Clinical trial NCT02372799
Conditions: Major Depressive Disorder
Sponsor: Forest Laboratories
Start date: 2015-02-28; Completion date: 2018-09-11
Enrollment: 473 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy, safety, and tolerability of vilazodone compared with placebo in pediatric outpatients (7-17 years of age) with major depressive disorder.

Detailed description:

Arms: arm 1: Vilazodone tablets, 5mg, 10mg and 20mg. Oral administration, once per day. arm 2: Dose-matched placebo tablets or capsules, oral administration, once per day. arm 3: Fluoxetine capsules, 10mg and 20 mg. Oral administration, once per day.
Interventions: intervention 1: Vilazodone intervention 2: Placebo intervention 3: Fluoxetine
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol documents:
Prot_000.pdf: 
NCT02372799 
 
 
Study ID: VLZ‐MD‐22 
 
 
 
Title: 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 Amendment 1 Date: 15  April 2015 
 
 
 


1.0
TITLE PAGE
Forest Research Institute, Inc., a subsidiary of Actavis, Inc.
Harborside Financial Center, Plaza V
Jersey City, NJ 07311
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
VLZ-MD-22
IND # 54,613
NDA # 22,567
Original Protocol Date:
26 Sep 2014
Amendment #1 (Canada):   15 Apr 2015
Confidentiality Statement
This document is the property of Forest Research Institute, Inc., an affiliate of 
Actavis, 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.
 
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2.0
SYNOPSIS AND SCHEDULE OF EVALUATIONS
CLINICAL STUDY SYNOPSIS: Study VLZ-MD-22
Title of Study
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  
Study Centers 
Approximately 60 study centers in the United States and Canada
Development Phase
3
Objective
To evaluate the efficacy, safety, and tolerability of vilazodone compared with 
placebo in pediatric outpatients (7-17 years of age) with major depressive 
disorder (MDD)
Methodology
A multicenter, randomized, double-blind, placebo- and active-controlled, 
parallel-group, flexible-dose study in pediatric patients
Number of Patients
Approximately 400 patients are planned (160 placebo patients, 160 vilazodone
patients, and 80 fluoxetine patients)
Diagnosis and 
Main Criteria for Inclusion
Male and female outpatients, ages 7 to 17 years, who meet Diagnostic and 
Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria 
for MDD (confirmed by the Kiddie Schedule for Affective Disorders and 
Schizophrenia–Present and Lifetime [K-SADS-PL]) and have a current 
depressive episode of ≥6 weeks duration at Screening (Visit 1). At Screening 
(Visit 1) and Baseline (Visit 2), the patient must have a Children’s Depression 
Rating Scale–Revised (CDRS-R) score ≥ 40 and a Clinical Global 
Impressions-Severity (CGI-S) score ≥ 4.
Test Product, Dosage, and Mode of 
Administration
Vilazodone HCl 5 mg, 10 mg, and 20 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 10 weeks in duration: approximately 1-week
screening/washout period, 8 weeks of double-blind treatment, and a 1-week 
double-blind down-taper period.
Reference Therapy, Dosage, and 
Mode of Administration
Encapsulated fluoxetine 10 and 20 mg, taken orally as a single dose, 
once-daily at the same time each day, with food
Matching placebo tablets for vilazodone HCl and matching placebo capsules 
for encapsulated fluoxetine, taken orally as a single dose, once-daily at the 
same time each day, with food
Criteria for Evaluation
Primary Outcome Measure
Change from baseline to Week 8 of the double-blind treatment period in 
CDRS-R total score
Key Secondary Outcome Measure Change from baseline to Week 8 of the double-blind treatment period in 
CGI-S score
Safety Measures
Adverse event (AE) recording, clinical laboratory tests, vital sign 
measurements including height and weight, electrocardiograms (ECGs), 
physical examinations, and Columbia-Suicide Severity Rating Scale 
(C-SSRS)
 
 
 
 
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Statistical Methods
The primary analysis for comparing vilazodone versus placebo, based on 
change from baseline to Week 8 in CDRS-R total score, will be performed 
using a mixed-effects model for repeated measures (MMRM) with treatment 
group, pooled study center, visit, and treatment group–by-visit interaction as 
the fixed effects, and the baseline value and baseline value-by-visit interaction 
as the covariates. An unstructured covariance matrix will be used to model the 
covariance of within-patient scores.
The secondary efficacy analysis for comparing vilazodone versus placebo 
based on change from baseline to Week 8 in CGI-S score will be performed
using an MMRM model similar to the one used for the primary efficacy 
parameter.
All safety parameters will be analyzed descriptively for the Safety Population,
defined as all randomized patients who received at least 1 dose of the 
investigational product. Efficacy analyses will be performed using the 
Intent-to-Treat (ITT) Population, defined as all patients in the Safety 
Population who had baseline and at least 1 postbaseline assessment of 
CDRS-R total score.
 
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3.1 OVERALL TABLE OF CONTENTS 
 
 
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1.0 TITLE PAGE ..............................................................................................
 
2.0 SYNOPSIS AND SCHEDULE OF EVALUATIONS ...............................
 
3.0 TABLE OF CONTENTS, TABLES AND FIGURES 
 
3.1 OVERALL TABLE OF CONTENTS ................................................
 
3.2 LIST OF IN-TEXT TABLES ..............................................................
 
3.3  LIST OF IN-TEXT FIGURES ...........................................................
 
4.0 LIST OF ABBREVIATIONS .....................................................................
 
5.0 ETHICAL CONSIDERATIONS ................................................................
 
5.1 INSTITUTIONAL REVIEW BOARD AND INDEPENDENT 
ETHICS COMMITTEE ................................................................................
 
5.2 ETHICAL CONDUCT OF THE STUDY...............................................
 
5.3 PATIENT INFORMATION AND INFORMED CONSENT.................
 
5.3.1 Patient Assent Form ..........................................................................
 
5.3.2 Parent, Legal Guardian, and Legally Authorized Representative 
Informed Consent .......................................................................................
 
5.3.3 Caregiver Consent .............................................................................
 
6.0 INVESTIGATORS AND STUDY ADMINISTRATIVE 
STRUCTURE ...................................................................................................
 
7.0 INTRODUCTION ......................................................................................
 
8.0 STUDY OBJECTIVES ...............................................................................
 
9.0 INVESTIGATIONAL PLAN .....................................................................
 
9.1 OVERALL STUDY DESIGN AND PLAN: DESCRIPTION ...............
 
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9.1.1 Screening Period ...............................................................................
 
9.1.2 Double-blind Treatment Period .........................................................
 
9.1.3 Double-blind Down-taper Period ......................................................
 
9.2 DISCUSSION OF STUDY DESIGN, INCLUDING THE CHOICE 
OF CONTROL GROUPS .............................................................................
 
9.3 SELECTION OF STUDY POPULATION .............................................
 
9.3.1 Inclusion Criteria ...............................................................................
 
9.3.2 Exclusion Criteria ..............................................................................
 
9.3.3 Removal of Patients from Therapy or Assessment ...........................
 
9.3.4 Patient Replacement Procedures .......................................................
 
9.4 TREATMENTS .......................................................................................
 
9.4.1 Treatments Administered ..................................................................
 
 
 
9.4.4 Selection of Dosages in the Study .....................................................
 
9.4.5 Selection and Timing of Dose for Each Patient ................................
 
9.4.5.1 Screening Period .........................................................................
 
9.4.5.2 Double-blind Treatment Period ..................................................
 
9.4.5.3 Double-blind Down-taper Period (End of Week 8/(Visit 8) .......
 
9.4.6 Blinding .............................................................................................
 
9.4.7 Unblinding .........................................................................................
 
 
 
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9.4.10 Treatment Following Investigational Product Discontinuation ......
 
9.5 EFFICACY AND SAFETY VARIABLES .............................................
 
9.5.1 Diagnostic and Efficacy Assessments ...............................................
 
9.5.1.1 Diagnostic Assessments ..............................................................
 
9.5.1.2 Efficacy Assessments..................................................................
 
9.5.2 Safety Assessments ...........................................................................
 
9.5.2.1 Adverse Events ...........................................................................
 
9.5.2.2 Causality Assessment..................................................................
 
9.5.2.3 Severity Assessment ...................................................................
 
9.5.2.4 Serious Adverse Events ..............................................................
 
9.5.2.5 Reporting Adverse Events and Serious Adverse Events ............
 
9.5.2.6 Immediate Reporting of Serious Adverse Events and Events 
of Special Interest ...................................................................................
 
9.5.2.7 Reporting of Pregnancies Occurring During the Study ..............
 
 
 
 
 
 
9.5.3 Investigational Product Concentration Measurements ......................
 
9.5.4 Health Economic and Outcomes Research Assessments ..................
 
9.5.5 Schedule of Assessments ..................................................................
 
 
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9.6 DATA QUALITY ASSURANCE ..........................................................
 
 
9.6.2 Data Recording and Documentation .................................................
 
9.7 STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE ..............................................................................................
 
9.7.1 Patient Populations ............................................................................
 
9.7.1.1 Screened Population ....................................................................
 
9.7.1.2 Randomized Population ..............................................................
 
9.7.1.3 Safety Population ........................................................................
 
9.7.1.4 Intent-to-Treat Population ...........................................................
 
9.7.2 Patient Disposition ............................................................................
 
9.7.3 Demographics and Other Baseline Characteristics ...........................
 
 
9.7.4 Extent of Exposure and Treatment Compliance ...............................
 
 
 
9.7.5 Efficacy Analyses ..............................................................................
 
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9.7.5.1 Primary Efficacy Parameter ........................................................
 
9.7.5.2 Secondary Efficacy Parameter ....................................................
 
 
9.7.6 Safety Analyses .................................................................................
 
9.7.6.1 Adverse Events ...........................................................................
 
 
 
 
 
9.7.6.6 Investigational Product Plasma Concentration Parameters 
and Exposure-Response Evaluation ........................................................
 
9.7.7 Health Economics and Outcomes Research Analyses ......................
 
9.7.8 Interim Analysis ................................................................................
 
9.7.9 Determination of Sample Size ...........................................................
 
 
9.8 CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED 
ANALYSES ..................................................................................................
 
9.9 PROTOCOL DEVIATIONS AND VIOLATIONS ................................
 
9.10 DATA MONITORING COMMITTEE .................................................
 
10.0 STUDY SPONSORSHIP..........................................................................
 
10.1 STUDY TERMINATION .....................................................................
 
10.2 REPORTING AND PUBLICATION ...................................................
 
11.0 INVESTIGATOR OBLIGATIONS .........................................................
 
 
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11.5 RETENTION AND REVIEW OF RECORDS .....................................
 
11.6 PATIENT CONFIDENTIALITY .........................................................
 
12.0 INVESTIGATOR’S STATEMENT .........................................................
 
13.0 APPENDICES ..........................................................................................
 
APPENDIX I. ELEMENTS OF INFORMED CONSENT .......................
 
APPENDIX II. CONTACT INFORMATION ..........................................
 
 ..............................
 
APPENDIX IV. BLOOD SAMPLING AND SHIPPING 
INSTRUCTIONS ......................................................................................
 
 
 
 
 
 
 
APPENDIX X. INVESTIGATIONAL PRODUCT FORMULATION ...
 
14.0 LITERATURE CITED .............................................................................
 
 
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3.2 LIST OF IN-TEXT TABLES 
 
 
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Table 9.4.5.3–1. Double-blind Dosing Regimen ..............................................
 
 
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3.3 LIST OF IN-TEXT FIGURES 
 
 
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Figure 9.1.3–1. Study Design ...........................................................................
 
 
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4.0
LIST OF ABBREVIATIONS
5-HT1A
5-hydroxytryptamine 1A 
AE
adverse event
ALT
alanine aminotransferase 
AST
aspartate aminotransferase
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
Food and Drug Administration
FR
Federal Register
FRI
Forest Research Institute, Inc.
GCP
good clinical practice
HIPAA
Health Insurance Portability and Accountability Act of 1996
ICF
informed consent form
ICH
International Conference on Harmonisation 
IEC
Independent Ethics Committee
 
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IND
Investigational New Drug (application)
IRB
Institutional Review Board
ITT
Intent-to-Treat
IWRS
interactive Web response system
K-SADS-PL
Kiddie Schedule for Affective Disorders and Schizophrenia–Present and 
Lifetime
LAR
legally authorized representative
LOCF
last-observation-carried-forward
MDD
Major Depressive Disorder
MMRM
Mixed-effect model for repeated measures
NDA
New Drug Application
PCS
potentially clinically significant
PID
patient identification
PK 
pharmacokinetic
PVC
premature ventricular contraction
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 
Forest Research 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 US 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 (Directive 
2001/20/EC), and local regulations.
5.2
ETHICAL CONDUCT OF THE STUDY
This clinical study will be conducted in accordance with the ethical principles that have 
their origins in the Declaration of Helsinki.
This clinical study will comply with the ICH Guidance on General Considerations for 
Clinical Trials (ICH-E8; 62 FR 66113, 17 Dec 1997) and GCP (ICH-E6; 62 FR 25692, 
09 May 1997), as well as Part 312 of the US 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 signed documents will be placed in the Investigator’s study files. A unique patient 
identification (PID) number will be assigned according to Section 9.4.3.
5.3.1
Patient Assent Form
To participate in the study, the patient will read, assent understanding of, sign the assent 
form, and be made aware they can withdraw from the study at any time. 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 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 instrument of informed consent or other locally 
applicable regulations and authorization form after having had an opportunity to discuss 
the forms with the Investigator before signing. 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 of age 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 60 study 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. An 
Investigator shall obtain the assent and informed consent for each patient prior to the 
patient enrolling in the study and/or prior to participating in any study-related activity. 
The Investigator at each study center must meet his or her obligations 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 center will 
be responsible 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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7.0
INTRODUCTION
Vilazodone is a selective serotonin reuptake inhibitor (SSRI) 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 6.0 nM
respectively). Vilazodone is more selective for inhibition of serotonin reuptake than for 
dopamine or norepinephrine (0.2 nM, 60.0 nM and 90.0 nM, respectively). In vitro 
studies also indicate that vilazodone binds with high affinity and is a more potent agonist 
of 5-HT1A receptors compared with specific 5-HT1A ligands such as buspirone, with IC50 
values of 0.5 nM for vilazodone and 30 nM for buspirone. A detailed description of the 
pharmacokinetics, chemistry, pharmacology, safety, and efficacy of vilazodone for the 
treatment of 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 2 pivotal, 
Phase 3, 8-week, multicenter, randomized, double-blind, placebo-controlled studies in 
adult outpatients with MDD. Vilazodone 40 mg/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 
(Zalsman et al, 2006). The American Academy of Child and Adolescent Psychiatry
(AACAP) consensus (AACAP, 1998) 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 are 
affected by serious emotional disturbances (Substance Abuse and Mental Health Services 
Administration [SAMHSA], 2009).
The National Comorbidity Survey – Adolescent Supplement (NCS-A) examines both 
dysthymic disorder and MDD together resulting in data showing approximately 11.2% of 
13 to 18 year olds in the United States are affected at some point during their lives and
3.3% have experienced a seriously debilitating depressive disorder. SAMHSA examines 
the national prevalence of depression each year through the National Survey on Drug Use 
and Health (NSDUH). Their 2008 data show an 8.3% prevalence of depression among 
12 to 17 year 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.
 
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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 (Grunbaum, 2002). Suicide is a leading cause of death in 
adolescents and is a major public health concern (NAHIC, 2006). A major risk factor for 
suicide in adolescents is major depression. In its 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 its efficacy and safety profile in this population.
To address an unmet need of treating MDD in the pediatric population, this study of 
vilazodone in children and adolescent patients (7-17 years of age) with MDD was agreed 
upon with the FDA. 
 
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8.0
STUDY OBJECTIVES
The objective of this study is to evaluate the efficacy, safety, and tolerability of 
vilazodone compared with placebo in pediatric outpatients (7-17 years of age) with 
MDD.
In addition, the study is designed to obtain pharmacokinetic (PK) data to define the 
PK profile of vilazodone in the pediatric population (7–17 years of age).
 
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9.0
INVESTIGATIONAL PLAN
9.1
OVERALL STUDY DESIGN AND PLAN: DESCRIPTION
Study VLZ-MD-22 will be a multicenter, randomized, double-blind, placebo- and 
active-controlled, parallel-group, flexible-dose study in pediatric patients, 7 to 17 years of 
age. The study will include a total of 9 visits and will be approximately 10 weeks in 
duration (Figure 9.1.3–1): 

1-week screening period 

8-week double-blind treatment period 

1-week double-blind down-taper period 
9.1.1
Screening Period
The screening/washout period will generally be 1 week prior to Baseline (Visit 2), but 
may be extended up to a total of 5 weeks to accommodate prior medication washout or to 
repeat assessments (with prior approval of the Study Physician or designee). Patients will 
not receive any investigational product during the screening period. Patients meeting the 
eligibility criteria at the end of Baseline (Visit 2) will be randomized in a ratio of 2:2:1 to 
1 of 3 treatment groups: placebo, vilazodone, or fluoxetine. 
9.1.2
Double-blind Treatment Period
Approximately 400 patients are planned for enrollment in the double-blind treatment 
period (160 placebo patients, 160 vilazodone patients, and 80 fluoxetine patients); 
randomization will be stratified by study center and by country. 
 
 
 
 
 
 
 
 
 
 
 
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9.1.3
Double-blind Down-taper Period
All patients who complete the 8-week double-blind treatment period and patients in the 
double-blind treatment period who prematurely discontinue from the study before 
completing 8 weeks of double-blind treatment should enter the 1-week, double-blind 
down-taper period when clinically appropriate (eg, when patients have not received
investigational product for ≤ 3 days). Patients who complete 8 weeks of double-blind 
treatment may be eligible to enter a 6-month, open-label, extension study
(Study VLZ-MD-23).
 
 
 
 
 
 
All randomized patients must complete Week 9 (Visit 9). Additional follow-up visits may 
be scheduled within 30 days, if necessary for safety reasons.
 
 
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9.2
DISCUSSION OF STUDY DESIGN, INCLUDING THE CHOICE 
OF CONTROL GROUPS
This multicenter, randomized, placebo- and active-controlled, parallel-group, 
flexible-dose study with an 8-week double-blind treatment was designed based on prior 
studies that established vilazodone efficacy and safety in adult patients with MDD.
Additionally, 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]; Kaufman et al, 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 9.5.1.1) will assess the MDD symptoms and severity.
Study centers will have experience with the study population and will be encouraged to 
apply available guidelines to minimize patient risk or distress (See European Medicines 
Agency (EMA): ICH Topic E 11, Note for Guidance on Clinical Investigation of 
Medicinal Products in the Paediatric Population, January 2001). To ensure accurate MDD 
diagnosis, both the K-SADS-PL and CDRS-R 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.
Dose selection information is presented in Section 9.4.4. The planned titration regimen is 
based on experience from vilazodone studies (Viibryd Package Insert, 2014; 
Study VLZ-MD-21, in progress). A titration period has been included to reduce the 
possibility of tolerability issues that may accompany the start of investigational product 
treatment at the dose levels to be studied. The 1-week, double-blind down-taper has been 
included to allow a gradual reduction in the concentration of the investigational product
to reduce the likelihood of emergence of discontinuation symptoms. 
 
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A placebo treatment group is included in the study to comply with worldwide regulatory 
preferences (Laughren, 2001; Gispen-de Wied et al, 2012), since placebo-controlled 
superiority trials have been shown to be conducive to higher quality studies and to 
provide more reliable outcomes (Feifel, 2008; Laughren, 2001; Gispen-de Wied et al, 
2012). Additionally, from a scientific point of view, randomized double-blind 
comparisons versus placebo are needed to permit adequate evaluation of efficacy. 
Comparison to a placebo treatment is also of value for distinguishing disease 
manifestations from adverse reactions of the investigational product (EMA guidance,
2013). The use of placebo in place of the standard therapy (fluoxetine) should not cause 
irreversible health problems or extreme suffering (depression is recognized by the FDA 
as a condition in which there is substantial improvement and variability in placebo 
groups) (FDA Guidance for Industry: E10, May 2001). 
The fluoxetine active comparator group is included as a reference treatment, since 
fluoxetine is currently the only drug approved in the United States for the treatment of 
MDD in both children and adolescents.
In Study VLZ-MD-22, safety and efficacy assessments are included during every visit to 
determine adequacy of response, safety, and tolerability. In the event of insufficient 
therapeutic response or worsening of the patient’s initial condition, investigational 
product should be discontinued, and an alternative treatment will then be allowed 
(Section 9.4.10). An independent Data Monitoring Committee will evaluate safety data 
during the study (Section 9.10).
9.3
SELECTION OF STUDY POPULATION
The number of males and females will be approximately equal in both age groups 
(7-11 years of age and 12-17 years of age) 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
To be eligible to participate in the study, patients must meet the following criteria:
1. Be able to provide informed assent and their parent/guardian/LAR and caregiver must 
provide written informed consent before the initiation of any study-specific 
procedures (Section 5.3) 
2. Be a male or female outpatient, 7 to 17 years of age, inclusive, at Screening (Visit 1)
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)
4. Have a score of ≥40 on the CDRS-R at Screening (Visit 1) and Baseline (Visit 2)
5. Have a Clinical Global Impressions-Severity (CGI-S) score ≥4 at Screening (Visit 1)
and Baseline (Visit 2)
 
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6. Have a caregiver who is willing and able to be responsible for safety monitoring of 
the patient, provide information about the patient’s condition, oversee the 
administration of investigational product, and accompany the patient to all study 
visits (Section 5.3) 
7. Have normal physical examination findings, vital sign values, clinical laboratory test 
results, and electrocardiograms (ECG) results, or abnormal results that are determined 
by the Investigator not to be clinically significant 
8. Must have a negative serum pregnancy test result if patient is female ≥9 years of age 
or has had onset of menses.
9.3.2
Exclusion Criteria
Patients who meet any of the following criteria will not be eligible to participate in the 
study:
Criteria to be assessed at Screening (Visit 1 [unless otherwise specified])
Psychiatric Criteria
1. A current (within 3 months of Screening) principal DSM-IV-TR–based diagnosis of 
an Axis I disorder other than MDD within 6 months before Screening (Visit 1) that is 
the primary focus of treatment. 
○
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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these cases):
○
 
 
 
 
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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
 
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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 
1 month 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
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.
 
 
 
 
 
 
 
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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 parent/guardian/LAR and/or caregiver 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 after careful 
consideration for one of the following reasons:

Screen failure (failure to meet inclusion/exclusion criteria)

Withdrawal of consent 

AE

Lack of efficacy

Protocol violation

Noncompliance with investigational product

Lost to follow-up

Study terminated by Sponsor

Site terminated by Sponsor

Other 
All randomized patients who prematurely discontinue from the study, regardless of cause, 
should be seen for a final assessment at an Early Termination (ET) Visit. A final 
assessment will be defined as completion of the evaluations scheduled for all patients at 
the end of Week 8 (Visit 8). All patients discontinuing the study prematurely should enter 
the 1-week, double-blind down-taper period when clinically appropriate.
 
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Patients who discontinue from the study and do not return to the study center for final 
assessments must be requested in writing to return to the study center for a final 
assessment and return any unused investigational product. A copy of the letter, together 
with the source documentation, will be kept in the Investigator’s files. The reason for 
premature discontinuation from the study will be recorded on the Study Termination Page 
of the eCRF. Study center staff will be contacted by the Sponsor after each premature 
discontinuation to ensure proper characterization of the reason for discontinuation is 
captured.
9.3.4
Patient Replacement Procedures
Patients in this study who prematurely discontinue treatment will not be replaced.
9.4
TREATMENTS
Patients meeting the eligibility criteria at the end of Baseline (Visit 2) will be randomized 
in a double-blind fashion to 1 of 3 treatment groups: placebo, vilazodone, or fluoxetine. 
9.4.1
Treatments Administered
At Screening (Visit 1) and after consent/assent is obtained, patients will be given 
3 placebo tablets and 1 placebo capsule to swallow to confirm their ability to swallow 
investigational product.
Investigational product in the form of tablets and capsules 
 
 
 
 
Throughout the study, it is recommended that patients take the investigational product at 
the same time each day with food (Section 9.4.5).
Patients should participate in the double-blind down-taper period unless it is deemed not 
to be clinically appropriate by the Investigator.
 
 
 
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9.4.4
Selection of Dosages in the Study
Doses of vilazodone in pediatric patients (7-17 years of age) were selected based on 
modeling of available PK data from the adult healthy volunteers, as well as adult and 
adolescent patients (12-17 years of age) with MDD. 
 
 
 
 
 
 
 
 
 
9.4.5
Selection and Timing of Dose for Each Patient
All investigational products should be taken orally as a single dose of 3 tablets and 
1 capsule, once-daily at the same time each day, with food (see Section 9.1).
 
 
 
 
 
 
 
 
 
 
 
 
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.
9.4.5.1
Screening Period
At Screening (Visit 1) after consent/assent is obtained, placebo capsules and placebo 
tablets will be administered for the purposes of eligibility determination. Patients will be 
given 3 placebo tablets and 1 placebo capsule to swallow. If a patient is unable to 
swallow either the placebo capsule and/or all placebo tablets, the patient will be ineligible 
for study participation.
9.4.5.2
Double-blind Treatment Period
Patients who meet all eligibility criteria at Screening (Visit 1) and who continue to meet 
all the eligibility criteria for participation in the study at the Baseline visit will be 
assigned a randomization number at Baseline (Visit 2) and dispensed the corresponding 
blister card containing tablets and capsules of double-blind investigational product for 
Week 1. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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9.4.5.3
Double-blind Down-taper Period (End of Week 8/(Visit 8)
Patients who complete 8 weeks of double-blind treatment at Week 8 (Visit 8) or patients 
who discontinue the study prematurely should enter the double-blind down-taper period 
when clinically appropriate. 
 
 
 
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9.4.6
Blinding
A list of patient randomization codes will be generated by 
 
 (an electronic version will be stored on a secure 
server). This list will identify each patient by randomization number and include the 
patient’s corresponding treatment assignment.
9.4.7
Unblinding
Any unblinding at the study center level should be done only in an emergency that 
requires for the investigational product to be identified for the medical management of 
the patient. The Investigator must notify the Study Physician immediately (refer to
Appendix II) and a full written explanation must be provided if the blind is broken. 
Before the investigational product is unblinded, every attempt should be made to discuss 
the case with the Study Physician. Breaking the code at the study center will immediately 
disqualify the patient from further participation in the study.
Treatment codes may be broken by FRI Global Drug Safety for regulatory reporting 
purposes. In such cases, the study staff will be kept blinded and the patient will not need 
to be disqualified from the study.
 
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9.4.8
Prior and Concomitant Therapy
 
 
 
 
 
9.4.9
Monitoring Treatment Compliance
 
 
 
 
 
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 double-blind treatment period will be 
allowed to discontinue the investigational product and start appropriate treatment at the 
Investigator’s discretion. This new treatment will not be provided by FRI. Patients who 
need to initiate a new treatment will be discontinued from the study.
9.5
EFFICACY AND SAFETY VARIABLES
9.5.1
Diagnostic and Efficacy Assessments
All diagnostic and efficacy assessments are not to be administered to the patient unless 
the patient is accompanied by his/her consented caregiver.
 
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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, Subinvestigator, or 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.
9.5.1.2.1
Primary Efficacy Assessment: Children’s Depression Rating 
Scale-Revised
The CDRS-R (Poznanski and Mokros, 1996) is a semi-structured, clinician-rated
instrument designed for use with children and adolescents between the ages of 6 to 
17 years. It contains 17 ordinally-scaled items that evaluate the presence and severity of 
symptoms commonly associated with depression in childhood. The CDRS-R score ranges 
from 17 to 113. 
The CDRS-R will be administered separately to the patient and to the caregiver. For each 
item, the rating that provides the best description of the patient will be selected by the 
clinician administering the interviews. 
A copy of the CDRS-R is provided in Appendix V.
9.5.1.2.2
Secondary Efficacy Assessment: 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, with 1 indicating a normal state and 7 indicating a patient who is among the most 
extremely ill patients. A copy of the CGI-S is provided in Appendix VI.
 
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9.5.1.2.3
Additional Efficacy Assessment: 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-I is provided in Appendix VII.
9.5.2
Safety Assessments
Patients must be evaluated by a physician or an appropriately trained health care 
professional at every 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 consented 
caregiver.
9.5.2.1
Adverse Events
An adverse event (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 
any unfavorable and unintended sign (including an abnormal laboratory finding, for 
example), symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product (ICH-E2A).
For the purpose of the site’s data collection responsibilities, any untoward event that was 
reported from the time the ICF was signed until 30 days after the final protocol-defined 
study visit or the last known dose of investigational product (if the final visit does not 
occur) is to be considered an AE.
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 center personnel

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
 
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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/concurrent disease, other 
investigational products, or other factors, and/or
○
Positive dechallenge and/or rechallenge exist
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
 
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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 of the patient’s eCRF. 
 
 
 
 
 
 
 
 
 
9.5.2.4
Serious Adverse Events
An SAE is any untoward medical occurrence that at any dose:

Results in death

Is life threatening

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity, or

Is a congenital anomaly/birth defect
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based on appropriate medical judgment, 
they may jeopardize the patient 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.
 
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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 Events and 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 causal relationship

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
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 poststudy 
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 one of the following conditions is met: 1) the event meets the criteria for an SAE 
(see Sections 9.5.2.4 and 9.5.2.6), and/or 2) the event is judged by the Investigator to be 
potentially 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.
 
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9.5.2.6
Immediate Reporting of Serious Adverse Events and Events of 
Special Interest
FRI is required to inform worldwide regulatory authorities of SAEs that meet specific 
criteria. Therefore, FRI must be notified immediately regarding any SAE that occurs after 
informed consent is obtained.
Within 24 hours of learning of any AE that meets one of the criteria for an SAE, the 
study center personnel must report the event to Global Drug Safety on the SAE Form for 
Clinical Trials. The Study 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.
The study center must transmit the SAE Form for Clinical Trials to the SAE fax number 
shown below. Even if an initial report is made by telephone, the SAE 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.
 
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/pregnancy 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. 
 
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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 9.5.2.6 with the appropriate serious criterion (eg, hospitalization) indicated in 
addition to the pregnancy form.
 
 
 
 
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9.5.4
Health Economic and Outcomes Research Assessments
Not applicable.
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 descriptions of the procedures to be performed at each 
visit are provided below. Study procedures are for the patient only, unless otherwise 
specified.
 
 
 
 
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9.6
DATA QUALITY ASSURANCE
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.6.2
Data Recording and Documentation
Data collection will involve the use of the 
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 patient confidentiality in accordance with the 
legal stipulations applying to confidentiality of data. Study records 
 
will be retained at the study 
center, along with adequate source documentation, according to FDA and ICH 
requirements. All study records must be available for inspection by its authorized 
representatives and the FDA or other health authorities.
9.7
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE
9.7.1
Patient Populations
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 underwent a Screening Visit, 
received a screening number, and for whom informed consent was obtained.
9.7.1.2
Randomized Population
The Randomized Population will consist of all patients in the Screened Population who 
were randomized to a treatment group in this study.
9.7.1.3
Safety Population
The Safety Population will consist of all patients in the Randomized Population who took 
at least 1 dose of double-blind investigational product.
 
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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 baseline and at least 1 postbaseline assessment of the CDRS-R total score.
9.7.2
Patient Disposition
The number of patients in the Screened Population will be summarized overall by study 
center. The number of patients in the Randomized, Safety, and ITT Populations will be 
summarized by treatment group and study center.
Screen failures (ie, patients who were screened but not included in the Randomized 
Population) and the associated reasons for failure will be tabulated overall. Patients 
completing 8 weeks of double-blind treatment (Baseline through Week 8 [Visits 2 - 8]) 
will be considered completers. The number and percentage of patients who complete the 
double-blind treatment period and of patients who prematurely discontinue during the 
same period will be presented for each treatment group and pooled across treatment 
groups. The reasons for premature discontinuation from the double-blind treatment 
period as recorded on the termination pages of the eCRF will be summarized (number 
and percentage) by treatment group for the Safety Population. The percentage of 
premature discontinuations will be compared overall and for each discontinuation reason 
between treatment groups using Fisher’s exact test.
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 by treatment group for the Safety 
and ITT Populations. 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.
Comparability among treatment groups will be tested using a two-way 
analysis-of-variance model, with treatment group and study center as the factors for 
continuous variables and the Cochran-Mantel-Haenszel test, controlling for study center, 
for categorical variables.
 
 
 
 
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9.7.4
Extent of Exposure and Treatment Compliance
 
 
 
 
 
 
 
 
 
 
 
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9.7.5
Efficacy Analyses
The efficacy analyses will be based on the ITT Population. Baseline for efficacy is 
defined as the last nonmissing efficacy assessment recorded at or prior to Baseline 
(Visit 2). All statistical tests will be 2-sided hypothesis tests performed at the 5% level of 
significance. All confidence intervals (CIs) will be 2-sided 95% CIs, unless stated 
otherwise.
For efficacy analyses in which study center is a factor, a small center will be defined as a 
center with < 2 patients in ≥ 1 treatment group in the ITT Population. Small centers will 
be pooled to form pseudo-centers so that each treatment group includes ≥ 2 ITT patients 
within the center. Pooling will be done using the following algorithm: 
Based on the number of ITT patients, small centers will be ordered from the largest to the 
smallest, and centers of the same size will be ordered from the largest center code to the 
smallest center code. The pooling process starts with the largest small center from the 
top, which will be pooled with the smallest from the bottom until a non-small center is 
formed. The process will be repeated using the small centers left out after the first pass. If 
any centers are left out at the end of the process, they will be pooled with the smallest 
pseudo-center. If there is > 1 smallest pseudo-center, the pseudo-center with the smallest 
center code will be selected. In case that the pseudo-center formed by pooling all small 
centers is still a small center, it will be pooled with the smallest non-small center. If there 
is > 1 smallest non-small center, the one with the smallest center code will be selected.
By-visit analysis based on the mixed-effects model for repeated measures (MMRM) 
using the observed case approach will be performed for all continuous efficacy 
parameters with multiple postbaseline measurements.
In addition, by-visit analyses using the last-observation-carried-forward (LOCF) 
approach will be presented for all efficacy parameters. For the LOCF approach, only the 
postbaseline total score of a parameter will be imputed using the LOCF approach; 
individual item scores will not be carried forward. 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.
 
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9.7.5.1
Primary Efficacy Parameter
The change from baseline to Week 8 of the double-blind treatment period in CDRS-R 
total score will be the primary efficacy parameter. The primary analysis for comparing 
vilazodone versus placebo will be performed with treatment group, pooled study center, 
visit, and treatment group–by-visit interaction as the fixed effects and the baseline value 
and baseline value-by-visit interaction as the covariates. An unstructured covariance 
matrix will be used to model the covariance of within-patient scores. The Kenward-Roger 
approximation (Kenward and Roger, 1997) will be used to estimate denominator degrees 
of freedom. This analysis will be performed based on all postbaseline scores using only 
the observed cases without imputation of missing values.
In addition, 2 sensitivity analyses, LOCF and pattern-mixture model approaches, will be 
performed on the primary efficacy parameter. The LOCF approach is based on an 
analysis-of-covariance model including treatment group and pooled study center as 
factors and baseline CDRS-R total score as a covariate.
The other sensitivity analysis using a pattern-mixture model based on nonfuture 
dependent missing value restrictions (Kenward et al, 2003) will be performed to assess 
the robustness of the primary MMRM results to the possible violation of the 
missing-at-random assumption. The details of this sensitivity analyses are as follows:
The pattern for the pattern-mixture model will be defined by the patient’s last visit with 
observed value. The observed CDRS-R total score at a visit is assumed to have a linear 
relationship with the patient’s prior measurements. The missing values will be imputed 
under the assumption that the distribution of a missing observation differs from the 
observed only by a shift parameter value Δ. The dataset with missing values will be 
analyzed using an analysis-of-covariance model with treatment group and pooled study 
center as factors and baseline CDRS-R total score as a covariate for between-treatment 
group comparisons at Week 8. The imputation of missing values and the analysis will be 
performed multiple times and the inference of this sensitivity analysis will be based on 
the combined estimates using the standard multiple imputation technique. The values for 
Δ will be selected as 0 to 6 based on experience with historical data.
The comparison of fluoxetine versus placebo will be performed to assess study assay 
sensitivity.
9.7.5.2
Secondary Efficacy Parameter
The key secondary efficacy parameter is the change from baseline to Week 8 in CGI-S 
score, which will be analyzed using the MMRM approach similar to the one used for the 
primary efficacy parameter.
 
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The overall family-wise type I error rate for testing the primary and secondary efficacy 
parameters will be controlled at the 0.05 significance level by using the fixed sequence 
testing procedure. The efficacy analysis of the secondary efficacy parameter will be 
carried out inferentially only if the null hypothesis for the primary efficacy parameter is 
rejected.
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9.7.6
Safety Analyses
The safety analysis will be performed for the double-blind treatment period and 
double-blind down-taper period separately using the Safety Population. 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 each safety parameter, the last 
assessment made before the first dose of double-blind investigational product will be 
used as the baseline for all analyses of that safety parameter.
 
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9.7.6.1
Adverse Events
An AE (classified by preferred term) that occurs during the double-blind treatment period 
or during the double-blind 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 or was present before the date of the first dose of 
double-blind investigational product and increased in severity during the double-blind 
treatment period or during the double-blind down-taper period, respectively. If more than 
1 AE is reported before the date of the first dose of double-blind 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 double-blind treatment 
period or during the double-blind 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 
double-blind investigational product will not be counted as a TEAE.
An AE occurring during the double-blind down-taper period will be considered a newly 
emergent AE if it is not present before the start of the double-blind down-taper period or 
was present before the start of the double-blind down-taper period but increased in 
severity during the double-blind down-taper period. The newly emergent AEs during the 
double-blind down-taper period will be summarized by body system, preferred term, and 
treatment group.
The number and percentage of patients reporting TEAEs in each treatment group will be 
tabulated by system organ class and preferred term; by system organ class, preferred 
term, and severity; and by system organ class, preferred term, and causal relationship to 
the investigational product. 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 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 summarized by treatment group.
The incidence of common (≥ 2% of patients in any treatment group) TEAEs during the 
double-blind treatment period will be summarized separately by preferred term, and 
treatment group. 
 
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An SAE that occurred between the date of the first dose of double-blind investigational 
product and 30 days after the date of the last dose of double-blind 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 class, preferred term, and treatment group. 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 30 days after the date of the last dose of the double-blind 
investigational product, and patients discontinuing due to AEs before the start of 
double-blind 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).
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9.7.6.6
Investigational Product Plasma Concentration Parameters and 
Exposure-Response Evaluation
Vilazodone plasma concentration data will be used to estimate population PK parameters, 
inter-patient, and residual variability using nonlinear mixed-effects modeling software. 
The study will be prospectively powered to target a 95% CI within 60% and 140% of the 
geometric mean estimates of clearance and volume of distribution for vilazodone, with at 
least 80% power. The effect of covariates on the vilazodone pharmacokinetics will also 
be investigated. The maximum plasma drug concentration, area under the plasma 
concentration versus time curve, time of maximum plasma drug concentration, half-life, 
apparent oral clearance and apparent volume of distribution for vilazodone will be 
determined and a summary (mean, median) will be reported. Vilazodone PK data will be 
used to support the evaluation of a potential exposure/dose-response relationship. The 
analysis results will be provided in a separate report. 
9.7.7
Health Economics and Outcomes Research Analyses
Not applicable.
 
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9.7.8
Interim Analysis
A blinded interim analysis will be conducted when approximately 75% of randomized 
patients have either completed the study or discontinued to obtain an estimate of the 
pooled standard deviation on change from baseline in the CDRS-R total score to Week 8 
of the double-blind treatment period. If the estimated pooled standard deviation is larger 
than the assumed pooled standard deviation in the sample size calculation 
(see Section 9.7.9), sample sizes in placebo and vilazodone treatment groups may be 
increased to ensure an adequate power. However, due to the difficulties in recruiting 
pediatric patients with MDD, the number of patients in placebo and vilazodone treatment 
groups will be capped at 200.
9.7.9
Determination of Sample Size
The primary efficacy parameter will be the change from baseline to Week 8 of the 
double-blind treatment period in CDRS-R total score.
 
 
 
 
 
9.8
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED 
ANALYSES
Any amendment to this protocol will be provided to the Investigator in writing by FRI. 
No protocol amendment may be implemented (with the exceptions noted below) before it 
has been approved by the IRB/IEC and the signature page, signed by the Investigator, has 
been received by FRI. If the protocol is amended to eliminate or reduce the risk to 
patients, the amendment may be implemented before IRB/IEC review and approval. 
However, the IRB/IEC must be informed in writing of such an amendment, and approval 
must be obtained within reasonable time limits. 
 
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9.9
PROTOCOL DEVIATIONS AND VIOLATIONS
A protocol deviation is any change, divergence, or departure from the study design or 
procedures that is under the Investigator’s responsibility and oversight (as defined by 
regulations) without prior written IRB/IEC approval or favorable opinion of an 
appropriate amendment and that does not have a major impact on the patient’s rights, 
safety, or well-being, or on the integrity and authenticity of the study data. Deviations 
may include, but are not limited to, departure from inclusion/exclusion criteria, allowed 
concomitant medications, dosing or duration of treatment, failure to follow withdrawal 
criteria or perform the required assessments at specified time points, scheduling of visits 
not in accordance with 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 should be reported to FRI (either verbally or electronically) in a timely manner
from the date of discovery.
Protocol deviations that may impact patient’s 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 data should be reported to FRI within 24 hours, if possible. 
The IRB/IEC must be notified according to the criteria and time period dictated by the 
IRB/IEC associated with this study. 
9.10
DATA MONITORING COMMITTEE
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 Clinical Trial 
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
FRI reserves 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 are the 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
 
 
 
 
 
 
 
 
 
 
11.2
PERFORMANCE
 
 
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11.5
RETENTION AND REVIEW OF RECORDS
Records and documents pertaining to the conduct of this study, including eCRFs, 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 FRI and 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 FRI or applicable regulatory authorities. If the Investigator for the study 
retires, relocates, or for other reasons withdraws from the responsibility of keeping the 
study records, custody must be transferred to a suitable alternate custodian employee of 
the institution or to a suitably qualified and responsible third party. FRI must 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 with the 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
I agree to conduct the study in accordance with this protocol amendment (VLZ-MD-22, 
Amendment #1, dated 15 Apr 2015) and with all applicable government regulations and 
good clinical practice guidance.
_______________________________________
_____/_____/______
Investigator’s Signature
Date
_______________________________________
Investigator’s Name
 
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13.0
APPENDICES
APPENDIX I.
ELEMENTS OF INFORMED CONSENT
Procedures will comply with 21 CFR, Parts 50 and 312. Signed informed consent will be 
obtained for each patient participating in a clinical research study 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 of the patient’s 
participation

A description of any reasonably foreseeable risks or discomforts to the patient

A description of any benefits to the patient or to others that may reasonably be 
expected from the research. If the patient is to be paid for participating in the study, 
the consent form must state the amount that he/she will receive and the schedule of 
payment (to ensure neither coercion nor undue influence)

A disclosure of appropriate alternative procedures or courses of treatment, if any, that 
might be advantageous to the patient

A statement describing the extent, if any, to which confidentiality of records 
identifying the patient will be maintained and noting the possibility that the FDA;
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 necessary to 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 
which the patient is otherwise entitled
 
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
A statement that the particular treatment or procedures may involve risks to the 
patient (or to the embryo or fetus if the patient is, or may become, pregnant) that are 
at present unforeseeable

The expected circumstances for which the patient’s participation may be terminated 
by the Investigator without regard to the patient’s consent

Any additional costs to the patient that may result from participation in the research

The consequences of a patient’s decision to withdraw from the research and 
procedures for an orderly termination of the patient’s participation

A statement that significant new findings developed during the course of the research 
that may relate to the patient’s willingness to continue participation will be provided 
to the patient

The approximate number of patients involved in the study

A statement of permission, providing consent for the patient to participate (eg, “I 
agree to allow (my child) to participate . . .”)

A place for the patient’s parent/guardian/LAR signature and date of signing of the 
ICF 

A statement indicating that information about this study has been, or will be, entered 
into a databank that is publicly accessible at www.ClinicalTrials.gov.
A copy of the signed consent form must be given to the patient’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.
BLOOD SAMPLING AND SHIPPING INSTRUCTIONS
Pharmacokinetic Blood Collection and Processing Procedure
Specimen Tube Collection Preparation

Adhere the FRI provided label to a Vacutainer® tube containing K2EDTA

Prechill (eg, in a an ice bath or refrigerator) the labeled Vacutainer tube and a 
polypropylene tube
Plasma Collection Procedure

Collect blood into the prechilled Vacutainer tube; invert the tube gently 8-10 times to 
mix the blood and anticoagulant. Place the tube in an ice-water bath (use crushed ice).

Centrifuge the tube (within 30 minutes from the time the blood is drawn) at a 
minimum 2500 rpm for 10 minute at approximately 4°C (ie, refrigerated centrifuge). 
In absence of a refrigerated centrifuge, the blood tubes should be chilled in ice for at 
least 10 minutes prior to centrifuging. Blood samples should still be centrifuged 
within 30 minutes of blood collection.

After centrifugation, transfer harvested plasma immediately into a prechilled, labeled, 
polypropylene tube provided by the central laboratory. Ensure the tube has the 
appropriate label marked with study number, subject identification number, date, and 
time of collection.

The tube will then be flash-frozen in a dry ice and alcohol bath (with isopropyl 
alcohol, ethanol, acetone, or methanol) and should be stored at approximately –70°C 
(or up to 6 weeks at –20°C). 

Enter the actual time that the blood sample was collected on the appropriate form of 
the eCRF.

Send the frozen sample to the central laboratory according to the central laboratory 
sample shipment guide.
Shipping Guide from the Study Center to the Central Laboratory
Samples will be shipped from the study center to the central laboratory on the 
first available appropriate date after sample collection, and can be batch-shipped but no 
later than six weeks after sample collection if stored at a temperature approximately
–20°C. The central laboratory will provide packaging, labeling, and shipping instructions 
to the study center. Plasma samples will be shipped on sufficient dry ice to keep them 
frozen for at least 96 hours.
 
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APPENDIX VIII.
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 IX.
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.
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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14.0
LITERATURE CITED
American Academy of Child & Adolescent Psychiatry (AACAP). Practice parameters for 
the assessment and treatment of children and adolescents with posttraumatic stress 
disorder. 1998; Journal of the American Academy of Child and Adolescent 
Psychiatry,37(10),4S-26S.
Cole TJ. The LMS method for constructing normalized growth standards. 1990; 
Eur J Clin Nutr.44:45-60.
Egger HL, Angold A. Common emotional and behavioral disorders in preschool children: 
presentation, nosology, and epidemiology. J Child Psychol Psychiatry 2006;47:313-337.
European Medicines Agency: ICH Topic E 11, Note for Guidance on Clinical 
Investigation of Medicinal Products in the Paediatric Population. January 2001.
FDA Guidance for Clinical Trial Sponsors: Establishment and Operation of Clinical Trial 
Data Monitoring Committees, March 2006 
http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm127073.pdf.
FDA Guidance for Industry: Drug Induced Liver Injury- Pre-Marketing Clinical 
Evaluation, July 2009.
FDA Guidance for Industry: E10, Choice of Control Group and Related Issues in 
Clinical Trials, May 2001.
FDA Guidance for Industry E11 Clinical Investigation of Medicinal Products in the 
Pediatric Population, Dec 2000.
Feifel D. The use of placebo-controlled clinical trials for the approval of psychiatric 
drugs: Part I—Statistics and the Case for the “Greater Good”. Psychiatry (Edgemont) 
2008;6(3):41–43.
Gispen-de Wied C, Stoyanova V, Yu Y, et al. The placebo arm in clinical studies for 
treatment of Psychiatric Disorders: A Regulatory Dilemma. Eur Neuropsychopharmacol, 
2012;14 June (published ahead of print).
Grunbaum JA. Youth Risk Surveillance- United States, 2001. MMWR Surveill Summ. 
2002;Jun 28;51(4):1-62.
Guy W: ECDEU Assessment Manual for Psychopharmacology - Revised, in 
(ed DHEW Publ No ADM 76-338). Rockville, MD, U.S., U.S. Department of Health, 
Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health 
Administration, NIMH Psychopharmacology Research Branch, Division of Extramural 
Research Programs, 1976, pp 218-222.
 
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Hammad TA, Laughren T, Racoosin J. Suicidality in pediatric patients treated with 
antidepressant drugs. Arch Gen Psychiatry 2006;63(3):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 Am Acad Child Adolesc Psychiatry.
1997;36(7):980-8.
Kenward MG, Molenberghs G, Thijs H. Pattern-mixture models with proper time 
dependence. Biometrika 2003;90(1):53-71.
Kenward MG, Roger JH. Small sample inference for fixed effects from restricted 
maximum likelihood. Biometrics 1997;53:983-97.
Laughren TP. The scientific and ethical basis for placebo-controlled trials in depression 
and schizophrenia: an FDA perspective. Eur Psychiatry. 2001;16(7):418-23.
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 (NAHIC). Fact Sheet on Suicide:
Adolescents and Young Adults, San Francisco, CA: University of CA, San Francisco, 
2006.
Poznanski EO, Mokros HB. Children’s Depression rating Scale Revised (CDRS R), 
Western Psychological Services, Los Angeles, 1996.
Study VLZ-MD-21: a double-blind, placebo-controlled, evaluation of the safety and 
efficacy of vilazodone in adolescent patients with major depressive disorder. Jersey City, 
NJ: Forest Research Institute, Inc. Ongoing protocol 29 Mar 2013.
Substance Abuse and Mental Health Services Administration [SAMHSA], 
www.mentalhealth.samhsa.gov, accessed March 18, 2009.
Vilazodone Hydrochloride: Investigator’s Brochure. Edition 14. Jersey City, NJ: 
Forest Research Institute, Inc.; 09 August 2013.
Viibryd [package insert]. St. Louis, MO: Forest Laboratories, Inc.; 2014 Apr.
Zalsman G, Brent DA, Weersing VR: Depressive disorders in childhood and 
adolescence: an overview: epidemiology, clinical manifestation and risk factors. 
Child Adolesc Psychiatr Clin N Am 15:827-41, vii, 2006.
 
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SAP_001.pdf: 
NCT02372799 
 
 
Study ID: VLZ‐MD‐22 
 
 
 
Title: 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 
 
 
Statistical Analysis Plan Amendment 1 Date: 05 October 2018 
 
 
 


SAP VLZ-MD-22
Forest Research Institute, Inc.                                                                                                      Page 1 of 50
Final                                                                                                                                            05 Oct 2018
1.0
TITLE PAGE
Forest Research Institute, Inc., a Subsidiary of Actavis plc
Harborside Financial Center, Plaza V
Jersey City, NJ 07311
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
STATISTICAL ANALYSIS PLAN
Final: 05 May 2015
Amendment #1: 5 October 2018
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 to any person, or submitted to 
any regulatory authority without the express written permission of Forest Research 
Institute, Inc.


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Forest Research Institute, Inc.                                                                                                      Page 2 of 50
Final                                                                                                                                            05 Oct 2018
2.0
OVERALL TABLE OF CONTENTS
1.0
TITLE PAGE....................................................................................................................................1
2.0
overall table of contents ....................................................................................................................2
2.1
list of in-text tables .............................................................................................................4
2.2
list of in-text figures............................................................................................................5
3.0
LIST OF ABBREVIATIONS...........................................................................................................6
4.0
INTRODUCTION ............................................................................................................................8
5.0
OBJECTIVES.................................................................................................................................13
6.0
PATIENT POPULATIONS............................................................................................................14
6.1
SCREENED POPULATION............................................................................................14
6.2
RANDOMIZED POPULATION......................................................................................14
6.3
SAFETY POPULATION .................................................................................................14
6.4
INTENT-TO-TREAT POPULATION .............................................................................14
7.0
PATIENT DISPOSITION ..............................................................................................................15
8.0
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS........................................16
9.0
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE................................................18
9.1
EXTENT OF EXPOSURE ...............................................................................................18
10.0
EFFICACY ANALYSES ...............................................................................................................19
10.1
PRIMARY EFFICACY PARAMETER...........................................................................20
10.2
SECONDARY EFFICACY PARAMETER(S)................................................................21
11.0
SAFETY ANALYSES....................................................................................................................22
11.1
ADVERSE EVENTS........................................................................................................22
11.2
CLINICAL LABORATORY PARAMETERS ................................................................24
11.3
VITAL SIGNS..................................................................................................................27
11.4
ELECTROCARDIOGRAM .............................................................................................28
12.0
HEALTH OUTCOMES ANALYSES............................................................................................31
13.0
BLINDED INTERIM ANALYSIS.................................................................................................32
14.0
DETERMINATION OF SAMPLE SIZE .......................................................................................33
15.0
STATISTICAL SOFTWARE.........................................................................................................34


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16.0
DATA HANDLING CONVENTIONS ..........................................................................................35
16.1
VISIT TIME WINDOWS.................................................................................................35
16.2
DERIVED EFFICACY VARIABLES .............................................................................36
16.3
AGE-AND-GENDER-CORRELATED VALUES FOR WEIGHT AND HEIGHT........36
16.4
REPEATED OR UNSCHEDULED ASSESSMENTS OF SAFETY PARAMETERS ...37
16.5
MISSING DATE OF THE LAST DOSE OF INVESTIGATIONAL PRODUCT...........37
16.6
MISSING SEVERITY ASSESSMENT FOR ADVERSE EVENTS...............................38
16.7
MISSING CAUSAL RELATIONSHIP TO INVESTIGATIONAL PRODUCT FOR 
ADVERSE EVENTS........................................................................................................38
16.8
MISSING DATE INFORMATION FOR ADVERSE EVENTS .....................................38
16.10
CHARACTER VALUES OF CLINICAL LABORATORY PARAMETERS.................41
17.0
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL..........................................................43
18.0
REFERENCES ...............................................................................................................................44
19.0
APPENDICES ................................................................................................................................45
APPENDIX I
PATTERN-MIXTURE MODEL DETAILS......................................................45


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2.1
LIST OF IN-TEXT TABLES
 


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Final                                                                                                                                            05 Oct 2018
2.2
LIST OF IN-TEXT FIGURES
Figure 4–1.
Study Design............................................................................................. 10


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Forest Research Institute, Inc.                                                                                                      Page 6 of 50
Final                                                                                                                                            05 Oct 2018
3.0
LIST OF ABBREVIATIONS
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
ANOVA
analysis of variance
AST
aspartate aminotransferase
BP
blood pressure
CDRS-R
Children’s Depression Rating Scale-Revised
CGI-I
Clinical Global Impression - Improvement
CGI-S
Clinical Global Impression - Severity
CMH
Cochran-Mantel-Haenszel
CRF
case report form
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
ET
early termination
GLMM
generalized linear mixed model
IP
investigational product
ITT
intent to treat
LAR
legally authorized representative
LOCF
last observation carried forward
MDD
major depressive disorder
MedDRA
Medical Dictionary for Regulatory Activities


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Final                                                                                                                                            05 Oct 2018
MMRM
mixed-effects model for repeated measures
OC
observed cases
PCS
potentially clinically significant
PID
patient identification
PK
pharmacokinetic
QTc
QT interval corrected for heart rate
QTcB
QT interval corrected for heart rate using the Bazett formula 
QTcF
QT interval corrected for heart rate using the Fridericia formula 
SAE
serious adverse event
SAP
statistical analysis plan
SI
Le Système International d’Unités (International System of Units)
TBL
total bilirubin
TEAE
treatment-emergent adverse event
ULN
upper limit of normal laboratory reference range


SAP VLZ-MD-22
Forest Research Institute, Inc.                                                                                                      Page 8 of 50
Final                                                                                                                                            05 Oct 2018
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-22. Specifications of tables, figures, and data listings are 
contained in a separate document. The statistical analysis for 
pharmacokinetic/pharmacodynamic parameters will be specified in a separate document.
Study VLZ-MD-22 is a multicenter, randomized, double-blind, placebo- and 
active-controlled, parallel-group, flexible-dose study in pediatric patients, 
ages 7-17 years, who have been diagnosed with major depressive disorder (MDD) using 
the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision
(DSM-IV-TR) diagnostic criteria for a minimum duration of 6 weeks. This study includes 
3 treatment groups: placebo, vilazodone, and fluoxetine. A total of 400 patients (160 per 
group for placebo and vilazodone, 80 for fluoxetine) are planned to be randomized. 
The study duration will be 10 weeks, starting with a 1-week screening period, followed 
by an 8-week of double-blind treatment period, and a 1-week of down-taper period. 
Patients must provide assent to participate and their parent/guardian/ legally authorized 
representative (LAR), and caregiver must provide written informed consent prior to the 
conduct of any study-specific procedures. 
 
 
 
 
 
 
 
 


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Final                                                                                                                                            05 Oct 2018


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Final                                                                                                                                            05 Oct 2018


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Forest Research Institute, Inc.                                                                                                      Page 13 of 50
Final                                                                                                                                            05 Oct 2018
5.0
OBJECTIVES
The objective of this study is to evaluate the efficacy, safety, and tolerability of 
vilazodone compared with placebo in pediatric outpatients (7-17 years of age) with 
MDD.
In addition, the study is designed to obtain pharmacokinetic (PK) data to define the PK 
profile of vilazodone in the pediatric population (7–17 years of age).


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Forest Research Institute, Inc.                                                                                                      Page 14 of 50
Final                                                                                                                                            05 Oct 2018
6.0
PATIENT POPULATIONS
Four populations will be considered in the statistical analysis of the study.
6.1
SCREENED POPULATION
The Screened Population will consist of all patients who underwent a Screening Visit and 
received a screening number, and for whom the informed consent was obtained.
6.2
RANDOMIZED POPULATION
The Randomized Population will consist of all patients in the Screened Population who
were randomized to a treatment group in the study.
6.3
SAFETY POPULATION
The Safety Population will consist of all patients in the Randomized Population who 
received at least 1 dose of double-blind 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 baseline and at least 1 postbaseline assessment of the Children’s Depression 
Rating Scale-Revised (CDRS-R) total score.


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Forest Research Institute, Inc.                                                                                                      Page 15 of 50
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7.0
PATIENT DISPOSITION
The number of patients in 3 of the study populations (Randomized, Safety, and ITT) will 
be summarized by treatment group and study center; the Screened Population will be 
summarized overall only by study center.
Screen-failure patients (i.e., patients screened but not randomized) and the associated 
reasons for failure to randomize will be tabulated overall for the Screened Population. 
The number and percentage of patients who complete the double-blind treatment period 
and of patients who prematurely discontinue during the same period will be presented for 
each treatment group and pooled across treatment groups for the Safety Population. The 
number and percentage of patients who enter the down-taper period and of patients who 
complete the down-taper period will be presented for each treatment group and pooled 
across treatment groups for the Safety Population.
The reasons for premature discontinuation from the double-blind treatment period as 
recorded on the disposition pages of the electronic case report forms will be summarized 
(number and percentage) by treatment group for the Safety Population. Percentage of 
premature discontinuations will be compared overall and for each discontinuation reason 
between treatment groups using Fisher’s exact test. All patients who prematurely 
discontinue during the double-blind treatment period will be listed by discontinuation 
reason for the Safety Population.


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Forest Research Institute, Inc.                                                                                                      Page 16 of 50
Final                                                                                                                                            05 Oct 2018
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 treatment group 
for the Safety and ITT populations, respectively. Baseline efficacy variables will be 
summarized by 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.
Comparability between treatment groups will be tested using a 2-way 
analysis-of-variance (ANOVA) model with treatment group and study center as the 
factors for continuous variables and a Cochran-Mantel-Haenszel (CMH) test, controlling 
for study center, for categorical variables. 
Medical and surgical history/physical findings will be classified by system organ class 
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 system organ class and preferred term will be summarized by 
treatment group for the Safety Population. Psychiatric history of major depressive 
disorder, other psychiatric history, prior treatment with psychotropic medication, and 
nondrug psychiatric treatment history will also be summarized by 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 medication is defined as any recorded medication taken before the date of the first 
dose of double-blind investigational product. Concomitant medication is defined as any 
medication taken on or after the date of the first dose of double-blind investigational 
product. 
Both prior and concomitant medications use will be coded by drug name and therapeutic 
class. The use of prior and concomitant medications will be summarized by the number 
and percentage of patients receiving each drug within each therapeutic class in each
treatment group for the Safety Population. If a patient took a specific medication multiple 
times or took multiple medications within a specific therapeutic class, that patient would 
be counted only once for the coded drug name or therapeutic class.


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Forest Research Institute, Inc.                                                                                                      Page 17 of 50
Final                                                                                                                                            05 Oct 2018
Summaries for concomitant medication use will be presented for the double-blind 
treatment period and the down-taper period, separately. Any concomitant medications 
taken after the date of the last dose of double-blind investigational product in the study 
will not be presented in the summary tables but will be included in the patient data 
listings.


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Forest Research Institute, Inc.                                                                                                      Page 18 of 50
Final                                                                                                                                            05 Oct 2018
9.0
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE
9.1
EXTENT OF EXPOSURE
Exposure to double-blind investigational product for the Safety Population during the 
double-blind treatment period will be summarized in terms of treatment duration, 
calculated as the number of days from the date of the first dose of double-blind 
investigational product to the date of the last dose of double-blind investigational product
during the double-blind treatment period, inclusive. Descriptive statistics (number of 
patients, mean, SD, median, minimum, and maximum) will be presented by treatment 
group. The number and percentage of patients will be presented for specific intervals of 
exposure by treatment group.
Patient-years, defined as total exposure to double-blind investigational product in years
(excluding the down-taper period), will be summarized by treatment group for the Safety 
Population.
In addition, weekly and overall mean daily dose, overall modal daily dose, and final daily
dose of investigational product during the double-blind treatment period will be 
summarized by treatment group for the Safety Population.
9.2
MEASUREMENT OF TREATMENT COMPLIANCE
 
 
 
 
 
 


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Forest Research Institute, Inc.                                                                                                      Page 19 of 50
Final                                                                                                                                            05 Oct 2018
10.0
EFFICACY ANALYSES
The efficacy analyses will be based on the ITT Population. Baseline for efficacy is 
defined as the last nonmissing efficacy assessment (at or prior to Visit 2) before the 
first dose of double-blind investigational product. All statistical tests will be 2-sided 
hypothesis tests performed at the 5% level of significance for main effects. All 
confidence intervals will be 2-sided 95% confidence intervals, unless stated otherwise.
For efficacy analyses in which study center is a factor, a small center will be defined as a 
center with fewer than 2 patients in any treatment group in the ITT Population. Small 
centers will be pooled to form pseudo-centers so that each treatment group includes at 
least 2 ITT patients within the center. Pooling will be done (within each country first)
using the following algorithm:
Based on the number of ITT patients, small centers will be ordered from the largest to the 
smallest, and centers of the same size will be ordered from the largest center code to the 
smallest center code. The pooling process starts with the largest small center from the 
top, which will be pooled with the smallest from the bottom until a non-small pseudo 
center is formed. The process will be repeated using the small centers left out after the 
first pass. If any centers are left out at the end of the process, they will be pooled with the 
smallest pseudo center. If there is more than 1 smallest pseudo center, the pseudo center 
with the smallest center code will be selected. In case that the pseudo center formed by 
pooling all small centers is still a small center, it will be pooled with the smallest non-
small center. If there is more than 1 smallest non-small center, the one with the smallest 
center code will be selected.  
These pseudo-centers will be used for all efficacy analyses when the model is adjusted 
for study center. 
By-visit analyses based on the mixed-effects model for repeated measures (MMRM) 
using the observed case (OC) approach will be performed for all continuous efficacy 
parameters with multiple post-baseline measurements. 
In addition, by-visit analyses using the last-observation-carried-forward (LOCF)
approach will be presented for all 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. 


SAP VLZ-MD-22
Forest Research Institute, Inc.                                                                                                      Page 20 of 50
Final                                                                                                                                            05 Oct 2018
10.1
PRIMARY EFFICACY PARAMETER
The primary efficacy parameter is the change from baseline to Week 8 in CDRS-R total 
score. The primary analysis for comparing vilazodone vs placebo will be performed using 
an MMRM with treatment group, pooled study center, visit, and treatment-group-by-visit 
interaction as the fixed effects and the baseline value and baseline-value-by-visit 
interaction as the covariates.  An unstructured covariance matrix will be used to model 
the covariance of within-patient scores. The Kenward-Roger approximation 
(Kenward and Roger, 1997) will be used to estimate denominator degrees of freedom. 
This analysis will only use the observed cases of postbaseline scores without imputation 
of missing values. 
To control the overall type I error rate for the multiple comparisons across the primary 
and the secondary hypotheses, a fixed sequence procedure will be applied. Details are 
provided in Section 10.2.
In addition, two sensitivity analyses, LOCF and pattern-mixture model approaches, will 
be performed on the primary efficacy parameter. The LOCF approach is based on an 
analysis-of-covariance (ANCOVA) model including treatment group and pooled study 
center as factors and baseline CDRS-R total score as a covariate. Another sensitivity 
analysis using a pattern-mixture model approach based on non-future dependent missing 
value restrictions (Kenward et al., 2003) will be performed to assess the robustness of the 
primary MMRM results to the possible violation of the missing-at-random assumption. 
The details of this sensitivity analysis are as follows:
The pattern for the pattern-mixture model will be defined by the patient’s last visit with 
an observed value. The observed CDRS-R total score at a visit is assumed to have a 
linear relationship with the patient’s prior measurements. The missing values will be 
imputed under the assumption that the distribution of the missing observations differs 
from that of the observed only by a shift parameter value ∆. The dataset with missing 
values imputed will be analyzed using an ANCOVA model with treatment group and 
pooled study center as factors and baseline CDRS-R total score as a covariate for 
between–treatment group comparisons at Week 8. The imputation of missing values and 
the analysis will be performed multiple times and the inference of this sensitivity analysis 
will be based on the combined estimates using the standard multiple imputation 
technique. The range of values for the shift parameter ∆is selected as 0 to 6 based on 
experience with historical data.
More details of the proposed pattern-mixture model approach (e.g., the models for the 
pattern-specific identifiable densities and the unidentified conditional distributions, the 
shift parameter Δ, and the multiple imputation algorithm) are provided in Appendix I to 
this SAP. 


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Final                                                                                                                                            05 Oct 2018
To examine the consistency of the primary efficacy results across study centers, the 
treatment differences versus placebo treatment groups (mean ± SE) in the change from 
baseline to Week 8 in CDRS-R total score will be graphed by pooled study center.
The comparison of fluoxetine vs. placebo will be performed to assess study assay 
sensitivity.
10.2
SECONDARY EFFICACY PARAMETER(S)
The secondary efficacy parameter is the change from baseline to Week 8 in CGI-S score, 
which will be analyzed using the MMRM approach similar to the one used for the 
primary efficacy parameter. A sensitivity analysis will also be performed using the LOCF 
approach as described in Section 10.1.
To control the overall family-wise type I error rate for multiple comparisons across the
primary and the secondary efficacy parameters, the fixed sequence testing procedure will 
be implemented, i.e., the efficacy analysis of the secondary efficacy parameter will be 
carried out inferentially only if the null hypothesis for the primary efficacy parameter is 
rejected. 
 
 
 
 
 
 
 
.


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Forest Research Institute, Inc.                                                                                                      Page 22 of 50
Final                                                                                                                                            05 Oct 2018
11.0
SAFETY ANALYSES
The safety analysis will be performed for the double-blind treatment period and the 
down-taper period (only for safety parameters collected during the down-taper period), 
separately, using the Safety Population unless stated otherwise. 
The safety parameters include adverse events (AEs), clinical laboratory parameters, vital 
signs, electrocardiographic (ECG) parameters, suicide risk assessment using the 
Columbia-Suicide Severity Rating Scale (C-SSRS), and the change from baseline in the 
age and gender adjusted height (evaluation of growth). For each safety parameter, the 
last nonmissing safety assessment before the first dose of double-blind investigational 
product will be used as baseline for all analyses of that safety parameter. 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.
For patients who take the down-taper investigational product, the double-blind treatment 
period starts with the first dose of double-blind investigational product and ends with the 
last assessment date up to the first dose of the down-taper investigational product. The 
double-blind down-taper period starts one day after the end of the double-blind treatment 
period and ends with the last dose of the down-taper investigational product or the last 
visit, whichever is later.
For patients who do not take the double-blind down-taper investigational product, the 
double-blind treatment period starts with the first dose of double-blind investigational 
product and ends with the last dose of the double-blind investigational product or the last 
visit, whichever is later.
11.1
ADVERSE EVENTS
Adverse events will be coded by system organ class and preferred term using the Medical 
Dictionary for Regulatory Activities, version 17.0 or newer.


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An AE (classified by preferred term) that occurs during the double-blind 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, or was present before the date of the first dose of double-blind 
investigational product and increased in severity during the double-blind treatment period 
or during the down-taper period, respectively. If more than 1 AE was reported before the 
date of the first dose of double-blind 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 double-blind 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 double-blind investigational product 
in the study will not be counted as a TEAE but will be included in the listings.
An AE occurring during the down-taper period will be considered a newly emergent AE
(NEAE) if it is 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. 
The NEAEs during the down-taper period will be summarized by body system, preferred 
term, and treatment group.
The number and percentage of patients reporting TEAEs in each treatment group will be 
tabulated by system organ class and preferred term and further categorized by severity 
and causal relationship to the investigational product, for both the double-blind treatment 
period and the double-blind 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 by treatment group separately for the double-blind treatment
period and the double-blind down-taper period, separately.
A common TEAE during the double-blind treatment period will be summarized in 
2 ways: ≥ 1% of patients in any treatment group and ≥ 2% of patients in any treatment 
group. The incidence of common TEAEs will be summarized separately by preferred
term and treatment group and will be sorted by decreasing frequency for the vilazodone
treatment group.
A serious adverse event (SAE) that occurred on the date of the first dose of double-blind 
investigational product and up to 30 days after the date of the last dose of double-blind 
investigational product, inclusive, will be considered an on-therapy SAE. The number 
and percentage of patients who have on-therapy SAEs will be summarized by preferred 
term and treatment group and will be sorted by decreasing frequency for the vilazodone
treatment group. In addition, the incidence of on-therapy SAEs that led to death will be 
summarized separately by treatment group and preferred term.


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Final                                                                                                                                            05 Oct 2018
The number and percentage of patients in the Safety Population who have AEs leading to 
premature discontinuation of the investigational product will be summarized by preferred 
term and treatment group and will be sorted by decreasing frequency for the vilazodone
treatment group.
Listings will be presented for patients with SAEs, patients with AEs leading to
discontinuation, and patients who die (if any) for the Screened Population. All patients
with SAEs, including those reported during the screening period or more than 30 days 
after the date of the last dose of the double-blind investigational product, and patients 
discontinuing because of AEs before taking double-blind investigational product will be 
included in these listings.
11.2
CLINICAL LABORATORY PARAMETERS
Descriptive statistics for clinical laboratory values (in SI units) and changes from the 
baseline values at each assessment time point (including the end of the double-blind 
treatment period) will be presented by treatment group for the following laboratory 
parameters:


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Final                                                                                                                                            05 Oct 2018
 
 
 
 
 
 
 
 
 
 
11.3
VITAL SIGNS
Descriptive statistics for vital signs (sitting radial pulse rate, sitting systolic and diastolic 
blood pressure, body weight and height) and their changes from baseline values at each 
visit, at the end of double-blind treatment period, and at the end of double-blind 
down-taper period will be presented by treatment group. Only patients with available 
baseline and at least 1 postbaseline assessment will be included in the summary.


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Final                                                                                                                                            05 Oct 2018
Vital sign values will be considered PCS if they meet both the observed-value criteria and 
the change-from-baseline criteria listed in Table 11.3–1. The number and percentage of 
patients with PCS postbaseline values will be tabulated by treatment group separately for 
the double-blind treatment period and the double-blind down-taper period. The 
percentages will be calculated relative to the number of patients with available baseline
and at least 1 postbaseline assessment. The numerator will be the 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, and 
baseline and all postbaseline (including non-PCS) values.
11.4
ELECTROCARDIOGRAM
Descriptive statistics for ECG parameters (heart rate, PR interval, QRS interval, RR 
interval, QT interval, and QTc interval) at baseline and changes from baseline values at 
each assessment time point (including the end of the double-blind treatment period) will 
be presented by treatment group. The QTc will be calculated using both the Bazett and 
Fridericia corrections. Only patients with available baseline and at least 1 postbaseline 
assessment will be included in the summary.


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Final                                                                                                                                            05 Oct 2018


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Final                                                                                                                                            05 Oct 2018
12.0
HEALTH OUTCOMES ANALYSES
Not applicable. 


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Final                                                                                                                                            05 Oct 2018
13.0
BLINDED INTERIM ANALYSIS
A blinded interim analysis will be conducted when approximately 75% of randomized 
patients have either completed the study or discontinued from the study. The blinded 
interim analysis is to obtain an estimate of the pooled standard deviation of the change 
from baseline to Week 8 in the CDRS-R total score. If the estimated pooled standard 
deviation is larger than the assumed pooled standard deviation specified in Determination 
of Sample Size (Section 14.0), the sample size may be increased to ensure an adequate 
power. However, due to the difficulties in recruiting pediatric patients with MDD, the 
total number of patients of the study will be capped at 500 (200 per treatment group for 
placebo and vilazodone, 100 for the fluoxetine treatment group). Detailed specification of 
the blinded interim analysis will be provided in the blinded interim analysis plan, a 
separate document. The interim analysis of sample size re-estimation will be performed 
by an independent statistician.


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Forest Research Institute, Inc.                                                                                                      Page 33 of 50
Final                                                                                                                                            05 Oct 2018
14.0
DETERMINATION OF SAMPLE SIZE
The primary efficacy parameter is the change from baseline to Week 8 during the 
double-blind treatment period in CDRS-R total score. A sample size of 400 patients 
(160 per group for placebo and vilazodone, and 80 for fluoxetine) was initially planned to
provide 85% power to detect an effect size of 0.36 (treatment group difference of 4 units 
relative to pooled standard deviation of 11.1) for the primary efficacy parameter, based 
on an MMRM model using simulation method (Lu, 2012). The simulation assumed a 
correlation of 0.7 between the repeated measures, and a dropout rate of 17%, based on 
historical studies in pediatric patients with MDD.
Based on the planned blinded interim analysis which included the first 300 randomized 
patients (75% of the initial sample size), the study sample size was increased to a total of 
455 patients (182 per group for placebo and vilazodone, and 91 fluoxetine patients) based 
on a pooled standard deviation of 12.3. During the teleconference with the FDA on the 
increased sample size, the FDA recommended a second interim analysis to be performed 
when the study enrolled the initially planned sample size of 400 patients. The second 
interim analysis included 427 randomized patients and the pooled standard deviation was 
12.43. Therefore, a sample size of 470 patients (188 per group for placebo and 
vilazodone, and 94 for fluoxetine) is required to maintain the 85% statistical power to 
detect a treatment difference of 4 units for the primary efficacy endpoint. 


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Final                                                                                                                                            05 Oct 2018
15.0
STATISTICAL SOFTWARE
Statistical analyses will be performed using version 


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Final                                                                                                                                            05 Oct 2018
16.0
DATA HANDLING CONVENTIONS
16.1
VISIT TIME WINDOWS
Table 16.1–1 and Table 16.1–2 present the visits assigned for efficacy and safety 
analyses and the corresponding ranges of treatment days (window) during which an 
actual visit may occur.


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Final                                                                                                                                            05 Oct 2018
 
 
 
 
16.2
DERIVED EFFICACY VARIABLES
The efficacy variables are derived as follows:

CDRS-R responders are defined as patients with a ≥40% reduction from baseline in 
CDRS-R total score. The value is 1 for CDRS-R responders and 0 otherwise

CDRS-R remitters are defined as patients with CDRS-R ≤ 28. The value is 1 for 
CDRS-R remitters and 0 otherwise
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 1, the baseline value will be carried forward for Week 1, provided that at least 
1 subsequent 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


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Final                                                                                                                                            05 Oct 2018
The z-score is calculated as below
, if L ≠ 0 and
, if 
,
where X is the physical measurement (e.g. weight 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). X must 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 standard deviation, respectively, in the reference data, 
which again are provided in the reference data tables.
16.4
REPEATED OR UNSCHEDULED ASSESSMENTS OF SAFETY 
PARAMETERS
If a patient has repeated assessments before the date of first dose of double-blind 
investigational product, the results from the final nonmissing assessment made before the 
date of the first dose of double-blind investigational product will be used as baseline. If 
end-of-double-blind-treatment period assessments are repeated or if unscheduled visits 
occur, the last nonmissing postbaseline assessment during the double-blind treatment 
period will be used as the end-of-double-blind-treatment-period assessment for 
generating summary statistics. Likewise, if end of double-blind down-taper period
assessments are repeated or if unscheduled visits occur, the last non-missing assessment 
during the double-blind down-taper period will be used as the end-of-double-blind-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 THE LAST DOSE OF 
INVESTIGATIONAL PRODUCT
When the date of the last dose of investigational product in the study taken during the 
double-blind treatment period is missing for a patient in the Safety Population, all efforts 
should be made to obtain the date from the Investigator. If it is still missing after all 
efforts, then the last 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


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Final                                                                                                                                            05 Oct 2018
16.6
MISSING SEVERITY ASSESSMENT FOR ADVERSE EVENTS
If severity is missing for an AE that started before the date of the first dose of 
double-blind investigational product, an intensity of mild will be assigned. If severity is 
missing for an AE that started on or after the date of the first dose of double-blind 
investigational product, an intensity of severe will be assigned. The imputed values for 
severity assessment will be used for the incidence summary; the values will be shown as 
missing in the data listings.
16.7
MISSING CAUSAL RELATIONSHIP TO INVESTIGATIONAL 
PRODUCT FOR ADVERSE EVENTS
If the causal relationship to the investigational product is missing for an AE that started
on or after the date of the first dose of double-blind investigational product, a causality of 
yes will be assigned. The imputed values for causal relationship to double-blind treatment 
will be used for the incidence summary; the values will be shown as missing in the data 
listings.
16.8
MISSING DATE INFORMATION FOR ADVERSE EVENTS
The following imputation rules only apply to cases in which the start date for AEs is 
incomplete (i.e., partly missing).
 
 
 
 
 


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Final                                                                                                                                            05 Oct 2018
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Forest Research Institute, Inc.                                                                                                      Page 40 of 50
Final                                                                                                                                            05 Oct 2018
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Final                                                                                                                                            05 Oct 2018
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 because, for example, a character string is reported for a parameter of the 
numeric type, a coded value must be appropriately determined for use in the statistical 
analyses. The actual values, as reported in the database will be presented in the 
data listings.


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Final                                                                                                                                            05 Oct 2018


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Final                                                                                                                                            05 Oct 2018
17.0
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL
No major changes have been made to the original protocol dated 26 Sep 2014.


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Final                                                                                                                                            05 Oct 2018
18.0
REFERENCES
Cole TJ. The LMS method for constructing normalized growth standards. Eur J Clin 
Nutr., 44: 45-60, 1990.
Kenward MG, Molenberghs G, Thijs H. Pattern-mixure models with proper time 
dependence. Biometrika, 2003;90:53-71.
Kenward MG, Roger JH. Small sample inference for fixed effects from restricted 
maximum likelihood. Biometrics, 1997;53:983-997.
Lu K. Sample size calculations with multiplicity adjustment for longitudinal clinical trials 
with missing data. Stat Med 2012;31:19-28.


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Forest Research Institute, Inc.                                                                                                      Page 45 of 50
Final                                                                                                                                            05 Oct 2018
19.0
APPENDICES
APPENDIX I
PATTERN-MIXTURE MODEL DETAILS
For repeated measures with the monotone missing mechanism, the pattern-mixture model 
with non-future dependent missing assumption, proposed by Kenward et al. (2003), 
provides a feasible solution to accommodate certain missing not at random (MNAR) 
mechanism. The methodology relies on constructing unidentifiable conditional densities 
using identifiable densities and borrows techniques from standard multiple imputation.
1. Non-Future Dependent Missing Assumption
Assume there are T designed visits in a longitudinal study and let 
)
,...,
2,1
(
T
i
yi

represent patient’s measurement at Visit i. When the missing mechanism is monotone, 
the pattern of missing data can be defined by the number of measurements (L) actually 
observed from the patient. Let 
)
|
,...,
(
t
L
y
y
f
j
i

denote the conditional density of 
yi ,... yj, given that the last observed measurement is at Visit t. Then the overall density 
function for Pattern t can be written as
f (y1,..., yT | L = t) = f (y1,..., yt | L = t) f (yt+1 | y1 ,..., yt, L = t)
(1)
×
T
f (ys | y1 ,..., ys-1, L = t)
Π
s = t+2
Note on the right hand side of (1) the first factor is clearly identifiable from the observed 
data, while the second and the beyond are not, due to lack of available data. The second 
factor 
)
,
,...,
|
(
1
1
t
L
y
y
y
f
t
t


could be identifiable based on an assumed relationship 
between 
)
,
,...,
|
(
1
1
t
L
y
y
y
f
t
t


and f (yt+1 | y1,...yt, L ≥ t + 1). The third and beyond 
factors 
)
,
,...,
|
(
1
1
t
L
y
y
y
f
s
s


(with all s ≥ t + 2) could be identifiable with the help of 
non-future dependent missing assumption.
For longitudinal data with dropouts, non-future dependent missing (NFD) mechanism 
(Kenward et al., 2003) assumes that the unidentifiable conditional distributions of 
sy
(s ≥t + 2), given earlier measurements, in Pattern t, is equal to the corresponding 
distribution in patterns L ≥ s – 1 :
f (ys | y1,..., ys-1, L = t) = f (ys | y1,..., ys-1, L ≥ s – 1)
(2)


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Forest Research Institute, Inc.                                                                                                      Page 46 of 50
Final                                                                                                                                            05 Oct 2018
The right hand side of (2) can further be partitioned into
f (ys | y1,..., ys-1, L ≥ s – 1) =
T
ωs-1, j · f (ys | y1,..., ys-1, L = j)
(3)
Σ
j = s-1
Where mixture probabilities ωs-1,j are:
ωs-1,j = 
αj f (y1,...,ys-1 | L = j)
, and αj represents the fraction of 
(4)
T
αt f (y1,...,ys-1 | L = t)
Σ
t = s-1
patients from Pattern j.
Each factor of the unidentifiable conditional distribution of
sy (s ≥ t + 2) on the right side 
of (1) can be expressed using the following:
-
)1
,
,...,
|
(
1
1



s
L
y
y
y
f
s
s
, the unidentifiable conditional distribution of the 
first missing in pattern 
1

s
, 
-
)
,
,...,
|
(
1
1
j
L
y
y
y
f
s
s


, the identifiable conditional distributions of
sy given
1
1,...,

sy
y
of pattern j (j ≥ s), and
- αj, the fraction of patients from pattern j (j ≥ s - 1). 
So under NFD, all the unidentifiable conditional distribution on the right side of (1) can 
be estimated and missing value could be therefore imputed based on the assumption for 
unidentifiable conditional distribution of the first missing.
We re-formulate the partition in (3), for s ≥ t +2, as the following:
f (ys | y1,..., ys-1, L = t) = δs-1 f (ys | y1,..., ys-1, L = s – 1)
(5)
+ (1 – δs-1) f (ys | y1,..., ys-1, L ≥ s)
for s ≥ t +2 with 
1
,1
1



s
s
s
ω
δ
.


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Forest Research Institute, Inc.                                                                                                      Page 47 of 50
Final                                                                                                                                            05 Oct 2018
Therefore, under monotone missing and NFD assumption, the unidentifiable conditional 
densities for Visit s in Pattern t (s ≥ t +2) can be expressed as a mixture distribution of 
)1
,
,...,
|
(
1
1



s
L
y
y
y
f
s
s
- the unidentifiable conditional distribution of the first missing 
measurement ys in Pattern
1

s
, and f (ys | y1,...,ys-1, L ≥ s) - the identifiable conditional 
distribution of ys from all the patterns with observed data at Visit s or beyond:
f (ys | y1,..., ys-1, L ≥ s) =
T
λs-1,j f (ys | y1,..., ys-1, L = j)
(6)
Σ
j = s
where the mixture probability 
λs - 1, j = ωs-1,j /(1 – ωs - 1, s - 1) =
αj f (y1,...,ys-1 | L = j)
for j ≥ s, where αj is the fraction of 
(7)
T
αt f (y1,...,ys-1 | L = t)
Σ
t = s
patients from Pattern j.
The conditional densities for the first missing are selected as:
f (ys | y1,..., ys-1, L = s – 1) = f (ys – Δ | y1,..., ys-1, L ≥ s) for s = 2, ..., T, (8)
Note that the two distributions only differ by a shift (Δ) parameter. When Δ = 0, the 
missing value ys in Pattern s-1 is imputed based on the distribution of all observed data up 
to Visit s, as a result, leading to missing at random (MAR) missingness. When Δ ≠0, (8) 
will introduce a scenario of MNAR. The similar idea was also presented in the recent 
publication “The Prevention and Treatment of Missing Data in Clinical Trials” by the 
National Academies Press. The selection of the plausible values for the shift parameter 
(Δ) is discussed in Section 3 of this appendix.
Note that per recommendation in Wang and Daniels (2011), only the observed data 
within pattern is assumed to be multivariate normal. The observed data distribution can 
be expressed in terms of the marginal distribution of baseline measurement and the 
conditional distributions of postbaseline measurements given earlier measurements. 
Assuming that these distributions are normal, the linear regression of each observation on 
prior observations will yield least-squares estimates of model parameters that can be 
utilized for independent posterior draws of model parameters for observed data. Multiple 
imputation approach will be used to estimate the overall mean at the final time point.


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Final                                                                                                                                            05 Oct 2018
2. Imputation Procedure
All the missing data will be imputed to create complete datasets, then statistical analysis 
can be performed using appropriate techniques such as ANCOVA. The imputation can 
accommodate MNAR missing data mechanisms, based on the theory discussed in the 
previous section. 
The model parameters for each dropout pattern, i.e., the mean, variance and proportions 
of observations in each pattern, are drawn from their posterior distributions prior to the 
imputation of missing data for a single imputation. 
The details of imputation within a pattern, say Pattern t, are as the following:
Step 1. Impute the first missing value yt+1 for each patient in Pattern t (t = 1,..., T – 1): 
a.
Compute estimates of mixture probabilities λs-1,j in (7) with s = t+1 given the 
posterior draw of proportions of observations in each pattern and the posterior draw 
of regression parameters for the observed data.
b. Draw a random integer from {s, ..T} to index a component distribution on the right 
hand side of (6), using mixture probabilities obtained in a). Draw 
*
1

ty
from the 
identified component normal distribution. Impute the missing yt+1 as 
*
1
1
~


t
t
y
y
+ Δ.
Step 2. Impute the rest of the missing values of yt+2, yt+3, ..., yT for patients in Pattern t:
Starting with imputation for yt+2, first, similar to Step 1, draw 
*
2

ty
from the normal 
mixture (6) based on the observed y1,...,yt and the already imputed 
1
~

ty
for the patient. 
Then the missing yt+2 is imputed as 
*
2
2
~


t
t
y
y
+ Δ with probability δt+1 and as 
*
2
2
~


t
t
y
y
with probability 1 – δt+1, where the mixture probability δt+1 = ωt+1,t+1 is 
obtained from (4) given the posterior draw of proportions of observations in each pattern 
and the posterior draw of regression parameters for the observed data.
Missing values of yt+3 through yT can be imputed similarly as yt+2. 
To summarize, the imputations of yt+1 through yT is done recursively within each Pattern t
(for all t = 1,...,T – 1) to create a complete dataset after imputation is done for all patterns 
with missing values. 


SAP VLZ-MD-22
Forest Research Institute, Inc.                                                                                                      Page 49 of 50
Final                                                                                                                                            05 Oct 2018
The above imputation procedure is applied to all subjects in each missing data pattern to 
create a single imputed data set. Repeating the process of drawing parameters from the 
posterior distribution and imputing missing data given the posterior draw m times will 
yield m imputed data sets. The observed or imputed values at the final data point are 
averaged to obtain the overall mean estimate for each imputed data set, and the multiple 
imputation estimate is obtained by averaging the estimates across m imputations. 
In this sensitivity analysis, m is set to equal to 20. The value of m is discussed in the 
context of imputation efficiency in standard multiple imputation theory (Rubin, 1987, 
p. 114), and m = 20 would provide at least 96% of relative efficiency as compared with 
using an large number of imputations (SAS/STAT User’s Guide, p. 3796). 
3. Determination of the Shift Parameter Values
The common shift parameter Δ is the difference between the mean of yt+1 among those 
who drop out at Visit t and those who remain beyond Visit t (1 ≤ t ≤ T – 1). The exact 
value of Δ is unknown and can’t be estimated from data because of missingness. The 
magnitude of Δ depends on the medical aspects of the trial. Using relevant historical data, 
one may select Δ as a proportion of the sample standard deviation or a proportion of 
observed treatment efficacy. 
References:
Kenward MG, Molenberghs G, Thijs H. Pattern-mixure models with proper time 
dependence. Biometrika, 2003;90:53-71.
Rubin DB. Multiple Imputation for Nonresponse in Surveys. J. Wiley & Sons, 
New York; 1987.
SAS Institute Inc. SAS/STAT 9.2 User’s Guide, Second Edition. Cary, NC: SAS Institute 
Inc; 2009.
Wang C, Daniels MJ. A note on MAR, identifying restrictions, model comparison, and 
sensitivity analysis in pattern mixture models with and without covariates for incomplete 
data. Biometrics, 2011; 67(3):810-818.