be immediately reported:  
• SAE, including death. 
• The incidence of pregnancy.  
The appropriate Pharmacovigilance (PVG) group must be contacted immediately upon first 
knowledge of the incident. 
Emergency contact information can be found in Table 1 of this protocol. 
An AE or suspected adverse reaction is considered “serious” if, in the view of either the 
investigator or Sponsor, it results in any of the following outcomes: death, a life-threatening AE, 
in-patient hospitalization or prolongation of existing hospitalization, a persistent or significant 
incapacity or substantial disruption of the ability to conduct normal life functions, or 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 upon appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition.  
Life-threatening means that the subject was, in the view of the investigator, at immediate risk of 
death from the event as it occurred. This definition does not include an event that, had it occurred 
in a more severe form might have caused death. 
If an investigator or study site staff becomes aware of a SAE that occurs in a study subject from 
the time that informed consent is signed through 14 days following the last dose of study 
medication, this must be reported immediately to PVG. 
In addition to the initial telephone notification, an initial SAE form as applicable must be 
completed and sent via fax to PVG within 1 business day of an investigator or study site staff 
becoming aware of the event. Sunovion Pharmaceuticals Inc. provides the SAE form used to 
report SAEs as a part of the document package necessary to conduct this clinical study.  
Sunovion Pharmaceuticals Inc. will promptly notify all research sites of an AE that is determined 
to be reportable to the Regulatory Authorities. These AEs must be promptly reported to the 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) by the Principal 
investigator. 
If a subject becomes pregnant during the course of the study, she will be instructed to 
immediately stop taking study medication. Further, the subject will be instructed to return within 
48 hours of the first notification of pregnancy to the research site and undergo a serum pregnancy 
test, as confirmation of pregnancy. If positive, the subject will no longer receive any additional 


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study medication and will continue to be followed. All pregnancies, whether or not the subject 
received any study medication, will be followed until resolution (ie, termination [voluntary or 
spontaneous] or birth).  
If a pregnancy is reported for the study subject’s partner, the Sponsor’s representative will 
provide instructions on how to collect pregnancy information in accordance with local 
requirements. Proper consent to collect the partner’s information will be obtained prior to the 
collection of any information. 
To report a pregnancy, the Pregnancy Event Form must be completed and sent via facsimile to 
PVG within 1 business day of first knowledge by the research personnel of the pregnancy. 
Sunovion Pharmaceuticals Inc. provides the Pregnancy Event Form as a part of the document 
package necessary to conduct this clinical study. Pregnancies occurring from the time the 
informed consent is signed through 7 days following the last dose of study medication, will be 
followed quarterly until birth or termination of the pregnancy.  
13.3.1. 
Bone Fractures 
All confirmed cases of bone fracture, regardless of seriousness or presumed relationship to study 
drug, must be reported as SAEs. All procedures for reporting of SAEs as detailed in the current 
protocol are to be followed for these events. 
13.4. 
Preplanned Hospitalizations or Procedures 
During the study, if a subject has a hospitalization or procedure (eg, elective surgery) that was 
scheduled prior to the subject entering the study (ie, before the subject signed the informed 
consent form [ICF]) for an event/condition that occurred before the study, the hospitalization is 
considered a therapeutic intervention and not the result of an SAE. It should have been clearly 
documented prior to signing the ICF. However, if the event/condition worsens during the study, 
it must be reported as an AE (or SAE, if the event/condition results in a serious outcome such as 
prolongation of hospitalization). 
13.5. 
Data and Safety Monitoring Board 
A DSMB will review safety and clinical outcome data including data on AEs and SAEs at 
regular intervals until the D1050301, D1050325, and D1050326 studies are complete and as long 
as necessary for the D1050302 study, as determined by the Sponsor. The DSMB will be 
independent of the Sponsor, CRO, and the investigators and will be empowered to recommend 
stopping the study due to safety concerns, but not for efficacy or futility. The membership of the 
DSMB and its mandate is denoted in the DSMB charter. 
 
 
 


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14. 
STATISTICS 
A Statistical Analysis Plan (SAP) will provide details on the statistical methods planned for this 
study and will be finalized prior to the 1st interim data cut, which will happen when at least 
100 subjects continued from studies D1050301 and D1050325 complete the Week 28 Visit. 
14.1. 
Randomization and Blinding 
This is an open-label study, therefore randomization and blinding will not be employed. 
14.2. 
Unblinding Procedures 
This section is not applicable to this study. 
14.3. 
Hypotheses 
Because of the nature of an open-labeled study, no hypotheses are planned. 
14.4. 
Variables and Timepoints 
14.4.1. 
Primary Safety Variables 
The primary safety variables include treatment-emergent AEs and SAEs, and discontinuations 
due to AEs. 
14.4.2. 
Other Safety Variables 
Safety and tolerability will further be assessed by the following variables: laboratory values, 
ECGs, physical examinations, movement disorders (AIMS, BARS, and SAS scores), vital signs, 
height, weight, BMI, waist circumference, tanner staging, menstrual cyclicity (female subjects), 
and hormonal parameters. For subjects previously enrolled in the D1050301 and D1050326, 
safety will further be assessed by CogState Cognitive Test Battery, C-SSRS, and UKU. In 
addition, for subjects previously enrolled in study D1050326, Young Mania Rating Scale 
(YMRS) will be also assessed. 
14.5. 
Sample Size Considerations 
Subjects who complete the respective double-blind studies D1050301, D1050325 or D1050326, 
sign the consent, and meet all entry criteria will be included in this study. Studies D1050301, 
D1050325, and D1050326 have finished, with a total of 271 subjects from D1050301, 
125 subjects from D1050325, and 306 subjects from D1050326 enrolling into D1050302. Based 
on an estimated attrition rate of approximately 30% of subjects over six months, it is expected 
that at least 100 subjects will be exposed to lurasidone for a minimum of 6 months for subjects 
continued from Studies D1050301 and D1050325 in Study D1050302. 
14.6. 
Data Analyses of Interim Data for FDA Filing 
After studies D1050301 and D1050325 are completed, when at least 100 subjects complete the 
Week 28 visit (ie, exposed to study drug for at least 6 months), data analyses based on these 


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interim data will be done to prepare a safety/effectiveness report in support of the initial health 
authority filing for US regulatory submission for the lurasidone pediatric program. A subsequent 
final analysis of study D1050302 will be performed after every subject previously enrolled from 
study D1050301, D1050325, and D1050326 complete the study. The details of the interim data 
analyses and final data analyses are provided below in Section 14.7, and the SAP. 
14.7. 
Data Analyses 
All data collected in this 104 week open-label study will be summarized and presented in final 
data analyses report. All data collected through the cut-off time point when at least 100 subjects 
previously from studies D1050301 and D1050325 complete the Week 28 Visit will be 
summarized separately for a study report for FDA filing. 
Continuous variables will be summarized using descriptive statistics (number of subjects, mean, 
median, standard deviation or standard error, minimum and maximum values, and 
95% confidence interval) by visit. Categorical variables will be reported as frequencies and 
percentages by visit. Standard laboratory shift tables will be reported. Where changes are 
reported, the reference will be to the pre-treatment baseline from double-blind studies D1050301, 
D1050325, or D1050326, as indicated as “DB baseline”. Where relevant, changes from baseline 
for the open-label study, as defined as the Week 6 assessment in the double-blind study or the 
last assessment prior to the first dose of the open label study, will also be reported, and will be 
referred to as the open-label study baseline or "OL baseline." 
14.7.1. 
Analysis Population 
Safety population: 
The safety population will consist of all subjects who receive at least one dose of study 
medication. 
14.7.2. 
Definitions of Assessments 
The following definitions will be used for efficacy assessments: 
• DB Baseline (ie, Baseline assessment of the double-blind studies [D1050301, 
D1050325, or D1050326]): the last assessment made on or before double-blind 
randomization as described in the protocols; 
• OL Baseline (ie, Endpoint assessment of the double-blind studies [D1050301, 
D1050325, or D1050326]) or Baseline assessment of the open-label study 
(D1050302): the last assessment made during the double-blind studies, as described 
in the protocols; 
• Week 28 Endpoint assessment: the last post-baseline assessment made prior to or at 
Week 28 visit. 
• Week 104 Endpoint assessment: the last post-baseline assessment made during the 
open-label study (D1050302), as described in the protocol; 
• Scheduled assessment: assessment made during the open-label study (D1050302). 


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14.7.3. 
Analysis Group 
A total of three analysis groups will be formed based on a subject’s previous participation in  
double-blind studies D1050301, D1050325, and D1050326: 
• All subjects previously enrolled in Study D1050301 and enrolled into this extension 
study. 
• All subjects previously enrolled in Study D1050325 and enrolled into this extension 
study. 
• All subjects previously enrolled in Study D1050326 and enrolled into this extension 
study. 
Summary tables, wherever applicable, will be presented for all subjects in the study by above 
analysis group, respectively. 
14.7.4. 
Statistical Methods 
Unless otherwise specified, analysis outputs will be presented for subjects who complete 
double-blind studies D1050301, D1050325, or D1050326, respectively and analyses presented 
will be based on the safety population. 
14.7.4.1. Efficacy Evaluation 
All efficacy evaluations will be summarized for all subjects and by analysis group listed 
Section 14.7.3. 
The efficacy variables to be summarized for this study will include: 
For subjects continued from Study D1050301: 
• Positive and Negative Syndrome Scale (PANSS) total, positive, negative, general 
psychopathology, cognition, and excitability subscale scores; 
• Clinical Global Impression severity (CGI-S) scale; 
• Clinician-rated Children’s Global Assessment Scale (CGAS); 
• Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q). 
For subjects continued from Study D1050325: 
• Aberrant Behavior Checklist (ABC) subscale scores (irritability, hyperactivity, 
stereotypy, inappropriate speech, and lethargy/social withdrawal); 
• Clinical Global Impression severity (CGI-S) scale; 
• Children's Yale-Brown Obsessive Compulsive Scales (CY-BOCS) modified for 
pervasive developmental disorders (PDDs); 
• Caregiver Strain Questionnaire (CGSQ). 
For subjects continued from Study D1050326: 
• Children's Depression Rating Scale, Revised (CDRS-R); 
• Clinical Global Impression Bipolar Version -Severity (CGI-BP-S) scale; 


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• Clinician-rated Children’s Global Assessment Scale (CGAS); 
• Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q); 
• Pediatric Anxiety Rating Scale (PARS); 
• Attention-Deficit/Hyperactivity Disorder Rating Scale (ADHD-RS). 
Since this is an uncontrolled open-label extension of studies D1050301, D1050325, and 
D1050326, no inferential statistics on efficacy will be presented. For all of the efficacy 
assessments, summary statistics (number of subjects, mean, standard deviation, minimum, 
median, and maximum and a 95% confidence interval) will be presented for all subjects by 
analysis group for the DB baseline, OL baseline, each of the scheduled assessments, and the 
endpoint assessments in the open-label study. All analyses for the scheduled assessments will be 
based on observed cases (OC). Confidence intervals will be based on means and standard 
deviations estimated without adjustment for any center or baseline effects. In addition, for all 
efficacy evaluations, differences from DB baseline and OL baseline will be presented in a similar 
way using summary statistics, as described above. 
For time to early discontinuation, Kaplan-Meier curves will be plotted by analysis group. 
14.7.4.2. Safety Evaluation 
All safety evaluations will be summarized for all subjects by analysis group for the safety 
population. 
Safety evaluations include: 
• AEs, SAEs, Discontinuation due to AEs and SAEs; 
• Laboratory safety tests (chemistry, including liver function tests and bilirubin; 
hematology including HbA1c; serum lipids; glucose; hormonal parameters; and 
urinalysis); 
• Body weight, height, BMI, waist circumference, vital signs, physical examinations, 
and ECG parameters; 
• Simpson-Angus Scale (SAS); 
• Barnes Akathisia Rating Scale (BARS); 
• Abnormal Involuntary Movement Scale (AIMS); 
• Tanner staging, and menstrual cyclicity (female subjects). 
For subjects continued from Study D1050301 and D1050326: 
• Columbia Suicide Severity Rating Scale (C-SSRS); 
• CogState Cognitive Test Battery; 
• Udvalg for Kliniske Undersogelser Side Effect Rating Scale (UKU). 
For subjects continued from Study D1050326: 
• Young Mania Rating Scale (YMRS) score. 


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The primary analysis for the study is to assess the incidence of AEs, SAEs, and discontinuations 
due to AEs. The terms used in the eCRFs by investigators to identify adverse events will be 
coded using the Medical Dictionary for Regulatory Activities (MedDRA). All reported adverse 
events with onset on or after the first dose of study drug during the treatment phase 
(ie, treatment-emergent adverse events) will be included in the analysis.  
AEs will be summarized by presenting the number and percentage of subjects having any AE, 
having an AE by body system, and having each individual AE. The incidence of an AE is 
determined by occurrence of at least one AE regardless of the frequency, severity and/or 
relationship to study medications. AEs will also be summarized by maximum severity and 
relationship to study medication (as assessed by the investigator), and action taken. 
Special attention will be given to those subjects who discontinue treatment due to an adverse 
event, or who experienced a severe or a serious adverse event (eg, summaries, listings, and 
narrative preparation may be provided, as appropriate). 
Descriptive statistics will be provided for the all other safety variables or tests and the 
corresponding changes from baseline (including double-blind study baseline and open-label 
study baseline) by scheduled visit. Notable values will be flagged, and any other information 
collected will be listed as appropriate. Continuous variables will be summarized using 
descriptive statistics (number of subjects, mean, standard deviation, median, minimum and 
maximum values). Categorical variables will be reported as frequencies and percentages. For 
weight, height, and BMI, descriptive statistics will be also summarized for the age-adjusted 
standardized scores. 
For subjects continued from study D1050301 and D1050326, descriptive statistics will be 
provided for Udvalg for Kliniske Undersogelser Side Effect Rating Scale (UKU) and the 
age-adjusted standardized CogState composite score. For C-SSRS, number and percentage of 
subjects with suicidal ideations and behaviors will be summarized.  
For subjects continued from study D1050326, descriptive statistics will be presented for YMRS 
result by analysis group and study visit. 
Frequency distribution of the tanner staging will be tabulated by visit and gender. 


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15. 
COMPUTERIZED SYSTEMS USED FOR SOURCE DATA 
A list of the computerized systems that will be used at each step to create, modify, maintain, 
archive, retrieve, or transmit source data are presented below, per the Guidance for Industry 
Computerized Systems Used in Clinical Investigations, May 2007. 
Table 8: 
Computerized Systems Used for Source Data 
Protocol Step  
Computerized System 
Type or Description 
Obtain informed consent/assent 
NA 
Inclusion/exclusion criteria 
A 
Prior/concomitant medication review 
A 
Interactive Voice/Web Response System (IXRS) subject registry/study medication 
assignment 
G 
Study drug accountability/assess compliance 
A 
Clinical and Laboratory Evaluations: ALL SUBJECTS 
 
Physical examination 
A 
Height as measured by stadiometer 
A 
Tanner staging 
A 
Vital signs 
A 
Weight  
A 
Waist circumference measurement 
A 
Electrocardiogram (ECG) 
C 
Hematology, chemistry, and urinalysis 
B 
Hormonal Parameters 
B 
Serum prolactin 
B 
Glycosylated hemoglobin (HbA1c) 
B 
Glucose and lipid panel 
B 
Serum insulin and C-reactive protein 
B 
Urine β-hCG 
NA 
Adverse event (AE) monitoring 
A 
Barnes Akathisia Rating Scale (BARS) 
A 
Abnormal Involuntary Movement Scale (AIMS) 
A 
Simpson-Angus Scale (SAS) 
A 
Clinical Evaluations: SUBJECTS from D1050301 ONLY 
 
Children’s Global Assessment Scale (CGAS) 
A 
Clinical Global Impression – Severity Scale (CGI-S) 
A 
Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q) 
A 
Udvalg for Kliniske Undersogelser Side Effect Rating Scale (UKU) 
A 


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Protocol Step  
Computerized System 
Type or Description 
Columbia Suicide Severity Rating Scale (C-SSRS) 
A 
Positive and Negative Syndrome Scale (PANSS) 
A 
CogState Cognitive Test Battery 
E 
Clinical Evaluations: SUBJECTS from D1050325 ONLY 
 
Aberrant Behavior Checklist (ABC) 
A 
Clinical Global Impression – Severity Scale (CGI-S) 
A 
Children's Yale-Brown Obsessive Compulsive Scales (CY-BOCS) modified for 
pervasive developmental disorders (PDDs) 
A 
Caregiver Strain Questionnaire (CGSQ) 
A 
Clinical Evaluations:  
SUBJECTS from D1050326 ONLY 
 
Children’s Depression Rating Scale, Revised (CDRS-R) 
A 
Clinical Global Impression-Bipolar Version, Severity of Illness (CGI BP-S) 
A 
Children’s Global Assessment Scale (CGAS) 
A 
Young Mania Rating Scale (YMRS) 
A 
Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q) 
A 
Columbia Suicide Severity Rating Scale (C-SSRS) 
A 
Udvalg for Kliniske Undersogelser Side Effect Rating Scale (UKU) 
A 
Pediatric Anxiety Rating Scale (PARS) 
A 
Attention-Deficit/Hyperactivity Disorder Rating Scale (ADHD-RS) 
A 
CogState Computerized Cognitive Test Battery 
E 
A = EDC (Medidata RAVE); B = LIMS; C = Core Lab Over-read; D = LIMS/ASCII; E = Computerized Assessment System; 
F = ePRO; G = IXRS.  
 Abbreviations: EDC = electronic data capture; CDR = clinical data repository; ePRO = electronic patient reported outcomes; 
IXRS = Interactive Voice/Web Response System; LIMS = laboratory information management system. 
 


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16. 
ETHICAL AND REGULATORY OBLIGATIONS 
16.1. 
Study Conduct 
The investigator agrees that the study will be conducted according to the protocol, the US Code 
of Federal Regulations (CFR), Good Clinical Practice (GCP) (E6) and the ethical principles that 
have their origin in the Declaration of Helsinki and the International Conference on 
Harmonisation (ICH) guidelines. The investigator will conduct all aspects of this study in 
accordance with all national, state, and local laws of the pertinent regulatory authorities. 
The investigator will assure proper implementation and conduct of the study including those 
study-related duties delegated to other appropriately qualified individuals. The investigator will 
assure that study staff cooperate with monitoring and current audits, and will demonstrate due 
diligence in recruiting and screening study subjects. 
The investigator must sign and return to CRO/Sponsor the "Study Acknowledgment" page and 
provide a copy of current curriculum vitae (CV), including a copy of a current medical license, 
current Drug Enforcement Agency (DEA) license, where applicable, and financial disclosure. In 
countries where medical licensure is not issued, the following documentation is acceptable, as 
applicable:  
• Registration number/stamp with a registration number stated on CV. 
• Appropriate diploma number stated on CV. 
• Copy of the diploma. 
For all studies conducted under an Investigational New Drug (IND), the investigator must sign 
and return a completed Form FDA 1572 "Statement of investigator" to CRO/Sponsor. 
16.2. 
Institutional Review Board or Independent Ethics Committee 
Before initiation of the study, the investigator/CRO must obtain approval or favorable opinion of 
the research protocol, informed consent form, and any advertisement for subject recruitment, 
from an IRB or IEC complying with the provisions specified in 21 CFR Part 56 or in ICH GCP, 
as applicable, and applicable pertinent government regulations. The investigator must assure IRB 
or IEC compliance with the applicable regulations. 
A copy of written IRB or IEC approval or favorable opinion of the protocol, informed consent 
form and advertising (if applicable) must be provided to CRO/Sponsor prior to initiation of the 
study. The approval or favorable opinion letter must be signed by the IRB or IEC chairman or 
designee, identify the IRB/IEC name and address, identify the clinical protocol by title and/or 
protocol number, and include the date that approval or favorable opinion was granted. The letter 
must also contain a statement that the IRB or IEC complies with the requirements in 21 CFR 
Part 56 for a study conducted under an IND or ICH GCP, as applicable. 
The investigator/CRO is responsible for obtaining continued review of the clinical research or 
submitting periodic progress reports, in accordance with applicable regulations, at intervals not 


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exceeding one year or otherwise specified by the IRB or IEC. The Sponsor must be supplied 
with written documentation of continued review of the clinical research. 
The investigator must promptly inform their IRB/IEC of all SAEs or other safety information 
reported from CRO/Sponsor in accordance with 21 CFR 312.66, or when dictated by applicable 
local regulations (ie, Directive 2001/20/EC), the Sponsor/CRO is responsible for reporting to the 
IEC (eg, reporting of serious AEs). 
16.3. 
Informed Consent 
The investigator will prepare the informed consent form and provide the form to CRO/Sponsor 
for approval prior to submission to the IRB or IEC. CRO/Sponsor may provide a template 
informed consent form to be qualified by each research facility to conform to local requirements. 
All informed consent forms must contain the minimum elements as mandated by the FDA or 
governing regulatory authority and ICH guidelines and will be subject to CRO/Sponsor approval 
as well as IRB or IEC approval. CRO/Sponsor may submit informed consent forms to a central 
IRB or IEC for review and approval or favorable opinion contingent upon prior investigator 
permission and review.  
Before recruitment and enrollment, where developmentally appropriate, each prospective 
candidate will be given a full explanation of the study, allowed to read the approved informed 
consent form or assent form for prospective candidates < 18 years of age and be provided ample 
time and the opportunity to ask any questions that may arise. Once all questions have been 
answered and the investigator is assured that the individual or parent or legal guardian for 
individuals < 18 years of age understands the implications of participating in the study, the 
subject will be asked to give consent or assent for subjects < 18 years of age to participate in the 
study by signing the informed consent/assent form. As part of the consent process, each subject 
must consent to direct access to his/her medical records for study-related monitoring, auditing, 
IRB/IEC review and regulatory inspection. The investigator will provide a copy of the signed 
informed consent form to each subject. For subjects < 18 years, the parent or legal guardian will 
be required to provide written informed consent. For subjects who become 18 years of age 
during the course of this study, they will need to give informed consent upon becoming 18 years 
of age (or as soon as possible thereafter). 
For this study, the parents or guardians must give permission for their children to participate and 
demonstrate their agreement by signing the informed consent document. The child or teenager 
will be provided with a form that explains, in age-appropriate terms, the purpose of the research, 
what they will be asked to do, and what procedures they will undergo. For this study, where 
developmentally appropriate, the assent of the child/or adolescent is deemed required. The assent 
process is an ongoing, interactive conversation between the research team and the child or young 
adult. If at any time the child or young adult shows signs of dissent, the assessment should be 
stopped, the situation assessed and assent established to continue. It should always be made clear 
that the young person has the right to leave the trial, at any time and for any reason, without 
penalty or consequences, and that any information gathered will be kept confidential. 
If an amendment to the protocol changes the subject participation schedule in scope or activity, 
or increases the potential risk to the subject, the informed consent form must be revised, 
submitted to the IRB or IEC for review and approval or favorable opinion. The revised informed 
consent form must be used to obtain consent from a subject currently enrolled in the study if he 


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or she is affected by the amendment. The revised informed consent form must be used to obtain 
consent from any new subjects who are enrolled into the study after the date of the approval or 
favorable opinion of the amendment. 
16.4. 
Subject Privacy 
The Sponsor’s staff or any designees affirm and uphold the subject’s confidentiality. Throughout 
this study, all data forward to the Sponsor will be identified only by an identification number, 
date of birth, gender, and initials. The investigator agrees that its representatives, its designee, 
representatives of the relevant IRB/IEC or representatives of the regulatory authorities will be 
allowed to review that portion of the subject’s primary medical records that directly concerns this 
study (including, but not limited to, clinical laboratory test result reports, ECG reports, 
admission/discharge summaries for hospital admissions occurring during a subject’s study 
participation and autopsy reports for deaths occurring during the study). 
For the studies conducted in the US, in accordance with the Healthcare Insurance, Portability, 
and Accountability Act of 1996, the investigator will prepare a privacy authorization form and 
provide the form to CRO/Sponsor for approval prior to submission to the IRB/IEC or to a 
Privacy Board. CRO/Sponsor may provide a template privacy authorization form to be qualified 
by each research facility to conform to local requirements. The content of the privacy 
authorization form must comply with the regulations governing the authorization. All 
prospective study candidates will be given full explanation of the privacy authorization form, 
allowed to read the approved form, and be provided the opportunity to ask any questions. Once 
all questions have been answered and the investigator is assured that the individual understands 
the implications of the privacy authorization form, the subject will be asked to sign the privacy 
authorization. The authorization remains in effect until revoked by the subject. The investigator 
will provide a copy of the signed privacy authorization form to each subject. Subjects who do not 
sign the privacy authorization form will not be permitted to participate in the study. 
16.5. 
Protocol Amendments and Emergency Deviations 
Changes to the research covered by this protocol must be implemented by formal protocol 
amendment. Amendments to the protocol may be initiated by the Sponsor or at the request of the 
investigator. In either case, a formal amendment cannot be initiated until the Sponsor has 
approved it, the investigator has signed it off, and it has been reviewed and has received approval 
or favorable opinion by the IRB or IEC. 
Emergency deviations or modifications may be initiated without the Sponsor’s or IRB/IEC 
approval or favorable opinion, only in cases where the change is necessary to eliminate an 
immediate apparent hazard to subjects. Emergency deviations or modifications must be reported 
to CRO/Sponsor and the IRB/IEC within five business days of the occurrence, or in accordance 
with applicable regulatory requirements. 
16.6. 
Monitoring and Auditing of the Study 
A clinical monitor, whether an employee of the Sponsor or its designated representative, has the 
obligation to follow this study closely. In doing so, the monitor will visit the clinical study sites 
at periodic intervals, in addition to maintaining necessary telephone and letter contact. The 
monitor will maintain current personal knowledge of the study through observation, review of 


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study records and source documentation, and discussion of the conduct of the study with the 
investigator and staff. Quality assurance auditors, whether an employee of the Sponsor or its 
designated representative, may evaluate the conduct of the study by the clinical study sites. 
These parties must have access to any and all study-related documentation including source 
documentation, regardless of location and format. The Sponsor audit reports will be kept highly 
confidential. 
16.7. 
Study Documentation 
As part of the responsibilities assumed by participating in the study, the investigator agrees to 
maintain adequate case histories for the subjects treated as part of the research under this 
protocol. The investigator agrees to maintain accurate source documentation and CRFs as part of 
the case histories. 
Study records are comprised of source documents, CRFs, and all other administrative 
documents, eg, IRB/IEC correspondence, clinical study materials and supplies shipment 
manifests, monitoring logs, Sponsor and CRO correspondence, etc. A study specific binder will 
be provided with instructions for the maintenance of study records. 
Source documentation is defined as any hand written or computer generated document that 
contains medical information or test results that have been collected for or is in support of the 
protocol specifications, eg, clinical lab reports, clinic notes, drug disbursement log, subject sign 
in sheets, subject completed questionnaires, telephone logs, ECGs, etc. All draft, preliminary and 
pre final iterations of a final report are also considered to be source documents, eg, faxed lab 
reports and hard copy lab reports, faxed initial results and hard copy, final report.  
CRO/Sponsor will supply CRFs. All requested information must be entered on the CRFs. Every 
effort should be made to complete all forms in their entirety. If an item is not available or is not 
applicable, this fact should be indicated; do not leave a space blank. Each set of completed CRFs 
must be reviewed, electronically signed and dated by the investigator.  
16.8. 
Laboratory Certification and Normal Values 
A central laboratory will be used for analysis for most of the clinical labs for this study. The 
central laboratory will provide the investigator, CRO, and Sponsor with laboratory 
certification(s), a dated copy of normal range values for the central clinical laboratory selected to 
analyze clinical specimens, and the lab director’s CV. If an exception is granted to use a local 
laboratory, the investigator must supply the CRO/Sponsor with laboratory certification, lab 
director’s CV and a current, dated copy of normal range values.  
16.9. 
Records Retention 
The investigator agrees to retain study records for the time periods stated below. The investigator 
agrees to contact CRO/Sponsor before destroying any study documentation. Should the 
investigator leave the site at which the study was conducted, CRO/Sponsor will be contacted 
regarding the disposition of document storage. 
Records will be retained until at least 2 years after the last approval of a marketing application in 
an ICH region and until there are no pending or contemplated marketing applications in an ICH 


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region or at least 2 years have elapsed since the formal discontinuation of clinical development 
of the investigational product. 
Dates marking the beginning of the final record retention periods will be sent in writing from 
CRO/Sponsor. If an investigator withdraws from the study (eg, relocation), the records will be 
transferred to a mutually agreed upon designee (ie, another investigator). This transfer is subject 
to Sponsor approval and will be documented in writing and a copy sent to the Sponsor. 
Electronic Data Capture/ePRO Data Archiving: 
In compliance with data retention requirements, and after the capture phase of the study is 
complete, the site will receive a copy of all eSource data and accompanying audit trail from the 
EDC and/or ePRO vendors. The vendors shall certify the integrity of the copy (certified copy) 
and send it on commonly readable storage material (CD or DVD); if necessary, software for 
viewing the data files and instruction on installation and use of the software will also be 
included. This read-only archive will be retained, protected, and made accessible by the site 
throughout the required retention period. 
16.10. 
Inspection of Records 
In the event of an inspection, the investigator agrees to allow representatives of the Sponsor, its 
representative, the Food and Drug Administration or other regulatory authorities’ access to all 
study records. The investigator will promptly notify CRO/Sponsor of all requests to inspect by 
government agencies and will promptly forward a copy of all such inspection reports. 
16.11. 
Financial Disclosure 
Prior to the start of the study, investigators will release sufficient and accurate financial 
information that permits CRO/Sponsor to demonstrate that an investigator and all sub-
investigators listed on the Form FDA 1572, if appropriate, have no personal or professional 
financial incentive regarding the future approval or disapproval of the study medication such that 
his or her research might be biased by such incentive. Investigators will provide an update of the 
above financial information at the end of the study and one year following the end of the study. 


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17. 
STUDY ACKNOWLEDGMENT 
I have read the foregoing protocol, D1050302, Version 4.0, “A 104-Week, Flexible-Dose, Open-
Label, Multicenter, Extension Study to Evaluate the Long-Term Safety and Effectiveness of 
Lurasidone in Pediatric Subjects”, and agree that it contains all necessary details for conducting 
this study and to conduct the study in strict accordance with the specifications outlined herein. 
By signing the protocol, the investigator agrees to keep all information provided by Sunovion 
Pharmaceuticals Inc. in strict confidence and to request the same from his/her staff and the 
Institutional Review Board/Independent Ethics Committee. Study documents provided by 
Sunovion Pharmaceuticals Inc. (protocols, Investigator Brochures, case report forms, and other 
materials) will be stored appropriately to ensure their confidentiality. The information provided 
by Sunovion Pharmaceuticals Inc. to the investigator may not be disclosed to others without 
direct written authorization from Sunovion Pharmaceuticals Inc., except to the extent necessary 
to conduct the study. 
I agree that no additional procedure(s) will be added during the conduct of the study except 
through protocol amendment by Sunovion Pharmaceuticals Inc. and after documentation of IRB 
or IEC approval. 
Investigator Signature: ____________________________________________________ 
Print Investigator Name: __________________________________________________ 
Date: ___________________________________________ 


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18. 
REFERENCES 
Barnes TRE. A rating scale for drug-induced akathisia. Br J Psychiatry 1989;154:672-676. 
Barnes TRE. The Barnes Akathisia Rating Scale – Revisited. J Psychopharmacology 
2003;17(4):365-370. 
Guy W. EDCEU Assessment Manual for Psychopharmacology – Revised (DHEW Publ No 
ADM 76-338). Rockville, MD, U.S. Department of Health, Education, and Welfare, Public 
Health Service, Alcohol, Drug Abuse, and Mental Health Administration, NIMH 
Psychopharmacology Research Branch, Division of Extramural Research Programs, 1976:534-
537. 
Kay SR, Opler LA, Fisbein A. Positive and Negative Syndrome Scale Manual. North 
Tonawanda, NY: Multi-Health Systems, 1994. 
Lingjaerde O, Ahlfors UG, Bech P, Dencker SJ, Elgen K. The UKU side effect rating scale. A 
new comprehensive rating scale for psychotropic drugs and a cross-sectional study of side effects 
in neuroleptic-treated patients. Acta Psychiatr Scand Suppl. 1987;334:1-100. 
Munetz MR, Benjamin S. How to examine subjects using the Abnormal Involuntary Movement 
Scale. Hospital and Community Psychiatry 1988;39:1172-1177. 
Opler LA, Kay SSR, Lindenmayer JP, Fiszbein A. Structured Clinical Interview for the Positive 
and Negative Syndrome Scale (SCI-PANSS). Toronto: Multi-Health Systems, 1992. 
Perkins DO, Stroup TS, Lieberman JA. Psychotic disorders measures. In Handbook of 
Psychiatric Measures. Washington, D.C.: American Psychiatric Association, 2000 p. 485-513.  
Scahill L, McDougle CJ, Williams SK, et al. Children's Yale-Brown Obsessive Compulsive 
Scale modified for pervasive developmental disorders. J Am Acad Child Adolesc Psychiatry. 
2006 Sep;45(9):1114-23. 
Schooler NR, Chengappa KNR. Adverse effects measures. In: Handbook of Psychiatric 
Measures. Washington, D.C.: American Psychiatric Association, 2000 p. 151-168. 
Sheehan DV. The Anxiety Disease. New York, Scribners, 1983. 
Simpson GM, Angus JWS. A rating scale for extrapyramidal side effects. Acta Psychiatrica 
Scandinavia, Suppl 1970; 212S:11-19. 
Williams JBW. Mental health status, functioning, and disabilities measures. In: Handbook of 
Psychiatric Measures. Washington, D.C.: American Psychiatric Association, 2000 p. 93-115. 
 
 


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APPENDIX A. CLINICAL LABORATORY TESTS 
The following laboratory tests are to be performed: 
 
Blood Chemistry Tests 
 
aspartate aminotransferase  
 
alanine aminotransferase  
 
albumin  
 
alkaline phosphatase  
 
bicarbonate  
 
blood urea nitrogen  
 
calcium  
 
chloride  
 
creatinine  
 
gamma-glutamyl transferase  
 
phosphorous  
 
potassium  
 
sodium  
 
total bilirubina 
 
total protein  
 
lactate dehydrogenase  
 
fasting (non-random) triglycerides 
 
fasting (non-random) serum cholesterol  
 
fasting (non-random) serum high-density lipoprotein cholesterol  
 
fasting (non-random) serum low-density lipoprotein cholesterol  
 
fasting glucose  
 
prolactin  
 
whole blood hemoglobin A1c 
 
creatine phosphokinase  
 
Endocrine Tests 
 
free thyroxine test 
 
thyroid-stimulating hormone test 
 
Hormonal Parameters 
 
follicle stimulating hormone (female subjects only) 
 
luteinizing hormone (female subjects only) 
 
testosterone (male subjects only) 
 
estradiol (female subjects only) 
 
serum human chorionic gonadotropin (β-hCG) (female subjects ≥ 11 years of age only) 
 
urine human chorionic gonadotropin (β-hCG) (female subjects ≥ 11 years of age only) 
 
Hematology Tests 
 
white blood cell count 
 
white blood cell differential 
 
eosinophilic leukocyte count 
 
basophilic leukocyte count 
 
neutrophil count 
 
lymphocyte count 
 
monocyte count 
 
platelet count 
 
hemoglobin  
 
blood hematocrit 
 
red blood cell count 


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red cell distribution width  
 
red blood cell indices: 
 
mean corpuscular volume 
 
mean corpuscular hemoglobin concentration 
 
mean corpuscular hemoglobin 
 
Urinalysis Tests 
 
color  
 
appearance  
 
total ketones  
 
urobilinogen  
 
bilirubin  
 
red blood cells 
 
leukocyte esterase  
 
nitrite  
 
pH  
 
protein  
 
specific gravity  
 
glucose  
 
microscopic evaluationb 
 
Urine Drug Screen 
 
amphetamines  
 
benzodiazepines  
 
barbiturates  
 
cocaine  
 
tetrahydrocannabinol  
 
ethanol  
 
methadone  
 
methamphetamine  
 
opiates  
 
phencyclidine  
a Bilirubin will be fractionated (direct serum bilirubin test/indirect serum bilirubin test) if elevated 2.0 times the 
upper limit of the normal range. 
b Microscopic evaluation will be performed if the Chemstrip 9™ (or equivalent dipstick analysis) indicates the 
presence of any significant abnormality. 
Table 9: 
Total Blood Drawn For Laboratory Tests 
Visit 
Total mL 
6E 
8.5 
10E 
8.5 
16E 
8.5 
22E 
8.5 
29E/ET 
8.5 
Total  
42.5 mL 
 


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APPENDIX B. POTENT INHIBITORS AND INDUCERS OF THE 
CYP3A4 ENZYME SYSTEM 
CYP3A4 Inhibitors: 
Azole antifungals 
• Butoconazole 
• Fluconazole 
• Itraconazole 
• Ketoconazole 
• Miconazole 
• Sulconazole 
• Tioconazole 
HIV protease inhibitors 
• Amprenavir 
• Indinavir 
• Nelfinavir 
• Ritonavir 
• Saquinavir 
Macrolide antibiotics 
• Clarithromycin 
• Dirithromycin 
• Erythromycin 
• Troleandomycin 
Miscellaneous 
• Nefazodone 
• Diltiazem 
• Verapamil 
• Amiodarone 
• Cimetidine 
• Grapefruit juice 
CYP3A4 Inducers: 
Barbiturates 
• Amobarbital 
• Butabarbital 
• Butalbital compound 
• Mephobarbital 
• Methohexital 
• Pentobarbital 
• Phenobarbital 
• Primidone 
• Secobarbital 
• Thiopental 
Miscellaneous 
• Carbamazepine 
• Hypericin (St. John’s Wort) 
• Phenytoin 
• Rifampin 
• Oxcarbazepine 
• Topiramate 
 
 


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APPENDIX C. DEFINITIONS FOR REPORTING ADVERSE EVENTS  
The investigator must assess the severity of the AE using the following: 
• Mild - awareness of event but easily tolerated. 
• Moderate - discomfort enough to cause some interference with normal activity. 
• Severe - inability to carry out usual activity. 
The investigator must assess the relationship of the AE to the study medication using the 
following: 
• Unrelated – improbable temporal relationship and is plausibly related to other drugs or 
underlying disease. 
• Unlikely - occurs with a temporal relationship to treatment administration that makes a 
causal relationship improbable, and in which other medications, chemicals, or underlying 
disease provide plausible explanations. 
• Possible - occurred in a reasonable time after study drug administration, but could be 
related to concurrent drugs or underlying disease. 
• Probable - occurred in a reasonable time after study drug administration, is unlikely to 
be attributable to concurrent drugs or underlying disease, and there is a plausible 
mechanism to implicate the study drug.  
• Related - occurred in a reasonable time after study drug administration and cannot be 
explained by concurrent drugs or underlying disease. The adverse event should respond 
to dechallenge/rechallenge, however, this is not mandatory before assigning a definite 
causality. 
Frequency will be defined using the following terms and definitions: 
• Once – an isolated episode. 
• Intermittent – occurs on two or more separate occasions. 
• Continuous – does not abate from date of onset to date of resolution. 
The action taken regarding study drug will be defined as follows: 
• Dose Not Changed – no change. 
• Dose Increased. 
• Dose Reduced. 
• Drug Interrupted – study drug stopped temporarily. 
• Drug Withdrawn – study drug stopped permanently. 
• Not Applicable. 
 

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3 
 
Table of contents 
1. 
INTRODUCTION ........................................................................................................9 
1.1. 
Study Objectives ...........................................................................................................9 
1.2. 
Study Design ...............................................................................................................10 
1.2.1. 
Determination of Sample Size ....................................................................................11 
1.2.2. 
Randomization and Blinding ......................................................................................11 
2. 
ANALYSES PLANNED ............................................................................................12 
2.1. 
General Analysis Definition .......................................................................................12 
2.1.1. 
Logic of Final Database Lock for Adolescent Subjects with Schizophrenia .............12 
2.1.2. 
Definition of Open-Label Treatment Phase in Extension Study ................................12 
2.1.3. 
Visit Windows ............................................................................................................12 
2.1.4. 
Pooling Strategy for Analysis of Centers ...................................................................14 
2.1.5. 
Definition of Baseline Assessments ...........................................................................14 
2.1.6. 
Definition of Endpoint Assessments for Final Analysis .............................................15 
2.1.7. 
Definition of Aggregated Analysis Timepoint ...........................................................15 
2.1.8. 
Analysis Population ....................................................................................................16 
2.1.9. 
Analysis Group and Analysis Subgroup .....................................................................16 
2.1.10. 
Average Dose and Predominant Dose ........................................................................17 
2.1.11. 
Presenting ‘Endpoint’ in Outputs for Final Analysis .................................................18 
2.1.12. 
Age over Time ............................................................................................................18 
2.1.13. 
Subgroup Analysis ......................................................................................................18 
2.1.14. 
Data Imputation Rules ................................................................................................18 
2.1.14.1. 
Composite Score .........................................................................................................18 
2.1.14.2. 
Incomplete/Missing Dates ..........................................................................................19 
2.1.14.3. 
BMI .............................................................................................................................20 
2.1.14.4. 
Z-score and Percentile of Height, Weight, and BMI per WHO and CDC 
Growth Reference .......................................................................................................20 
2.2. 
Methods of Analysis ...................................................................................................21 
2.2.1. 
Statistical Hypotheses for Trial Objectives ................................................................21 
2.2.2. 
Subject Information ....................................................................................................21 
2.2.2.1. 
Demographic and Baseline Characteristics ................................................................21 
2.2.2.2. 
Disposition Information ..............................................................................................22 


 
4 
 
2.2.2.3. 
Treatment Compliance ................................................................................................22 
2.2.2.4. 
Extent of Exposure .....................................................................................................23 
2.2.2.5. 
Study Medication and  Prior and Concomitant Medications ......................................24 
2.2.2.6. 
Psychiatric History and  Medical History Prior to DB Phase of Core Study .............25 
2.3. 
Efficacy .......................................................................................................................25 
2.3.1. 
Efficacy Analysis Specifications ................................................................................25 
2.3.1.1. 
Definition ....................................................................................................................25 
2.3.1.2. 
Analysis Methods .......................................................................................................29 
2.4. 
Pharmacokinetics (PK) Analysis ................................................................................30 
2.5. 
Multiplicity Adjustment..............................................................................................30 
2.6. 
Safety ..........................................................................................................................31 
2.6.1. 
Analysis Specifications ...............................................................................................31 
2.6.2. 
Age Over Time ...........................................................................................................31 
2.6.3. 
Definition of Treatment-Emergent Occurrences in Open-Label Extension 
Study ...........................................................................................................................31 
2.6.4. 
Adverse Events ...........................................................................................................31 
2.6.5. 
Laboratory Measurements ..........................................................................................34 
2.6.6. 
ECG Evaluations ........................................................................................................36 
2.6.7. 
Vital Signs, Weight, Waist Circumference, and BMI ................................................38 
2.6.8. 
Young Mania Rating Scale (YMRS) ..........................................................................40 
2.6.9. 
Extrapyramidal Symptoms Assessment Scales ..........................................................41 
2.6.9.1. 
Barnes Akathisia Rating Scale....................................................................................41 
2.6.9.2. 
Abnormal Involuntary Movement Scale ....................................................................41 
2.6.9.3. 
Simpson-Angus Scale .................................................................................................42 
2.6.10. 
CogState Computerized Cognitive Test Battery .........................................................43 
2.6.11. 
Columbia Suicide Severity Rating Scale (C-SSRS) ...................................................45 
2.6.12. 
Udvalg for Kliniske Undersogelser Side Effect Rating Scale (UKU) ........................48 
2.6.13. 
Tanner Staging and Menstrual Cyclicity ....................................................................51 
3. 
REFERENCES ...........................................................................................................53 
4. 
ATTACHMENTS .......................................................................................................54 
4.1. 
Computation of Centiles and Z-scores for Height-For-Age, Weight-For-Age 
(CDC only), and BMI-For-Age ..................................................................................54 
4.1.1. 
WHO 2007 Reference for Growth Charts ..................................................................54 


 
5 
 
4.1.2. 
2000 CDC  Growth Charts for the United States .......................................................60 
4.2. 
Cogstate Child and Adolescent Normative Data ........................................................66 
4.3. 
Clinical Laboratory Tests ...........................................................................................66 
4.4. 
Benzodiazepine Equivalence Table Conversion Factors to Convert 
Benzodiazepine Dose to Oral Equivalent Doses Standardized to Lorazepam ...........68 
4.5. 
Selected Adverse Events with Special Interest ...........................................................69 
4.5.1. 
Extrapyramidal Symptoms (EPS)-Related AEs .........................................................69 
4.5.2. 
Metabolic-Related AEs ...............................................................................................69 
4.5.3. 
Hypersensitivity Related AEs .....................................................................................70 
4.5.4. 
Suicidality and Self-Injury Related AEs.....................................................................70 
4.5.5. 
Hyperactivity Related AEs .........................................................................................71 
 
Table of tables 
Table 1 
List of Abbreviations and Definition of Terms ............................................................6 
Table 2 
Time Intervals for Analysis Visit Windows ...............................................................13 
Table 3.1 
Criteria for Potentially Markedly Abnormal Laboratory Values for Pediatric 
and Adolescent Subjects .............................................................................................35 
Table 3.2 
Thresholds for Selected Laboratory Parameters .........................................................36 
Table 4 
QTc Prolongation for Pediatric and Adolescent Subjects ..........................................37 
Table 5 
Definition of Abnormal ECG Values by Parameter for Pediatric and 
Adolescent Subjects ....................................................................................................37 
Table 6.1 
Weight Status Categories for Pediatric and Adolescent Subjects per WHO 
Standard ......................................................................................................................39 
Table 6.2 
Weight Status Categories for Pediatric and Adolescent Subjects per CDC 
Standard ......................................................................................................................39 
Table 7 
Criteria for Potentially Markedly Abnormal Vital Signs for Pediatric and 
Adolescent Subjects ....................................................................................................39 
Table 8 
Cognitive Domains Evaluated in CogState Tests .......................................................44 
Table 9 
Analysis TimePoint for C-SSRS ................................................................................46 
Table 10.1 Comparative Endpoint Relative to DB Baseline ........................................................46 
Table 10.2 Comparative Endpoint Relative to DB Treatment Period ..........................................47 
Table 11.1 Comparative Endpoint of UKU Relative to DB Baseline ..........................................50 
Table 11.2 Comparative Endpoint of UKU Relative to the Core DB Treatment Period .............50 
 


 
6 
 
Table 1 
List of Abbreviations and Definition of Terms 
ABC 
Aberrant Behavior Checklist 
ADHD-RS 
Attention-Deficit/ Hyperactivity Disorder Rating 
Scale 
ADI-R 
Autism Diagnostic Interview - Revised 
AE  
Adverse Event  
AIMS  
Abnormal Involuntary Movement Scale  
ANCOVA   
analysis of covariance  
ATC 
Anatomical Therapeutic Chemical 
BARS  
Barnes Akathisia Rating Scale  
β-hCG  
human chorionic gonadotropin, beta chain 
BMI  
body mass index  
CDC 
Centers for Disease Control and Prevention 
CDRS-R 
Children's Depression Rating Scale, Revised 
CGI-I 
Clinical Global Impression – Improvement 
CGI-S 
Clinical Global Impression – Severity 
CGI-BP-S 
Clinical Global Impression Bipolar Version – 
Severity 
CGAS 
Clinician-rated Children’s Global Assessment 
Scale 
CGSQ 
Caregiver Strain Questionnaire 
CI 
confidence interval 
CRO 
contract research organization  
CSR 
Clinical Study Report  
CY-BOCS 
Children's Yale-Brown Obsessive Compulsive 
Scales 
DSMB 
Data Safety Monitoring Board 
DSM-IV-TR  
Diagnostic and Statistical Manual of Mental 
Disorders, 4th Edition, Text Revision  
ECG  
electrocardiogram  
eCRF 
Electronic Case Report Form 
EMA 
European Medicine Agency 
EPS  
extrapyramidal symptoms  
FDA 
Food and Drug Administration 


 
7 
 
Table 1 
List of Abbreviations and Definition of Terms (Continued) 
FSH  
follicle stimulating hormone  
GCP  
Good Clinical Practices  
HbA1c  
Hemoglobin A1c  
HDL  
high-density lipoprotein  
HR 
Heart Rate 
ISAC 
Independent Statistical Analysis Center 
ITT  
intent-to-treat  
IXRS  
Interactive Voice Response/Web Response System  
LDL  
low-density lipoprotein  
LH 
luteinizing hormone 
LLOQ 
lower limit of quantification 
LOCF  
last observation carried forward  
LPO 
last patient out (LPO) 
LSD 
Lab Specification Document 
MedDRA  
Medical Dictionary for Regulatory Activities  
MMRM  
Mixed Model for Repeated Measures  
NA 
Not Applicable 
PANSS 
Positive and Negative Syndrome Scale 
PARS 
Pediatric Anxiety Rating Scale 
PMM 
Pattern mixture model 
PP  
per protocol  
PQ-LES-Q 
Pediatric Quality of Life Enjoyment and 
Satisfaction Questionnaire 
QTc  
QT interval corrected  
SAE  
serious adverse event  
SAS  
Simpson-Angus Scale  
SAP 
Statistical Analysis Plan 
SCHARP 
Statistical Center for HIV/AIDS Research & 
Prevention  
SD  
standard deviation  
SI 
International System of Units 


 
8 
 
Table 1 
List of Abbreviations and Definition of Terms (Continued) 
SOC 
System Organ Class 
sNDA 
Supplemental New Drug Application 
TEAE  
treatment-emergent adverse event 
ULOQ 
upper limit of quantification 
WHO 
World Health Organization 
YMRS 
Young Mania Rating Scale  
 


 
9 
 
1. 
INTRODUCTION 
This statistical analysis plan (SAP) contains the definitions of analysis populations, derived 
variables, and statistical methods for the analyses of safety and effectiveness data from study 
D1050302 for subjects who continued from core studies D1050301, D1050325, and D1050326.  
Study D1050302 enrolls pediatric or adolescent subjects with following 3 disease indications: 
• Adolescent subjects with schizophrenia (13-17 years) from the United States and 
Worldwide (Study D1050301) 
• Children and adolescent subjects (6-17 years) with irritability associated with autistic 
disorder from the United States (Study D1050325) 
• Children and adolescent subjects with bipolar I depression (10-17 years) from the 
United States and Worldwide (Study D1050326) 
Study completion status of above lurasidone pediatric core studies is given below: study 
D1050325 was completed and database was locked on Dec 16, 2014; study D1050301 was 
completed and database was locked on Feb 10, 2016; study D1050326 was completed by Oct 12, 
2016 and database was locked on Nov 22, 2016.   
Two interim analyses were planned and implemented. The first interim analysis (data cut date of 
Mar 01, 2016) was done to support the United States Supplemental New Drug Application 
(sNDA) for adolescent subjects with schizophrenia. The second interim analysis (data cut date of 
Oct 27, 2016) was conducted to support the United States sNDA for children and adolescent 
subjects with bipolar I depression disorder. For each of the interim analyses, separate and 
independent database lock was planned and separate interim SAPs were developed for study 
D1050302. Considering that there exists  a significant difference in study completion dates for 
subjects with schizophrenia and subjects with bipolar depression in study D1050302, to fulfill  
regulatory requests from both United  States Food and Drug Administration (FDA) and 
European Medicine Agency (EMA),final database lock are conducted in 2-batches  as described 
below: final database lock for adolescents with schizophrenia (hereafter, referred it as final 
database lock 1) occurred on June 15, 2018; final database lock for subjects with autistic disorder 
and subjects with bipolar  depression (hereafter, referred it as final database lock 2) will occur 
when every subject from study D1050326 completes the study D1050302, which is targeted to 
happen on November 21,   2018. Clinical study report (CSR) for subjects with schizophrenia has 
been completed based on the results per final database lock 1 for EMA submission. Full final 
clinical study report (CSR) for all subjects in study D1050302 will be completed after the final 
database lock 2 occurs. 
This SAP is developed based on the study protocol with Protocol Version 4.0 (Amendment 3.0) 
dated 30 June, 2017 for final analysis. It outlines analyses to be conducted per final database lock 
1 and final database lock 2.  SAPs for the interim analyses were prepared separately. 
1.1. 
Study Objectives 
Primary Objective 


 
10 
 
The primary objective of this study is to evaluate the long-term safety, tolerability, and 
effectiveness of lurasidone (20, 40, 60 or 80 mg/day, flexibly dosed) in pediatric subjects who 
have completed a prior lurasidone study. 
Secondary Objective 
For all subjects: 
• Proportions of subjects with adverse events (AEs), discontinuations due to AEs, and 
serious AEs (SAEs). 
For subjects continued from Study D1050301, the following will be assessed: 
• Change in Positive and Negative Syndrome Scale (PANSS) total, positive, negative, 
general psychopathology, and excitability subscale scores;  
• Change in the Clinical Global Impression – Severity (CGI-S); 
• Change in the Clinician-rated Children’s Global Assessment Scale (CGAS);  
• Change in the Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-
LES-Q). 
For subjects continued from Study D1050325, the following will be assessed: 
• Change in Aberrant Behavior Checklist (ABC) irritability subscale, and the following 
subscale scores (hyperactivity, stereotypy, inappropriate speech, and lethargy/social 
withdrawal); 
• Change in the Clinical Global Impression – Severity (CGI-S);  
• Change in Children's Yale-Brown Obsessive Compulsive Scales (CY-BOCS) modified 
for pervasive developmental disorders (PDDs); 
• Change in the Caregiver Strain Questionnaire (CGSQ). 
For subjects continued from Study D1050326, the following will be assessed: 
• Change in the Children's Depression Rating Scale, Revised (CDRS-R); 
• Change in the Clinical Global Impression Bipolar Version – Severity (CGI-BP-S); 
• Change in the Clinician-rated Children’s Global Assessment Scale (CGAS);  
• Change in the Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire 
(PQ-LES-Q); 
• Change in anxiety symptoms as measured by the Pediatric Anxiety Rating Scale (PARS); 
• Change in attention-deficit/hyperactivity symptoms as measured by the Attention-Deficit/ 
Hyperactivity Disorder Rating Scale (ADHD-RS) total score. 
 
1.2. 
Study Design 
This is an open-label, 104-week, multicenter, extension study designed to evaluate the long-term 
safety, tolerability and effectiveness of flexibly dosed lurasidone (20, 40, 60 or 80 mg/day) in 


 
11 
 
pediatric subjects who have completed a 6-week treatment period in one of the preceding studies, 
D1050301, D1050325, or D1050326.   
Subjects who complete participation in one of the preceding studies, D1050301, D1050325 or 
D1050326, are eligible for enrollment in this study. Informed consent/assent is obtained from all 
subjects (where developmentally appropriate) before any study procedures are performed. 
Subjects who meet entry criteria transition to this study directly from Study D1050301, 
D1050325 or D1050326. All subjects are treated with flexibly dosed lurasidone during the trial. 
All eligible subjects are treated with lurasidone 40 mg/day for Days 1-7. Beginning with Day 8, 
dose adjustments (20, 40, 60 or 80 mg/day) are permitted, based on investigator judgment, to 
optimize tolerability and effectiveness.  
Dose adjustment of study drug should occur at the regularly scheduled visits and in increments 
or decrements of 1 dose level. However, dose reductions for tolerability or safety purposes may 
occur beginning on Day 2, based on investigator judgment. These dose reductions may be 
between study visits and at more than 1 dose level at a time (maximum of 2 dose levels at a 
time). If dose reductions are required between regular study visits, the subject must return to the 
study site for an unscheduled visit to receive new medication kits and return all used/unused 
medication kits at the time of dose adjustment.  
Safety and effectiveness assessments are conducted at scheduled visits during the study.  A 
follow-up visit occurs 1 week post last dose of study drug. 
A Data and Safety Monitoring Board (DSMB) reviews safety and clinical outcome data 
including data on AEs and SAEs at regular intervals until the D1050301, D1050325, and 
D1050326 studies are complete and as long as necessary for the D1050302 study, as determined 
by the Sponsor. The DSMB is independent of the Sponsor, contract research organization 
(CRO), and the investigators and is empowered to recommend stopping the study due to safety 
concerns, but not for efficacy or futility.  
 
1.2.1. 
Determination of Sample Size 
Subjects who complete the respective double-blind studies D1050301, D1050325 or D1050326, 
sign the consent, and meet all entry criteria are included in this study.  Studies D1050301, 
D1050325, and D1050326 have finished, with a total of 271 subjects from D1050301, 125 
subjects from D1050325, and 306 subjects from D1050326 enrolling into D1050302. Based on 
an estimated attrition rate of approximately 30% of subjects over six months, it is expected that 
at least 100 subjects are to be exposed to lurasidone for a minimum of 6 months for subjects 
continued from studies D1050301 and D1050325 in study D1050302. 
1.2.2. 
Randomization and Blinding 
This is an open-label study, therefore randomization and blinding is not employed. 
 


 
12 
 
2. 
ANALYSES PLANNED  
2.1. 
General Analysis Definition 
2.1.1. 
Logic of Final Database Lock for Adolescent Subjects with Schizophrenia  
Final database lock 1 is expected to occur on June 15, 2018 for subjects who continued from 
study D1050301 (ie, adolescent subjects with schizophrenia). All data for these subjects will be 
cleaned and ‘frozen’ prior to the planned database lock (DBL) date and all related parties, 
including site personnel, clinical research organization (CRO), non-data management (DM) team 
of the sponsor will be removed access authority of the clinical database for adolescent subjects 
with schizophrenia. The CSR for adolescent subjects with schizophrenia will be based on the 
final database lock 1. In case there is a data error identified after the final database lock 1 for 
adolescent subjects with schizophrenia, depending on the nature of the issue, DM of the sponsor 
will re-grant the site an access permission to fix the data issue. Errata will be filed as needed and 
the error will be noted in the final full CSR after the final database lock 2, which will occur after 
all subjects in study D1050302 complete the study. 
 
2.1.2. 
Definition of Open-Label Treatment Phase in Extension Study 
The day of the 1st dose date in the extension study will be denoted as study Day 1. All 
measurements at each visit will be assigned a study day relative to this date. All data collected 
on/after Day 1 for subjects previously randomized to placebo group in core study or on/after the 
extension baseline visit for subjects previously randomized to lurasidone groups up to Week 104, 
including the End-of-treatment/Early Withdrawal visit, will be considered within the open-label 
treatment phase. That is to say, the start of the open-label treatment period is defined as Day 1 
for subjects previously randomized to placebo group and the OL Baseline visit date for subjects 
previously randomized to lurasidone groups; the end of the open-label treatment phase is defined 
as the maximum of the last date of administration of study medication and the withdrawal/ 
completion date for subjects who have completed the study. 
 
2.1.3. 
Visit Windows 
While the Time and Events Schedule of the protocol indicates the visit timing and procedures for 
each visit, the timing of a subject’s actual visit timing may not be exactly as per the protocol 
indicated target day/visit window (note that the protocol does not indicate required visit 
windows, but rather provides clear guidance for visit timing).  Consequently, for the purpose of 
analysis, the conventions outlined below will be used to allocate the data collected at each actual 
visit to a planned protocol visit by defining analysis visit windows. 
The reference day is study Day 1. Definition of baseline and endpoint is provided in 
Sections 2.1.5 - 2.1.6. 
If a subject has 2 or more visits (scheduled or unscheduled) in one analysis visit window, the 
visit closest to the target day will be used as the study visit for that analysis visit window. The 
other additional visit(s) in the same analysis visit window will not be included in the by-visit 


 
13 
 
descriptive summary analyses.   However, measurements from this/these other additional visit(s) 
will be included the subject listings and in the other safety analyses (eg, Potentially Markedly 
Abnormal Laboratory Values or the worst case analysis) to assure all on-treatment measurements 
are included. If 2 study visits occur the same number of days from the target day within the same 
visit window, the later one will be considered as the study visit for that target day.  
Although all (scheduled and unscheduled) visits will be allocated to an analysis visit window, 
only planned protocol visits for each measurement will be included in the by-visit analyses. All 
tables and figures presenting data by visit will present only those timepoints where the applicable 
assessment was scheduled to be collected, unless otherwise noted below.  Unscheduled and early 
termination data will be included for definition of endpoint or overall assessments.  Data listings 
will present all data, regardless of visit.   
Table 2 summarizes the analysis visit windows for all questionnaires, laboratory, weight, height, 
waist circumference, vital signs, ECG, cogstate, tanner stage, menstrual cyclicity, and other 
safety variables assessed at scheduled visits. 
 
 
Table 2 
Time Intervals for Analysis Visit Windows 
Scheduled Visit 
(label on output in 
Extension study) 
Target Day (a) 
Time Interval (Day) 
Day 1 
1 
<=1 
Week 2 
15 
2 – 21 
Week 4 
29 
22 – 35 
Week 6 
43 
36 – 49 
Week 8 
57 
50 - 70 
Week 12 
85 
71 - 98 
Week 16 
113 
99 - 126 
Week 20 
142 
127 - 154 
Week 24 
169 
155 - 182 
Week 28 
197 
183 - 210 
Table 2 
Time Intervals for Analysis Visit Windows (Continued) 
Scheduled Visit 
(label on output in 
Extension study) 
Target Day (a) 
Time Interval (Day) 
Week 32 
225 
211 - 238 
Week 36 
253 
239 - 266 
Week 40 
281 
267 - 294 
Week 44 
309 
295 - 322 


 
14 
 
Week 48 
337 
323 - 350 
Week 52 
365 
351 - 378 
Week 56 
393 
379 - 406 
Week 60 
421 
407 - 434 
Week 64 
449 
435 - 462 
Week 68 
477 
463 - 490 
Week 72 
505 
491 - 518 
Week 76 
533 
519 - 546 
Week 80 
561 
547 - 574 
Week 84 
589 
575 - 602 
Week 88 
617 
603 - 630 
Week 92 
645 
631 - 658 
Week 96 
673 
659 - 686 
Week 100 
701 
687 - 714 
Week 104 
729 
715 - EOT 
(a): Relative to the day of the 1st dose date  
 
2.1.4. 
Pooling Strategy for Analysis of Centers 
There will be no pooling of centers in this study. 
 
2.1.5. 
Definition of Baseline Assessments  
The following definitions will be used for effectiveness and safety assessments unless otherwise 
specified: 
• DB Baseline (ie, Baseline assessment of the double-blind studies [D1050301, D1050325, 
or D1050326]): the last assessment made on or before the 1st dose of double-blind study 
medication as described in the SAPs of the core studies; 
• OL Baseline (ie, Endpoint assessment of the double-blind studies [D1050301, 
D1050325, or D1050326] or Baseline assessment of the open-label study [D1050302]):  
the last assessment made on or before Day 1 of the extension study. 
According to the protocol, measurement collected at OL Baseline is same as the value at visit 9 
(ie, Week 6) (Study 301/325) or visit 8 (ie, Week 6) (study 326). For operation convenience, the 
protocol specified that data collected at the EOT visit of the core studies were to be recorded in 
core studies only and were not to be saved in the clinical database RAVE of the extension study. 
OL Baseline data in the Study Data Tabulation Model (SDTM) datasets of the study D1050302 
will be obtained from corresponding core studies directly.  


 
15 
 
 
Unless otherwise specified,  at each study visit of study D1050302, data derivation rule and 
missing imputation method for aggregated parameter that involves multiple individual items (eg, 
total score, subscale score, or composite score), are same as the corresponding ones in individual 
core study SAP.  DB Baseline is defined same as the Baseline in individual core study per core 
study SAPs.  DB Baseline used in the analysis of study D1050302 will be extracted from 
corresponding Analysis Data Set (ADS) of the core studies directly unless otherwise specified. 
 
2.1.6. 
Definition of Endpoint Assessments for Final Analysis  
• Endpoint: the last post-OL Baseline assessment during the open-label treatment 
period. 
• Week 52 LOCF/Week 52 Endpoint: the assessment at Week 52 visit or the last 
post-OL baseline assessment before the Week 52 visit if the value at the Week 52 
visit is missing  
Week 52 LOCF will be used to refer effectiveness data only and week 52 Endpoint will be used 
to summarize safety data.  Endpoint will be derived for both effectiveness and safety data. 
 
2.1.7. 
Definition of Aggregated Analysis Timepoint  
Unless otherwise specified, aggregated analysis timepoints will be derived for limited safety 
assessments (eg, the worst case analysis) as below. 
• Any visit in open-label treatment period (extension study): defined as any assessment 
collected in open-label treatment period.   
• Any visit in the first 52 week treatment period (extension study): defined as any 
assessment collected in the first 52-weeks open-label treatment period (ie, data up to 
Day 365). 
Definition of ‘Any visit in DB treatment period (core study)’ (ie, as any assessment collected in 
DB treatment period) is same as what were defined in the core studies.  
Specifically, above 3 aggregated analysis timepoints in extension study will be generated for the 
following worst-case analysis:   
• Potentially Markedly Abnormal Laboratory Values (PMALV) (Section 2.6.5, Table 
3.1)  
• Potentially Markedly Abnormal Vital Signs (PMAVS) (Section 2.6.7, Table 7)  
• OTc prolongation (Section 2.6.6, Table 4)  
• ECG abnormality (Section 2.6.6, Table 5).  
 


 
16 
 
See Sections 2.6.3 (Treatment-Emergent Occurrences in OL Period) and 2.6.10 (C-SSRS), and 
2.6.11 UKU for further details about the application of ‘Any visit in DB treatment period (core 
study)’ and ‘Any visit in open-label treatment period (extension study)’.  
2.1.8. 
Analysis Population 
The analysis population for the extension study analysis will be the Safety population.  The 
Safety population will consist of all subjects who receive at least one dose of study drug in this 
study. If a subject receives dispensed drug but has not returned the blister card (eg, lost follow-
up), the subject will be included in the Safety population (ie, treated as taking at least one dose). 
 
2.1.9. 
Analysis Group and Analysis Subgroup 
A total of three analysis groups will be formed based on a subject’s previous participation of 
double-blind core studies. Column group “301/325/326” that combines these three analysis 
groups will be also presented. Summary tables will be labeled as follows: 
 301-Lur: Subjects continued from Study D1050301  
 325-Lur: Subjects continued from Study D1050325   
 326-Lur: Subjects continued from Study D1050326 
 301/325/326-Lur: All subjects combined 
Subjects continued from Study D1050301 will be further grouped into 3 analysis subgroups 
(hereafter, referred as ‘Analysis Subgroup A’). Depending on the type of safety analysis in 
summary table they will be labeled as follows (ie, with 2 additional pooled groups: AllLur-Lur 
and 301-Lur):  
 Pbo-Lur: previously randomized to placebo  
 Lur40-Lur: previously randomized to lurasidone 40 mg/day   
 Lur80-Lur: previously randomized to lurasidone 80 mg/day 
 AllLur-Lur: previously randomized to lurasidone (40 mg/day or 80 mg/day) 
 301-Lur: subjects continued from study D1050301 
Subjects continued from Study D1050325 will be further grouped into 3 analysis subgroups 
(hereafter, referred as ‘Analysis Subgroup B’). Depending on the type of safety analysis in 
summary table they will be labeled as follows (ie, with 2 additional pooled groups: AllLur-Lur 
and 325-Lur):   
 Pbo-Lur: previously randomized to placebo  
 Lur20-Lur: previously randomized to lurasidone 20 mg/day   
 Lur60-Lur: previously randomized to lurasidone 60 mg/day 
 AllLur-Lur: previously randomized to lurasidone  (20 mg/day or 60 mg/day) 
 325-Lur: subjects from study D1050325 
Subjects continued from Study D1050326 will be further grouped into 2 analysis subgroups 
(hereafter, referred as ‘Analysis Subgroup C’). Depending on the type of safety analysis in 
summary table they will be labeled as follows (ie, with one additional pooled groups: 326-Lur):   


 
17 
 
 Pbo-Lur: previously randomized to placebo  
 Lur-Lur: previously randomized to lurasidone 20-80 mg/day   
 326-Lur: subjects from study D1050326 
Subjects may be further grouped into 4 analysis subgroups based on the age at OL baseline 
(years) as needed (hereafter, referred as ‘Analysis Subgroup D’).  Depending on the type of 
safety analysis in summary table they will be presented as follows follow (ie, with 2 additional 
pooled groups: 6-12 years old and ≥ 13 years old): 
 6-9 years old 
 10-12 years old 
 6-12 years old (ie, combined group of ‘6-9 years old’,’ 10-12 years old’) 
 13-15 years old 
 ≥ 16 years old 
 ≥ 13 years old (ie, combined group of ‘13-15 years old’,’ ≥ 16 years old’) 
To fulfill EMA’s request, for subjects continued from study D1050301, selected safety summary 
will be also presented by following age subgroup as needed: 
• 13 to 14 years old 
• ≥ 15 years old  
 
Summary tables, wherever applicable, will be presented for all subjects in the study by analysis 
group and by analysis subgroup as needed. 
 
2.1.10. 
Average Dose and Predominant Dose 
The predominant dose (ie, modal dose, used interchangeably hereafter in this document) in the 
open-label treatment period is defined as the lurasidone dose to which the subject was exposed 
for the greatest. If a subject has 2 or more doses with the great duration, the one with higher 
dosage will be selected as predominant treatment.  
The average total daily dose during the open-label treatment phase will be calculated as the sum 
of the total daily dose divided the treatment duration (see Section 2.2.2.4). The average total 
daily dose during a visit period is defined in a similar way.  
The predominant dose and average total daily dose in the first 52-weeks period are defined in a 
similar way; specifically, for a subject, the treatment duration in the first 52-weeks period (in 
days) is defined to be same as the treatment duration in open-label treatment period if the subject 
was early terminated by Week 52 visit; otherwise, it is defined as the amount of elapsed time 
between the first day that study medication was taken and the Week 52 visit date (inclusive).  
For any study visit , if medication kit usage information is incomplete (ie, meet one of following 
conditions: any dispensed medication kit at the visit has missing number of tables returned, or 


 
18 
 
has missing dosing start or ending date), average total daily dose at the visit will not be derived 
and will be set as missing.  For an assessment period that involves multiple study visits (eg, the 
open-label treatment period), if at some visit(s) the drug usage information is incomplete, then 
the other visits with complete information of kit usage will be used to derive the average daily 
dose and predominant dose accordingly. 
 
2.1.11. 
Presenting ‘Endpoint’ in Outputs for Final Analysis 
For safety summary, data will be summarized by visit, Week 52 Endpoint, and ‘Endpoint’ .  For 
effectiveness summary, data will be presented by study visit, ’Week 52 LOCF’, and ‘Endpoint’.   
 
2.1.12. 
Age over Time  
The following ages will be derived:  age (years) at DB Screening, age (years) at OL Baseline, 
age (years) at Endpoint.  
 
2.1.13. 
Subgroup Analysis 
For a limited number of descriptive analyses, data will be presented for analysis group and   
analysis subgroup C by subgroup as below as needed:  
• Age group at OL Baseline (years): “6-9 years”, “10-12 years”, “6-12 years”, “13-15 
years”, “≥ 16 years”, “≥ 13 years”.  
• Country: US, Non-US. 
 
For analysis subgroup C, age subgroups to be displayed in output will be “10-12 years”, “13-15 
years”, “≥ 16 years”, “≥ 13 years”. 
 
2.1.14. 
Data Imputation Rules 
 
2.1.14.1. Composite Score 
Imputation rule of each assessment in this extension study will be consistent with what was 
specified in core studies. That is to say, unless otherwise specified, any individual missing item 
in any scale will not be imputed. When calculating a total score, subscale score, composite score, 
or any assessment with more than one item (e.g., CDRS-R total score, ABC subscale scores, CY-
BOCS, CGSQ , PANSS total score, PQ-LES-Q, BARS, SAS, AIMS, etc.), if one or more items 
are missing at a visit, then the associated score (ie, total score or subscale score) will be set to 
missing.  Same as the core studies, the only exceptions are the standardized composite score of 
the CogState Computerized Cognitive Test Battery, and the category scores of UKU. See 


 
19 
 
Section 2.6.9 for missing imputation rule of Cogstate standardized composite score and 
Section 2.6.11 for missing imputation rule of the UKU category scores and UKU total score. 
Endpoint  
In the event of missing data at Endpoint, the last post-OL baseline observation carried forward 
approach prior to Endpoint  will be used to impute missing values to obtain Endpoint; 
Week 52 LOCF/Week 52 Endpoint 
In the event of missing data at Week 52 (per visit window in Section 2.1.3), the last post-OL 
baseline observation carried forward approach prior to Week 52 will be used to impute missing 
values. 
OL Baseline Assessment 
If a value at OL Baseline visit (ie, Week 6 visit in core study) is missing, no imputation will be 
made. 
 
2.1.14.2. Incomplete/Missing Dates 
2.1.14.2.1. Start/End Date for Adverse Event 
Treatment-emergent adverse events (AEs) are those events defined in Section 2.6.4.  A 
conservative approach will be used to handle the missing dates for AE onset date and end date to 
identify the treatment-emergent AE (ie, if the available incomplete date cannot determine 
treatment emergent status, the AE will be considered as a treatment-emergent AE).  No 
imputation will be done to calculate AE duration.  
2.1.14.2.2. Start/End Date for Prior/Concomitant Medication 
Partial dates of non-study medication start/end date need to be imputed in order to classify the 
medications as prior or concomitant medications. A conservative approach will be used to handle 
the incomplete date(s) for medication start/end date (ie, if the available incomplete date(s) cannot 
determine the concomitant relationship relative to the open-label treatment period, the 
medication will be considered as a concomitant medication).  
 
2.1.14.2.3. Start/End Date of Psychiatric Hospitalization 
The duration (days) of the hospitalization during the open-label treatment period is calculated as 
discharge date – hospitalization admission date +1. If the admission date and the discharge date 
are completely or partially missing, no imputation will be done. If admission date is prior to the 
start of open-label treatment period, it will be imputed by the start date of open-label treatment 
period; if discharge date is after the last day of OL treatment phase, it will be imputed by the last 
day of the OL treatment period. See Section 2.1.2 for definition of start/end of open-label 
treatment period. 


 
20 
 
2.1.14.2.4. First Menses Date 
A conservative approach will be used to handle the incomplete date of the first menses date. The 
partial first menses date will be imputed as follows: (1) If year and month are known, and if the 
year or month is previous to Screening, use the 15th of the month; otherwise, if the month is the 
month of Screening, use the 1st of the month. (2) If only year is known, and it is previous to the 
year of Screening, use June 30th of that year; otherwise, if the year is the year of Screening, use 
the Jan 01 of the year. No imputation will be done if the first menses date is completely missing.  
 
2.1.14.2.5. Adverse Event Grade and Relationship to Study Medication 
The Adverse Event with missing severity will be classified as ‘unspecified’; similarly, the AE 
with missing causality to study medications will be classified as ‘unspecified’ as well. 
 
 
2.1.14.2.6. Lab Data 
Where applicable, the upper limit of quantification (ULOQ) will be substituted for chemistry, 
hematology, urinalysis, and urine microscopic values that are greater than the ULOQ. Similarly, 
if the value is below the lower limit of quantification (LLOQ), then the LLOQ will be 
substituted.  
 
2.1.14.3. BMI 
At each visit, BMI will be derived only when both height and weight are available at the visit 
and no imputation will be made if one or two of them are missing. 
 
2.1.14.4. Z-score and Percentile of Height, Weight, and BMI per WHO and CDC Growth 
Reference 
Age-and-sex specific z-scores and percentiles in height and BMI will be derived at each assessed 
visit using WHO 2007 growth reference for each subject. Considering that no weight related 
growth reference is available per WHO standard, for each subject (US and non-US), CDC 2000 
growth chart for weight will be used to derive age-and-sex specific z-scores and percentiles in 
weight. In addition, for US subjects, age-and-sex specific z-scores and percentiles in height and 
BMI will be also derived using CDC 2000 growth chart. 
 
For height and BMI,  for summary of z-score and percentile of analysis group or analysis 
subgroups A and C (ie, studies D1050301 and  D1050326), WHO based ones will be reported; 
for summary of analysis subgroup B (ie, study D1050325) or US only population, the ones per 
CDC growth chart will be displayed. 
 


 
21 
 
For weight, for summary of z-score and percentile of analysis group or analysis subgroup, CDC 
based ones will be reported consistently. 
 
2.2. 
Methods of Analysis  
2.2.1. 
Statistical Hypotheses for Trial Objectives 
Because of the nature of an open-labeled study, no hypotheses are planned and to be tested. 
2.2.2. 
Subject Information  
Unless otherwise specified, subject information will be presented by analysis group and analysis 
subgroup as needed (see Section 2.1.9) for the safety population.   
 
2.2.2.1. 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized by analysis group and analysis 
subgroup for the safety population. 
Baseline descriptive statistics (N, mean, SD, median, and range) of demographic characteristics 
will be provided by analysis group and analysis subgroup for age at OL baseline (in years), body 
weight, height, body mass index (BMI, calculated as weight(kg)/ [height(m)2]), and waist 
circumference. At OL Baseline, age-and-sex specific z-scores and percentiles in height and BMI 
will be obtained using WHO 2007 growth reference (see Attachment 4.1); corresponding z-score 
and percentile in weight will be obtained using CDC 2000 growth chart. In addition, age-and-sex 
specific z-scores and percentiles in height weight and BMI at OL Baseline will be reported using 
CDC 2000 growth chart for US subjects as well. 
The number and percentage of subjects in each of the following categories (and sub-categories) 
at OL baseline will also be summarized by analysis group and by analysis subgroup: 
• Gender: Male, Female;  
• Race: white, black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or other Pacific Islander, Other; 
• Ethnicity: Hispanic or Latino, Not Hispanic or Latino; 
• Age at OL Baseline group 1: ≤12 years, 13-17, 18-20 years; 
• Age at OL Baseline  group 2: ≤9 years, 10-12 years, 13-15 years, 16-17, 18-20 years; 
• OL Baseline category for height (WHO): <5th, 5th to <95th,  >95th percentile; 
• OL Baseline category for weight (CDC): <5th, 5th to <95th,  >95th percentile; 
• OL Baseline BMI category  (WHO): <3th, 3th to 85th, >85th to 97th , >97th percentile;  
• Country: US, non-US; 
• Region: North America, South America, Europe, and Asia; 


 
22 
 
The number and percentage of subjects in each of the following categories (and sub-categories) 
at OL baseline will also be summarized by analysis subgroup for subjects from D1050325 or 
overall US subjects from D1050301, D1050325, and D1050326 as well: 
• OL Baseline category for height (CDC): <5th, 5th to <95th,  >95th percentile; 
• OL Baseline category for weight (CDC): <5th, 5th to <95th,  >95th percentile; 
• OL Baseline BMI category  (CDC): <5th, 5th to 85th, >85th to 95th , >95th percentile;  
Baseline summary statistics (N, mean, SD, median, and range) of disease characteristics will be 
provided by analysis subgroup for subjects continued from Study D1050301 
• DB Baseline and OL Baseline of PANSS total score 
• DB Baseline and OL Baseline of CGI-S score  
Baseline summary statistics (N, mean, SD, median, and range) of disease characteristics will be 
provided by analysis subgroup for subjects continued from Study D1050326 
• DB Baseline and OL Baseline of CDRS-R total score 
• DB Baseline and OL Baseline of CGI-BP-S score  
 
2.2.2.2. 
Disposition Information 
Subject disposition for all enrolled subjects will be summarized by analysis group and analysis 
subgroup using the following categories: 
• Subjects who entered the extension study; 
• Subjects who entered the extension study, but not dosed; 
• Subjects in the Safety population; 
• Subjects in the Safety who completed the study; 
• Subjects who discontinued. 
 
Subject disposition for one year study (ie, at Week 52) will be also presented using a similar way 
for the above categories with one more category for number and percentage of subjects who 
were still ongoing at 1-year cut. 
For subjects who are consented and discontinue from the study, the corresponding reasons for 
discontinuation will be summarized. Kaplan-Meier plot of the time to early discontinuation will 
be presented by analysis group. 
 
2.2.2.3. 
Treatment Compliance 
At each post OL-baseline (Weeks 2 – 104) visit, prior to dispensing study medication, previously 
dispensed study medication will be retrieved and assessed by tablet count.  


 
23 
 
Compliance in the open-label treatment phase will be calculated for each post-OL baseline visit, 
the first 52-weeks treatment period, and overall as follows: 
• Percent compliance = (number of tablets taken / number of tablets should have taken) 
x 100. 
• Number of tablets taken = number of tablets dispensed – number of tablets returned. 
• Number of tablets should have taken = (number of tablets supposed to take in a day) x 
(number of exposure days). 
• Number of exposure days = last dose date – first dose date + 1. 
For subjects assigned to the 20 mg per day or 40 mg per day dose, number of tablets supposed to 
be taken in a day is 1 tablet; for subjects assigned to the 60 mg per day or 80 mg per day, number 
of tablets supposed to be taken in a day is 2 tablets.  If the number of tablets returned is missing, 
compliance will be set as missing.  
For any study visit, if medication kit usage information is incomplete (ie, meet one of following 
conditions: any dispensed medication kit at the visit has missing number of tables returned, or 
has missing dosing start or ending date), compliance rate at the visit will not be derived and will 
be set as missing.  For an assessment period that involves multiple study visits (eg, the open-
label treatment period), if at some visit(s) the drug usage information is incomplete, then the 
other visits with complete information of kit usage will be used to derive the compliance rate. 
Non-compliance is defined as less than 75% or more than 125% non-missing compliance with 
the study medication. Subjects with missing compliance are not classified as non-compliant.  
Descriptive summary statistics (N, mean, median, and range) will be provided by analysis group 
and by analysis subgroup, respectively, for percent compliance by study visit. In addition, the 
number and percentage of subjects in the categories of the following variables will be also 
summarized by study visit: 
• Compliant;  
• Non-compliant (<75% or >125%); 
• Non-compliant: <75%;  
• Non-complaint: >125%; 
• Missing.  
 
Incomplete medication kit usage information will be summarized for overall OL treatment period 
by analysis group as follows: incomplete kit usage for 1 visit period, 2 visit periods, 3 visit 
periods, ≥ 4 visit periods. 
 
2.2.2.4. 
Extent of Exposure 
Treatment duration is defined as the amount of elapsed time between the first and the last day 
that study medication was taken (inclusive). It will be calculated (in days) in terms of the 


 
24 
 
difference in relative study days between the last and first dose of study medication, plus one 
day. If the end date of the medication intake is unknown for subjects who either completed or 
early terminated the study (eg, subject is lost to follow-up), it will be imputed as the earlier of the 
disposition date (ie, date of the last contact with subject) and 14 days from the date that the last 
medication kit is dispensed if the last contact visit is either V1E (OL baseline), V2E (W2), V3E 
(W4) , or V4E (W6), and 28 days from the date that the last medication kit is dispensed is V5E 
(W8) or after.  
Descriptive statistics (N, mean, standard deviation, median, and range) will be presented by 
analysis group and analysis subgroup for treatment duration. Number of subjects with duration in 
each of following categories (days): ≥ 14, ≥ 28, ≥ 56, ≥ 84, ≥ 112, ≥ 140, ≥ 168, ≥ 196, ≥ 252, 
≥ 308, and ≥ 364; 1-13, 14-27, 28-55, 56-83, 84-111, 112-139,140-167,168-195, 196-251, 
252-307, 308-363, ≥ 364 days will also be presented. Return of the blister card at any given visit 
is not a prerequisite for inclusion in exposure summary statistics if corresponding dose start and 
end dates are reported. 
 
2.2.2.5. 
Study Medication and  Prior and Concomitant Medications 
2.2.2.5.1. Study Medication 
Descriptive summary statistics (N, mean, median) for the mean daily dose will be provided by 
analysis group and analysis subgroup, respectively, at each post-baseline visit, in the first 52-
weeks treatment period, and overall treatment period. In addition, frequency distribution of the 
following dose information will be summarized: 
• dispensed dose by study visit.  
• predominant dose in the first 52-weeks treatment period, and during the open-label 
treatment period, respectively.  
Return of the blister card at any given visit is not a prerequisite for inclusion in average daily 
dose summary statistics or predominant dose summary statistics if corresponding dose start and 
end dates and amount are reported. 
 
2.2.2.5.2. Concomitant Medications 
Concomitant medications during the open-label treatment period (see Section 2.1.2) (ie, 
medications taken during the OL treatment period) are coded using World Health Organization 
(WHO) Drug Dictionary and Anatomical Therapeutic Chemical (ATC) codes. 
Number and percentage of subjects taking concomitant medications will be provided by level 3 
ATC classification and preferred name by analysis group. Since medications are coded to ATC 
classification by indication, preferred names may appear under multiple ATC classifications. 
Medications started and stopped before the open-label treatment period as well as the 
medications started after last dose of study drug will be included in the prior and concomitant 
medication listing only. 
For subjects continued from Study D1050326 


 
25 
 
The number and percentage of subjects taking the following categories of concomitant 
medications will be provided: 
• With Concomitant Mood Stabilizer; 
• With Concomitant Antidepressant; 
• With Concomitant Mood Stabilizer or Antidepressant; 
• With Concomitant treatment of ADHD; 
• With Concomitant treatment of ADHD continuing from core study 
 
Mood stabilizers, antidepressants, and treatment of ADHD will be determined by medical review 
prior to sign-off of the SAP.   
 
2.2.2.5.3. Concomitant Use of Benzodiazepine  
The number and percentage of subjects, who received benzodiazepine medications during the 
open-label treatment phase, will be summarized by preferred term and analysis group, 
respectively.  
For subjects continued from Studies D1050301 and D1050326 
A conversion chart for standardizing selected benzodiazepines to an equivalent dosage of 
Lorazepam is provided in Attachment 4.4. Specifically, for each subject, a weight value 
corresponding to the number of days of benzodiazepine use in a given study visit will be used for 
calculating the mean daily dose for each study visit; the average total daily dose during the open-
label treatment phase will be calculated as the sum of the total daily dose divided by the total 
days of the benzodiazepine medication administration. The usages of each benzodiazepine 
medication, including average total daily dose and equivalent dosage to Lorazepam over time, 
will be provided in a listing.  
 
2.2.2.6. 
Psychiatric History and  Medical History Prior to DB Phase of Core Study 
Psychiatric history and medical history prior to DB phase of core study will be summarized in 
the same way as in the core study. 
 
2.3. 
Efficacy 
2.3.1. 
Efficacy Analysis Specifications 
2.3.1.1. 
Definition 
The effectiveness endpoints in this study are: 
For subjects continued from Study D1050301 


 
26 
 
• Change in PANSS total, positive, negative, general psychopathology, and excitability 
subscale scores 
• Change in the CGI-S  
• Change in the PQ-LES-Q percentage maximum possible score 
• Change in the CGAS total score 
 
For subjects continued from Study D1050325 
• Change in the ABC irritability subscale score and the other subscale scores 
(hyperactivity, stereotypy, inappropriate speech, and lethargy/social withdrawal) 
• Change in the CGI-S 
• Change in the CY-BOCS modified for pervasive developmental disorders (PDDs) 
• Change in the CGSQ 
 
For subjects continued from Study D1050326 
• Change in the CDRS-R total score 
• Change in CGI-BP-S score (depression, mania, overall bipolar illness) 
• Proportion of subjects who meet symptom remission, defined as CDRS-R Total Score 
≤ 28 and YMRS total score ≤ 8 and CGI-BP-S depression score ≤ 3 at study visit 
• Change in the PARS total score 
• Change in the PQ-LES-Q score 
• Change in the CGAS score 
• Change in the ADHD-RS total score 
 
 
2.3.1.1.1. Positive and Negative Syndrome Scale PANSS 
The PANSS is only applied to subjects who continued from Study D1050301. 
The PANSS is comprised of 30 items and three scales:  
• the Positive scale contains seven questions to assess delusions, conceptual 
disorganization, hallucinations behavior, excitement, grandiosity, suspiciousness 
/persecution, and hostility;  Positive subscale (range 7-49) is calculated as sum of 
Items P1 to P7 in the positive subscale; 
• the Negative scale contains seven questions to assess blunted effect, emotional 
withdrawal, poor rapport, passive/apathetic social withdrawal, lack of motivation, and 


 
27 
 
similar symptoms; Negative subscale (range 7-49) is calculated as sum of Items N1 to 
N7 in the negative subscale; 
• the General Psychopathology subscale addresses other symptoms such as anxiety, 
somatic concern, and disorientation; General psychopathology subscale (range 16-
112) is calculated as sum of Items G1 to G16 in the general psychopathology 
subscale.  
 
An anchored Likert scale from 1-7, where values of 2 and above indicate the presence of 
progressively more severe symptoms, is used to score each item. Individual items are then 
summed to determine scores for the three scales, as well as a total score. As a result, the total 
score may range from 30 to 210, positive and negative sub-scores may range from 7 to 49, and 
the general psychopathology sub-scores may range from 16 to 112. In addition, a subscale of 
excitability will be derived, which consists of the following four items from the PANSS: 
excitement, hostility, uncooperativeness, and poor impulse control. The sum of the four items 
ranges from 4 to 28.  
In general, higher values of PANSS scores represent greater severity of illness. If one or more 
items are missing, no imputation will be performed and the total score and the scores of the 
subscales that include these items will be left missing. 
 
2.3.1.1.2. Clinical Global Impression – Severity 
The CGI-S is applied to subjects who continued from Study D1050301 and Study D1050325. 
The CGI-S is a single value, clinician-rated assessment of illness severity, and 7-point scale with 
range from 1=’Normal, not at all ill’ to 7=’Among the most extremely ill patients’.  A higher 
score is associated with greater illness severity. 
 
2.3.1.1.3. Quality of Life Enjoyment and Satisfaction Questionnaire (Pediatric Q-LES-Q) 
The Pediatric Q-LES-Q is applied to subjects who continued from Study D1050301 and Study 
D1050326. 
The Pediatric Q-LES-Q is a 15-item self-report measure of the degree of enjoyment and 
satisfaction in various areas of daily living, based on the content of the Short From of the Q-
LES-Q. Each item is rated on a 5-point scale, ranging from 1 (very poor) to 5 (very good). The 
first 14 items are the same as the General Activities section of the regular Q-LES-Q form and are 
used to compute the raw score. The PQ-LES-Q-SF percentage maximum possible score is 
calculated as follows: 
% Max = 100 × (Raw Score – Minimum Score) / (Maximum Score – Minimum Score), 
where the Minimum Score equals 14 and the Maximum Score equals 70, and the % maximum 
possible score can range from 0% to 100%. Higher scores indicate better quality of life. 
 


 
28 
 
2.3.1.1.4. Clinician- rated Children’s Global Assessment Scale (CGAS) 
The CGAS is applied to subjects who continued from Study D1050301and Study D1050326. 
The Children’s Global Assessment Scale (CGAS) is a numeric scale (1 through 100) used by 
mental health clinicians to rate the general functioning of children under the age of 18, where 1 
represents the most impaired functioning and 100, superior functioning. Each decile (e.g., 1–10, 
11–20) has a descriptive header (e.g., “Moderate impairment in functioning in most domains”) 
and examples of behaviors and types of environmental accommodations that might be seen at 
that level of functioning. Scores above 70 on the CGAS indicate functioning within the range of 
typically developing children of the same age as the child being rated while scores below 60 
indicate a definite clinical case. 
 
 
2.3.1.1.5. Children’s Depression Rating Scale, Revised (CDRS-R)  
The CDRS-R is only applied to subjects who continued from Study D1050326. 
The CDRS-R is a semi-structured, clinician-rated instrument designed for use with children and 
adolescents between the ages of 6-17 years. It contains 17 ordinally-scaled items that evaluate 
the presence and severity of symptoms commonly associated with depression in childhood. The 
CDRS-R is administered separately to the patient and to the caregiver; among 17 items, 14 items 
are based on separate interviews with child and parent, 3 items are based solely on the rater’s 
observation of child (ie, no questions). The 14 items (see below) are rated on a 1 (no 
psychopathology) to 7 (most psychopathology) scale, where a rating of 3 represents mild 
psychopathology. The 3 items (sleep disturbance, appetite disturbance, listless speech) are rated 
on a 1 (no pathology) to 5 (most pathology) scale. 
1) Impaired Schoolwork 
 
 
8) Irritability 
2) Difficulty Having Fun  
 
9) Excessive Guilt 
3) Social Withdrawal  
 
 
10) Low Self-Esteem 
4) Sleep Disturbance  
 
 
11) Depressed Feelings 
5) Appetite Disturbance 
 
 
12) Morbid Ideation 
6) Excessive Fatigue  
 
 
13) Suicidal Ideation 
7) Physical Complaints 
 
 
14) Excessive Weeping 
 
The CDRS-R total score ranges from 17-113. In general, higher values of CDRS-R total score 
represent greater severity of illness 
2.3.1.1.6. Clinical Global Impression-Bipolar Version, Severity of Illness (CGI-BP-S) 
The CGI-BP-S is only applied to subjects who continued from Study D1050326. 
The CGI-BP-S is a three-question clinician-rated assessment of the subject’s current illness state 
(depression, mania, and overall) using a 7-point scale (1(normal, not ill) to 7 (very severely ill)) 
for each question, where a higher score is associated with greater illness severity. 
 


 
29 
 
 
2.3.1.1.7. Pediatric Anxiety Rating Scale (PARS) 
The PARS is only applied to subjects who continued from Study D1050326. 
The PARS is a clinician-rated instrument for assessing over time the severity of anxiety 
symptoms associated with common DSM-IV anxiety disorders (generalized anxiety disorder, 
separation anxiety, and social phobia) in children ages 6-17 years. The PARS is administered 
separately to the subject and to the caregiver. The instrument has 2 sections.  The first section 
includes a 50-item symptom checklist, which the clinician rates as present or absent during the 
past week. The second section is comprised of 7 severity impairment items reflecting the 
severity/impairment of all symptoms endorsed in Section 1 of the PARS (during the past week).  
Each question is answered on a 0-5 Likert scale (0 for none, and 1-5 for minimal to extreme) 
with alternative responses of 8=Not Applicable and 9=Does Not Know.  Scores of 8 or 9 are not 
counted in the summation as per the PARS instructions.  The PARS total score over all 7 
questions ranges in value from 0 to 35.  
 
2.3.1.1.8. Attention-Deficit/ Hyperactivity Disorder Rating Scale (ADHD-RS) 
The ADHD-RS IV is only applied to subjects who continued from Study D1050326. 
The ADHD-RS IV is a validated scale that measures the behaviors of children with ADHD. The 
ADHD-RS IV consists of 18 items reflecting current symptomatology of ADHD based on DSM-
IV-TR criteria. Each item is scored from a range of 0 (no symptoms) to 3 (severe symptoms) 
with total scores ranging from 0 to 54. The 18 items may be grouped into two sub-scales: 
hyperactivity/impulsivity (even number items 2 through 18) and inattentiveness (odd number 
items 1 through 17), ranging from 0 to 27.  
 
2.3.1.2. 
Analysis Methods 
No inferential statistics on effectiveness will be presented. For all of the continuous effectiveness 
assessments, descriptive summary statistics (N, mean, standard deviation, median, range, and a 
95% confidence interval) will be presented by analysis subgroup, at DB baseline, OL baseline, 
each of post-OL visit, Week 52 LOCF, and the endpoint in the open-label study. All analyses for 
the scheduled assessments will be based on observed cases (OC). In addition, for all 
effectiveness evaluations, changes from DB baseline and OL baseline will be presented in a 
similar way using summary statistics, as described above.  
For subjects continued from study D1050301 
At a visit in extension study, responders relative to DB Baseline are defined as those who show a 
20% or more reduction (i.e., improvement) from baseline in the PANSS total score from DB 
Baseline. The percent change of PANSS total score relative to DB Baseline is defined as 
[100*Change from DB Baseline/(DB Baseline – 30)] since 30 is the lowest possible value for 
PANSS. At a post-OL Baseline visit, responders relative to OL Baseline are defined as those 


 
30 
 
who show a 20% or more reduction (i.e., improvement) from OL Baseline. The percent change 
of PANSS total score relative to OL Baseline is defined as [100*Change from OL Baseline/(OL 
Baseline – 30)].  
 
For subjects continued from study D1050325 
At a visit in extension study, responders relative to DB Baseline are defined as those who show a 
25% or more reduction (i.e., improvement) from baseline in the ABC irritability subscale score 
from DB Baseline. The percent change of ABC irritability subscale score relative to DB Baseline 
is defined as [100*Change from DB Baseline/(DB Baseline)]. At a post-OL Baseline visit, 
responders relative to OL Baseline are defined as those who show a 25% or more reduction (i.e., 
improvement) from OL Baseline. The percent change of ABC irritability score relative to OL 
Baseline is defined as [100*Change from OL Baseline/(OL Baseline)]. 
For subjects continued from study D1050326 
At a visit in extension study, responders relative to DB Baseline are defined as those who show a 
50% or more reduction (i.e., improvement) from DB Baseline in CDRS-R total score. The 
percent change of CDRS-R total score relative to DB Baseline is defined as [100*Change from 
DB Baseline/(DB Baseline – 17)] since 17 is the lowest possible value for CDRS-R total score; 
At a post-OL Baseline visit, responders relative to OL Baseline are defined as those who show a 
50% or more reduction (i.e., improvement) from OL Baseline. The percent change of CDRS-R 
total score relative to OL Baseline is defined as [100*Change from OL Baseline/(OL Baseline – 
17)].  
 
Frequencies and percentages of CDRS-R responders relative to both DB Baseline and OL 
Baseline over time will be reported by analysis subgroup, respectively. Frequencies and 
proportions of remitters as well as the corresponding 95% Clopper-Pearson (ie, exact) CI of the 
proportion at DB baseline, OL baseline, each of post-OL visit, Week 52 LOCF, and endpoint 
will be reported by analysis subgroup.  
Subgroup analyses for CDRS-R total score and CGI-BP-S depression score will be conducted on 
observed values and changes from DB baseline and OL baseline by study visit, W52 LOCF, and 
endpoint by analysis subgroup, to examine the effects of geographic region (US, non-US) in a 
similar approach as described above.   
 
2.4. 
Pharmacokinetics (PK) Analysis 
Not applicable. 
 
2.5. 
Multiplicity Adjustment  
Not applicable. 
 


 
31 
 
2.6. 
Safety  
2.6.1. 
Analysis Specifications 
All safety analyses and summaries will be based on the safety analysis population.  Subgroup 
analysis per age group may be conducted as needed. 
There will be no imputation of missing values for clinical laboratory test results, vital sign 
measurements, and ECG evaluations in the by-visit analyses.  
 
2.6.2. 
Age Over Time 
Descriptive statistics (N, mean, SD, median, and range) of age will be provided by analysis 
group at DB screening, OL baseline, and endpoint by analysis group. Shifts from DB screening 
to endpoint and from OL Baseline to endpoint in age group (years) below will be produced by 
analysis group to show the percentage of subjects within the age categories: 
• Age group 2: 6-9 years, 10-12 years, 13-15 years, 16-17, 18-20 years. 
 
2.6.3. 
Definition of Treatment-Emergent Occurrences in Open-Label Extension Study 
Definition of treatment-emergent adverse event is provided in Section 2.6.4. Treatment-emergent 
occurrences of adverse reactions, including Potentially Markedly Abnormal Laboratory Values 
(PMALV), Potentially Markedly Abnormal Vital Signs (PMAVS), and abnormal ECG values, 
are defined as the assessment values that meet specific safety criteria within the open-label 
treatment phase (see Section 2.1.2).   
 
2.6.4. 
Adverse Events 
A treatment-emergent adverse event (TEAE) is defined as an AE onset on or after the start of 
open-label treatment period through 7 days after study drug discontinuation (14 days for serious 
adverse events and deaths). For sake of simplicity, hereafter TEAE is referred as AE in the 
section.  
The overall incidence (ie, number and percent of subjects with one or more AE in each category) 
of AEs, serious AEs, deaths, AEs leading to discontinuation, drug-related AEs, serious drug-
related AEs, drug-related AEs leading to discontinuation, serious AEs leading to discontinuation, 
and serious drug-related AEs will be summarized by analysis group and by analysis subgroup, 
separately.  
AEs by system organ class (SOC) (number and proportion of subjects with one or more AEs 
within a system organ class) will be summarized by analysis group.  For each AE, the percentage 
of subjects who experienced at least one occurrence of the given event will be provided by 
preferred term, grouped by system organ class, and presented by analysis group and by analysis 
subgroup. AEs for age subgroup summary will be also presented by SOC and preferred term and 
by analysis group and analysis subgroup.  


 
32 
 
Furthermore, additional summaries will be created based on the following combined preferred 
terms:  
• Dystonia - preferred terms: dystonia, trismus, oculogyric crisis, oromandibular 
dystonia, tongue spasm, torticollis 
• Parkinsonism - preferred terms: bradykinesia, drooling, extrapyramidal disorder, 
glabellar reflex abnormal, hypokinesia, parkinsonism, psychomotor retardation 
• Somnolence - preferred terms: hypersomnia, sedation, somnolence, hypersomnolence 
According to MedDRA coding guidelines for Lurasidone pediatric program,  
• EPS-related reported terms for Tremor, Rigidity or Muscle Rigidity will be queried 
for further specificity. Sites will qualify if the reported term is Parkinsonian or non-
Parkinsonian in nature; if confirmed, the reported term will be coded to lowest level 
terms of Parkinsonism; if not, the term will be coded to specific symptom.  
• For reported term Restlessness, sites will qualify if the reported term is Akathisia or 
non-Akathisia in nature; if confirmed, the reported term will be coded to lowest level 
terms of Akathisia; if not, the term will be coded to specific symptom. 
In clinical database of this study, AEs with preferred term of Tremor, Muscle Rigidity, and 
Cogwheel Rigidity should be read as non-Parkinsonian; AEs with preferred term of Restlessness 
should be read as non-Akathisia. Due to above reasons, preferred terms Tremor, Muscle 
Rigidity, and Cogwheel Rigidity are not included in the list for combined preferred terms of 
‘Parkinsonism’. In addition, these three preferred terms plus term Restlessness are not included 
in the list for extra-pyramidal symptoms (EPS)-related AEs in Attachment 4.5.1. 
Summaries of AEs by preferred term only by analysis group for both combined and uncombined 
terms will be generated as well, respectively. 
In addition, the incidence of AEs (by preferred term, grouped by SOC, and presented by analysis 
group and by analysis subgroup) will also be summarized by severity, by the relationship to 
study medication, by the action taken regarding the study medication, as well as by the outcome. 
The relationship to study medication will be presented by 2 categories: related (which includes 
possibly related, probably related, and related, as determined by investigators), and not related 
(which includes unrelated and unlikely to be related, as determined by investigators). Listings 
will also be generated for deaths, SAEs, and discontinuations due to AEs. All adverse events 
regardless of treatment emergent status will be provided in the AE data listing. 
 
AEs with Special Interest 
A list of preferred terms that are to be combined for the assessment of each of the pre-specified 
adverse events (including Extrapyramidal Symptoms (EPS)-related AEs, metabolic-related AEs, 
hypersensitivity-related AEs, and suicidality and self-injury related AEs) is provided in 
Attachments 4.5.1 - 4.5.4. These AE preferred terms are determined and verified by medical 
review of coded AE terms during data review meeting and finalized prior to database lock.  The 
incidence and exposure adjusted incidence rates of EPS-related AEs, metabolic-related AEs, 


 
33 
 
hypersensitivity-related AEs, and suicidality and self-injury related AEs will be summarized by 
analysis group and by analysis subgroup, respectively. In addition, EPS-related AEs will be 
summarized for akathisia and non-akathisia event as well. 
 
AEs by Exposure 
The TEAEs will be summarized by exposure to study drug using time intervals beginning with 
the earliest concurrent exposure to study drug for following AE summary as needed. 
Denominators for exposure intervals will be based on the number of subjects who were exposed 
as of the first day of the interval; for cases where events meet the treatment-emergent definition 
but start after the last dose, the exposure interval for the event will be considered the interval of 
the last day of exposure to study medication. 
• AEs by system organ class (SOC) and preferred term, Serious AEs by SOC and 
preferred term, and AEs leading to discontinuation by SOC and preferred term (sorted 
alphabetically by SOC and preferred term within SOC). 
• AEs by preferred term, AEs with special interest by preferred term (sorted by 
descending order per frequency count) 
Exposure category to be assessed is given below: 
• Exposure categories : 1-13 days, 14-27 days, 28-55 days, 56-83 days, 84-167 days, 
168-363, and ≥ 364 days.  
 
Summary of AEs Onset after the Last Study Dose 
For subjects who either complete or are early terminated the study, incidence of hyperactivity- 
related AEs will be summarized by analysis group. Attachment 4.5.5 provides the definition of 
hyperactivity-related AEs per preferred term and lower level term. These terms were originally 
defined in Appendix 2 of SN-0434 and were communicated with the Psychiatry Division of FDA 
on Oct 24, 2014.  
 
Subjects continued from Study D1050326 
Treatment-Emergent Mania: 
Treatment-emergent mania is defined as a YMRS score of ≥ 20 on any 2 consecutive OL visits 
(ie, including OL baseline visit for subjects who were randomized to lurasidone group in the core 
study or excluding the visit(s) with study day ≤ Day 1 for subjects randomized to placebo group) 
or at the final assessment in OL treatment period, or any TEAE of mania or hypomania.   
Frequency and percentage of subjects experiencing treatment-emergent mania in the first 52-
week treatment period and during the overall open-label treatment period will be presented by 
analysis subgroup, respectively. 
In addition, frequency and percentage of subjects of following categories will be presented for 
the first 52-week treatment period and the overall open-label treatment period, accordingly. 


 
34 
 
• YMRS score of ≥ 20 on any 2 consecutive OL visits or at the final assessment  
• YMRS score of ≥ 16 on any 2 consecutive OL visits or at the final assessment  
• YMRS score of ≥ 15 on any 2 consecutive OL visits or at the final assessment  
• Any TEAE of mania or hypomania 
• Any TEAE of mania or hypomania or YMRS score of ≥ 16 on any 2 consecutive OL 
visits or at the final assessment 
• Any TEAE of mania or hypomania or YMRS score of ≥ 15 on any 2 consecutive OL 
visits or at the final assessment  
 
 
2.6.5. 
Laboratory Measurements 
Laboratory data will be summarized for each laboratory test listed in Attachment 4.3.  
Descriptive statistics (N, mean, standard deviation, median, and range) will be reported by 
analysis group and analysis subgroup for each continuous laboratory analyte at the DB baseline, 
OL baseline, each post-OL baseline visit, W52 endpoint, and endpoint for absolute value as well 
as changes from DB baseline and OL baseline, respectively. Categorical results (eg, urinalysis 
tests) will be summarized at DB baseline, OL baseline, each post-OL baseline visit, W52 
endpoint, and endpoint by analysis group using frequency and percentage. All lab values will be 
presented in the data listings. 
 
Per a notice from lab vendor of the study, the test agent or assay for Estradiol was switched from 
Estradiol II to Estradiol III during the mid-course of the study. Lab Specification Document 
(LSD) was updated on Sep 01, 2015 to add normal reference range for Estradiol III. Due to this 
change, Estradiol data are presented under 2 test names (ie,‘Estradiol II’ and ‘Estradiol III’) in 
the raw lab dataset. It should be noted that for three completed core studies (D1050325, 
D1050301, D1050326), only Estradiol II was used and reported in the raw lab dataset; ‘Estradiol 
II’ in raw data was mapped as ‘Estradiol’ in the lab analysis dataset of the core studies. In the lab 
analysis dataset of study D1050302, all data under test name of ‘Estradiol’, ‘Estradiol II’, or 
‘Estradiol III’ will be mapped to ‘Estradiol (overall)’; Estradiol results under different test agents 
will be kept as is (ie, mapped as ‘Estradiol II’, and ‘Estradiol III’, respectively). In summary 
output, results for ‘Estradiol (overall)’, ‘Estradiol II’, and ‘Estradiol III’ will be presented, 
separately.  
 
Prolactin values will be summarized by analysis group and gender (male, female, and overall). 
Results for glucose, insulin, and lipid tests (HDL cholesterol, LDL cholesterol, total cholesterol, 
and triglycerides), along with a derived variable for homeostasis model assessment of insulin 
resistance (HOMA-IR), will be presented separately by fasting status, which includes fasting 
only, and overall (fasting, non-fasting, or unknown). HOMA-IR will be derived based on glucose 
and insulin results as follows: 


 
35 
 
                      HOMA-IR = Glucose (mg/dL) x Insulin (mU/L) / 405 for conventional unit; 
                      HOMA-IR = Glucose (mmol/L) x Insulin (µU/L) /22.5) for SI unit. 
The normal reference ranges for laboratory tests will be used to determine whether the laboratory 
test value is below, within, or above the normal range. Shifts from DB baseline and shifts from 
OL baseline over time will be produced by analysis group to show the percentage of subjects 
with laboratory test values below, within, and above the normal range. 
Potentially Markedly Abnormal Laboratory Values (PMALV) per conventional unit and the 
equivalent International System of Units (SI) for selected laboratory parameters can be found in 
Table 3.1.  The criterion of PMALV is satisfied if a value falls into the potentially markedly 
abnormal range. The number and percentage of subjects with treatment emergent PMALV in the 
first 52-weeks treatment period and during overall treatment period, and the number and 
percentage of subjects who meet the threshold in Table 3.2 per conventional unit and the 
equivalent International System of Units (SI) by study visit will be presented by analysis group 
and by analysis subgroup as needed. 
Table 1.1 
Criteria for Potentially Markedly Abnormal Laboratory Values for Pediatric 
and Adolescent Subjects  
Conventional Unit 
SI Unit 
Parameter (Unit) 
 
Potentially Markedly 
Abnormal Range 
Parameter (Unit) 
Potentially Markedly 
Abnormal Range 
Hematology 
 Hemoglobin (g/dL) 
Female: ≤9.5, Male: ≤ 11.5 
Female or Male: ≥ 17.2 
Hemoglobin (g/L) 
Female: ≤95,  
Male: ≤ 115 
Female or Male: ≥ 172 
 Haematocrit (fraction, %) 
≤30, ≥ 50 
Haematocrit (V/V) 
≤0.3, ≥ 0.5 
 WBC (10 3/µL) 
≤2.8, ≥16 
WBC (109/L) 
≤2.8, ≥16 
 RBC (10 6/µL) 
≤3.0, ≥6.0 
RBC (1012/L) 
≤3.0, ≥6.0 
Platelet Count (10 3/µL) 
≤100, ≥ 500 
Platelet Count (109)/L) 
≤100, ≥ 500 
Eosinophils (%) 
≥ 10 
Eosinophils (%) 
≥ 10 
Neutrophils (%) 
≤ 15 
Neutrophils (%) 
≤ 15 
Clinical Chemistry 
 
 ALP (U/L) 
≥ 3 x ULN 
  ALP (U/L) 
≥ 3 x ULN 
 ALT (U/L) 
≥ 2 x ULN 
  ALT (U/L) 
≥ 2 x ULN 
 AST (U/L) 
≥ 2 x ULN 
  AST (U/L)  
≥ 2 x ULN 
 Total Bilirubin (mg/dL) 
≥ 2.0 
  Total Bilirubin (umol/L) 
≥ 34.2 
 Albumin (g/dL) 
 < 50% LLN 
  Albumin (g/L) 
< 50% LLN 
 Creatinine (mg/dL) 
≥ 2.0  
Creatinine (umol/L) 
≥ 176.8 
 Creatine Phosphokinase  
   (CPK) (U/L) 
≥ 450 
  Creatine Phosphokinase  
    (CPK) (U/L) 
≥ 450 
 LDH (U/L) 
≥ 3 x ULN 
  LDH (U/L) 
≥ 3 x ULN 
 GGT (U/L) 
≥ 150 
  GGT (U/L) 
≥ 150 
 Sodium (mEq/L) 
≤130, ≥150 
 Sodium (mmol/L) 
≤130, ≥150 
 Potassium (mEq/L) 
≤3, ≥5.5 
Potassium (mmol/L) 
≤3, ≥5.5  
 Bicarbonate (mEq/L) 
<18, >30 
Bicarbonate (mmol/L) 
<18, >30  
 Calcium (mg/dL) 
< 8.4,  >11.5 
Calcium (mmol/L) 
< 2.1,  > 2.875 
 Chloride (mEq/L) 
< 90, > 115  
Chloride (mmol/L) 
< 90, > 115  
 Blood Urea Nitrogen 
 (mg/dL) 
≥ 30  
Blood Urea Nitrogen 
(mmol/L) 
≥ 11.25 


 
36 
 
 Glucose  
    (fasting) (mg/dL) 
    (random) (mg/dL) 
 
≤45, ≥126 
≤45,  >200 
 Glucose  
    (fasting) (mmol/L) 
    (random) (mmol/L) 
 
≤2.4975,  ≥ 6.993 
     ≤2.4975,   > 11.1 
 Prolactin (ng/mL) 
≥ 1 x ULN 
  Prolactin (mIU/L) 
≥ 1 x ULN 
Lipid Panel (Fasting) 
 Total Cholesterol  (mg/dL) 
≥ 240 
  Total Cholesterol (mmol/L) 
≥ 6.216 
 Triglycerides  (mg/dL) 
Female: ≥170, Male: ≥ 200 
  Triglycerides (mmol/L) 
Female: ≥ 1.921 ,  
Male: ≥  2.26  
 HDL-C (mg/dL) 
≤40 
   HDL-C (mmol/L) 
≤ 1.036 
 LDL-C (mg/dL) 
≥160 
   LDL-C (mmol/L)  
≥ 4.144 
Urinalysis 
 RBC (hpf) 
>25 
  RBC (hpf) 
>25 
 WBC (hpf) 
>25 
  WBC (hpf) 
>25 
                    ULN = Upper Limit of the Normal range. LLN = Lower Limit of the Normal range. 
 
Table 3.2 
Thresholds for Selected Laboratory Parameters 
Conventional Unit 
SI Unit 
Parameter (Unit) 
Threshold 
Parameter (Unit) 
Threshold 
  Prolactin (ng/mL) 
≥ 1 x ULN 
  Prolactin (mIU/L) 
≥ 1 x ULN 
≥ 2 x ULN 
≥ 2 x ULN 
≥ 3 x ULN 
≥ 3 x ULN 
≥ 5 x ULN 
≥ 5 x ULN 
   HDL-C (mg/dL) 
≤30 
HDL-C (mmol/L) 
≤ 0.777 
≤40 
≤ 1.036 
   LDL-C (mg/dL) 
≥ 160 
LDL-C (mmol/L) 
≥ 4.144 
≥ 200 
≥ 5.180 
 Total Cholesterol  
(mg/dL) 
≥ 200 
Total Cholesterol 
(mmol/L) 
≥ 5.180 
≥ 240 
≥ 6.216 
 
A listing of subject data for those who have experienced at least once PMALV in the open-label 
study will be generated. 
Urine drug screen results will be presented for each parameter at DB baseline, OL baseline, post-
OL baseline visit, W52 endpoint, and endpoint. Number and percentage of positive and negative 
results will be displayed by analysis group. 
 
2.6.6. 
ECG Evaluations 
As a part of each ECG, heart rate (HR), axis, and the following intervals will be measured:  RR, 
PR, QRS, and QT. Corrected QT intervals (QTcB and QTcF) values are based on the following 
formula: 
• Bazett: QTcB (msec) = QT (msec) / (RR/1000)1/2 
• Fridericia: QTcF (msec) = QT (msec) / (RR/1000)1/3  


 
37 
 
where RR is reported in milliseconds (msec). 
Descriptive statistics (eg, mean, SD, median, range, 95% CI) for observed value at the DB 
baseline, OL baseline, each post-OL baseline visit, W52 endpoint, and endpoint and changes 
from DB baseline and OL baseline, respectively will be displayed for continuous variables (ie, 
HR, QRS, QTcF, etc) by analysis group.  
The overall ECG assessment and ECG tracing results (T wave, U wave, ST segment etc.) are 
conducted by central reading and a determination is made whether the reading is normal (or 
absent if applicable) or abnormal. Shifts from OL baseline and Shifts from DB baseline over 
time will be produced by analysis group. 
Bazett and Fridericia corrected QTc values will be classified as having QTc prolongation 
according to Table 4. 
Table 4 
QTc Prolongation for Pediatric and Adolescent Subjects 
QTc Prolongation 
QTc >460 msec  
QTc >480 msec  
QTc >500 msec  
Increase from OL baseline QTc ≥ 30 msec 
Increase from DB baseline QTc ≥ 30 msec 
Increase from OL baseline QTc ≥ 60 msec 
Increase from DB baseline QTc ≥ 60 msec 
The number and percentage of subjects having a QTc prolongation using Fridericia correction 
method for DB baseline, OL baseline, post-OL baseline visit, W52 endpoint, endpoint, and any 
treatment emergent occurrence in the first 52-weeks treatment period, and during the open-label 
treatment period (the worst case), will be summarized by analysis group. A listing of ECG data 
for subjects with at least one prolonged QTc will also be produced. 
For other ECG parameters, subjects will be classified as normal or abnormal using the limits 
specified in Table 5. For abnormal ECG parameter reporting, counts and percentages of subjects 
will be presented for DB baseline, OL baseline, each post-OL baseline visit, W52 endpoint, 
endpoint, and any treatment emergent occurrence in the first 52-weeks treatment period, and 
during the open-label treatment phase by analysis group. 
Table 2 
Definition of Abnormal ECG Values by Parameter for Pediatric and 
Adolescent Subjects 
ECG parameter (unit) 
Age (years old) 
Abnormally Low 
Abnormally High 
HR (bpm) 
6 to <8 
<65 
> 115 
8 to <12 
<55 
>110 
12 to <16 
<50 
>105 
≥16 
<50 
>100 
PR interval (msec) 
6 to <8 
-- 
>160 
8 to <12 
-- 
>175 
12 to <16 
-- 
>180 
≥16 
-- 
>200 
QRS interval (msec) 
6 to <8 
-- 
>100 


 
38 
 
8 to <12 
-- 
>105 
12 to <16 
-- 
>110 
≥16 
-- 
>120 
 
2.6.7. 
Vital Signs, Weight, Waist Circumference, and BMI 
Descriptive statistics (mean, SD etc.) will be provided for observed at the DB baseline, OL 
baseline, post-OL baseline visit, W52 endpoint, and endpoint, and change from DB baseline and 
OL baseline values, respectively of each vital sign parameters, weight, height, BMI, waist 
circumference listed below:  
• Systolic blood pressure (SBP) in supine and standing positions 
• Diastolic blood pressure (DBP) in supine and standing positions 
• Heart rate in supine and standing positions 
• Orthostatic change in SBP 
• Orthostatic change in DBP 
• Orthostatic change in heart rate 
• Respiratory rate  
• Temperature 
• Body weight, height, BMI, and waist circumference, 
• Age-and-sex specific z-scores of height and BMI (WHO) 
• Age-and-sex specific z-score of weight (CDC) 
WHO 2007 growth reference provides the reference information up to age of 19 years and 0 
month while CDC 2000 growth chart provides the reference for United State subjects up to age 
of 20 years and 0 month. A small proportion of subjects in study 302 will reach 19 years old and 
a few subjects may reach 20 years old during in the extension study. For each subject, WHO 
2007 growth reference at 19 years and 0 month will be used to derive the z-score and percentile 
of height and BMI for data collected after 19 years old; CDC 2000 growth chart at 20 years and 
0 month will be used to derive the z-score and percentile of weight for data collected after 20 
years old. For US subjects, CDC 2000 growth chart at 20 years and 0 month will be used to 
derive the z-score and percentile of height and BMI for data collected after 20 years old.   
For analysis group and analysis subgroups A and C, WHO based z-scores and percentiles will be 
reported for height and BMI and CDC based z-score and percentile will be reported for weight. 
For analysis subgroup B and the output specific for US subjects, CDC based z-scores and 
percentiles of height, weight, and BMI will be summarized accordingly.  
To better interpret these growth indexes, the expected value of height and BMI relative to DB 
baseline per WHO and the expected value of height, weight, and BMI relative to DB baseline per 
CDC at each open-label visits will be derived; corresponding changes in expected value from DB 
baseline will be generated as well. The number and percentage of subjects with weight status 
categories, defined as a value falling into the categories in Table 6.1 and Table 6.2, will be 


 
39 
 
summarized by analysis group and by analysis subgroup, respectively. This includes subjects 
having experienced at least one occurrence during the open-label extension study, up to and 
including endpoint.  
 
Table 6.1 
Weight Status Categories for Pediatric and Adolescent Subjects per WHO 
Standard 
BMI (kg/m2) 
Weight Status 
< 3th percentile 
Underweight 
3th percentile ≤ BMI ≤ 85th percentile 
Normal 
85th percentile < BMI ≤ 97th percentile 
Overweight 
> 97th percentile 
Obese 
 
Table 6.2 
Weight Status Categories for Pediatric and Adolescent Subjects per CDC 
Standard 
BMI (kg/m2) 
Weight Status 
< 5th percentile 
Underweight 
5th percentile ≤ BMI ≤ 85th 
percentile 
Normal 
85th percentile < BMI ≤ 95th 
percentile 
Overweight 
>95th percentile 
Obese 
 
Shifts from OL baseline and shifts from DB baseline over time for weight status categories 
(Tables 6.1) will be summarized by analysis group to show the number and percentage of 
subjects that fall into above categories. A similar shift analysis will be done for US subjects 
(Table 6.2) by analysis subgroup D. 
The number and percentage of subjects with Potentially Markedly Abnormal Vital Signs 
(PMAVS), defined in Table 7, will be presented by analysis group at DB baseline and OL 
baseline (when applicable), post-OL baseline visits, W52 endpoint, endpoint, and in the first 52-
weeks treatment period, and any treatment-emergent occurrence during the open-label treatment 
phase (the worst case).  
 
Table 7 
Criteria for Potentially Markedly Abnormal Vital Signs for Pediatric and 
Adolescent Subjects 
Parameter 
(unit) 
Age 
(years 
old) 
Markedly Low 
Markedly High 
SBP (supine, 
standing) 
(mmHg) 
6-12 
Value ≤ 70 and 
≥ 20 decrease from baseline 
Value ≥ 120 and 
≥ 20 increase from baseline 
13-18 
Value ≤ 90 and 
≥ 20 decrease from baseline 
Value ≥ 135 and 
≥ 20 increase from baseline 
≥ 19  
Value ≤ 90 and 
Value ≥ 180 and 


 
40 
 
≥ 20 decrease from baseline 
≥ 20 increase from baseline 
DBP (supine, 
standing) 
(mmHg) 
6-12 
Value ≤ 40 and 
≥ 15 decrease from baseline 
Value ≥ 80 and 
≥ 15 increase from baseline 
13-18 
Value ≤ 50 and 
≥ 15 decrease from baseline 
Value ≥ 90 and 
≥ 15 increase from baseline 
≥ 19 
Value ≤ 50 and 
≥ 15 decrease from baseline 
Value ≥ 105 and 
≥ 15 increase from baseline 
Pulse rate 
(supine, 
standing) (bpm) 
6-10 
Value ≤ 60 and 
≥ 15 decrease from baseline 
Value ≥ 135 and 
≥ 15 increase from baseline 
11-18 
Value ≤ 50 and 
≥ 15 decrease from baseline 
Value ≥ 120 and 
≥ 15 increase from baseline 
≥ 19 
Value ≤ 50 and 
≥ 15 decrease from baseline 
Value ≥ 120 and 
≥ 15 increase from baseline 
SBP orthostatic 
criteria (mmHg) 
~ 
≥ 20 decrease from supine to 
standing position 
NA 
DBP orthostatic 
criteria (mmHg) 
~ 
≥ 10 decrease from supine to 
standing position 
NA 
Pulse rate 
orthostatic 
criteria (bpm) 
~ 
NA 
≥ 20 increase from supine to 
standing position 
Temperature 
(˚C) 
~ 
NA 
Value ≥ 38.3°C and ≥0.8°C  
increase from baseline 
  Note: ~ means that the abnormal range is applicable for all subjects;  
             Baseline represents ‘DB baseline’ and ‘OL baseline’ respectively. 
 
A listing of subject data for those who satisfy MAPVS during the open-label study will be 
presented.  
 
2.6.8. 
Young Mania Rating Scale (YMRS) 
The YMRS is only applied to subjects who continued from Study D1050326. 
The YMRS is an 11-item instrument used to assess the severity of mania in patients with a 
diagnosis of bipolar disorder. Ratings are based on patient self-reporting, combined with 
clinician observation.   Seven items are rated on a 5-point scale, ranging from 0 to 4, and four 
items are rated on a 9-point scale, ranging from 0 to 8.   
• Seven Items that are scored 0 to 4 are: 
− Elevated mood 
− Increased Motor Activity – Energy 
− Sexual Interest 
− Sleep 
− Language/Thought Disorder 
− Appearance 
− Insight 
• Four items that are scored 0 to 8  are 
− Irritability 


 
41 
 
− Speech (Rate and Amount) 
− Content 
− Disruptive/Aggressive Behavior 
The YMRS total score is the sum of the 11 individual items and ranges from 0 to 60. A higher 
score is associated with a greater severity of mania.  
 
Analysis Methods 
Subjects continued from Study D1050326 
Summary statistics for the observed at the DB baseline, OL baseline, each post-OL baseline time 
point, W52 endpoint, and endpoint, change from DB baseline, and change from OL baseline in 
YMRS total score will be presented by analysis subgroup.  
 
2.6.9. 
Extrapyramidal Symptoms Assessment Scales 
2.6.9.1. 
Barnes Akathisia Rating Scale  
The Barnes Akathisia Rating Scale (BARS) consists of four items: an objective rating (ranging 0 
to 3), 2 subjective ratings of symptoms of akathisia (awareness of restlessness and reported 
distress related to restlessness: ranging 0 to 3), and a global clinical rating of akathisia, ranging 
from 0 (absent) to 5 (severe).  The global rating score (item 4), that is scored separately, is the 
most relevant measure of severity of akathisia. Higher scores denote worsening akathisia. The 
subjective and objective items (items 1 through 3) are summed to yield a BARS total score with 
a range of 0 to 9. Higher values of the BARS total score indicate higher severity of akathisia.  
 
For subjects continued from Studies D1050301 and D1050326  
Two items for subjective ratings of symptoms of akathisia (awareness of restlessness and 
reported distress related to restlessness) range from 0 to 3. 
For subjects continued from Study D1050325 
Two items for subjective ratings of symptoms of akathisia (awareness of restlessness and 
reported distress related to restlessness) range from 0 to 3, and Not Applicable (NA). When any 
subjective rating is recorded as NA, the BARS total score will not be calculated and will be set 
as NA as well. 
2.6.9.2. 
Abnormal Involuntary Movement Scale  
The Abnormal Involuntary Movement Scale (AIMS) contains items related to:  facial and oral 
movements; extremity movements; trunk movements; global judgments and dental status. The 
individual items on the AIMS range from 0= ‘None’ to 4= ‘Severe’. Three other items assess the 
subject at a global level, and two items assess dental status. The individual items on the AIMS 
are rated from 0= ‘None’ to 4= ‘Severe’. The (non-global) total AIMS score is the sum of items 
1 through 7 (ranging from 0 to 28). Items 8 through 12 will not be calculated in total AIMS 


 
42 
 
score. Higher values of the total AIMS score indicate increased severity in abnormal movement.  
The global severity score (Item 8) is the response to, “Severity of abnormal movements”, found 
within the global judgments section (0 - None, normal, 1 – Minimal, 2 – Mild, 3 – Moderate and 
4 – Severe) and will be summarized separately. 
 
2.6.9.3. 
Simpson-Angus Scale 
The Simpson-Angus Scale (SAS) is a clinician-rated assessment of neuroleptic-induced 
Parkinsonism consisting of 10 items. Items are anchor-based, rated on a 5-point scale (0-4), and 
address rigidity, gait (bradykinesia), tremor, glabellar tap, and salivation. Each individual item 
on the SAS ranges from 0= ‘Normal’ to 4= ‘Extreme Symptoms’. The SAS mean score is 
defined as the average of all 10 items and ranges between 0 and 4. Higher value of the SAS mean 
score indicates more severe condition of EPS symptom 
SAS version 2 was to be used in studies D1050301, D1050325, D1050326, and D1050302. It 
was noticed on December 9, 2016 that all Hungarian sites in studies D1050301, D1050326, and 
D1050302 used SAS version 1 instead. There is no plan to update the SAS version for Hungarian 
sites; ie,  Hungarian subjects will keep use SAS version 1 till the end of study D1050302. 
The difference between SAS version 1 and version 2 is highlighted below: 
Version 2  
Version 1 (Hungarian Sites Only) 
1. Gait 
1. Gait 
2. Arm dropping 
2. Arm dropping 
3. Shoulder shaking 
3. Shoulder shaking 
4. Elbow rigidity 
4. Elbow rigidity 
5. Wrist rigidity or fixation of position 
5. Wrist rigidity or fixation of 
position 
6. Head rotation 
6. Leg Pendulousness  
7. Glabella Tap 
7. Head rotation 
8. Tremor 
8. Glabella Tap 
9. Salivation 
9. Tremor 
10. Akathisia 
10. Salivation 
 
The SAS total score per V1 and V2 will be derived, separately. Since the SAS version related 
issue was found after the DBL of studies D1050301 and D1050326, DB baseline and OL 
baseline associated with these two SAS versions was derived and will be used in final analysis. 
Analysis Methods 
Summary statistics for the observed at the DB baseline, OL baseline, each post-OL baseline time 
point, W52 endpoint, and endpoint, change from DB baseline, and change from OL baseline in 
BARS total score, BARS global clinical assessment of akathisia score, AIMS total score, SAS 
10-item mean score (all versions combined) will be presented by analysis group, and by analysis 
subgroup.  


 
43 
 
The post-OL baseline BARS global clinical assessment of Akathisia responses and the post-OL 
baseline AIMS global severity scores will be classified as ‘worsened’, ‘unchanged’, or 
‘improved’, relative to a subject’s corresponding DB baseline response and OL baseline 
response, respectively. A higher post-OL baseline response than that of DB baseline or OL 
baseline would be classified as ‘worsened’ relative to DB baseline and OL baseline, respectively. 
Conversely, a lower value than that of DB baseline or OL baseline would be classified as 
‘improved, respectively. Frequency distribution over time of these variables will be summarized 
at each post-OL visit and endpoint by analysis group. 
The AIMS total score at DB baseline, OL baseline, each post-OL visit, W52 endpoint, and 
endpoint will also be classified as ‘abnormal’ if either:  at least two items have a response of 
‘mild’ or higher; or at least one item has a response of ‘moderate’ or higher; otherwise, non-
missing total scores will be classified as ‘normal’. This is a modification of the Schooler-Kane 
Criteria for Tardive Dyskinesia. The SAS 10-item mean score (all versions combined) at DB 
baseline, OL baseline, each post-OL visit, W52 endpoint, and endpoint will be classified as 
‘abnormal’ if it exceeds 0.3; otherwise, non-missing mean scores will be classified as ‘normal.’ 
Shifts from OL baseline and shifts from DB baseline will be summarized for these variables (ie, 
abnormality status of the AIMS total score and the SAS 10-item mean score) at each assessed 
visit, endpoint, and overall for the open-label study up to and including endpoint (based on 
maximum severity) by analysis group.  
 
2.6.10. 
CogState Computerized Cognitive Test Battery 
Cogstate is only applied to the subjects continued from Studies D1050301 and D1050326. 
The CogState Computerized Cognitive Test Battery consists of 4 primary, individually 
administered tests in 4 distinct MATRICS cognitive domains, as detailed in Table 8. 
Components of the CogState Computerized Cognitive Test Battery: 
• Detection Task 
In this task, subjects must respond to a card being displayed face up on the screen as quickly as 
possible. The score will be calculated as the mean of log10 transformed reaction times for correct 
responses. Lower scores indicate better performance. 
• Identification Task 
Subject must identify the color of a card as quickly as possible in this task. The score will be 
calculated as the mean of log10 transformed reaction times for correct responses. Lower scores 
indicate better performance. 
• One Card Learning Task 
In this task, subjects must remember which cards have been shown before in the task. The 
arcsine transformation of the square root of the proportion of correct responses will be recorded. 
Higher scores indicate better performance. 
• One Back Task 
In this task, subjects must  


 
44 
 
(1) decide if each card is exactly the same as the previous card presented. The score will be 
calculated as the arcsine transformation of the square root of the proportion of correct 
responses. Higher scores indicate better performance. 
(2) identify the color of a card as quickly as possible in this task. The score will be calculated 
as the mean of log10 transformed reaction times for correct responses. Lower scores 
indicate better performance. 
 
Table 8 
Cognitive Domains Evaluated in CogState Tests 
MATRICS 
Cognitive Domain 
CogState Test 
 
Data Type 
 
Transformed Data from CogState 
Psychomotor speed 
Detection Task 
Speed 
Log10(S), 
S= reaction times for correct responses 
Attention 
Identification Task 
Speed 
Log10(S), 
S= reaction times for correct responses 
Learning/Memory   
One Card Learning Task  
Accuracy 
arcsine
R ,  
R=proportion of correct responses 
Working Memory  
One Back Task  
Speed  
Log10(S), 
S= reaction times for correct responses 
Accuracy 
arcsine
R ,  
R=proportion of correct responses 
 
A normative table of CogState Computerized Cognitive Test Battery for children and adolescent 
subjects is provided in Attachment 4.2. For an individual domain, the age-specific standardized 
score for each task and data type is derived as below based on the subject’s age (in years) at the 
study visit. The standardized scores are calculated by CogStat vendor (COGSTATE CT). 
(Score – 
domain
age,
m
) × Multiplicand / 
domain
age
SD
,
, 
Where 
domain
age,
m
 : mean of the norm group at the age (in years)  
domain
age
SD
,
: standard deviation of the norm group at the age (in years)  
Score : individual subject performance 
      Multiplicand: an indicator, 
• Multiplicand = −1 when a lower score indicates improved performance (e.g. 
Detection task (speed), Identification task (speed), One Back Task (speed));  
• Multiplicand = +1 when a higher score indicates improved performance (e.g. One 
Card Learning Task (accuracy), One Back Task (accuracy)). 
Based on the standardized scores of individual task and data type (accuracy, speed) provided by 
the vendor, the sponsor will further derive the following composite scores for final analyses:  
(1) The standardized composite score is calculated as the mean of the standardized scores of 
Detection Task (speed), Identification Task (speed), One Back Task (speed), and One 


 
45 
 
Card Learning Task (accuracy).  If two or more components are missing at a visit, the 
composite score will be set to missing. 
(2) For each subject, change from baseline in standardized score for each of the 4 cognitive 
domains, and the standardized composite score will be derived at each assessed visit.   
Definition of the standardized composite score in this SAP is same as the one in SAPs of interim 
analysis 1 and study D1050326 and is also same as the standardized composite score 2 in clinical 
study report of study D1050301.  
 
Analysis Methods 
For subjects continued from Studies D1050301 and D1050326 
For CogState computerized cognitive composite standardized score and individual standardized 
domains scores, descriptive summaries (N, mean, standard deviation, median, and range) of 
observed and change from DB Baseline and OL Baseline will be provided by visit, W52 
endpoint, and endpoint and analysis group and analysis subgroup, respectively.  
 
2.6.11. 
Columbia Suicide Severity Rating Scale (C-SSRS) 
C-SSRS is applied to the subjects continued from Study D1050301 and C-SSRS children version 
is applied to the subjects continued from Study D1050326.The C-SSRS Childrens’ Version is 
distinguished from the adult version by the absence of questions regarding the duration, 
controllability, deterrents and reasons for ideation. 
Severity of suicidal ideation is rated on a 6-point scale from 0=’No ideation present’ to 
5=’Active ideation with plan and intent’. A score of 4 or 5 on this scale indicates serious suicidal 
ideation.  Suicidal ideation score is defined as the most severe suicidal ideation score (1-5 on the 
CSSRS) present at the assessment; assign a score of 0 if no ideation is present.  
For subjects continued from study D 1050301, the ideation intensity total score is calculated as 
summation of the five items from the Ideation Intensity scale: frequency, duration, 
controllability, deterrents, and reasons for ideation. If one or more of these 5 items are missing at 
a visit, no imputation will be made and the corresponding ideation intensity total score will be set 
as missing. Items corresponding to frequency and duration are each rated on a scale from 1 to 5 
and items corresponding to controllability, deterrents, and reasons for ideation are each rated on 
a scale from 0 to 5. If the patient did not endorse any suicidal ideation, set the intensity rating to 
0. Thus, the possible range for the intensity total score is 0 to 25. For subjects continued from 
study D 1050326, the ideation intensity total score is not applicable and therefore will not be 
derived. 
Suicidal behavior is collected as presence/absence of actual attempts, non-suicidal self-injurious 
behavior, interrupted attempts, aborted attempts, preparatory acts or behavior, and any suicidal 
behavior. In addition, the number of actual attempts, interrupted attempts, and aborted attempts 
are captured. Any attempt will be defined as suicidal behavior.  
The lethality associated with actual attempts is rated on a 6-point scale from 0=’No physical 
damage or very minor physical damage’ to 5=’Death’. Potential lethality of attempts is rated on a 


 
46 
 
3-point scale from 0=’Behavior not likely to result in injury’ to 2=’Behavior likely to result in 
death despite available medical care’.  
According to FDA draft guidance for suicidal ideation and behavior ([5], Appendix A), the 
following C-SSRS outcomes, which have binary responses (yes/no), are re-ordered and 
numbered to facilitate the further definitions of the composite endpoint and comparative 
endpoint of C-SSRS as below.   
Category 1 – Wish to be Dead 
Category 2 – Non-specific Active Suicidal Thoughts 
Category 3 – Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
Category 4 – Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Category 5 – Active Suicidal Ideation with Specific Plan and Intent 
 
Category 6 – Preparatory Acts or Behavior 
Category 7 – Aborted Attempt 
Category 8 – Interrupted Attempt 
Category 9 – Actual Attempt  
Category 10 – Completed Suicide 
Category 11– Self-injurious behavior without suicidal intent 
Unless otherwise specified, C-SSRS table outputs will be presented by analysis subgroup for one 
analysis time point ‘Any extension’, whose definition is given in Table 9.  
 
Table 9 
Analysis TimePoint for C-SSRS 
Analysis Timepoint 
eCRF Visit(s) to be 
Involved 
C-SSRS Version 
/Assessment 
Period 
Derivation Rule 
Any extension visit* 
Up to EOT   
Since last visit 
Most severe value  
*: including all visits in open-label treatment period (see Section 2.1.2). 
Comparative endpoints for ‘Emergence’ (outcomes that include events that first emerge) and 
‘Worsen’ (outcomes that include events that worsen) will be derived below).  
 
Table 10.1 
Comparative Endpoint Relative to DB Baseline 
Comparative 
Endpoints  
Analysis  
Time Points 
Involved 
Derivation Rule 
Emergence of 
Suicidal Ideation 
DB Baseline(a) 
Any extension 
visit(b)  
 
No suicidal ideation at DB Baseline, and any type of 
suicidal ideation in ‘any extension visit’ 
Emergence of Serious 
Suicidal Ideation 
No suicidal ideation at DB Baseline, and any serious 
suicidal ideation [ideation score of 4 or 5] in ‘any 
extension visit’  


 
47 
 
Emergence of 
Suicidal Behavior  
No suicidal behavior at DB Baseline, and any type of 
suicidal behavior in ‘any extension visit’ 
Emergence of 
Suicidality 
No suicidality at DB Baseline, and any suicidality in 
‘any extension visit’ 
Worsening of 
Suicidal Ideation 
Most severe suicidal ideation in ‘any extension visit’ is 
more severe than the most severe value at DB Baseline 
(a): Definition of DB Baseline: see Table 9 in D1050301 SAP, and Table 9 in D1050326 SAP ;  
(b): see Table 9. 
 
Table 10.2 
Comparative Endpoint Relative to DB Treatment Period 
Comparative 
Endpoints  
Analysis  
Time Points 
Involved 
Derivation Rule 
Emergence of 
Suicidal Ideation 
Any DB treatment 
period (a) 
Any extension visit(b)  
 
No suicidal ideation in DB treatment period, and any 
type of suicidal ideation in ‘any extension visit’ 
Emergence of Serious 
Suicidal Ideation 
No suicidal ideation in DB treatment period, and any 
serious suicidal ideation [ideation score of 4 or 5] in 
‘any extension visit’  
Emergence of 
Suicidal Behavior  
No suicidal behavior in DB treatment period, and any 
type of suicidal behavior in ‘any extension visit’ 
Emergence of 
Suicidality 
No suicidality in DB treatment period, and any 
suicidality in ‘any extension visit’ 
Worsening of 
Suicidal Ideation 
Most severe suicidal ideation in ‘any extension visit’ is 
more severe than the most severe value in any DB 
treatment period 
(a): Definition of ‘any DB treatment period’: see ‘any post-baseline’ in Table 9 of D1050301 SAP, and 
‘any post-baseline’ in Table 9 of D1050326 SAP ;  
(b): see Table 9. 
 
Analysis Methods 
For subjects continued from Studies D1050301 and D1050326 
The number and percentage of subjects with following categories will be summarized by 
analysis group and analysis subgroup for any extension visit. 
• each type of suicidal ideation,  
• any suicidal ideation,  
• each type of suicidal behavior, 
• any suicidal behavior,  


 
48 
 
• any having self-injurious behavior without suicidal intent, 
• any suicidality 
 
In addition, for any extension visit, the number and percentage of subjects with following 
categories will be also summarized by analysis group and analysis subgroup. 
• emergence of suicidal ideation,  
• emergence of serious suicidal ideation,  
• worsening of suicidal ideation,  
• emergence of suicidal behavior, 
• emergence of suicidality 
 
Shifts from DB baseline and OL baseline to any post-OL baseline visit (ie, the worst case) in 
suicidal ideation score will be presented by analysis group and analysis subgroup, to show the 
percentage of subjects with values 0 (’No ideation present’) to 5 (’Active ideation with plan and 
intent’). For subjects continued from study D1050301, ideation intensity total score will be 
provided in data listing. Data collected on actual suicide attempts (lethality of actual attempts 
and potential lethality of attempts) will be presented in a data listing. 
 
2.6.12. 
Udvalg for Kliniske Undersogelser Side Effect Rating Scale (UKU) 
UKU is only applied to the subjects continued from Studies D1050301 and D1050326. 
The UKU consists of 48 adverse effects items, divided into 4 categories: psychic (10 items), 
neurologic (8 items), autonomic (11 items), and other (19 items). Each item is rated on a 0-3 
point scale: 0– no side effects, 1– mild, 2– moderate, 3– severe with causal relationship 
(‘improbable’, ‘possible’, ‘probable’) also assessed for scores of 1-3. Score of 9 is given if 
symptom is not assessed or cannot be assessed if it does not apply to a subject (gender, age, 
sexual maturation); for individual items that are not able to be assessed the rater would line out 
the item and enter N/A and not assessed would be checked in the symptom checklist. 
Specifically, male subjects and female subjects who have not achieved menarche will be rated 
with a 9 (‘Not Assessed) for items 4.7, 4.8, and 4.16, since these items are designed only for 
female subjects who have achieved menarche; likewise, female subjects will be rated with a 9 
(‘Not Assessed) for items 4.10, 4.13, and 4.14, since these items are designed for male subjects 
only.  
Unlike other UKU adverse effect item, which is composed of a single assessment, UKU items 
4.1 (rash, sub-items: 4.1a~4.1e) and 4.17 (headache, sub-items: 4.17a~4.17c) contains 
assessments for multiple sub-categories. For these two items, eCRF collects data in the following 
way: when an adverse event exists, a rating score is to be collected at a specific sub-item level 
only; when none of these sub-items show adverse event, only item 4.1 (or 4.17) will have value 0 
(or 9 when applicable). The rating score related to items 4.1 and 4.17 will be further derived as 
below:  


 
49 
 
• If the rating score for at least one of its sub-items is 1 and higher (ie, 1~3), the rating 
score of item 4.1 (or 4.17) will be set as the most severe value among its sub-items; 
• If item 4.1 (or 4.17) has value 0 or 9, its corresponding sub-items will be set as 0 or 9. 
In addition to the 48 questions for symptom, two global assessment of effect on functioning are 
collected in UKU (one by clinician and one by patient); clinical “consequence” with respect to 
management will be rated by clinician only.  
The following four UKU category scores will be calculated as the summation of the assessed 
individual scores within each category: 
• psychic side effects score (range from 0 up to 30),  
• neurologic side effects score (range from 0 up to 24),  
• and autonomic side effects score (range from 0 up to 33)  
• other side effects score (range from 0 up to 48) 
Specifically, item with value 9 (‘Not Assessed’) will not be included in calculation of these 
category scores. Particularly, UKU other side effects score is gender-specific, ie, items 4.10, 4.13 
and 4.14 will not be included in UKU other side effects score calculation for female subjects 
while items 4.7, 4.8, and 4.16 will not be included in UKU other side effects score calculation for 
male subjects. 
If two or more components are missing (not ‘Not Assessed’) at a visit, the corresponding UKU 
category score will be set as missing; when only one component item is missing, the UKU 
category scores will be calculated based on the available items at a visit. The total UKU score is 
calculated as the sum of four UKU category scores (ranging from 0 up to 135). If one UKU 
category score is missing, the total UKU score will be set as missing. Higher values of the total 
UKU score and four category scores indicate more severe side effects.   
Unless otherwise specified, UKU table outputs for following binary effect and the corresponding 
drug-related effect will be presented by analysis subgroup for analysis timepoint ‘any extension 
visit’. 
• Any psychic side effect (ie, Items 1.1 – 1.10) 
• Any neurologic side effect (ie, Items 2.1 – 2.8) 
• Any autonomic side effect (ie, Items 3.1 – 3.11) 
• Any other side effect (ie, Items 4.1 – 4.17) 
For UKU assessed in the open-label treatment period, causal relationship to study medication 
will be grouped into 2 categories (determined by investigators): related (which includes 
‘possible’, ‘probable’), and not related (‘improbable’). For any UKU assessment prior to the start 
of the open-label treatment period, causal relationship for UKU items will be ‘not related’ for 
previously placebo subjects. During the any open-label treatment, drug-related effect will be 
defined similarly as above based on the worst case related to the study medication.  
 
A score of 1, 2 or 3 on any UKU item that first occurred or worsened during the open-label 
treatment period indicated ‘cases’ of adverse events. Adverse events were conceptualized as a 


 
50 
 
dichotomous variable, either ‘present’ (1 (mild) or higher) or ‘not present’ (0, 9). The severe 
order is defined as 3>2> 1> 0, 9. Both DB baseline and ‘the worst case of DB treatment period’ 
will be used to derive the ‘Emergence’ and ‘Worsen’ for ‘Any extension visit’ respectively for 
the parameters below. 
• Any Individual side effect (by individual item) 
• Any psychic side effect, 
• Any neurologic side effect, 
• Any autonomic side effect, 
• Any other side effect 
 
If one or more of the two required values are missing for ‘emergence of side effect’ or ‘worsen 
of side effect’, corresponding side effect value will be set as missing. 
 
Table 11.1 
Comparative Endpoint of UKU Relative to DB Baseline  
Comparative Endpoints 
Derivation Rule 
Emergence of side effect 
Relative to DB Baseline 
‘not present’ at DB Baseline and any ‘present’ in the open-label treatment 
period 
Emergence of drug- 
related side effect 
Relative to DB Baseline 
‘not present’ at DB Baseline and any drug-related ‘present’ in the open-label 
treatment period 
Worsening of side effect 
Relative to DB Baseline 
the most severe rating in  the open-label treatment period is more severe than it 
was at DB Baseline 
Worsening of drug-
related side effect 
Relative to DB Baseline 
the most severe drug-related rating in  the open-label treatment period is more 
severe than it was at DB Baseline 
*: the value of the open-label treatment period is defined as the worst case in the open-label treatment 
period. 
 
Table 11.2 
Comparative Endpoint of UKU Relative to the Core DB Treatment Period 
Comparative 
Endpoints 
Derivation Rule 
Emergence of side 
effect Relative to 
Core  DB Treatment 
Period  
‘not present’ in any core DB treatment period* and any ‘present’ at any open-label 
treatment period 
Emergence of drug-
related side effect 
Relative to Core  DB 
‘no drug-related present’ in any core DB treatment period* and any drug-related 
‘present’ in open-label treatment period 


 
51 
 
Treatment Period  
Worsening of side 
effect Relative to 
Core  DB Treatment 
Period  
the most severe rating at any open-label treatment period is more severe than the 
worst case of any core DB treatment period* 
 
Worsening of drug-
related side effect 
Relative to Core  DB 
Treatment Period  
the most severe drug-related rating in open-label treatment period is more severe 
than  any drug-related rating in core DB treatment period* 
 
Note:  *: is referred to any post-DB baseline visit in DB treatment period of the core study (see Table 11 of 
D1050301 SAP or Table 11 of D1050326 SAP). 
 
 
Analysis Methods 
For subjects continued from Studies D1050301 and D1050326 
For individual item and four side effect categories, numbers and percentages of subjects who 
experience any side effect and any drug-related side effect will be summarized by analysis 
subgroup at DB baseline, any core DB treatment period,  and any extension treatment period 
(when applicable),  respectively.  
In addition, numbers and percentages of subjects with emergence of side effect and worsening of 
side effect relative to DB baseline and to the core DB treatment period will be summarized by 
analysis group and analysis subgroup for each individual item and each side effect category, 
respectively. 
For each side effect category score and UKU total score, descriptive summaries (N, mean, SD, 
median etc.) of observed and change from DB Baseline and change from OL baseline in four 
UKU four category side effects scores and UKU total score will be presented by analysis group 
and analysis subgroup at each assessment point,  W52 endpoint, and end point. 
Frequency distribution of clinical global assessment of effect, patient global assessment of effect, 
consequence assessed by clinician will be also tabulated by visit, W52 endpoint, and endpoint 
and by analysis group and analysis subgroup.  
 
 
2.6.13. 
Tanner Staging and Menstrual Cyclicity 
The tanner staging is a scale of physical development in children, adolescents and adults. The 
scale defines physical measurements of development based on external primary and secondary 
sex characteristics, such as the size of the breasts, genitalia, testicular volume and development 
of pubic and axillary hair. Tanner staging for each measurement ranges from Stage I (Preado-
lescent) (numeric value 1) to Stage V (numeric value 5).  


 
52 
 
Analysis Methods 
All outputs for tanner staging will be tabulated separately by gender. The frequency distribution 
of each category of the tanner staging will be tabulated at DB baseline, OL Baseline, post-OL 
Baseline visit, W52 endpoint, and endpoint by analysis group. In addition, frequency distribution 
of changes from DB baseline and OL baseline for each category of the tanner staging will be 
summarized for each post-OL visit, W52 endpoint, and endpoint by analysis group. Shifts from 
DB baseline and OL baseline to Endpoint in tanner stage will be presented by analysis group. 
The frequency distribution of quality and frequency of menstrual cyclicity will be presented by 
analysis group.  
 


 
53 
 
3. 
REFERENCES 
 
1. FDA (2012), FDA written request for Latuda (lurasidone) pediatric program: NDA 200603, 
Reference ID: 3118727 
2. WHO Growth reference 5-19 years, 2007,  http://www.who.int/growthref/en/ 
3. WHO AnthroPlus software: http://www.who.int/growthref/tools/en/ 
4. Kuczmarski RJ, Ogden CL, Guo SS, et al. 2000 CDC growth charts for the United States: 
Methods and development. National Center for Health Statistics. Vital Health Stat 11(246). 
2002 (http://www.cdc.gov/growthcharts/2000growthchart-us.pdf). 
5. Food and Drug Administration, Center for Drug Evaluation and Research (CDER), 2012. 
Guidance for Industry Suicidal Ideation and Behavior: Prospective Assessment of 
Occurrence in Clinical Trials 
 
 
 
 
 


 
54 
 
4. 
ATTACHMENTS 
4.1. 
Computation of Centiles and Z-scores for Height-For-Age, Weight-
For-Age (CDC only), and BMI-For-Age 
4.1.1. 
WHO 2007 Reference for Growth Charts 


 
55 
 
 
 
 


 
 
56 
 
 


 
 
57 
 
 


 
 
58 
 
 


 
 
59 
 
 
 


 
 
60 
 
4.1.2. 
2000 CDC  Growth Charts for the United States 
 
 


 
 
 
61 
 
 


 
 
 
62 
 
 


 
 
 
63 
 
 


 
 
 
64 
 
 


 
 
 
65 
 


 
 
 
66 
 
4.2. 
Cogstate Child and Adolescent Normative Data 
The Cogstate normative data from healthy children and adolescents aged between 10 and 20 
years are provide by Cogstate and displayed below. 
Cogstate Normative Data for Children and Adolescent Subjects 
Age 
(years) 
 Detection − Speed 
Identification – Speed 
One Back – Speed 
Mean 
SD 
Mean 
SD 
Mean 
SD 
10 
2.57 
0.084 
2.77 
0.075 
2.95 
0.095 
11 
2.54 
0.081 
2.74 
0.074 
2.92 
0.089 
12 
2.54 
0.081 
2.72 
0.075 
2.90 
0.091 
13 
2.52 
0.078 
2.70 
0.071 
2.88 
0.088 
14 
2.52 
0.081 
2.69 
0.074 
2.87 
0.090 
15 
2.51 
0.078 
2.68 
0.071 
2.86 
0.089 
16 
2.51 
0.077 
2.68 
0.069 
2.85 
0.090 
17 
2.50 
0.075 
2.67 
0.066 
2.84 
0.090 
18 
2.51 
0.072 
2.67 
0.066 
2.84 
0.089 
19 
2.50 
0.066 
2.67 
0.060 
2.83 
0.085 
20 
2.50 
0.069 
2.66 
0.060 
2.82 
0.089 
 
 
Age 
(years) 
One Card Learning  − Accuracy 
One Back − Accuracy 
Mean 
SD 
Mean 
SD 
10 
0.98 
0.098 
1.28 
0.18 
11 
0.98 
0.096 
1.30 
0.17 
12 
0.98 
0.092 
1.31 
0.16 
13 
0.98 
0.089 
1.32 
0.15 
14 
0.98 
0.088 
1.32 
0.16 
15 
0.98 
0.088 
1.33 
0.16 
16 
0.99 
0.088 
1.34 
0.15 
17 
0.99 
0.090 
1.34 
0.15 
18 
1.00 
0.089 
1.35 
0.15 
19 
1.01 
0.086 
1.37 
0.14 
20 
1.02 
0.090 
1.38 
0.13 
 
4.3. 
Clinical Laboratory Tests 
 
 
Blood Chemistry Tests 
 
aspartate aminotransferase  
 
alanine aminotransferase  
 
albumin  
 
alkaline phosphatase  
 
bicarbonate  
 
blood urea nitrogen  
 
calcium  
 
chloride  
 
creatinine  
 
gamma-glutamyl transferase  
 
phosphorous  


 
 
 
67 
 
 
potassium  
 
sodium  
 
total bilirubina 
 
total protein  
 
lactate dehydrogenase  
 
fasting (non-random) triglycerides 
 
fasting (non-random) serum cholesterol  
 
fasting (non-random) serum high-density lipoprotein cholesterol  
 
fasting (non-random) serum low-density lipoprotein cholesterol  
 
fasting glucose  
 
prolactin  
 
whole blood hemoglobin A1c 
 
creatine phosphokinase  
 
Endocrine Tests 
 
free thyroxine test 
 
thyroid-stimulating hormone test 
 
Hormonal Parameters 
 
follicle stimulating hormone (female subjects only) 
 
luteinizing hormone (female subjects only) 
 
testosterone (male subjects only) 
 
estradiol (female subjects only) 
 
serum human chorionic gonadotropin (β-hCG) (female subjects ≥ 11 years of age only) 
 
urine human chorionic gonadotropin (β-hCG) (female subjects ≥ 11 years of age only) 
 
Hematology Tests 
 
white blood cell count 
 
white blood cell differential 
 
eosinophilic leukocyte count 
 
basophilic leukocyte count 
 
neutrophil count 
 
lymphocyte count 
 
monocyte count 
 
platelet count 
 
hemoglobin  
 
blood hematocrit 
 
red blood cell count 
 
red cell distribution width  
 
red blood cell indices: 
 
mean corpuscular volume 
 
mean corpuscular hemoglobin concentration 
 
mean corpuscular hemoglobin 
 
Urinalysis Tests 
 
color  
 
appearance  
 
total ketones  
 
urobilinogen  
 
bilirubin  
 
red blood cells 
 
leukocyte esterase  
 
nitrite  
 
pH  
 
protein  
 
specific gravity  


 
 
 
68 
 
 
glucose  
 
microscopic evaluationb 
 
Urine Drug Screen 
 
amphetamines  
 
benzodiazepines  
 
barbiturates  
 
cocaine  
 
tetrahydrocannabinol  
 
ethanol  
 
methadone  
 
methamphetamine  
 
opiates  
 
phencyclidine  
 
 
 
4.4. 
Benzodiazepine Equivalence Table Conversion Factors to Convert 
Benzodiazepine Dose to Oral Equivalent Doses Standardized to 
Lorazepam 
Benzodiazepine 
Comparative 
dose 
Benzodiazepine 
Comparative 
dose 
Alprazolam 
0.5 Ketazolam 
7.5 
Amobarbital * 
50 Loflazepate * 
1.67 
Barbital * 
75 Lorazepam 
1 
Bromazepam 
3 Lormetazepam * 
1 
Bromvalerylurea * 
500 Medazepam * 
10 
Brotizolam * 
0.5 Mexazolam * 
1.67 
Butoctamide * 
500 Midazolam ** 
5 – 7.5 
Chloral hydrate * 
250 Nimetazepam * 
5 
Clobazam * 
10 Nitrazepam 
2.5 
Clonazepam 
0.25 Nordiazepam 
5 
Clorazepate 
10 Oxazepam 
15 
Chlordiazepoxide 
25 Oxazolam * 
20 
Cinolazepam ** 
40 Passiflora * 
100 
Clotiazepam * 
10 Pentobarbital * 
50 
Cloxazolam * 
1.5 Phenazepam 
0.5 
Delorazepam 
1 Phenobarbital * 
15 
Diazepam 
5 Prazepam 
10 
Estazolam 
1 Quazepam 
7.5 
Etizolam * 
1 Rilmazafone * 
2 
Gidazepam 
50  
 


 
 
 
69 
 
Fludiazepam * 
0.5 Secobarbital * 
50 
Flunitrazepam * 
1 Tandospirone * 
25 
Flurazepam 
15 Tofisopam * 
125 
Flutazolam * 
15 Temazepam 
10 
Flutoprazepam * 
1.67 Triazolam 
0.25 
Halazepam 
40 Zolpidem * 
10 
Haloxazolam * 
5 Zopiclone * 
7.5 
From: Virani AS, Bezchlibnyk-Butler KZ, Jeffries JJ. Clinical handbook of psychotropic drugs.  
18th revised version. Ashland, OH: Hogrefe & Huber Publishers; 2009.  
* Japanese Journal of Clinical Psychophamacology 9: 1446, 2006. 
** Sostmann HJ, Sostmann H, Crevoisier C, Bircher J (1989). "Dose equivalence of midazolam and triazolam. A 
psychometric study based on flicker sensitivity, reaction time and digit symbol substitution test". Eur. J. Clin. 
Pharmacol. 36 (2): 181–7. PMID 2721543. 
Benzodiazepine equivalence table; V1.6     24-Feb-2012 
 
 
4.5. 
Selected Adverse Events with Special Interest  
 
4.5.1. 
Extrapyramidal Symptoms (EPS)-Related AEs  
 
BRADYKINESIA 
PARKINSONISM 
DROOLING 
PSYCHOMOTOR RETARDATION 
DYSTONIA 
TORTICOLLIS 
GLABELLAR REFLEX ABNORMAL 
TRISMUS 
HYPOKINESIA 
PSYCHOMOTOR HYPERACTIVITY 
OCULOGYRIC CRISIS 
AKATHISIA  
OROMANDIBULAR DYSTONIA 
DYSKINESIA 
EXTRAPYRAMIDAL DISORDER 
TARDIVE DYSKINESIA 
SALIVARY HYPERSECRETION 
 
 
4.5.2. 
Metabolic-Related AEs 
 
BLOOD CHOLESTEROL INCREASED 
HYPERCHOLESTEROLAEMIA 
BLOOD GLUCOSE INCREASED 
HYPERGLYCAEMIA 
BLOOD INSULIN INCREASED 
HYPERINSULINAEMIA 
BLOOD TRIGLYCERIDES INCREASED 
HYPERLIPIDAEMIA 
DIABETES MELLITUS 
HYPERTRIGLYCERIDAEMIA 
DYSLIPIDAEMIA 
IMPAIRED FASTING GLUCOSE 
GLUCOSE TOLERANCE IMPAIRED 
LOW DENSITY LIPOPROTEIN INCREASED 
GLYCOSURIA 
METABOLIC SYNDROME 
GLUCOSE URINE PRESENT 
TYPE 2 DIABETES MELLITUS 


 
 
 
70 
 
GLYCOSYLATED HAEMOGLOBIN INCREASED 
TYPE 1 DIABETES MELLITUS 
HIGH DENSITY LIPOPROTEIN DECREASED 
WEIGHT INCREASED 
WEIGHT DECREASED 
LOW BLOOD SUGAR 
 
 
4.5.3. 
Hypersensitivity Related AEs 
 
ANAPHYLACTIC SHOCK 
LIP SWELLING 
ANGIOEDEMA 
LIP OEDEMA 
BUTTERFLY RASH 
OEDEMA PERIPHERAL 
CHEST DISCOMFORT 
PHOTOSENSITIVITY ALLERGIC REACTION 
CONJUNCTIVITIS 
PRURITUS 
DERMATITIS ALLERGIC 
PRURITUS GENERALISED 
DYSPNOEA 
RASH 
EYE PRURITUS 
RASH GENERALIZED 
FACE OEDEMA 
RASH PRURITIC 
GLOSSODYNIA 
RASH PUSTULAR 
HYPERSENSITIVITY 
URTICARIA 
MOUTH ULCERATION 
WHEEZING 
PRURITUS GENITAL 
SWOLLEN TONGUE 
 
PHOTOSENSITIVITY REACTION 
 
4.5.4. 
Suicidality and Self-Injury Related AEs 
 
• 
COMPLETED SUICIDE 
COMPLETED SUICIDE 
 
• 
SUICIDE ATTEMPT  
INTENTIONAL SELF-INJURY 
INTENTIONAL OVERDOSE 
SELF INJURIOUS BEHAVIOUR 
MULTIPLE DRUG OVERDOSE INTENTIONAL 
SUICIDAL BEHAVIOUR 
POISONING DELIBERATE 
 SUICIDE THREAT 
INTENTIONAL DRUG MISUSE 
SUICIDE ATTEMPT 
 
• 
SUICIDAL IDEATION 
DEPRESSION SUICIDAL 
SELF-INJURIOUS IDEATION 
SUICIDAL IDEATION 
 
 
 
 


 
 
 
71 
 
4.5.5. 
Hyperactivity Related AEs 
 
High-level Term 
Increased Physical Activity 
Levels 
Increased Physical Activity 
Levels 
Attention Deficit and Disruptive 
Behavior Disorders 
Preferred Term 
Psychomotor Hyperactivity 
Restlessness 
Attention Deficit/Hyperactivity 
Disorder 
Lower Level Term 
Activity motor exaggerated 
Activity motor exaggerated 
Marked restlessness 
Behavior hyperactive 
ADHD, combined type 
Muscular unrest 
Behaviour hyperactive 
ADHD, predominantly 
hyperactive-impulsive type 
Physically restless 
Hyper 
Attention deficit disorder of 
childhood with hyperactivity 
Psychomotor restlessness 
Hyperactive 
Hyperactive child syndrome 
Restless 
Hyperactivity 
Hyperactivity syndrome 
aggravated 
Restlessness 
Increased activity 
Hyperkinesis of childhood 
with developmental delay 
Restlessness (drug related) 
Irritable hyperkinesis 
Hyperkinetic conduct 
disorder of childhood 
Restlessness aggravated 
Motor activity exaggerated 
Hyperkinetic syndrome 
Restlessness marked 
Muscular hyperactivity 
Hyperkinetic syndrome of 
childhood 
Unrest 
Overactive 
Other specified manifestations of 
hyperkinetic syndrome of 
childhood 
 
Overactivity 
Overactive child 
 
Pedaling 
Syndrome hyperkinetic 
 
Psychomotor agitation 
Unspecified hyperkinetic 
syndrome of childhood 
 
Psychomotor excitability 
 
 
Psychomotor hyperactivity 
 
 
Source: Lurasidone IND 61292 SN0434, Communicated with FDA on 10/24/2014