Clinical trial NCT02436239
Conditions: Major Depressive Disorder
Sponsor: Forest Laboratories
Start date: 2015-05-02; Completion date: 2018-07-23
Enrollment: 330 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to evaluate the long-term safety and tolerability of vilazodone for the treatment of MDD in pediatric outpatients (7-17 years).

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Vilazodone
Intervention descriptions: intervention 1: Vilazodone tablets, once daily, oral administration

Protocol documents:
Prot_000.pdf: 


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SYNOPSIS AND SCHEDULE OF EVALUATIONS
CLINICAL STUDY SYNOPSIS: Study VLZ-MD-23
Title of Study
An Open-label Long-term Safety Study of Vilazodone in Pediatric Patients 
With Major Depressive Disorder
Study Centers (Country)
Approximately 60 study centersin the United States and Canada
Development Phase
3
Objective
To evaluate the long-term safety and tolerability of vilazodone for the 
treatment of major depressive disorder in pediatric outpatients (7-17 years) 
Methodology
A multicenter, open-label, flexible-dose, 28-week studyin pediatric patients
Number of Patients
Approximately 315planned
Diagnosis and 
Main Criteria for Inclusion
Male and female outpatients who have completed Study VLZ-MD-22,or for 
de novopatients, male and female outpatients, ages 7 to 17 years, who meet 
Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text 
Revision criteria for major depressive disorder(confirmed by the Kiddie 
Schedule for Affective Disordersand Schizophrenia–Present and Lifetime) 
and have a current depressive episode of ≥ 6 weeks duration at Screening 
(Visit 1). At both Screening (Visit 1) and Baseline (Visit 2), de novo patients 
must have a score of ≥ 40 on the a Children’s Depression Rating Scale–
Revisedand a Clinical Global Impressions–Severity score ≥ 4 
Test Product, Dosage, and Mode of 
Administration
Vilazodone HCl 5mg and 10 mg tablets, taken orally as a single dose, once
daily at the same time each day, with food
Duration of Treatment
The study will be 28weeks in duration: approximately 1-week 
screening/washout period, 26-week open-labeltreatment period, and a 
1-week down-taper period
Reference Therapy, Dosage, and Mode 
of Administration
None
Criteria for Evaluation
Efficacy Measures
Children’s Depression Rating Scale–Revised
Clinical Global Impressions–Severity
Clinical Global Impressions–Improvement
Safety Measures
Adverse event recording, clinical laboratory assessments, vital sign 
measurements (including height and weight), electrocardiograms, physical 
examinations, and Columbia–Suicide Severity Ratings Scale
Statistical Methods
Descriptive statistics will be presented for all efficacy and safety parameters. 
No inferential statistical analyses will be performed. All safety parameters 
will be summarized for the Safety Population, defined as all patients who 
receive at least 1 dose of open-label vilazodone. Efficacy parameters will be 
summarized using the Intent-to-Treat Population, defined as all patients in the 
Safety Population who had baseline andat least 1 postbaseline Children’s 
Depression Rating Scale–Revisedtotal score.


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Table 2–1.
SCHEDULE OF EVALUATIONS: Study VLZ-MD-23


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Table 2–1.
SCHEDULE OF EVALUATIONS: Study VLZ-MD-23


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TABLE OF CONTENTS, TABLES AND FIGURES
3.1
OVERALL TABLE OF CONTENTS
1.0
TITLE PAGE....................................................................................................................................1
2.0
SYNOPSIS AND SCHEDULE OF EVALUATIONS.....................................................................2
3.0
TABLE OF CONTENTS, Tables and Figures..................................................................................5
3.1
Overall Table of Contents...................................................................................................5
3.2
List of In-Text Tables.........................................................................................................8
3.3
List of In-Text Figures........................................................................................................9
4.0
LIST OF ABBREVIATIONS.........................................................................................................10
5.0
ETHICAL CONSIDERATIONS....................................................................................................12
5.1
INSTITUTIONAL REVIEW BOARD AND INDEPENDENT ETHICS 
COMMITTEE...................................................................................................................12
5.2
ETHICAL CONDUCT OF THE STUDY........................................................................12
5.3
PATIENT INFORMATION AND INFORMED CONSENT..........................................13
5.3.1
Patient Assent Form...........................................................................................13
5.3.2
Parent, Legal Guardian, and Legally Authorized Representative Informed 
Consent...............................................................................................................13
5.3.3
Caregiver Consent..............................................................................................14
6.0
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE......................................15
7.0
INTRODUCTION..........................................................................................................................16
8.0
STUDY OBJECTIVE.....................................................................................................................18
9.0
INVESTIGATIONAL PLAN.........................................................................................................19
9.1
OVERALL STUDY DESIGN AND PLAN: DESCRIPTION.........................................19
9.1.1
Screening Period.................................................................................................19
9.1.2
Treatment Period................................................................................................19
9.1.3
Down-taper Period..............................................................................................20
9.2
Discussion of Study Design..............................................................................................22
9.3
SELECTION OF STUDY POPULATION......................................................................23
9.3.1
Inclusion Criteria................................................................................................23
9.3.2
Exclusion Criteria...............................................................................................24
9.3.3
Removal of Patients from Therapy or Assessment.............................................28
9.3.4
Patient Replacement Procedures........................................................................29
9.4
TREATMENTS................................................................................................................29
9.4.1
Treatments Administered...................................................................................29
9.4.2
Identity of Investigational Products....................................................................30
9.4.3
Method of Assigning Patients to Treatment.......................................................31
9.4.4
Selection of Dosages in the Study......................................................................31
9.4.5
Selection and Timing of Dose for Each Patient..................................................32
9.4.6
Blinding..............................................................................................................33
9.4.7
Unblinding..........................................................................................................33


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9.4.8
Prior and Concomitant Therapy.........................................................................33
9.4.9
Monitoring Treatment Compliance....................................................................33
9.4.10 Treatment Following Investigational Product Discontinuation..........................34
9.5
EFFICACY AND SAFETY VARIABLES......................................................................34
9.5.1
Diagnostic and Efficacy Assessments................................................................34
9.5.2
Safety Assessments............................................................................................35
9.5.3
Investigational Product Concentration Measurements.......................................44
9.5.4
Health Economic and Outcomes Research Assessments....................................44
9.5.5
Schedule of Assessments....................................................................................45
9.6
DATA QUALITY ASSURANCE....................................................................................58
9.6.1
Data Monitoring.................................................................................................58
9.6.2
Data Recording and Documentation...................................................................58
9.7
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE.................59
9.7.1
Patient Populations.............................................................................................59
9.7.2
Patient Disposition.............................................................................................59
9.7.3
Demographics and Other Baseline Characteristics.............................................60
9.7.4
Extent of Exposure and Treatment Compliance.................................................60
9.7.5
Efficacy Analyses...............................................................................................61
9.7.6
Safety Analyses..................................................................................................62
9.7.7
Health Economics and Outcomes Research Analyses........................................66
9.7.8
Interim Analysis.................................................................................................66
9.7.9
Determination of Sample Size............................................................................66
9.7.10 Computer Methods.............................................................................................66
9.8
Changes in the Conduct of the Study or Planned Analyses..............................................66
9.9
Protocol Deviations..........................................................................................................66
9.10
Data Monitoring Committee.............................................................................................67
10.0
STUDY SPONSORSHIP................................................................................................................68
10.1
STUDY TERMINATION................................................................................................68
10.2
REPORTING AND PUBLICATION...............................................................................68
11.0
INVESTIGATOR OBLIGATIONS................................................................................................69
11.1
DOCUMENTATION.......................................................................................................69
11.2
PERFORMANCE.............................................................................................................69
11.3
USE OF INVESTIGATIONAL MATERIALS................................................................70
11.4
CASE REPORT FORMS.................................................................................................70
11.5
RETENTION AND REVIEW OF RECORDS................................................................70
11.6
PATIENT CONFIDENTIALITY.....................................................................................71
12.0
INVESTIGATOR’S STATEMENT...............................................................................................72
13.0
APPENDICES................................................................................................................................73
Appendix I.
Elements of Informed Consent...........................................................................73
Appendix II.
Contact Information............................................................................................75
Appendix III.
Concomitant Medications...................................................................................76
Appendix IV.
CHILDREN’S DEPRESSION RATING SCALE–REVISED...........................80
Appendix V.
CLINICAL GLOBAL IMPRESSIONS–SEVERITY........................................86
Appendix VI.
CLINICAL GLOBAL IMPRESSIONS–IMPROVEMENT..............................87
Appendix VII.
COLUMBIA–SUICIDE SEVERITY RATING SCALE -BASELINE.............88
Appendix VIII. COLUMBIA–SUICIDE SEVERITY RATING SCALE -SINCE LAST 
VISIT...................................................................................................................92
Appendix IX.
INVESTIGATIONAL PRODUCT FORMULATION......................................96


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LITERATURE CITED...................................................................................................................97


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3.2
LIST OF IN-TEXT TABLES
Table 2–1.
SCHEDULE OF EVALUATIONS: Study VLZ-MD-23...........................3
Table 9.4.5.2–1.
Open-label Dosing Regimen.........................................................33


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3.3
LIST OF IN-TEXT FIGURES
Figure9.1.3–1.
Study Design.................................................................................21


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LIST OF ABBREVIATIONS
5-HT1A
5-hydroxytryptamine 1A 
AE
adverse event
ALT
alanine aminotransferase 
AST
aspartate aminotransferase
β-hCG
β-human chorionic gonadotropin
BP
blood pressure
CDRS-R
Children’s Depression Rating Scale–Revised
CFR
Code of Federal Regulations
CGI-I
Clinical Global Impressions–Improvement
CGI-S
Clinical Global Impressions–Severity
CI
confidence interval
C-SSRS
Columbia–Suicide Severity Rating Scale
DSM-IV-TR
Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, text 
revision
ECG
electrocardiogram, electrocardiographic
eCRF
electronic case report form
EDC
electronic data capture
ET
early termination
FDA
US Food and Drug Administration
FR
Federal Register
FRI
Forest Research Institute, Inc.
GCP
good clinical practice
HIPAA
Health Insurance Portability and Accountability Act
ICF
informed consent form
ICH
International Conference on Harmonisation 
IEC
Independent Ethics Committee
IND
Investigational New Drug (application)
IRB
Institutional Review Board
ITT
intentto treat
IWRS
interactive Web response system


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K-SADS-PL
Kiddie Schedule for Affective Disorders and Schizophrenia–Present and 
Lifetime
LAR
legally authorized representative
MDD
major depressive disorder
NEAE
newly emergentadverse event
NDA
New Drug Application
PCS
potentially clinically significant
PID
patient identification
QTc
QT interval corrected for heart rate
QTcB
QT interval corrected for heart rate using the Bazett formula 
(QTcB=QT/[RR]
½)
QTcF
QT interval corrected for heart rate using the Fridericia formula 
(QTcF=QT/[RR]
⅓)
SAE
serious adverse event
TEAE
treatment-emergent adverse event
UDS
urine drug screen
ULN
upper limit of normal


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5.0
ETHICAL CONSIDERATIONS
5.1
INSTITUTIONAL REVIEW BOARD AND INDEPENDENT 
ETHICS COMMITTEE
United States
Approval by the Institutional Review Board (IRB) before the start of the study will be the 
responsibility of the Investigator. A copy of the approval letter will be supplied to 
ForestResearch Institute, Inc. (FRI [the Sponsor]), along with a roster of IRB members 
or the US Department of Health and Human Services general assurance number. During 
the course of the study, the Investigator will provide timely and accurate reports to the 
IRB on the progress of the study, at intervals not exceeding 1 year (or as appropriate), 
and will notify the IRB of serious adverse events (SAEs) or other significant safety 
findings. The study protocol, informed consent form (ICF), information sheet 
advertisements, and amendments (if any) will be approved by the IRBs at the study 
centers in conformance with the CFR, Title 21, Part 56.
Outside the United States
This study will be carried out in full compliance with the guidelines of the Independent 
Ethics Committee (IEC) and government agencies of each respective country as well as 
the European Union Clinical Trial Directive (Directive 2001/20/EC), where applicable. 
Before the study begins, the study center will require approval from an IEC and 
government agency. During the course of the study, FRI or authorized representative will 
provide timely and accurate reports to the IEC on the progress of the study, at intervals 
not exceeding 1 year (or as appropriate) and will notify the IEC of SAEs or other 
significant safety findings. The study protocol, ICF, information sheet advertisements, 
and amendments (if any) will be approved by the IEC at the study center in conformance 
with CFR, Title 21, Part 56, the European Union Clinical Trial Directive 
(Directive2001/20/EC), and local regulations.
5.2
ETHICAL CONDUCT OF THE STUDY
This clinical study will beconducted in accordance with the ethical principles that have 
their origins in the Declaration of Helsinki.
This clinical study will complywith the ICH Guidance on General Considerations for 
Clinical Trials (ICH-E8; 62FR66113, 17Dec 1997) and GCP(ICH-E6; 62 FR 25692, 
09 May 1997), as well as Part 312 of the CFR.


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5.3
PATIENT INFORMATION AND INFORMED CONSENT
After being given an explanation of the study and before participating in any study 
procedures,each patient, if developmentally appropriate, must provide written assent, and 
his or her parent(s), legal guardian(s), or legally authorized representative (LAR) 
(hereafter referred to as parent/guardian/LAR) must provide voluntary and written 
informed consent in compliance with 21 CFR, Parts 50 and 312 and give HIPAA 
authorization (or an equivalent of HIPAA authorization in non-US countries). The 
elements of informed consent are listed in Appendix Iof this protocol.
The signed documents will be placed in the Investigator’s study files. A unique patient 
identification (PID) number will be assigned 
5.3.1
Patient Assent Form
To participate in the study, the patient will read, assent to an understanding of, and sign 
the assent form.The patient will be made aware of the ability to withdraw from the study 
at any time, without prejudice. Patients who are unable to read the assent form will have 
the statements read to them. If the patient cannot sign the form, a witness will be allowed 
to provide written verification of oral assent. A copy of the signed assent form will be 
given to the patient’s parent/guardian/LAR.
5.3.2
Parent, Legal Guardian, and Legally Authorized Representative 
Informed Consent
Written informed consent will be obtained from the patient’s parent/guardian/LAR before 
the patient participates in any study-related procedure. To provide consent for the 
patient’s participation in the study, the patient’s parent/guardian/LAR will read, assent to 
an understanding of, and sign an ICFor other locally applicable regulations and 
authorization form after having had an opportunity to discuss the forms with the 
Investigator. The parent/guardian/LAR will be made aware that the patient may withdraw 
from the study at any time and will receive a copy of the signed ICF. Patients who reach 
the age of majority (ie, 18 years in most jurisdictions) during the course of the study are 
required to be re-consented.


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5.3.3
Caregiver Consent
A caregiver is a person identified as able and willing to provide safety and efficacy 
information about the patient and oversee the administration of investigational product, 
and may be a different individual than the parent/guardian/LAR. The caregiver must 
commit to accompanying the patient to each study visit. To be eligible for the study, the 
caregiver, whether or not he or she is the parent/guardian/LAR, must read and sign the 
caregiver consent and meet the relevant inclusion/exclusion criteria. If the 
parent/guardian/LAR is the caregiver, he or she will be asked to sign both the parent/legal 
guardian permission (ICF) and the caregiver consent. If a caregiver is replaced during the 
study, each caregiver must provide separate ICF/caregiver consents and will be given a 
signed copy of his/her caregiver consent.


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6.0
INVESTIGATORS AND STUDY ADMINISTRATIVE 
STRUCTURE
This study will be performed at approximately 60study centers.
The Investigator is responsible for ensuring that an investigation is conducted according 
to the signed Investigator statement, the investigational plan, GCP guidelines, and 
applicable regulations; for protecting the rights, safety, and welfare of patients under the 
Investigator’s care; and for the control of investigational products under investigation. 
AnInvestigator shall obtain the assent and informed consent foreach patient prior to the 
patient enrolling in the study and/or prior to participating in any study-related activity. 
The Investigator at each study centermust meet his or herobligations to the patients, 
ethics committee, FRI, and regulatory authorities by maintaining oversight and control of 
the study’s conduct and the study staff. It is the responsibility of the Investigator to 
ensure that any and all delegated duties be assigned to qualified staff by education, 
experience, and licensure (in accordance with local regulations) and that the Investigator 
oversight is documented and assessment of staff capabilities and performance is 
consistent with the study investigational plan. The Investigator at each study centerwill 
beresponsible for the management of the study, including maintaining the study file and 
the patient records, corresponding with the IRB/IEC, and completing the electronic case 
report forms (eCRFs).


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INTRODUCTION
Vilazodone is a selective serotonin reuptake inhibitor and a partial agonist of the 
5-hydroxytryptamine 1A (5-HT1A) receptor. Vilazodone has greater in vitro potency for 
serotonin reuptake inhibition than compounds such as fluoxetine (0.2 nM versus 6.0nM 
respectively). Vilazodone is more selective for inhibition of serotonin reuptake than 
dopamine or norepinephrine(0.2 nM, 60.0 nM and 90.0nM, respectively). In vitro 
studies also indicate that vilazodone binds with high affinity and is a more potent agonist 
of 5-HT1Areceptors compared with specific 5-HT1Aligands such as buspirone, with IC50
values of 0.5 nM and 30 nM, respectively. A detailed description of the 
pharmacokinetics, chemistry, pharmacology, safety, and efficacy of vilazodone for the 
treatment of major depressive disorder (MDD)is provided in the US prescribing 
information (Viibryd, 2014) and in the Investigator’s Brochure (Vilazodone HCl, 2013). 
Viibryd was approved by the FDA for the treatment of MDD on 21 Jan 2011.
Approval for the use of Viibryd for the treatment of MDD was based on 2pivotal, 
Phase3, 8-week, multicenter, randomized, double-blind, placebo-controlled studies in 
adult outpatients with MDD. Vilazodone 40mg/day demonstrated superiority over 
placebo in the improvement of depressive symptoms as measured by the mean change 
from baseline to Week 8 in the Montgomery-Åsberg Depression Rating Scale total score 
(Montgomery and Åsberg, 1979).
MDD is a common and serious illness in children and adolescents. Epidemiological 
studies from community and clinical samples estimate the prevalence of MDD as 
approximately 0.3%-1.4% of preschoolers (2-5 years of age) (Egger and Angold, 2006), 
1%-2% of prepubertal children, and between 3% and 8%of adolescents 
(Zalsmanetal,2006). The American Academy of Child and Adolescent Psychiatry 
(1998) consensus estimated the cumulative incidence of MDD in adolescence by the age 
of 18 to be as high as 20%, while 65% report transient, less severe depressive symptoms. 
At any point in time, 1 in every 10 children and adolescents isaffected by serious 
emotional disturbances (Substance Abuse and Mental Health Services Administration, 
2009). 
The National Comorbidity SurveyAdolescent Supplement examinedboth dysthymic 
disorder and MDD together resulting in data showing approximately 11.2% of 13 to 
18year olds in the United States are affected at some point during their lives,and 3.3% 
have experienced a seriously debilitating depressive disorder. The Substance Abuse and 
Mental Health Services Administrationexamines the national prevalence of depression 
each year through the National Survey on Drug Use and Health. Their 2008 data show an 
8.3% prevalence of depression among 12 to 17year olds in the United States,noting that 
among 13 to 17 year olds the prevalence of depression among girls is nearly 3 times as 
high as that for boys. Additionally, while approximately 4% of 13 year olds experience 
depression, the rate increases to 11.6% among 16 year olds(Substance Abuse and Mental
Health Services Administration, 2009).


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MDD compromises the development process; feelings of worthlessness, low self-esteem, 
and thoughts of suicide are common. Patients also experience difficulties with 
concentration and motivation. Each year as many as 20% of adolescents have suicidal 
ideation,and 9% attempt suicide (Grunbaumet al, 2002). Suicide is a leading cause of 
death in adolescents and is a major public health concern (National Adolescent Health
Information Center, 2006). A major risk factor for suicide in adolescents is major 
depression. In a review and meta-analysis of placebo controlled trials assessing use of 
antidepressant medications among children and adolescents, the FDA concluded that 
these medications pose an increased risk (4% vs 2%) for suicidal behavior or suicidal 
ideation, although no suicides were reported (Hammad et al, 2006). Subsequently, the 
FDA mandated a boxed warning be put on the labels of all antidepressants indicating an 
increased risk of suicidal thoughts and behavior in youth taking these medications, but 
did not prohibit their use.
MDD in children and adolescents can be chronic and recurrent. The mean length of 
pediatric depressive episodes appears to be approximately 7 months, and in the course of 
a first episode, up to 40% of patients appear to recover without specific treatment. 
However, patients who do not recover appear to be at high risk of chronic depression, and 
those who do recover have high rates of recurrence and dysthymia (Zalsman et al, 2006). 
Current drug treatment options for pediatric MDD are very limited (ie, FDA approved 
fluoxetine for children and adolescents 8-18 years of age and escitalopram for 
adolescents 12-17 years of age). Therefore, it is important that novel treatment options, 
such as vilazodone, be evaluated systematically for the treatment of MDD in children and 
adolescents to characterize theirefficacy and safety profile in this population.
To address an unmet need of treating MDD in the pediatric population, this study of 
vilazodonein children and adolescent patients (7-17 years of age) with MDD was agreed 
upon with the FDA. 


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STUDY OBJECTIVE
The objective of this study is to evaluate the long-term safety and tolerability of 
vilazodone forthe treatment of MDDin pediatric outpatients (7-17 years).


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9.0
INVESTIGATIONAL PLAN
9.1
OVERALL STUDY DESIGN AND PLAN: DESCRIPTION
Study VLZ-MD-23 will be a multicenter, open-label, flexible-dose study in pediatric 
patients, ages 7 to 17 years with MDD. Eligible patients will include new patients 
meeting the inclusion/exclusion criteria defined in Section 9.3and patients who 
completed the lead-in study (VLZ-MD-22). Study centers will enrolleither de novo
patients or patients who completed the lead in study.Patients whocomplete Study 
VLZ-MD-22 will have the option to participate in Study VLZ-MD-23. Entry into Study 
VLZ-MD-23 will continue until the enrollment goalsare met.
The study will include a total of 17visits and will be approximately 28weeks in duration 
(Figure9.1.3–1): 
Approximately 1-week screening/washoutperiod 
26-week open-labeltreatment period
1-week down-taper period
9.1.1
Screening Period
Patients who completed lead-in study VLZ-MD-22 will have completed a down-taper 
period at the end of study VLZ-MD-22 and will not be required to undergo a washout 
period.
For de novo patients, the screening/washout period will generally be 1 week prior to 
Visit2 (Baseline), but may be extended up to a total of 5 weeks to accommodate prior 
medication washout or repeat assessments (with prior approval of the Study Physician or 
designee). At the end of Visit 2(Baseline),patients who meet the eligibility criteriawill 
be enrolled into the study. 
9.1.2
TreatmentPeriod
Approximately 315patients are planned for enrollment in this open-label safety study.


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9.1.3
Down-taper Period
All patients who complete the 26-week treatment period and patients who prematurely 
discontinue before completing 26 weeks of treatment will be eligible to enter the 1-week 
down-taper period.
Ifthe Investigator determines that it is not clinically appropriate for a patient to enterthe 
down-taper period, investigational product may be discontinued,and the patient should 
be managed in a clinically appropriate manner.
All enrolledpatients must complete the Safety Follow-up Visit(Visit 17/Week 27). 
Additional follow-up visits may be scheduled within 30 days if necessary for 
safetyreasons.


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Study Design


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9.2
DISCUSSION OF STUDY DESIGN
This multicenter, flexible-dose study with a26-week open-label treatment is designedto 
evaluate the long-term safety and tolerability of flexible doses of vilazodone (15and 
30mg/day) in pediatric patients with MDD. Anopen-label study design with no control 
group was chosen to meet this objective.
The flexible-dose design was selected to examine the relative safety and tolerability of a 
range of doses of vilazodone based on the Investigator’s judgment (ie, in a manner
applicable to the expected clinical use).Also, this study was designed with reference to 
the FDA Guidance for Industry E11 Clinical Investigation of Medicinal Products in the 
Pediatric Population. 
In this pediatric study, Investigators will enroll pediatric patients ages 7 through 17 who 
met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text 
Revision (DSM-IV-TR) criteria for MDD. The MDD diagnosis will be confirmed using 
the Kiddie Schedule for Affective Disorders and Schizophrenia–Present and Lifetime
([K-SADS-PL]; Kaufmanetal, 1997), a reliable and valid semi-structured interview 
designed to assess current and past episodes of psychopathology in children and 
adolescents,covering a broad spectrum of psychiatric diagnoses through separate 
interviews with the patient and the caregiver. The Children’s Depression Rating 
Scale-Revised (CDRS-R) (Section 9.5.1.2.1) will assess the MDD symptoms 
andseverity.
The 1-week down-taper has been included to 
allow a gradual reduction in the concentration of the investigational product to reduce the 
likelihood of emergence of discontinuationsymptoms.


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9.3
SELECTION OF STUDY POPULATION
The number of males and females will be approximately equal in both age groups 
(7-11years and 12-17 years) with at least 40% of the patients between 7 to 11 years of 
age. There should be reasonable representation overall of ethnic and racial minorities, 
reflecting the proportions in the disease population.
9.3.1
Inclusion Criteria
Tobe eligible to participate in the study, patients must meet the following criteria:
Note: Inclusion criteria #2through#5 are considered to havebeen met for patients who 
completed the lead-in study(VLZ-MD-22).For patients who completed the lead-in study 
(VLZ-MD-22), medical, psychiatric and medication histories from Screening (Visit 1)of 
the lead-in study will be used.
1. Beable to provide informed assent and their parent/guardian/LAR and caregiver must 
provide written informed consent before the initiation of any study-specific 
procedures (Section5.3) 
2. Be a male or female outpatient, 7 to 17 years of age, inclusive, at Screening (Visit1; 
de novopatients only)
3. Meet DSM-IV-TR criteria for MDD, confirmed by K-SADS-PL, with a current 
depressive episode of ≥ 6 weeks duration at Screening (Visit 1; de novopatients only)
4. Have a score of ≥40 on the CDRS-R at Screening and Baseline (Visits 1 and 2, 
respectively; de novopatients only)
5. Have a Clinical Global Impressions–Severity (CGI-S)score ≥4 at Screening and 
Baseline (Visits 1 and 2, respectively; de novopatients only)
6. Have a caregiver who is willingandableand provides consentto be responsible for 
safety monitoring of the patient, providinginformation about the patient’s condition, 
overseeingthe administration of investigational product, and accompanyingthe 
patient to all study visits (Section5.3)
7. Have normal physical examination findings, vital sign values, clinical laboratory test 
results, and electrocardiogram (ECG) results, or abnormal results that are determined 
by the Investigator not to be clinically significant 
8. Have a negative serumβ-human chorionic gonadotropin (β-hCG)pregnancy test 
result if patient is female ≥9years of age or has had onset of menses


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9.3.2
Exclusion Criteria
Patients who meet any of the following criteria will not be eligible to participate in the 
study:
Note: For patients who completed the lead-in study (VLZ-MD-22), medical, psychiatric 
and medication histories from Screening (Visit 1)of the lead-in study will be used.
Psychiatric Criteria
1. A current (within 3 monthsof Screening) principal DSM-IV-TR–based diagnosis of 
an Axis I disorder other than MDD that is the primary focus of treatment (de novo
patients only)
○Patients with comorbid diagnoses of learning disorders, attention deficit disorder 
(with or without hyperactivity), communication disorders, separation anxiety 
disorder, oppositional defiant disorder, and anxiety disorders will be allowed to 
participate in the study if these conditions are not the primary focus of treatment 
and all concomitant medications/limitations comply with Appendix III
○Patients with conduct disorder will not be allowed to participate
2. A prior diagnosis of mental retardation or amnesic or other cognitive disorders based 
on DSM-IV-TR criteria
3. An imminent risk of injuring self or others or causing damage to property as judged 
by the Investigator
4. A suicide risk as determined by meeting any of the following criteria: 
○Any suicide attempt within the past year
○A significant risk, as judged by the Investigator on the psychiatric interview or 
information collected in the C-SSRS)


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19.Pregnant, breastfeeding, and/or planning to become pregnant and/or breastfeed during 
the study or within 30 days following the end of study participation
20.Females who are sexually active:
Who are not practicing a reliable method of contraception that will continue for the 
duration of the study and within 30 days following the end of study participation. 
Reliable contraception is defined as:
○Surgical sterilization (eg, tubal ligation or hysterectomy) 
○Oral contraceptives (consisting of an estrogen-progestin combination or progestin 
alone)
○Transdermally delivered contraceptives (eg, Ortho-Evra), depot injections 
(eg,Depo-Provera)
○Vaginal contraceptive ring (eg, NuvaRing), contraceptive implants (eg, Implanon, 
Norplant II/Jadelle)
Note: Females using hormonal contraceptives must have been doing so for at least 
1month before Screening (Visit 1)and must follow that product’s package insert 
instructions concerning additional protection at times when doses might be missed.
Intrauterine device
Double-barrier method (ie, diaphragm plus condom)
Exclusively sexually active with a female partner


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For females who are sexually active, rhythm, withdrawal, single-barrier methods 
(eg,contraceptive sponge, female condom or male condom, diaphragm alone or with 
spermicide), emergency contraceptives (eg, Plan B as the sole plan), and abstinence are 
not acceptable methods of contraception during study participation.
Criteria to be assessed at Baseline (Visit 2)
27.A suicide risk, as determined by meeting the following criterion:
○A significant risk, as judged by the Investigator, based on the psychiatric
interview or information collected in the C-SSRS
9.3.3
Removal of Patients from Therapy or Assessment
A premature discontinuation will occur when a patient who gave voluntary assent and/or 
whose LAR signed the ICF ceases participation in the study, regardless of circumstances, 
before the completion of the study visits and procedures. Patients can be prematurely 
discontinued from the study for any of the following reasons:
Failure to meet inclusion/exclusion criteria 
Withdrawal of assent or consent (a reason must be documented) 
Adverse event (AE)




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9.4.2
Identity of Investigational Products






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9.4.6
Blinding
This study will be conducted as an open-label investigation; no blinding of assigned 
treatment will occur.
9.4.7
Unblinding
Not applicable.
9.4.8
Prior and Concomitant Therapy
9.4.9
Monitoring Treatment Compliance


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9.4.10
Treatment Following Investigational Product Discontinuation
Patients whose MDD symptoms worsen or are determined by the Investigator not to be 
adequately controlled prior to completing the open-label treatment period will be allowed 
to discontinue the investigational product, will be discontinued from the study, and may
startan alternate treatment at the Investigator’s discretion. An alternate treatment will not 
be provided by FRI. In addition, patients who need to start an alternate treatment will be 
discontinued from the study.
9.5
EFFICACY AND SAFETY VARIABLES
9.5.1
Diagnostic and Efficacy Assessments
Nodiagnostic and efficacy assessments are to be administered to the patient unless the 
patient is accompanied by his/her consented caregiver.
9.5.1.1
Diagnostic Assessments
The K-SADS-PL will be administered during the screening interviews by a child 
psychiatrist or doctoral level clinical psychologist or other clinician who has extensive 
professional training and experience in the diagnosis of mental illness in pediatric 
patients and who meets the training requirements and qualifications standards set by FRI 
and rater training vendor.
9.5.1.2
Efficacy Assessments
All efficacy assessments (CDRS-R, CGI-S, and Clinical Global Impressions–
Improvement [CGI-I]) will be administered by the Investigator, Sub-investigator, or a 
child psychiatrist, doctoral level clinical psychologist, or other clinician who has 
extensive professional training and experience in the diagnosis of mental illness in 
pediatric patients and who meets the training requirements and qualifications standards 
set by FRI and rater training vendor.
9.5.1.2.1 
Children’s Depression Rating Scale–Revised
The CDRS-R (Poznanski and Mokros, 1996) is a semistructured, clinician-rated 
instrument designed for use with children and adolescents between 6 to 17 years of age 
and their caregivers. 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. The clinician 
selects a rating for each item that provides the best description of the patient’s symptoms 
resulting in a score ranging from 17 to 113. The CDRS-R total score refers to the raw 
scale scores. 


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A copy of the CDRS-R is provided in Appendix IV.
9.5.1.2.2
The Clinical Global Impressions–Severity
The CGI-S (Guy, 1976) is a clinician-rated instrument used to rate the severity of the 
patient’s current state of mental illness compared with the clinician’s total experience 
with patients with MDD. The severity of the patient’s MDD will be rated on a scale from 
1 to 7, with1 indicating a normal state and 7 indicating a patient who is among the most 
extremely ill patients. A copy of the CGI-Sis provided in Appendix V.
9.5.1.2.3
Clinical Global Impressions–Improvement
The CGI-I (Guy, 1976) is a clinician rated instrument that will be used to rate total 
improvement or worsening of mental illness from Baseline (Visit 2), regardless of 
whether the Investigator considers it to be a result of treatment with the investigational 
product. The CGI-I will be used to rate the patient’s improvement on a scale from 1 to 7, 
with 1 indicating that the patient is very much improved and 7 indicating the patient is 
very much worse. A copy of the CGI-Iis provided in Appendix VI.
9.5.2
Safety Assessments
Patients must be evaluated by a physician or an appropriately trained health care 
professional atevery visit,and the evaluation must be documented. The procedures 
discussed below will be completed at the designated visits. Safety assessments should not 
be administered to the patient unless the patient is accompanied by his or her 
consentedcaregiver.
9.5.2.1
Adverse Events
An AE is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment. An AE can therefore be anyunfavorable and 
unintended sign (including an abnormal laboratory finding, for example), symptom, or 
disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product (ICH-E2A).
For the purpose ofthe site’sdata collectionresponsibilities, any untoward event that is
reported from the time the ICF was signed until 30days after the final protocol-defined 
study visit or the last knowndose of investigational product (if the final visit does not 
occur)is to be considered an AE.


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Examples of AEs are as follows:
Changes in the general condition of the patient
Subjective symptoms offered by or elicited from the patient
Objective signs observed by the Investigator or other study centerpersonnel
All diseases that occur after signing inform consent, including any change in severity 
or frequency of preexisting disease
All clinically relevant abnormalities in laboratory values or clinically relevant 
physical findings that occur during the study schedule
Particular attention must be given to AEs that were identified in the adult MDD 
vilazodone program: nausea, vomiting, decreased appetite, and weight loss.
Please note medical procedures scheduled prior to consenting, but occurring during the 
study,should not be captured as AEs, but should be listed in the medical history if related 
to a pre-existing condition.
9.5.2.2
Causality Assessment
For each AE, the Investigator must provide an assessment of causal relationship to the 
investigational product. The causality assessment must be recorded on the appropriate AE 
reporting page of the patient’s eCRF. Causal relationship must be assessed by answering 
the following question:
Is there a reasonable possibility the investigational product caused the event?
Yes:
There is evidence to suggest a causal relationship between the investigational 
product and AE,ie: 
○There is a reasonable temporal relationship between the investigational product 
and the event, and/or 
○The event is unlikely to be attributed to underlying/concurrentdisease, other 
investigational products, or other factors, and/or
○Positive dechallenge and/or rechallenge exist


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No:
There is no evidence to suggest a causal relationship between the 
investigational product and AE, ie:
○There is no reasonable temporal relationship between the investigational product 
and the event, or
○The patient did not take the investigational product, or
○The event is likely to be attributed to underlying/concurrent disease, other 
investigational products, or other factors, or
○The event is commonly occurring in the (study) population independent of 
investigational product exposure
9.5.2.3
Severity Assessment
The Investigator will provide an assessment of the severity of each AE by recording a 
severity rating on the appropriate AE reporting page 
9.5.2.4
Serious Adverse Events
AnSAEis any untoward medical occurrence that at any dose:
Results in death
Is life threatening
Requires inpatient hospitalization or prolongation of existing hospitalization


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Results in persistent or significant disability/incapacity, or
Is a congenital anomaly/birth defect
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based on appropriate medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in patient 
hospitalization, or the development of investigational product dependency or drug abuse.
Emergency room visits that do not result in hospitalization should be evaluated for one of 
the other serious outcomes to determine whether they qualify as SAEs.
Preplanned hospitalizations (eg, elective procedures for preexisting conditions that did 
not worsen, such as cosmetic surgery and hysterectomy) are excluded from SAE 
reporting.
9.5.2.5
Reporting Adverse Eventsand Serious Adverse Events
At each visit, patients are to be queried regarding any AEs or SAEs that have occurred 
since the previous visit. Patients will be asked to volunteer information with a nonleading 
question such as, “How do you feel since your last visit?” Study center personnel will 
record all pertinent information in the patient’s eCRF.
All AEs must be recorded on the appropriate AE reporting page of the patient’s eCRF
whether or not they are considered causally related to the investigational product.
For every AE, the Investigator must:
Provide an assessment of the seriousness of the event (ie, is it an SAE?), as well as 
the severity and causalrelationship
Document all actions taken with regard to the investigational product
Detail any other treatment measures taken for the AE
Document the outcome of the AE


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In addition, patients are to be reminded, as described in the ICF and in accordance with 
Section 9.5.2.1, to notify site personnel of any AEs occurring during the 30-day 
post-study period. Any AEs reported by the patient (or patient representative) during this 
period are to be recorded in original source documents. AEs are also to be recorded in the 
eCRF if at least 1of the following conditions is met: 1) the event meets the criteria for an 
SAE (see Sections 9.5.2.4and 9.5.2.6), and/or 2) the event is judged by the Investigator 
to bepotentially causally related to investigational product.
Any AEs that are ongoing at the time of the final protocol-defined study visit will be 
followed until the condition returns to prestudy status, has resolved or stabilized, or can 
be explained as being unrelated to the investigational product. If a follow-up visit is 
deemed necessary for appropriate safety surveillance, it will take place within 30 days of 
the final protocol-defined study visit.
9.5.2.6
ImmediateReporting of Serious Adverse Eventsand Events of 
Special Interest
FRIis required to inform worldwide regulatory authorities of SAEs that meet specific 
criteria. Therefore, FRImust be notified immediately regarding any SAE that occurs after 
informed consent is obtained.
Within 24 hours oflearning of any AE that meets oneof the criteria for an SAE, the 
study centerpersonnel must report the event to Global Drug Safety on the SAE Form for 
Clinical Trials. TheStudy Physician may also be notified by telephone.
If, during follow-up, any nonserious AE worsens and eventually meets the criteria for an 
SAE, that AE should be recorded as a new SAE. 
Thestudy centermust transmit the SAE Form for Clinical Trials to the SAE fax number 
shown below. Even if an initial report is made by telephone, theSAE Form for Clinical 
Trials completed with all available details must still be faxed within 24 hours of 
knowledge of the event at the study center.
Supplemental information should be submitted as soon as available and may include 
laboratory results, radiology reports, progress notes, hospital admission and emergency 
room notes, holding and observation notes, discharge summaries, autopsy reports, and 
death certificates.
The Investigator is expected to take all therapeutic measures necessary for resolution of 
the SAE. Any medications or procedures necessary for treatment of the SAE must be 
recorded on the appropriate pages of the patient’s eCRF. All SAEs are to be followed by 
the study staff until resolution or until the SAE is deemed stable. FRI may contactthe 
study centerto solicit additional information or follow upon the event.


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Fax the SAE Form for Clinical Trials to FRI.
United States and Canada: 631-858-7964
Medical Emergency phone number: 732-640-7482
9.5.2.7
Reporting of Pregnancies Occurring During the Study
Study center personnel must report every pregnancy from the time the ICF was signed 
until 30 days after the last dose of investigational product. Within 24 hours of learning of 
the pregnancy, the study center personnel must report the event to FRI Global Drug 
Safety on the Clinical Trial Pregnancy Form and fax it to the SAE fax number stated in 
Section 9.5.2.6, even if no AE has occurred. Pregnancies in female partners of male 
patients occurring during the time frame described above must also be reported. 
Any pregnancy of a patient treated with investigational product must be followed to term 
and the outcome reported by completing a follow-up Clinical Trial Pregnancy Form. If 
the pregnancy is associated with an SAE (eg, if the mother is hospitalized for 
hemorrhage), a separate SAE Form for Clinical Trials must be filed as described in 
Section 9.5.2.6with the appropriate serious criterion (eg, hospitalization) indicated in
addition to the pregnancy form.
9.5.2.8
Potential Hy’s Law Cases


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9.5.2.9
Clinical Laboratory Determinations


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9.5.2.10
Vital SignsIncluding Height and Weight
9.5.2.11
Electrocardiograms
9.5.2.12
Other Safety Assessments
9.5.2.12.1
Physical Examination
A complete physical examination will be done at Screening (Visit 1) and at Week 26
(Visit 16/ET)by a professionally trained physician or health professional listed on Form 
FDA 1572 and licensed to perform physical examinations.


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9.5.2.12.2
Columbia–Suicide Severity Rating Scale
The Columbia–Suicide Severity Rating Scale (C-SSRS) is an instrument that reports the 
severity of both suicidal ideation and behavior. Suicidal ideation is classified on a 5-item 
scale: 1 (wish to be dead), 2 (nonspecific active suicidal thoughts), 3 (active suicidal 
ideation with any methods [not plan] without intent to act), 4 (active suicidal ideation 
with some intent to act, without specific plan), and 5 (active suicidal ideation with 
specific plan and intent). The C-SSRS also captures information aboutthe intensity of 
ideation, specifically the frequency, duration, controllability, deterrents, and reasons for 
the most severe types of ideation. Suicidal behavior is classified on a 5-item scale: 
0(nosuicidal behavior), 1 (preparatory acts or behavior),2 (aborted attempt), 
3(interrupted attempt), and 4 (actual attempt). More than 1 classification can be selected 
provided they represent separate episodes. For actual attempts only, the actual or 
potential lethality is classified for the initial, most lethal, and most recent attempts. 
The paper version of the C-SSRS will be completed at all study visits. At Screening 
(Visit 1) the C-SSRS will be completed for the patient
's lifetime history of suicidal 
ideation and behavior for denovo patients only; for rollover patients, patient
's lifetime 
history of suicidal ideation and behavior data will be copied from Visit 1 in Study 
VLZ-MD-22 and kept with patients
' source documents for this study.At all other visits,
the C-SSRS will be completed for ideation and behavior since the previous visit
(Appendix VIII). The C-SSRS will be evaluated and signed at each visit by a qualified 
staff member (ie, the Investigator or designee that has extensive professional training and 
experience in assessing mental illness) before the patient leaves the study center.
The patient should not be released from the study center until the results of the C-SSRS 
are reviewed and the patient is not considered to be at risk. If there is doubt about 
whether a patient is at risk, the Investigator must obtain appropriate psychiatric 
consultation. The results of the C-SSRS will be recorded in the eCRF.A copy of the 
C-SSRSis provided in Appendix VII.
9.5.3
Investigational Product Concentration Measurements
Not applicable.
9.5.4
Health Economic and Outcomes Research Assessments
Not applicable.


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9.5.5
Schedule of Assessments
The schedule of study procedures and assessments is tabulated by visit in the Schedule of 
Evaluations in Section 2.0. The descriptionsof the procedures to be performed at each 
visit are provided below. Study procedures are for the patient only, unless 
otherwisespecified.
9.5.5.1
Screening (Visit 1)


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9.5.5.2
Baseline (Visit 2)


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9.5.5.3
End of Weeks 2and 3(Visits 3and4)


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9.5.5.4
End of Week 4 (Visit 5)


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9.5.5.5
End of Week 6 (Visit 6)
At Visit 6, the following procedures will be performed:


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9.5.5.6
End of Week 8 (Visit 7)
At Visit 7, the following procedures will be performed:
9.5.5.7
End of Week 10 (Visit 8)


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9.5.5.8
End of Week 12 (Visit 9)


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9.5.5.9
End of Week 14 (Visit 10)
9.5.5.10
End of Week 16 (Visit 11)


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9.5.5.11
End of Week 18 (Visit 12)
At Visit 12, the following procedures will be performed:


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9.5.5.12
End of Week 20 (Visit 13)
At Visit 13, the following procedures will be performed:


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9.5.5.13
End of Week 22 (Visit 14)
9.5.5.14
End of Week 24 (Visit 15)


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9.5.5.15
Final or Early Termination Visit, End of Week 26(Visit 16)


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Schedule next visit:
○Week 27(Visit 17) (1week [±3 days] relative to Week 26 (Visit16)
9.5.5.16
Down-taper, End of Week 27(Safety Follow-up Visit/Visit 17)
All enrolled patients must complete a Safety Follow-up Visit (Week 27[Visit 17]).   
Any clinical findings obtained during the final assessment, including clinically significant 
laboratory abnormalities, will be followed until the condition returns to prestudy status, 
resolves or stabilizes, or can be explained as being unrelated to the investigational 
product. If a follow-up visit is necessary, it should take place within 30 days of 
investigationalproduct termination.
9.5.5.17
Unscheduled Visits
Unscheduled visits may be conducted by the Investigator as necessary for any safety 
reason. Assessmentsto be conducted at these visits will be at the discretion of 
theInvestigator.


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9.6
DATA QUALITY ASSURANCE
9.6.1
Data Monitoring
9.6.2
Data Recording and Documentation
Data collection will involve the use of the Forest EDC system, to which only authorized 
personnel will have access.


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All data collected in the context of this study will be stored and evaluated per regulatory 
requirements and applicable guidance for electronic records. Also, data will be stored and 
evaluated in such a way as to guarantee patientconfidentiality in accordance with the 
legal stipulations applying to confidentiality of data. Study records 
 
 will be retained at the site, 
along with adequate source documentation, according to FDA and ICH requirements. All 
study records must be available for inspection by FRI,its authorized representatives,and 
the FDA or other health authorities.
9.7
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE
9.7.1
PatientPopulations
Four populations will be considered in the statistical analysis of the study, as specified 
below.
9.7.1.1
Screened Population
The Screened Population will consist of all patients who signed informed consent for this 
study.
9.7.1.2
EnrolledPopulation
The EnrolledPopulation will consist of all patients in the Screened Population who were 
dispensed investigational product.
9.7.1.3
Safety Population
The Safety Population will consist of all patients who took at least 1 dose of open-label
investigational product
9.7.1.4
Intent-to-Treat Population
The Intent-to-Treat (ITT) Population will consist of all patients in the Safety Population 
who had a baseline and at least 1 postbaseline assessment of the CDRS-R total score.
9.7.2
PatientDisposition
The number of patients in the Screened Population will be summarized overall by study 
center. The number of patients in the Enrolled, Safety, and ITT populations will be 
summarized by study center.


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Screen failures (ie, patients who were screened but not included in the Enrolled 
Population) and the associated reasons for failure will be tabulated. The number and 
percentage of patients who complete the open-labeltreatment period and of patients who 
prematurely discontinue during the same period will be presented. The reasons for 
premature discontinuation from the open-labeltreatment period as recorded on the 
termination pages of the eCRF will be summarized (number and percentage) for the 
Safety Population.
All summaries in this section will be presented by patient cohort (rollover patients from 
Study VLZ-MD-22 and de novopatients) and overall.
9.7.3
Demographics and Other Baseline Characteristics
Demographic parameters (eg, age, race, ethnicity, sex, weight, height, body mass index) 
and other baseline characteristics will be summarized for the Safety and ITTpopulations. 
Descriptive statistics (n, mean, SD, minimum, median, and maximum) will be presented 
for continuous variables, and frequency distributions (counts and percentages) will be 
presented for categorical variables.Summaries of demographic parameters will be 
presented by patient cohort (rollover patients from Study VLZ-MD-22, de novopatients) 
and overall.
9.7.3.1
Prior and Concomitant Medication
9.7.4
Extent of Exposure and Treatment Compliance
All summaries in this section will be presented by patient cohort (rollover patients from 
Study VLZ-MD-22 and de novopatients) and overall.


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9.7.4.1
Extent of Exposure
9.7.4.2
Measurement of Treatment Compliance
9.7.5
Efficacy Analyses
For patients who completed the lead-in study (VLZ-MD-22), the baseline for efficacy 
from the lead-in study will be used as the baseline for this study. For de novopatients, the
latest nonmissing evaluation of efficacy variables before the first dose of open-label 
investigational product will be used as baseline.  
The efficacy parameters will include the following at selected postbaseline visits:
Change from baseline in CDRS-R total score
Change from baseline in CGI-S score
CGI-I score


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Summaries of efficacy parameters will be presented by patient cohort (rollover patients 
from Study VLZ-MD-22andde novopatients) and overall. Descriptive statistics will be 
provided by visit forefficacyparameters for the ITTPopulation during the open-label 
treatment period, using both last‑observation-carried forward and observed-cases 
approaches. The last‑observation-carried forward approach will be used to impute 
missing postbaseline values.
9.7.5.1
Primary Efficacy Parameter
No efficacy assessments are considered primary in this open-label safety study.
9.7.6
Safety Analyses
The safety analysis will be performed for the open-labeltreatment period and down-taper 
period separately using the Safety Population. The safety analyses will be presented by 
patient cohort (rollover patients from Study VLZ-MD-22 and de novo patients) 
andoverall.
The safety parameters will include AEs, clinical laboratory parameters, vital sign 
measurements, ECG parameters, C-SSRS evaluations, and the change from baseline in 
the age-and gender-adjusted height (evaluation of growth). For patients who completed 
the lead-in study (VLZ-MD-22), the baseline for safety from the lead-in study will be 
used as the baseline for this study. For de novopatients, the latest nonmissing evaluation 
of safety variables before the first dose of open-label investigational product will be used 
as baseline.
9.7.6.1
Adverse Events
For patients who completed the lead-in study (VLZ-MD-22), an AE (classified by 
preferred term) that occurs during the open-label treatment period or during the 
down-taper period will be considered a treatment-emergent adverse event (TEAE) if it 
was not present before the date of the firstdose of double-blind investigational product in 
the lead-in study or if it was present before the date of the first dose of double-blind 
investigational product in the lead-in study and increased in severity during the 
open-label treatment period or during the down-taper period. If more than 1AE is 
reported before the date of the first dose of double-blind investigational product in the 
lead-in study and coded to the same preferred term, the AE with the greatest severity will 
be used as the benchmark for comparison with the AEs occurring during the treatment 
period or during the down-taper period that were also coded to that preferred term. An 
AE that occurs more than 30 days after the date of the last dose of investigational product 
will not be counted asa TEAE.


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For de novopatients, an AE (classified by preferred term) that occurs during the 
open-label treatment period or during the down-taper period will be considered a TEAE 
if the AE was not present before the date of the first dose of open-label investigational 
product or if it was present before the date of the first dose of open-label investigational 
product and increased in severity during the open-label treatment period or during the 
down-taper period,. If more than 1 AE is reported before the dateof the first dose of 
open-label investigational product and coded to the same preferred term, the AE with the 
greatest severity will be used as the benchmark for comparison with the AEs occurring 
during the open-label treatment period or during the down-taper period that were also 
coded to that preferred term. An AE that occurs more than 30 days after the date of the 
last dose of investigational product will not be counted as a TEAE.
An AE occurring during the down-taper period will be considered a newly emergent 
adverse event (NEAE) if it was not present before the start of the down-taper period or 
was present before the start of the down-taper period but increased in severity during the 
down-taper period. An AE that occurs more than 30 days after the date of the last dose of 
investigational product will not be counted as a NEAE.
NEAEs reported during the down-taper period will be summarized separately by body 
systemandpreferred term.
The number and percentage of patients reporting TEAEs during the open-label treatment 
period and during the down-taper period will be tabulated separately by system organ 
class, preferred term, and causal relationship to the investigational product. If more than 
1AE is coded to the same preferred term for the same patient, the patient will be counted 
only once for that preferred term using the most severe and most related occurrence for 
the summarization by severity and by causal relationship to the investigational product.
The distribution of TEAEs by severity and causal relationship to the investigational 
product will be summarizedseparately for the open-label treatment period and the 
down-taper period.
The incidence of common (≥ 2% of patients) TEAEs during the open-label treatment 
period will be summarized separately by preferred term. 
An SAE that occurred between the date of the first dose of open-label investigational 
product and 30 days after the date of the last dose of open-label investigational product in 
the study, inclusive, will be considered an on therapy SAE. The incidence of SAEs and 
AEs leading to premature discontinuation of the study will also be summarized by study 
period, system organ classandpreferred term. Listings will be presented for patients with 
SAEs,patients with AEs leading to premature discontinuation, and patients who died. All 
patients with SAEs, including those reported during the screening period or more than 
30days after the date of the last dose of the open-labelinvestigational product, and
patients discontinuing due to AEs before the start of open label investigational product 
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Listings will be presented for patients with SAEs, patients with AEs leading to 
discontinuation, and patients who die (if any).
9.7.6.2
Clinical Laboratory Parameters
Descriptive statistics for clinical laboratory values (in SI units) and changes from the 
baseline values at each assessment time point will be presented for each clinical 
laboratory parameter.
The number and percentage of patients with potentially clinically significant (PCS) 
postbaseline clinical laboratory values will be tabulated. The criteria for PCS laboratory 
values will be detailed in the statistical analysis plan. The percentages will be calculated 
relative to the numberof patients with available non-PCS baseline values and at least 
1postbaseline assessment. The numerator will be the total number of patients with 
available non-PCS baseline values and at least 1 PCS postbaseline value. A supportive 
listing of patients with PCS postbaseline values will be provided, including the PID 
number, study center number, and baseline and postbaseline values. A listing of all AEs 
that occur inpatients who havePCS laboratory values will also be provided.
9.7.6.3
Vital Signs
Descriptive statistics for vital signs (ie, sitting radial pulse rate, sitting systolic and 
diastolic BP, body weight,and height) and changes from baseline values at each visit and 
at end of study will be presented. In addition, height and weight z scores will be 
calculated based on growth charts (see Section 9.7.6.5.2).
Vital sign values will be PCS if they meet both the observed-value criteria and the 
change-from-baselinevalue criteria. The criteria for PCS vital sign values will be detailed 
in the Statistical Analysis Plan. The percentages will be calculated relative to the number 
of patients with baseline values and at least 1 postbaseline assessment. The numerator 
will bethe total number of patients with available baseline values and at least 1 PCS 
postbaseline value. A supportive listing of patients with PCS postbaseline values will be 
provided, including the PID number, study center number, and baseline and postbaseline
values. A listing of all AEs that occur in patients who have PCS vital sign values will also 
be provided.
9.7.6.4
Electrocardiograms
Descriptive statistics for ECG parameters (ie, ventricular heart rate, RR interval, 
PRinterval, QRS interval, QT interval, and QTc) and changes from baseline values at 
each assessment time point will be presented. The QTc is calculated using both the Bazett 
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The number and percentage of patients with PCS postbaseline ECG values will be 
tabulated. The criteria for PCS ECG values will be detailed in the statistical analysis plan. 
The percentages will be calculated relative to the number of patients with available 
non-PCS baseline values and at least 1 postbaseline assessment. The numerator will be 
the totalnumber of patients with available non-PCS baseline values and at least 1 PCS 
postbaseline value. A supportive listing of patients with PCS postbaseline values will be 
provided, including the PID number, study center number, and baseline and postbaseline 
values. A listing of all AEs that occur inpatients who havePCS ECG values will also 
beprovided.
A listing of patients with postbaseline clinically significant ECG abnormalities, as 
reported by the Investigator or by the central cardiologist, will also beprovided.
The number and percentage of patients with an increase > 30 msec but ≤ 60 msec, and 
with an increase > 60 msec in QTcB or QTcF will be tabulated. A supportive listing of 
patients with postbaseline QTcB or QTcF increases > 30 msec will be provided, 
including the PID number, study centernumber, and all QTcB and QTcF values 
(including changes from baseline). A listing of all AEs that occur inpatients who have
postbaseline QTcB or QTcF increases > 30 msec will also be provided.
9.7.6.5
Other Safety Parameters
9.7.6.5.1
Columbia–Suicide Severity Rating Scale
For the C-SSRS, the number and percentage of patients with suicidal ideation or suicidal 
behavior as recorded on the C-SSRS scale will be presented. The distribution of 
responses for most severe suicidal ideation and suicidal behavior during the lifetime 
history, the open-labeltreatment period, and the down-taper period will also be presented 
for the Safety Population. Supportive listings will be provided and will include the PID 
number, visit number, lifetime history, and postbaseline values for each patient. Intensity 
of ideation, suicidal behavior type, and lethality of suicidal behavior will also be included 
in these listings.
9.7.6.5.2
Growth Evaluation
Weight and height will be presented as standardized z scoresadjusted for gender and age, 
using the lambda-mu-sigmamethod (Cole, 1990).
9.7.6.6
Investigational ProductPlasma Concentration Parameters
Not applicable




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Departure from inclusion/exclusion criteria
Taking prohibited medications
Departure from prescribed dosing or duration of treatment
Failure to follow withdrawal criteria
Failure to perform the required assessments at specified time points
Scheduling of visits not in accordance with protocol specifications
Deviating from the protocol is permitted only if absolutely necessary for the safety or 
clinical management of the patients and must immediately be reported to FRI.Protocol 
deviations shouldbe reported to FRI (either verbally or electronically)in a timely manner
from the dateof discovery.
Protocol deviationsthat mayimpact patients’rights(eg, failure to obtain informed 
consent prior to initiating study procedures), safety, or well-being(eg, deviations that 
resulted in an SAE, exposure during pregnancy),or the integrity and authenticity of the 
study datashouldbe reported to FRIwithin 24hours, if possible. 
The IRB/IEC must be notified according to the criteria andtime period dictated by the 
IRB/IEC associated with this study.
9.10
DATA MONITORINGCOMMITTEE
An independent Data Monitoring Committee to evaluate safety study outcomes such as 
suicidal ideation and suicidal behavior during study conduct will be established and will 
operate based on a charter drafted to comply with FDA Guidance for ClinicalTrial 
Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees, 
2006.


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10.0
STUDY SPONSORSHIP
This study is sponsored by Forest Research Institute, Inc.
10.1
STUDY TERMINATION
FRIreserves the right to terminate the study in its entirety or at a specific study center
before study completion. 
10.2
REPORTING AND PUBLICATION
All data generated in this study arethe property of FRI. An integrated clinical and 
statistical report will be prepared at the completion of the study.
Publication of the results by the Investigator will be subject to mutual agreement between 
the Investigator and FRI and will follow FRI’s standard operating procedures on 
publications.


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11.0
INVESTIGATOR OBLIGATIONS
11.1
DOCUMENTATION
11.2
PERFORMANCE


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11.3
USE OF INVESTIGATIONAL MATERIALS
11.4
CASE REPORT FORMS
11.5
RETENTION AND REVIEW OF RECORDS
Records and documents pertaining to the conduct of this study, includingeCRFs, source 
documents, consent forms, regulatory documents, clinical laboratory results, calibration 
logs, or reports (including, but not limited to, all local and central laboratory results and 
ECG reports), and medication inventory records in all formats (including, but not limited 
to, written, electronic, magnetic, and optical records, and scans, x-rays, and ECGs) must 
be retained by the Investigator for a period of at least 15 years after study completion 
unless local regulations or institutional policies require a longer retention period or 
otherwise notified in writing by FRI. 
No study records shall be destroyed without notifying FRIand providing FRI the 
opportunity to arrange long-term storage for such study records or authorizing in writing 
the destruction of records after the required retention period.
The Investigator must permit access to any documentation relating to the study upon 
request of FRIor applicable regulatory authorities. If the Investigator for the study 
retires, relocates, or for other reasons withdraws from the responsibilityof keeping the 
study records, custody must be transferred to a suitable alternate custodian employee of 
the institution or to a suitably qualified and responsible third party. FRImust be notified 
in writing of the name and address of the new custodian in advance of the transfer.


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For Canadian study centers only:All records and documents pertaining to the conduct of 
the study must be retained for a 25-year period in accordance withthe Canadian Food 
and Drugs Act and Regulations.
11.6
PATIENT CONFIDENTIALITY
All patient records will only be identified by initials and PID number. Patients’ names are 
not to be transmitted to FRI. The Investigator will keep a master patient list on which the 
PID number and the full name, address, and telephone number of each patient are listed.


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12.0
INVESTIGATOR’S STATEMENT


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13.0
APPENDICES
APPENDIX I. 
ELEMENTS OF INFORMEDCONSENT
Procedures will comply with 21 CFR, Parts 50 and 312. Signed informed consent will be 
obtained foreach patient participating in a clinical research study or from the patient’s 
parent/guardian/LAR. This consent must include the following items:
A statement that the study involves research and an explanation of the purposes of the 
research; a description of the procedures to be followed and the identification of any 
procedures that are experimental; and the expected duration ofthe patient’s 
participation
A description of any reasonably foreseeable risks or discomforts to the patient
A description of any benefits to the patient or to others that may reasonably be 
expected from the research. If the patient is to be paid for participating in the study, 
the consent form must state the amount that he/she will receive and the schedule of 
payment (to ensure neither coercion nor undue influence)
A disclosure of appropriate alternative procedures or courses of treatment, if any, that 
might be advantageous to the patient
A statement describing the extent, if any, to which confidentiality of records 
identifying the patient will be maintained and noting the possibility that the FDA; 
FRI,the IRB; or an authorized contract research organization may inspect the records
For research involving more than minimal risk, an explanation of whether any 
medical treatment is available if injury occurs and, if so, what it consists of or where 
further information may be obtained
An explanation of whom to contact, including the relevant telephone number, for 
answers to pertinent questions about the research and the research patient’s rights and 
whom to contact in the event of a research-related injury to the patient. (Note: In 
some cases, it may be necessaryto identify a person other than the Investigator as the 
contact. The guidance of the IRB/EC may be required)
A statement that participation is voluntary, that refusal to participate will involve no 
penalty or loss of benefits to which the patient is otherwise entitled, and that the 
patient may discontinue participation at any time without penalty or loss of benefits to 
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A statement that the particular treatment or procedures may involve risks to the 
patient (or to theembryo or fetus if the patient is, or may become, pregnant) that are 
at present unforeseeable
The expected circumstances for which the patient’s participation may be terminated 
by the Investigator without regard to the patient’s consent
Any additional costs to the patient that may result from participation in the research
The consequences of a patient’s decision to withdraw from the research and 
procedures for an orderly termination of the patient’s participation
A statement that significant new findings developed during the course of the research 
that may relate to the patient’s willingness to continue participation will be provided 
to the patient
The approximate number of patients involved in the study
A statement of permission, providing consent for the patient to participate(eg, 
“Iagree toallow(my child) to participate . . .”)
A place for the patient’s parent/guardian/LAR signature and date of signingof the 
ICF 
A statement indicating that information about this study has been, or will be, entered 
into a databank that is publicly accessible at www.ClinicalTrials.gov.
A copy of the signed consent form must be given to the patient’s parent/guardian/LAR.
In addition, the patient will be asked to provide assent that will include a statement 
agreeing to participate in the study.


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APPENDIX II.
CONTACT INFORMATION 
Contact information for FRI personnel is maintained in the Study Reference Binder.


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APPENDIX III.
CONCOMITANT MEDICATIONS


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APPENDIX IV. 
CHILDREN’S DEPRESSION RATING SCALE–REVISED


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APPENDIX V.
CLINICAL GLOBAL IMPRESSIONS–SEVERITY


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APPENDIX VI.
CLINICAL GLOBAL IMPRESSIONS–IMPROVEMENT
GLOBAL IMPROVEMENT


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APPENDIX VII.
COLUMBIA–SUICIDE SEVERITY RATING SCALE -
BASELINE
COLUMBIA–SUICIDE SEVERITY
RATING SCALE
(C-SSRS)
Baseline
Version 1/14/09
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; 
Zelazny, J.; Burke, A.; Oquendo, M.; Mann, J.
Disclaimer: 
This scale is intended for use by trained clinicians. The questions contained in the 
Columbia-Suicide Severity Rating Scale are suggested probes. Ultimately, the 
determination of the presence of suicidality depends on clinical judgment.
Definitions of behavioral suicidal events in this scale are based on those used in The 
Columbia Suicide History Form, developed by John Mann, MD and Maria Oquendo, 
MD, Conte Center for the Neuroscience of Mental Disorders (CCNMD), New York State 
Psychiatric Institute, 1051 Riverside Drive, New York, NY, 10032. (Oquendo M. A., 
Halberstam B. & Mann J. J., Risk factors for suicidal behavior: utility and limitations of 
research instruments. In M.B. First [Ed.] Standardized Evaluation in Clinical Practice, 
pp. 103 -130, 2003.) 
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric 
Institute, 1051 Riverside Drive, New York, New York, 10032; inquiries and training 
requirements contact posnerk@childpsych.columbia.edu
© 2008 The Research Foundation for Mental Hygiene, Inc.


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APPENDIX VIII. COLUMBIA–SUICIDE SEVERITY RATING SCALE -
SINCE LAST VISIT
COLUMBIA–SUICIDE SEVERITY
RATING SCALE
(C-SSRS)
Since Last Visit
Version 1/14/09
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; 
Zelazny, J.; Burke, A.; Oquendo, M.; Mann, J.
D
isc
la
imer
: 
This scale is intended for use by trained clinicians. The questions contained in the Columbia-Suicide 
Severity Rating Scale are suggested probes. Ultimately, the determination of the presence of suicidality 
depends on clinical judgment. 
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia Suicide 
History Form, developed by John Mann, MD and Maria Oquendo, MD, Conte Center for the Neuroscience 
of Mental Disorders (CCNMD), New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY, 
10032. (Oquendo M. A., Halberstam B. & Mann J. J., Risk factors for suicidal behavior: utility and 
limitations of research instruments. In M.B. First [Ed.] Standardized Evaluation in Clinical Practice, 
pp.103 -130, 2003.) 
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, 1051 
Riverside Drive, New York, New York, 10032; inquiries and training requirements contact 
posnerk@childpsych.columbia.edu
© 2008 The Research Foundation for Mental Hygiene, Inc.


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APPENDIX IX.
INVESTIGATIONAL PRODUCT FORMULATION
Ingredients of vilazodone 


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14.0
LITERATURE CITED
American Academy of Child and Adolescent Psychiatry. Practice parameters for the 
assessment and treatment of children and adolescents with posttraumatic stress disorder. 
JAmAcad Child AdolescPsychiatry1998;37(10Suppl):4S-26S.
Cole TJ. The LMS method for constructing normalized growth standards. EurJClin Nutr
1990;44:45-60.
Egger HL, Angold A. Common emotional and behavioral disorders in preschool children: 
presentation, nosology, and epidemiology. J Child Psychol Psychiatry 2006;47:313-37.
European Medicines Agency. ICH topic E11: note for guidance on clinical investigation 
of medicinal products in the paediatric population. 2001 Jan. Available from: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/
WC500002926.pdf. Accessed 2014 Aug 5.
Grunbaum JA, Kann L, Kinchen SA, et al. Youth risk behavior surveillance—United 
States, 2001. MMWR Surveill Summ 2002;51:1-62.
Guy W: ECDEU Assessment Manual for Psychopharmacology.Revised. 
DHEWpublication no.(ADM)76-338. Rockville, MD;U.S., US Deptof Health, 
Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health 
Administration, NIMH Psychopharmacology Research Branch, Division of Extramural 
Research Programs, 1976, pp 218-22.
Hammad TA, Laughren T, Racoosin J. Suicidality in pediatric patients treated with 
antidepressant drugs. Arch Gen Psychiatry 2006;63:332-9.
Kaufman J, Birmaher B, Brent D, et al. Schedule for Affective Disorders and 
Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL): 
initial reliability and validity data. J AmAcad Child Adolesc Psychiatry 1997;36:980-8.
Montgomery SA, Åsberg M. A new depression scale designed to be sensitive to change. 
Br J Psychiatry 1979;134:382-9.
National Adolescent Health Information Center. 2006 fact sheet on suicide:adolescents 
& young adults.San Francisco, CA: University of California, San Francisco. Available 
from: http://nahic.ucsf.edu/downloads/Suicide.pdf. Accessed 2014 Sep 20.
Poznanski EO, Mokros HB. Children’s Depression Rating Scale,Revised (CDRS-R). Los 
Angeles, CA:Western Psychological Services.1996.


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Study VLZ-MD-21: a double-blind, placebo-controlled, evaluation of the safety and 
efficacy of vilazodone in adolescent patients with major depressive disorder[protocol]. 
Jersey City, NJ: Forest Research Institute, Inc.Study in progress.
Study VLZ-MD-22: a multicenter, double-blind, placebo-and active-controlled 
parallel-group evaluation of the safety and efficacy of vilazodone in pediatric patients 
with major depressive disorder[protocol]. Jersey City, NJ: Forest Research Institute, Inc.
Substance Abuse and Mental Health Services Administration.2009. Results from the 
2008 National Survey on Drug Use and Health: national findings. Available from: 
http://www.samhsa.gov/data/NSDUH/2k8nsduh/2k8Results.htm. Accessed 2014 Sep20. 
US Food and Drug Administration. Guidance for industry E11: clinical investigation of 
medicinal products in the pediatric population. 2000 Dec. Available from: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM073143.pdf. Accessed 2014 Aug 5.
US Food and Drug Administration. Guidance for clinical trial sponsors: establishment 
and operation of clinical trial data monitoring committees. 2006 Mar. Available from: 
http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm127073.pdf. 
Accessed 2014 Sep 22.
US Food and Drug Administration. Guidance for industry: drug-induced liver injury: 
premarketing clinical evaluation. 2009 Jul. Available from: 
http://www.fda.gov/downloads/Drugs/.../Guidances/UCM174090.pdf. Accessed 
2014Aug 5.
Viibryd [package insert]. St. Louis, MO: Forest Laboratories, Inc. 2014 Jul. Available 
from: http://www.frx.com/pi/viibryd_pi.pdf. Accessed 2014 Sep 20.
Vilazodone hydrochloride: Investigator’s brochure. Edition 14. Jersey City, NJ: 
ForestResearch Institute, Inc. 2013 Aug 9.
Zalsman G, Brent DA, Weersing VR.Depressive disorders in childhood and adolescence: 
an overview: epidemiology, clinical manifestation and risk factors. ChildAdolesc 
Psychiatr Clin N Am 2006;15:827-41.

SAP_001.pdf: 
1.0
TITLE PAGE
Forest Research Institute
Harborside Financial Center, Plaza V
Jersey City, NJ  07311
PROTOCOL VLZ-MD-23
An Open-label Long-term Safety Study of Vilazodone in Pediatric Patients With
Major Depressive Disorder
STATISTICAL ANALYSIS PLAN 
Final: 10 Feb 2016
Confidentiality Statement
This document is the property of Forest Research Institute, Inc., and may not—in full or 
part—be passed on, reproduced, published, distributed, or submitted to any regulatory 
authority without the express written permission of Forest Research Institute, Inc.
 
Forest Research Institute, Inc. 
Page 1 of 40
APPROVED
10 Feb 2016
SAP VLZ-MD-23


2.0
TABLE OF CONTENTS
1.0 
TITLE PAGE....................................................................................................................................1
2.0 
TABLE OF CONTENTS..................................................................................................................2
2.1 
listof in-text tables.............................................................................................................4
3.0 
LIST OF ABBREVIATIONS...........................................................................................................5
4.0 
INTRODUCTION............................................................................................................................6
5.0 
OBJECTIVE.....................................................................................................................................9
6.0 
PATIENT POPULATIONS............................................................................................................10
6.1 
Screened Population.........................................................................................................10
6.2 
Enrolled Population..........................................................................................................10
6.3 
Safety Population..............................................................................................................10
6.4 
Intent-to-Treat Population.................................................................................................10
7.0 
PATIENT DISPOSITION..............................................................................................................11
8.0 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS........................................12
9.0 
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE................................................13
9.1 
Extent of Exposure...........................................................................................................13
9.2 
Measurement of Treatment Compliance...........................................................................13
10.0 EFFICACY ANALYSES...............................................................................................................14
11.0 SAFETY ANALYSES....................................................................................................................15
11.1 Adverse Events.................................................................................................................15
11.2 Clinical Laboratory Parameters........................................................................................17
11.3 Vital Signs........................................................................................................................20
11.4 Electrocardiogram (ECG).................................................................................................21
11.5 Other Safety Parameters...................................................................................................22
11.5.1 Suicidality Assessment.......................................................................................22
11.5.2 Growth Evaluation..............................................................................................23
12.0 Health outcome analyses.................................................................................................................24
13.0 INTERIM ANALYSIS...................................................................................................................25
14.0 DETERMINATION OF SAMPLE SIZE.......................................................................................26
15.0 COMPUTER METHODS...............................................................................................................27
16.0 DATA HANDLING CONVENTIONS..........................................................................................28
16.1 Visit Time Windows.........................................................................................................28
16.2 Derived Efficacy Variables...............................................................................................29
16.3 AGE-AND-GENDER_CORRELATED VALUES FOR WEIGHT AND HEIGHT.......29


16.4 Repeated or Unscheduled Assessments of Safety Parameters..........................................30
16.5 Missing Date of Investigational Product...........................................................................30
16.6 Missing Severity to INVESTIGATIONAL PRODUCT in Adverse Events....................31
16.7 Missing Relationship to INVESTIGATIONALPRODUCT for Adverse Events............31
16.8 Missing Date Information for Adverse Events.................................................................31
16.9 Missing Date Information for Concomitant Medications.................................................32
16.10
Character Values of Clinical Laboratory Parameters........................................................35
17.0 CHANGES TO ANALYSES SPECIFIED IN PROTOCOL..........................................................36
18.0 REFERENCES...............................................................................................................................37
19.0 APPENDICES................................................................................................................................38
APPENDIX I. 
REPORTING SELECTED LABORATORY PARAMETERS IN 
CONVENTIONAL UNIT................................................................................................38


2.1
LIST OF IN-TEXT TABLES
Table 4–1. SCHEDULE OF EVALUATIONS: Study VLZ-MD-23...........................7
Table 11.2–1. 
Criteria for Potentially Clinically Significant Laboratory Values18
Table 11.3–1. 
Criteria for Potentially Clinically Significant Vital Signs............20
Table 11.4–1. 
Criteria for Potentially Clinically Significant Electrocardiographic 
Parameters 
22
Table 16.1–1. 
Visit Time Windows for the Open-Label Treatment Period........28
Table 16.1–2. 
Visit Time Windows for the Open-label Down-Taper Period......29
Table 16.10–1.  
Examples of Coding Special Character Values for Clinical 
Laboratory Parameters......................................................................................................35
Table 19–1. List of Selected Parameters Reported in Conventional Unit....................38
Table 19–2. Presenting Laboratory Data Using SI and Conventional Units in 
Narratives 
39


3.0
LIST OF ABBREVIATIONS
AE
adverse event
ALT 
alanine aminotransferase
AST
aspartate aminotransferase
ALP
alanine phosphatase
BP
blood pressure
CDR-S
Children’s Depression Rating Scale–Revised
CGI-I
Clinical Global Impression-Improvement
CGI-S
Clinical Global Impression-Severity
C-SSRS
Columbia Suicide Severity Rating Scale
ECG
Electrocardiogram
ITT
Intent-to-Treat
LLN
lower limit of normal
LOCF
last observation carried forward
MedDRA
Medical Dictionary for Regulatory Activities
NEAE
newly emergent adverse event
PCS
potentially clinically significant
SAE
serious adverse event
SAP
Statistical Analysis Plan
SI
Le Système International d’Unités(International System ofUnits)
SOC
system organ class
TBL
total bilirubin
TEAE
treatment emergent adverse event
ULN
upper limit of normal


4.0
INTRODUCTION
This statistical analysis plan (SAP) provides a more technical and detailed elaboration of 
the statistical analyses of the efficacy and safety data as outlined and/or specified in the 
protocol of Study VLZ-MD-23. Specifications of tables, figures, and data listings are 
contained in a separate document. The statistical analysis for pharmacokinetic parameters 
will be specified in a separate document.
Study VLZ-MD-23 will be an open-label, long-term safety study in pediatric patients, 
ages 7 to 17 years with major depressive disorder (MDD). Eligible patients will include 
de novo patients meeting the inclusion/exclusion criteria and patients who completed the 
lead-in study (VLZ-MD-22). Study centers will enroll either de novopatients or patients 
who completed the lead in study. Patients who complete Study VLZ-MD-22 will have the 
option to participate in Study VLZ-MD-23.
The study will be approximately 28weeks in duration, including approximately a 1-week 
screening/washout period, a 26-week open-label treatment period, and a 1-week 
down-taper period. During the open-label treatment period, study visits will be conducted 
after 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, and 26 weeks of treatment 
(see Table 4–1). Safety and efficacy assessments will be performed at the designated 
visits. Patients prematurely discontinuing from the study, regardless of cause, will be 
seen for a final evaluation. 
This statistical analysis plan (SAP) provides a more technical and detailed elaboration of 
the statistical analyses for efficacy and safety assessmentsas outlined and/or specified in 
the final study protocol (version dated 15 Dec 2014).Specifications of tables, figures, and 
data listings are contained in a separate document. 


Table 4–1. 
SCHEDULE OF EVALUATIONS: Study VLZ-MD-23


Table 4–1. 
SCHEDULE OF EVALUATIONS: Study VLZ-MD-23


5.0
OBJECTIVE
The objective of this study is to evaluate the long-term safety and tolerability of 
vilazodone for the treatment of MDD in pediatric outpatients (7-17 years).  


6.0
PATIENT POPULATIONS
Four populations will be considered in the statistical analysis of the study, as specified 
below.
6.1
SCREENED POPULATION
The Screened Population will consist of all patients who signed informed consent for this 
study.
6.2
ENROLLED POPULATION
The Enrolled Population will consist of all patients in the Screened Population who were 
dispensed investigational product.
6.3
SAFETY POPULATION
The Safety Population will consist of all patients who took at least 1 dose of open-label 
investigational product.
6.4
INTENT-TO-TREAT POPULATION
The Intent-to-Treat (ITT) Population will consist of all patients in the Safety Population 
who had a baseline and at least 1 postbaseline assessment of the Children’s Depression 
Rating Scale–Revised (CDRS-R) total score.


7.0
PATIENT DISPOSITION
The number of patients in the Screened Population will be summarized overall by study 
center. The number of patients in the Enrolled, Safety, and ITT populations will be 
summarized by study center.  
Screen failures (ie, patients who were screened but not included in the Enrolled 
Population) and the associated reasons for failure will be tabulated. The number and 
percentage of patients who complete the open-label treatment period and of patients who 
prematurely discontinue during the same period will be presented. The reasons for 
premature discontinuation from the open-label treatment period as recorded on the 
disposition pages of the electronic case report forms will be summarized (number and 
percentage) for the Safety Population. All patients who prematurely discontinue during 
the open-label treatment period will be listed by discontinuation reason for the Safety 
Population.
All summaries in this section will be presented by patient cohort (rollover patients from 
Study VLZ-MD-22 or de novopatients) and overall. The rollover patients from Study 
VLZ-MD-22 will be summarized by lead-in treatment group.


8.0
DEMOGRAPHICS AND OTHER BASELINE 
CHARACTERISTICS
Demographic parameters (age, sex, race, ethnicity) and other baseline characteristics 
(weight, height, body mass index) will be summarized descriptively by cohort and by 
lead-in treatment group for the Safety and ITT populations, respectively. Baseline 
efficacy variables will be summarized by cohort and by lead-in treatment group for the 
ITT Population.
Continuous variables will be summarized by number of patients and mean, SD, median, 
minimum, and maximum values. Categorical variables will be summarized by number 
and percentage of patients.
Medical and surgical history/physical findings will be classified by system organ class 
(SOC) and preferred term using the Medical Dictionary for Regulatory Activities, version 
17.0 or newer. The number and percentage of patients with abnormalities in medical and 
surgical histories in each SOC and preferred term will be summarized by cohort and by 
lead-in treatment group for the Safety Population. Psychiatric history of MDD, other 
psychiatric history, prior treatment with psychotropic medication, and non-drug 
psychiatric treatment history will also be summarized by cohort and by lead-in treatment 
group for the Safety Population.
The World Health Organization Drug Dictionary, version March 2014 or newer, will be 
used to classify prior and concomitant medications by therapeutic class and drug name.
Prior medicationis defined as any recorded medication taken before the date of thefirst 
dose of open-label investigational product. Concomitant medicationis defined as any 
medication taken on or after the date of the first dose of open-label investigational 
product. 


9.0
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE
9.1
EXTENT OF EXPOSURE 
Exposure to open-label investigational product for the Safety Population during the open-
label treatment period will be summarized in terms oftreatment duration, calculated as 
the number of days from the date of the first dose of open-label investigational product to 
taken the date of the last dose of open-label investigational product taken during the 
open-label treatment period, inclusive. Descriptive statistics (number of patients, mean, 
SD, median, minimum, and maximum) will be presented by cohort and by lead-in 
treatment group. The number and percentage of patients by exposure will be presented 
for specific intervals by cohort.
9.2
MEASUREMENT OF TREATMENT COMPLIANCE


10.0
EFFICACY ANALYSES
All efficacy analyses will be based on the ITT Population. For patients who completed 
the lead-in study (VLZ-MD-22), the baseline for efficacy from the lead-in study will be 
used asthe baseline for this study. For de novopatients, the latest nonmissing evaluation 
of efficacy variables (at or prior to Visit 2) before the first dose of open-label 
investigational product will be used as baseline.  Descriptive statistics for each efficacy 
parameter (n, mean, SD, SEM, median, minimum, and maximum) will be presented for 
each visit, by cohort and by lead-in treatment group for continuous variables using 
observed case (OC) approach. At a specific visit, only patients in the ITT Population with 
both baseline and post-baseline values will be included in the summary. 
In addition, by-visit analyses using the last-observation-carried-forward (LOCF) 
approach will be presented for each efficacy parameters. For the LOCF approach, only 
the postbaseline total score of a parameter will be imputed; individual item scores will 
not be carried forward to derive the total score. Baseline total score will be carried 
forward only for the intermittent missing scores immediately after baseline. If all the 
postbaseline values are missing, the baseline value will not be carried forward.
The efficacy parameters will include the following at selected postbaseline visits:
Change from baseline in CDRS-R total score
Change from baseline in Clinical Global Impressions –Severity (CGI-S) score
Clinical Global Impressions –Improvement (CGI-I) score


11.0
SAFETY ANALYSES
The safety analysis will be performed for the open-label treatment period and down-taper 
period separately using the Safety Population. The safety analyses willbe presented by 
patient cohort (rollover patients from Study VLZ-MD-22 and de novo patients) and 
overall. The rollover patients from Study VLZ-MD-22 will also be presented by lead-in 
treatment group.
The safety parameters will include adverse events (AEs), clinical laboratory parameters, 
vital sign measurements, electrocardiogram (ECG) parameters, Columbia Suicide 
Severity Rating Scale (C-SSRS) evaluations, and the change from baseline in the age-
and gender-adjusted height (evaluation of growth). For patients who completed the 
lead-in study (VLZ-MD-22), the baseline for safety parameters from the lead-in study 
will be used as the baseline for this study. For de novopatients, the latest nonmissing 
evaluation of safety parameters before the first dose of open-label investigational product 
will be used as the baseline.
11.1
ADVERSE EVENTS
AEs will be coded by SOC and preferred term using the Medical Dictionary for 
Regulatory Activities,version 17.0 or newer.
For patients who completed the lead-in study (VLZ-MD-22), an AE (classified by 
preferred term) that occurs during the open-label treatment period or during the 
down-taper period will be considered a treatment-emergent adverse event (TEAE) if it 
was not present before the date of the first dose of double-blind investigational product in 
the lead-in study or if it was present before the date of the first dose of double-blind 
investigational product in the lead-in study and increased in severity during the 
open-label treatment period or during the down-taper period. If more than 1AE is 
reported before the date of the first dose of double-blind investigational product in the 
lead-in study and coded to the same preferred term, the AE with the greatest severity will 
be used as the benchmark for comparison with the AEs occurring during the open-label 
treatment period or during the open-label down-taper period that were also coded to that 
preferred term. An AE that occurs more than 30 days after the date of the last dose of 
investigational product will not be counted asa TEAE.


For de novopatients, an AE (classified by preferred term) that occurs during the 
open-label treatment period or during the open-label down-taper period will be 
considered a TEAE if the AE was not present before the date of the first dose of 
open-label investigational product or if it was present before the date of the first dose of 
open-label investigational product and increased in severity during the open-label 
treatment period or during the open-label down-taper period. If more than 1 AE is 
reported before the date of the first dose of open-label investigational product and coded 
to the same preferred term, the AE with the greatest severity will be used as the 
benchmark for comparison with the AEs occurring during the open-label treatment period
or during the open-label down-taper period that were also coded to that preferred term. 
An AE that occurs more than 30 days after the date of the last dose of investigational 
product will not be counted as a TEAE.
For patients who completed the lead-in study (VLZ-MD-22), an AE (classified by 
preferred term) occurring during the open-label treatment period will be considered a 
newly emergent adverse event (NEAE) if the AE was not present before the first dose of 
the open-label treatment period investigational product or it was present before the first 
dose of the open-label treatment period investigational product and increased in severity 
during the open-label treatment period. If more than 1 AE was reported before the first 
dose of the open-label investigational product and coded to the same preferred term, the 
AE with the greatest severity will be used as the benchmark for comparison with the AEs 
occurring during the open-label treatment period that were also coded to that preferred 
term.
An AE occurringduring the open-label down-taper period will be considered an NEAE if 
it was not present before the start of the down-taper period or was present before the start 
of the down-taper period but increased in severity during the down-taper period. An AE 
that occurs more than 30 days after the date of the last dose of investigational product 
will not be counted as a NEAE.
The number and percentage of patients reporting TEAEs during the open-label treatment 
period and during the open-label down-taper period willbe tabulated by SOC and 
preferred term, for both the open-label treatment period and the open-label down-taper 
period, separately. If more than 1 AE is coded to the same preferred term for the same 
patient, the patient will be counted only once for that preferred term using the greatest 
severity and strictest causality for the summarization by severity and by causal 
relationship to the investigational product, respectively.  
The distribution of TEAEs by severity and causal relationship to the investigational 
product will be summarized separately for the open-label treatment period and the 
open-label down-taper period.


A common TEAE during the open-label treatment period will be summarized in 2 ways: 
≥ 1% of patients and ≥ 2% of patients in any cohort or any lead-in treatment group. The 
incidence of common TEAEs will be summarized separately by preferred term and 
cohort and lead-in treatment group and will be sorted by decreasing frequency for the 
total group.
NEAEs reported during the open-label treatment period and the during open-label 
down-taper period will be summarized separately by body system and preferred term. 
A serious adverse event (SAE) that occurred between the date of the first dose of 
open-label investigational product and 30 days after the date of the last dose of open-label 
investigational product in the study, inclusive, will be considered an on-therapy SAE. 
The incidence of SAEs and AEs leading to premature discontinuation of the study will 
also be summarized by study period, SOC and preferred term. Listings will be presented 
for patients with SAEs, patients with AEs leading to premature discontinuation, and 
patients who died (if any). All patients with SAEs, including those reported during the 
screening period or more than 30days after the date of the last dose of the open-label 
investigational product, and patients discontinuing due to AEs before the start of open 
label investigational product will be included in these listings.
Listings will be presented for patients with SAEs, patients with AEs leading to 
discontinuation, and patients who die (if any).
11.2
CLINICAL LABORATORY PARAMETERS
Descriptive statisticsfor clinical laboratory values(in SI units) and changes from the 
baseline values at each assessment time point (including the end of the open-label 
treatment period) will be presented for the following laboratory parameters:






11.3
VITAL SIGNS
Descriptive statistics for vital signs (ie, sitting radial pulse rate, sitting systolic and 
diastolic blood pressure (BP), body weight, and height) and changes from baseline values 
at each visit and at the end of the open-label treatment period will be presented. In 
addition, height and weight z scores will be calculated based on growth charts. 


11.4
ELECTROCARDIOGRAM (ECG)
Descriptive statistics for ECG parameters (ie, ventricular heart rate, RR interval, 
PRinterval, QRS interval, QT interval, and QTc) and changes from baseline values at 
each assessment time point will be presented. The QTc is calculated using both the Bazett 
and Fridericia corrections.


11.5
OTHER SAFETY PARAMETERS
Other safety parameters include C-SSRS and growth.
11.5.1 
Suicidality Assessment 
For the C-SSRS, the number and percentage of patients with any suicidal ideation or 
suicidal behavior will be presented by cohort, separately for the lifetime history, the 
open-label treatment period and the open-label down-taper period. The distribution of 
responses for the most severesuicidal ideation and suicidal behavior will be summarized 
by cohort and by lead-in treatment group, separately for the lifetime history, the 
open-label treatment period, and the open-label down-taper period. Supportive listings 
will be provided and will include the patient identification number, treatment group, visit 
number, lifetime history, and postbaseline values for each patient. Intensity of ideation, 
suicidal behavior type, and lethality of suicidal behavior will also be included in these 
listings.A listing of all AEs occurring in patients who have suicidal ideation or suicidal 
behavior will also be provided.


11.5.2 
Growth Evaluation 
Weight and height will be presented in raw score and standardized z-scores adjusted for 
gender and age, using the LMS method (Cole TJ, 1990). 
Descriptive statistics for raw scores of height and weight, age-and-gender-adjusted height 
and weight, and changes from baseline values at each visit and at the end of the 
open-label treatment group will be presented.


12.0
HEALTH OUTCOME ANALYSES
Not applicable. 


13.0
INTERIM ANALYSIS
No interim analysis is planned for this study.




15.0
COMPUTER METHODS
Statistical analyses will be performed 
 


16.0
DATA HANDLING CONVENTIONS
16.1
VISIT TIME WINDOWS 
Table 16.1–1below presents the visits assigned for efficacy and safety analyses 
corresponding to the range of treatment days (window) in the open-label treatment period 
during which an actual visit may have occurred.


16.2
DERIVED EFFICACY VARIABLES
The total score at a particular visit will be calculated using (sum of nonmissing 
items)×(total number of items) / (number of nonmissing items) only if the number of 
missing items is ≤ 2 for the CDRS-R score.
If a patient misses a postbaseline visit or if his/her postbaseline visit is outside of the visit 
time window, a record for the scheduled visit will be imputed using the last observed 
nonmissing value immediately before the missing value. If the missing value occurs at 
Week 2, the baseline value will be carried forward for Week 2, provided that at least 
1subsequent postbaseline assessment is available. For a composite scale such as 
CDRS-R total score, individual items of the rating scale will not be carried forward. Only 
total scores will be carried forward using the LOCF approach.
16.3
AGE-AND-GENDER_CORRELATED VALUES FOR WEIGHT 
AND HEIGHT
To adjust weight (kg) and height (cm) for sex and age, one needs to compare them to 
standard reference values for the same sex and age group, which are available in the 
United States Growth Charts and can be downloaded from: 
http://www.cdc.gov/growthcharts/percentile_data_files.htm


The z-score is calculated as below
, if L ≠ 0 and
, if  
,
where X is the physical measurement (egweight and height) and L, M, and S are the 
values from the appropriate table corresponding to the age in months (or length/stature) 
and sex (1 = male; 2 = female). Xmust be in metric measurements (kilograms or meters). 
This is called LMS method (Cole TJ,1990), and parameters L, M, and S are the Box-Cox 
transformation power, median, and SD, respectively, in the reference data, which are 
provided in the reference data tables.
16.4
REPEATED OR UNSCHEDULED ASSESSMENTS OF SAFETY 
PARAMETERS
For roll-over patients, the corresponding baseline of the double-blind lead-in study will 
be used. If a de novo patient has repeated assessments before the date of the first dose of 
open-label investigational product, the results from the final nonmissing assessment made 
before the date of the first dose of open-label investigational product will be used as 
baseline. If the end-of-open-label-treatment period assessments are repeated or if 
unscheduled visits occur, the last nonmissingpostbaseline assessment during the 
open-label treatment period will be used as the end-of-open-label-treatment-period 
assessment for generating summary statistics. Likewise, if the end of open-label 
down-taper period assessments are repeated or if unscheduled visits occur, the last 
non-missingassessment during the open-label down-taper period will be used as the 
end-of-open-label-down-taper-period assessment for generating summary statistics. 
However, all postbaseline assessments will be used to determine PCS values for 
laboratory parameters, vital signs and ECG parameters, and to determine most severe 
suicidal ideation and most severe suicidal behavior from C-SSRS. All assessments will 
be presented in the data listings.
16.5
MISSING DATE OF INVESTIGATIONAL PRODUCT
When the date of the last dose of the open-label investigational product during the study 
treatment period is missing for a patient in the Safety Population, all efforts should be 
made to obtain the date from the Investigator. If it is still missing after all efforts have 
been made, then the last available dosing record date will be used as the last dose date. 
SL
M
X
z
L 1
)
/
( 


S
M
X
z
)
/
ln(

0

L


16.6
MISSING SEVERITY TO INVESTIGATIONAL PRODUCT IN
ADVERSE EVENTS
If the severity is missing for an AE started on or after the date of the first dose of the 
open-label investigational product, then a severity of “Severe” will be assigned. The 
imputed values for severity assessment will be used for incidence summary, while the 
actual values should be presented in data listings.
16.7
MISSING RELATIONSHIPTO INVESTIGATIONAL 
PRODUCT FOR ADVERSE EVENTS
If the relationship to the investigational product is missing for an AE started on or after 
the date of the first dose of the open-label investigational product, a causality of 
“Related” will be assigned. The imputed values for relationship to the investigational 
product will be used for incidence summary, while the actual values should be presented 
in data listings. 








16.10 
CHARACTER VALUES OF CLINICAL LABORATORY 
PARAMETERS
If the reported value of a clinical laboratory parameter cannot be used in a statistical 
summary table due, for example, to the fact that a character value is reported for a 
parameter of the numerical type, a coded value needs to be appropriately determined and 
used in the statistical analyses. However, the actual values as reported in the database will 
be presented in data listings.


17.0
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL
No major changes have been made to the original protocol dated 15 Dec 2014.


18.0
REFERENCES
Cole TJ. The LMS method for constructing normalized growth standards. Eur J Clin 
Nutr.1990,44: 45-60.


19.0
APPENDICES
APPENDIX I.  
REPORTING SELECTED LABORATORY PARAMETERS IN 
CONVENTIONAL UNIT
All clinical laboratory parameters will bereported in the International System (SI) units 
as standard practice. In addition, descriptive statistics for values and changes from 
baseline in conventional units at all assessed visits will be reported for selected laboratory 
parameters