Clinical trial NCT02431806
Conditions: Major Depressive Disorder
Sponsor: Forest Laboratories
Start date: 2015-06-23; Completion date: 2019-08-19
Enrollment: 552 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy, safety, and tolerability of levomilnacipran ER relative to placebo in adolescent outpatients (12-17 years) with Major Depressive Disorder (MDD). In addition, the study is designed to obtain pharmacokinetics (PK) data to guide dose selection for future pediatric studies of levomilnacipran.

Detailed description:
Study LVM-MD-11 is a randomized, double-blind, placebo- and active-controlled, parallel group, fixed-dose study in adolescent patients, ages 12-17 years. The study will be approximately 10 weeks in duration:

* 1-week screening/washout period
* 8-week double-blind treatment period
* 1-week double-blind down-taper period

Participants who meet the eligibility criteria at Visit 2 (Baseline) will be randomized to 1 of 4 treatment groups: placebo, levomilnacipran 40 mg/day, levomilnacipran 80 mg/day, or fluoxetine 20 mg/day.

Arms: arm 1: Participants received 2 dose matched over-encapsulated placebo capsules, once daily, orally during the Double-blind Treatment Period up to 8 weeks followed by a 1 week Taper-down Period if applicable as determined by the investigator. arm 2: Participants received over-encapsulated levomilnacipran extended release (ER) 40 mg/day capsules orally starting at a dose of 10 mg/day on Day 1-2, 20 mg/day on Days 3-7 and 40 mg/day on Week 2 through Week 8 during the Double-Blind Treatment Period, followed by a 1-week Double-Blind Taper-down Period if applicable as determined by the investigator. Participants received 1 dose matched placebo capsule each day to maintain the blind. arm 3: Participants received over-encapsulated levomilnacipran ER two 40 mg/day capsules (80 mg/day) orally starting at a dose of 10 mg/day on Day 1-2, 20 mg/day on Day 3-4, 40 mg/day on Day 5-7 and 80 mg/day on Week 2 through Week 8 during the Double-blind Treatment Period, followed by a 1-week Double-blind Taper-down Period if applicable as determined by the investigator. Participants received 1 dose matched placebo capsule the first week and during the taper-down period to maintain the blind. arm 4: Participants received over-encapsulated fluoxetine 20 mg/day tablets orally starting at a dose of 10 mg/day in Week 1 and 20 mg/day in Week 2 through Week 8 during the Double-blind Treatment Period, followed by a 1-week Double-blind Taper-down Period if applicable as determined by the investigator. Participants received 1 dose matched placebo capsule each day to maintain the blind.
Interventions: intervention 1: Placebo intervention 2: Levomilnacipran intervention 3: Fluoxetine
Intervention descriptions: intervention 1: Matched over-encapsulated placebo capsules administered orally on Day 1 to Week 8. intervention 2: Over-encapsulated levomilnacipran ER capsules administered orally on Day 1 to Week 8. intervention 3: Over-encapsulated fluoxetine tablets administered orally on Day 1 to Week 8.

Protocol documents:
Prot_001.pdf: 
NCT02431806 
 
Study ID: LVM-MD-11 
 
 
 
Title: A Double-blind, Placebo- and Active-Controlled Evaluation of the Safety and Efficacy of 
Levomilnacipran ER in Adolescent Patients With Major Depressive Disorder 
 
Protocol Amendment 3 Date: 25 Mar 2019 
 
 


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TITLE PAGE
Forest Research Institute, Inc., an Allergan affiliate
Harborside Financial Center, Plaza V
Jersey City, NJ 07311
A Double-blind, Placebo- and Active-Controlled Evaluation of the Safety and 
Efficacy of Levomilnacipran ER in Adolescent Patients with Major Depressive 
Disorder 
LVM-MD-11
Original Protocol Date:
01 Dec 2014
Amendment #1:
08 Jun 2015
Amendment #2:
08 Aug 2016
Amendment #3:
25 Mar 2019
Confidentiality Statement
This document is the property of Forest Research Institute, Inc., and may not—in full or 
part—be passed on, reproduced, published, distributed, or submitted to any regulatory 
authority without the express written permission of Forest Research Institute, Inc.
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SYNOPSIS AND SCHEDULE OF EVALUATIONS
CLINICAL STUDY SYNOPSIS: Study LVM-MD-11
Title of Study
A Double-blind, Placebo- and Active-Controlled Evaluation of the Safety and 
Efficacy of Levomilnacipran ER in Adolescent Patients With Major 
Depressive Disorder 
Study Centers
Approximately 80 study centers
Development Phase
3
Objective
To evaluate the efficacy, safety, and tolerability of levomilnacipran relative to 
placebo in adolescent outpatients (12-17 years) with major depressive disorder 
(MDD). In addition, the study is designed to obtain pharmacokinetic (PK) 
data to guide dose selection for future pediatric studies of levomilnacipran.
Methodology
Multicenter, randomized, double-blind, placebo- and active-controlled, 
fixed-dose study
Number of Patients
544 planned (136 per treatment group for placebo, levomilnacipran 
40 mg/day, levomilnacipran 80 mg/day, and fluoxetine 20 mg/day) 
Diagnosis and 
Main Criteria for Inclusion
Male and female outpatients, 12 to 17 years of age, who meet Diagnostic and 
Statistical Manual of Mental Disorders, Fourth Edition, Text Revision 
(DSM-IV-TR) criteria for MDD; have a score of ≥ 40 on the Children’s 
Depression Rating Scale–Revised (CDRS-R) at Visits 1 and 2, and Clinical 
Global Impressions-Severity (CGI-S) ≥ 4 at Visits 1 and 2. The Kiddie 
Schedule for Affective Disorders–Present and Lifetime (K-SADS–PL) will be 
used to confirm the diagnosis of MDD and to document the patient’s 
psychiatric history.
Test Product, Dosage, and Mode of 
Administration
Encapsulated Levomilnacipran extended release (ER) 10 mg, 20 mg, and 40 
mg capsules; once daily oral administration, at the same time each day
Duration of Treatment
9 weeks in duration: 8 weeks of double-blind treatment and a 1-week double-
blind down-taper period
Reference Therapy, Dosage, and 
Mode of Administration
Placebo capsules, once-daily oral administration, at the same time each day
Encapsulated fluoxetine 10 mg capsules and encapsulated fluoxetine 20 mg 
tablets; once-daily oral administration, at the same time each day
Criteria for Evaluation
Primary Outcome Measure
CDRS-R change from baseline at Week 8
Secondary Outcome Measure
CGI-S change from baseline at Week 8
 
 
 
 
 
 
 
 
 
 
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Statistical Methods
The primary efficacy parameter is the change from baseline to end of Week 8 
of the double-blind treatment period in the CDRS-R total score.
The primary analysis will be performed using a mixed-effects model for 
repeated measures (MMRM) with treatment group, 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. This analysis will be performed based on all postbaseline scores using 
only the observed cases without imputation of missing values.
The secondary efficacy parameter is the change from baseline to end of 
Week 8 of the double-blind treatment period in CGI-S. This parameter will be 
analyzed using an MMRM similarly to the primary efficacy parameter.
Multiple comparisons for the primary and secondary efficacy parameters will 
be addressed using the matched parallel gatekeeping procedure.
All safety parameters will be analyzed descriptively. The safety analysis will 
be performed using 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 the baseline and at least 
1 postbaseline assessment of CDRS-R total score.
 
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TABLE OF CONTENTS
1.0
TITLE PAGE....................................................................................................................................1
2.0
SYNOPSIS AND SCHEDULE OF EVALUATIONS .....................................................................2
3.0
TABLE OF CONTENTS..................................................................................................................6
List of Tables...................................................................................................................................................8
List of Figures .................................................................................................................................................8
4.0
LIST OF ABBREVIATIONS...........................................................................................................9
5.0
ETHICAL CONSIDERATIONS....................................................................................................11
5.1
INSTITUTIONAL REVIEW BOARD AND INDEPENDENT ETHICS 
COMMITTEE...................................................................................................................11
5.2
ETHICAL CONDUCT OF THE STUDY........................................................................11
5.3
PATIENT INFORMATION AND INFORMED CONSENT ..........................................12
6.0
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ......................................13
7.0
INTRODUCTION ..........................................................................................................................14
8.0
STUDY OBJECTIVES...................................................................................................................16
9.0
INVESTIGATIONAL PLAN .........................................................................................................17
9.1
OVERALL STUDY DESIGN AND PLAN: DESCRIPTION.........................................17
9.2
DISCUSSION OF STUDY DESIGN, INCLUDING THE CHOICE OF CONTROL 
GROUPS ..........................................................................................................................18
9.3
SELECTION OF STUDY POPULATION ......................................................................19
9.3.1
Inclusion Criteria................................................................................................19
9.3.2
Exclusion Criteria...............................................................................................20
9.3.3
Removal of Patients from Therapy or Assessment.............................................24
9.3.4
Patient Replacement Procedures ........................................................................25
9.3.5
Demographic Considerations .............................................................................25
9.4
TREATMENTS................................................................................................................25
9.4.1
Treatments Administered ...................................................................................25
9.4.2
Identity of Investigational Products....................................................................25
9.4.3
Method of Assigning Patients to Treatment Groups ..........................................26
9.4.4
Selection of Dosages in the Study ......................................................................27
9.4.5
Selection and Timing of Dose for Each Patient..................................................27
9.4.5.1
Double-blind Treatment Period ........................................................27
9.4.5.2
Double-Blind Down-Taper Period....................................................28
9.4.6
Blinding..............................................................................................................29
9.4.7
Unblinding..........................................................................................................29
9.4.8
Prior and Concomitant Therapy .........................................................................29
9.4.9
Monitoring Treatment Compliance ....................................................................30
9.4.10
Treatment After Discontinuation........................................................................30
9.5
EFFICACY AND SAFETY VARIABLES ......................................................................30
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9.5.1
Efficacy Assessments .........................................................................................30
9.5.1.1
Primary Efficacy Assessment...........................................................30
9.5.1.2
Secondary Efficacy Assessment.......................................................31
9.5.2
Safety Assessments ............................................................................................31
9.5.2.1
Adverse Events.................................................................................31
9.5.2.2
Causality Assessment .......................................................................32
9.5.2.3
Severity Assessment.........................................................................33
9.5.2.4
Serious Adverse Events....................................................................33
9.5.2.5
Reporting Adverse Events and Serious Adverse Events ..................34
9.5.2.6
Immediate Reporting of Serious Adverse Events and Events of 
Special Interest .................................................................................35
9.5.2.7
Reporting of Pregnancies Occurring During the Study ....................35
9.5.3
Investigational Product Concentration Measurements .......................................41
9.5.4
Health Economic and Outcomes Research Assessments....................................42
9.6
DATA QUALITY ASSURANCE....................................................................................48
9.6.1
Data Monitoring .................................................................................................48
9.6.2
Data Recording and Documentation...................................................................48
9.7
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE .................49
9.7.1
Patient Populations.............................................................................................49
9.7.1.1
Screened Population .........................................................................49
9.7.1.2
Randomized Population....................................................................49
9.7.1.3
Safety Population..............................................................................49
9.7.1.4
Intent-to-Treat Population ................................................................50
9.7.2
Patient Disposition .............................................................................................50
9.7.3
Demographics and Other Baseline Characteristics.............................................50
9.7.4
Extent of Exposure and Treatment Compliance.................................................51
9.7.4.1
Extent of Exposure ...........................................................................51
9.7.4.1.1Investigational Product ..........................................................51
9.7.4.2
Measurement of Treatment Compliance...........................................51
9.7.5
Efficacy Analyses...............................................................................................52
9.7.5.1
Primary Efficacy Parameter..............................................................53
9.7.5.2
Secondary Efficacy Parameter..........................................................54
9.7.6.1
Adverse Events.................................................................................55
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9.7.6.6
Investigational Product Plasma Concentration Parameters ..............58
9.7.7
Health Economics and Outcomes Research Analyses........................................58
9.7.8
Blinded Interim Analysis....................................................................................59
9.7.9
Determination of Sample Size............................................................................59
9.7.10
COMPUTER METHODS..................................................................................60
9.8
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES.........60
9.9
Protocol Deviations and Violations ..................................................................................60
9.10
DATA MONITORING COMMITTEE............................................................................61
10.0
STUDY SPONSORSHIP................................................................................................................62
10.1
STUDY TERMINATION ................................................................................................62
10.2
REPORTING AND PUBLICATION...............................................................................62
11.0
INVESTIGATOR OBLIGATIONS................................................................................................63
11.1
DOCUMENTATION .......................................................................................................63
11.2
PERFORMANCE.............................................................................................................63
11.3
USE OF INVESTIGATIONAL MATERIALS................................................................64
11.4
CASE REPORT FORMS .................................................................................................64
11.5
RETENTION AND REVIEW OF RECORDS ................................................................64
11.6
PATIENT CONFIDENTIALITY.....................................................................................65
12.0
INVESTIGATOR’S STATEMENT ...............................................................................................66
13.0
APPENDICES ................................................................................................................................67
APPENDIX I.
ELEMENTS OF INFORMED CONSENT ....................................................67
APPENDIX II.
CONTACT INFORMATION.........................................................................69
 
14.0
LITERATURE CITED ...................................................................................................................93
List of Tables
List of Figures
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LIST OF ABBREVIATIONS
5-HT
5-hydroxytryptamine (serotonin)
AE
adverse event
ALT
alanine aminotransferase 
AST
aspartate aminotransferase
BP
blood pressure
AUC
area under the plasma concentration versus time curve
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
DSM-IV-TR
Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, text
revision
ECG
electrocardiogram, electrocardiographic
eCRF
electronic case report form
ER
extended release 
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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IRB
Institutional Review Board
ITT
intent to treat
IVRS
interactive voice response system
IWRS
interactive Web response system
K-SADS-PL
Kiddie Schedule for Affective Disorders–Present and Lifetime
LAR
legally authorized representative
LOCF
last observation carried forward
MDD
major depressive disorder
MMRM
mixed-effects model for repeated measures
NDA
New Drug Application
NE
norepinephrine
PCS
potentially clinically significant
PID
patient identification
PK
pharmacokinetic, pharmacokinetics
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
SFU
safety follow-up
SNRI
serotonin and norepinephrine reuptake inhibitors
SSRI
selective serotonin reuptake inhibitors
TEAE
treatment-emergent adverse event
UDS
urine drug screen
ULN
upper limit of normal
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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 (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, patients will give voluntary and written 
informed assent and the parent(s)/legal guardian, or legally authorized representative 
(LAR) will provide voluntary and written informed consent and HIPAA authorization 
(in compliance with 21 CFR, Parts 50 and 312) before participating in any study-related 
procedures.
Patients unable to give written informed assent must orally assent to the procedures; and 
written consent must be obtained from their parent(s)/legal guardian (either parent or 
legal guardian will be referred to as the LAR) in accordance with the appropriate local 
laws, where applicable.
Each patient and his/her LAR will read, assent to an understanding of, and sign an 
assent/ICF, the HIPAA authorization form, or other locally applicable regulations and
authorization form after having had an opportunity to discuss the documents with the 
study staff before signing. Each patient and his/her LAR will be made aware that he or 
she may withdraw from the study at any time.
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. 
He/she may be a different individual than the LAR. In order for the patient to be eligible 
for the study, the caregiver, whether or not the LAR, must read and sign the caregiver 
consent and meet the relevant inclusion/exclusion criteria. If the LAR is the caregiver, 
he/she will be asked to sign both the parent/legal guardian consent and the caregiver 
consent.
Signed copies of the ICF will be given to the patient and LAR. In addition, a signed copy 
of the caregiver consent will be given to the caregiver. All original ICF documents will 
be placed in the Investigator’s study files. The informed consent statement contains all 
the elements of informed consent listed in Appendix I of this protocol.
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6.0
INVESTIGATORS AND STUDY ADMINISTRATIVE 
STRUCTURE
This study will be performed at approximately 80 study centers.
The Investigator is responsible for ensuring that the investigation is conducted according 
to the signed Investigator’s 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 informed consent of each human patient prior to the patient 
enrolling in the study and/or prior to participating in any study-related activity. 
The Investigator at each site 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 their capabilities and performance consistent with the 
study investigational plan. The Investigator at each site 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
Major depressive disorder (MDD) is a common and serious illness in children and 
adolescents. Epidemiological studies and clinical samples estimate the prevalence of 
MDD as approximately 1%-2% of prepubertal children, and between 3% and 8% of 
adolescents (Zalsman et al, 2006). By the ages of 10 to 15, girls appear to be more likely 
to experience depression than boys (Angold et al, 1998).
MDD is commonly associated with feelings of worthlessness, low self-esteem, and 
thoughts of suicide and its psychosocial burden in the formative years can compromise 
the developmental process. Patients also experience difficulties with concentration and 
motivation, impairing functioning in this critical period. Each year as many as 20% of 
adolescents have suicidal ideation and 9% attempt suicide (Grunbaum JA, 2002). Suicide 
is a leading cause of death in adolescents and is a major public health concern 
(CDC, 2014). A major risk factor for suicide in adolescents is major depression.
MDD in children and adolescents can be chronic and recurrent. The mean length of 
pediatric depressive episodes is 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).
As a pharmacological treatment, the use of selective serotonin reuptake inhibitors 
(SSRIs) for children and adults increased approximately 7-fold during the 1990s. 
Fluoxetine (Prozac®), an SSRI, is approved by the FDA for the treatment of MDD in 
children and adolescents 8 years and older. Escitalopram (Lexapro®), another SSRI, is 
approved for the treatment of MDD in patients aged 12 and over. Currently, no serotonin 
and norepinephrine reuptake inhibitors (SNRIs) have been approved for the treatment of 
MDD in children or adolescents.
Levomilnacipran is an SNRI approved for the treatment of MDD in adults in the United 
States. The pharmacologic mechanism of the antidepressant activity of levomilnacipran 
and other SNRIs (ie, duloxetine, venlafaxine, and desvenlafaxine) is thought to be 
mediated through inhibition of norepinephrine (NE) and 5-hydroxytryptamine (serotonin) 
(5-HT) reuptake in the central nervous system. Although all SNRIs (as a class) block 
5-HT and NE reuptake, currently marketed SNRIs (duloxetine, venlafaxine, and 
desvenlafaxine) are more potent inhibitors of 5-HT reuptake than of NE reuptake 
(Deecher et al, 2006; Vaishnavi et al, 2004). Levomilnacipran exhibits a distinct in vitro
profile, exhibiting more potent inhibition of NE reuptake than 5-HT reuptake 
(Auclair et al, 2013). This greater potency at the NE transporter may confer additional 
improvements specifically in those domains associated with noradrenergic 
neurotransmission; for example: alertness, energy, attention, and anhedonia
(Montgomery and Briley, 2011).
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The efficacy of levomilnacipran as measured by the Montgomery-Åsberg Depression 
Rating Scale total score was established in 3 pivotal studies of adult patients with MDD. 
Levomilnacipran also demonstrated superiority over placebo as measured by
improvement in the Sheehan Disability Scale functional impairment total score. These 
studies, which were conducted in the United States and Canada, were placebo-controlled; 
no active comparator was included. Two of the studies were fixed-dose studies 
(LVM-MD-01: placebo, levomilnacipran 40 mg/day, 80 mg/day, and 120 mg/day, and 
LVM-MD-10: placebo, levomilnacipran 40 and 80 mg/day) and 1 study was
flexible-dose (LVM-MD-03: placebo, levomilnacipran 40 mg/day to 120 mg/day).
In summary, MDD is a condition common in children and adolescents and is a major 
public health concern. Current approved treatment options for this condition are limited 
to the 2 aforementioned SSRI products. Since the modulation of energy, vigilance, and 
arousal can be directly linked to the noradrenergic system, it has been suggested that 
antidepressants with a prominent noradrenergic component, such as levomilnacipran, 
may be particularly effective in addressing functional impairment, decreased 
concentration, lassitude, mental and physical slowing, and decreased self-care 
(Citrome, 2013). Brain serotonin and norepinephrine systems continue to mature through 
childhood and adolescence, however, and these maturational effects may generate 
age-related differences in patients’ responses to pharmacotherapy. Thus, it is important 
that further investigation of SNRI treatment options such as levomilnacipran be evaluated 
systematically for the treatment of MDD in children and adolescents, so that an SNRI’s 
efficacy and safety profile can be characterized in this population.
The current study of levomilnacipran extended release (ER) in adolescent patients 
(12-17 years old) with MDD will be conducted as required under the Pediatric Research 
Equity Act and as agreed upon with the FDA as a part of Postmarketing Requirement 
studies. 
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8.0
STUDY OBJECTIVES
The objective of this study is to evaluate the efficacy, safety, and tolerability of 
levomilnacipran relative to placebo in adolescent outpatients (12-17 years) with MDD. In 
addition, the study is designed to obtain pharmacokinetic (PK) data to guide dose 
selection for future pediatric studies of levomilnacipran.
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9.0
INVESTIGATIONAL PLAN
9.1
OVERALL STUDY DESIGN AND PLAN: DESCRIPTION
Study LVM-MD-11 will be a randomized, double-blind, placebo- and active-controlled, 
parallel group, fixed-dose study in adolescent patients, ages 12-17 years. The study will 
be approximately 10 weeks in duration:

1-week screening/washout period

8-week double-blind treatment period 

1-week double-blind down-taper period 
The screening/washout period will generally be 1 week (± 3 days) prior to Visit 2, but 
may be extended up to a total of 5 weeks to accommodate prior medication washout or to 
repeat assessments. Patients will not receive any investigational product during the 
screening period. 
Patients who meet the eligibility criteria at Visit 2 (Baseline) will be randomized to 1 of 
4 treatment groups: placebo, levomilnacipran 40 mg/day, levomilnacipran 80 mg/day, or 
fluoxetine 20 mg/day. See Section 9.4.5 for details regarding dose selection and timing. 
All randomized patients who complete the 8-week double-blind treatment period and 
patients who prematurely discontinue from the study before completing 8 weeks of 
double-blind treatment should enter the 1-week, double-blind down-taper period unless it 
is considered not clinically appropriate by the Investigator. 
All patients must complete Visit 8/Early Termination (ET) Visit and, at the end of the 
down-taper period, return for Visit 9/Safety Follow-up (SFU) Visit. Patients who do not 
enter the down-taper period must return for Visit 9/SFU Visit approximately 1 week after 
Visit 8/ET Visit.
Approximately 544 patients (136 per treatment group) are planned to be randomized in 
the study.
Figure 9.1–1 provides a schematic of the study design. The Schedule of Evaluations is 
presented in Section 2.0. Detailed descriptions of each study visit are provided in 
Section 9.5.5.
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9.2
DISCUSSION OF STUDY DESIGN, INCLUDING THE CHOICE 
OF CONTROL GROUPS
This placebo- and active-controlled, fixed-dose design with an 8-week, double-blind 
treatment period was chosen based on prior studies that established the efficacy and 
safety of levomilnacipran in adult patients with MDD. In this study, Investigators must
use a valid and reliable diagnostic method for recruiting and enrolling adolescents 
meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text 
Revision (DSM-IV-TR) criteria for MDD.
A placebo arm is included for comparison since placebo-controlled superiority trials have 
been shown to be conducive to higher quality studies and to provide more reliable 
outcomes than non-inferiority comparisons to a previously approved drug (Feifel, 2008; 
Laughren, 2001; Gispen-de Wied et al, 2012). In addition, placebo in place of the 
(limited) standard therapy 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; see FDA Guidance for 
Industry: E10, May 2001). 
Fluoxetine was selected as an active comparator for the present study because it is an 
SSRI approved by the FDA for the treatment of MDD in children and adolescents 8 years 
and older.
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In the current study, safety and efficacy assessments are included in every visit to 
determine adequacy of response, safety, and tolerability for all patients. 
9.3
SELECTION OF STUDY POPULATION
9.3.1
Inclusion Criteria
Patients must provide assent to participate and their LAR and caregiver (even if the same 
as the LAR) must provide written informed consent prior to the conduct of any 
study-specific procedures (see also Section 5.3). 
To be eligible to participate in the study, patients must meet the following criteria:
1. Male or female outpatients between 12-17 years of age, inclusive, at Visit 1 
2. Patients must meet DSM-IV-TR criteria for MDD, confirmed by K-SADS-PL
3. Patients must have a score ≥ 40 on the Children’s Depression Rating Scale-
Revised (CDRS-R) at Visits 1 and 2
4. Patients must have a Clinical Global Impressions-Severity (CGI-S) score ≥4 at 
Visits 1 and 2
5. Patients must have a caregiver who can and is willing to consent 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 (see Section 5.3) 
6. Patients must have normal physical examination findings, vital sign values, 
clinical laboratory test results, and electrocardiogram (ECG) results or abnormal 
results that are judged not clinically significant by the Investigator
7. Female patients must have a negative serum β-human chorionic gonadotropin 
(β-hCG) pregnancy test result at Visit 1
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9.3.2
Exclusion Criteria
Patients who meet any of the following criteria at Visit 1 (Screening) or Visit 2 
(Baseline) will not be eligible to participate in the study:
Psychiatric Criteria
1. DSM-IV-TR–based diagnosis of an axis I disorder other than MDD that is the 
primary focus of treatment. Patients with conduct disorder will not be allowed to 
participate. Patients with comorbid diagnoses of learning disorders, attention 
deficit disorder (with or without hyperactivity), communication disorders, 
separation anxiety disorder, dysthymic disorder, oppositional defiant disorder, and 
anxiety disorders will be allowed to participate in the study as long as these 
conditions are not the primary focus of any treatment and they comply with 
concomitant medication limitations as listed in Appendix III
2. Prior diagnosis of mental retardation or amnestic or other cognitive disorders 
based on DSM-IV-TR criteria
3.
 
4. Suicide risk as determined by meeting either of the following criteria: 
○
Any suicide attempt within the past year
○
Significant risk at Visit 1 (Screening) or Visit 2 (Baseline), as judged 
by the Investigator based on the psychiatric interview or information 
collected in the Columbia-Suicide Severity Rating Scale (C-SSRS)
Treatment-Related Criteria
5. History of allergy, intolerance, or hypersensitivity to levomilnacipran, 
milnacipran, fluoxetine, or any other SSRI or SNRI or known hypersensitivity to 
the investigational products’ non-medicinal ingredients including gelatin and 
cellulose
6. Patients requiring prohibited concomitant medication or herbal supplements that 
could not be discontinued or switched to an allowable alternative medication and 
stabilized for at least 2 weeks preceding Visit 2 (Baseline)
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Other Medical criteria
9. Any concurrent medical condition that might interfere with the conduct of the 
study, confounds the interpretation of study results, or endangers the patient’s 
well-being. 
 
 
 
 
10. Any cardiovascular disease or condition that is clinically significant, unstable, or 
decompensated. Additionally, patients with any of the following conditions are 
excluded from participation in the study:
 
 
 
 
 
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13. History of seizure disorder (except simple childhood febrile seizures before age 
5), unexplained syncope or black-out episodes, stroke, significant head injury, 
tumor of the central nervous system, or any other condition that predisposes the 
patient toward a risk for seizure 
14. Liver enzyme tests (aspartate aminotransferase [AST] and/or alanine 
aminotransferase [ALT]) > 2 times the upper limit of normal (ULN)
 
16. History of drug or alcohol abuse or dependence within the past year
17. Positive result from the blood alcohol test or the urine drug screen (UDS) for 
prohibited substance, with the following exceptions: 
 
 
 
 
 
 
 
 
 
 
 
 
 
18. 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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9.3.3
Removal of Patients from Therapy or Assessment
A premature discontinuation will occur when a patient who gave voluntary assent and/or 
whose LAR and/or caregiver signed the ICF ceases participation in the study, regardless 
of circumstances, before the completion of the study. Patients can be prematurely 
discontinued from the study for any of the following reasons:

Screen failure (failure to meet inclusion/exclusion criteria) 

Withdrawal of consent

Adverse event (AE)

Lack of efficacy

Protocol violation 

Non-compliance with investigational product

Lost to follow-up

Study terminated by Sponsor 

Site terminated by Sponsor

Other
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All randomized patients who prematurely discontinue from the study, regardless of cause, 
should be seen for a final assessment at ET (see Section 9.5.5.6 for details on assessments 
performed at Visit 8/ET). Patients who discontinued from the study and did not return to 
the site for final assessments must be requested in writing to do so and to return any 
unused investigational product. A copy of the letter, together with the source 
documentation, will be kept by the Investigator. The reasons for premature 
discontinuation from the study will be recorded on the Study Disposition Pages of the 
eCRF.
All randomized patients must complete Visit 8/ET Visit and return for Visit 9/SFU at the 
end of the down-taper period. Patients who do not enter the down-taper period must 
return for Visit 9/SFU approximately 1 week after Visit 8/ET Visit.
9.3.4
Patient Replacement Procedures
Patients in this study who prematurely discontinue treatment will not be replaced.
9.3.5
Demographic Considerations
Efforts will be made to have reasonable representation with respect to gender, race, and 
ethnicity, reflecting the proportions in the disease population. FRI will monitor 
enrollment and may instruct the sites accordingly.
9.4
TREATMENTS
Patients meeting the eligibility criteria at Visit 2 (Baseline) will be randomized in a 
double-blind fashion to 1 of 4 treatment groups: placebo, levomilnacipran 40 mg/day, 
levomilnacipran 80 mg/day, or fluoxetine 20 mg/day.
9.4.1
Treatments Administered
Investigational product in the form of over-encapsulated capsules and tablets will be 
packaged in blister cards and provided by FRI. Patients will be supplied with blinded 
investigational product and will be instructed to take 2 capsules orally each morning 
(see Section 9.4.5 for details). Confirmation that dosing scheme (including titration and 
down-taper) and dosing instructions were discussed with the patient and caregiver and 
that dosing instructions were provided will be recorded in the source documents.
9.4.2
Identity of Investigational Products
Investigational product will be supplied by FRI as capsules containing placebo or 
levomilnacipran 10 mg capsules, levomilnacipran 20 mg capsules, levomilnacipran 
40 mg capsules, fluoxetine 10 mg capsules, or fluoxetine 20 mg tablets packaged in 
blister cards.
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The blister cards will contain sufficient numbers of doses for the interval of days between 
scheduled visits plus additional doses to accommodate visit scheduling. 
The blister cards will be labeled with the protocol number, storage information, warning 
language (viz, “Caution: New Drug—Limited by Federal Law to Investigational Use”), 
and instructions to take as directed. The Investigator will write the date, visit number, 
study week, and patient identification (PID) number on the label.
All investigational product will be provided and shipped to the study centers by FRI and 
must be stored in an appropriate secure area (eg, a locked cabinet in a locked room) at 
room temperature 
 
and must be protected from light, heat, and moisture.
The Investigator is responsible for recording the receipt and use of all investigational 
product supplied and for ensuring the supervision of the storage and allocation of these 
supplies. All unused investigational product must be returned; and, whenever 
investigational product are returned, unit counts must be performed. All investigational 
product must be accounted for. At the end of the study, all unused investigational product 
and empty investigational product packages must be returned to the Sponsor at the 
address provided in the Study Reference Binder.
9.4.3
Method of Assigning Patients to Treatment Groups
After the patient, LAR, and caregiver provide assent and sign the ICF at Visit 1 
(Screening), study personnel will register the patient in the interactive Web response 
system (IWRS) system, and the system will assign the patient a sequential PID number. 
The first patient entered into the system at each site will be assigned the first number in 
the sequence by the system. 
 
 
 
 
 
The study center must contact the IWRS at Baseline (Visit 2) and all subsequent study 
visits in order to obtain the instructions on kit number for the investigational product to 
be dispensed to the patient at that visit. 
A detailed description of IWRS procedures is contained in the IWRS Site User Guide
that should be stored in the Study Reference Binder.
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9.4.4
Selection of Dosages in the Study
Doses were selected based on the population PK model submitted with NDA 204,168 
(Study LVM-MS-01, 2012). To determine the doses for this adolescent study, a 
simulation was performed to infer adolescent plasma concentrations from adult plasma 
concentrations for the 120-mg dose. The simulation found that comparable 
concentrations are expected to be obtained in adolescents at 75% of the adult dose. 
Levomilnacipran has linear PK in adults and a linear PK profile is expected in children 
and adolescents. Therefore, plasma concentrations from doses of 30 mg to 90 mg per day 
in adolescents are expected to correspond to the adult plasma concentrations for the 
approved adult therapeutic range of 40-120 mg/day. 
Levomilnacipran is currently available in 20 mg, 40 mg, 80 mg, and 120 mg capsules. In 
order to use existing strengths and to have more than 1 arm of levomilnacipran in this 
fixed-dose study, doses of 40 mg and 80 mg per day have been selected for the 
adolescent age range. A 10 mg capsule formulation is currently under development for 
the purpose of titration in this study. The corresponding plasma concentrations of these 
doses in adolescents are expected to remain within the plasma concentrations associated 
with the approved therapeutic dose range for adults.
9.4.5
Selection and Timing of Dose for Each Patient
Patients who meet all eligibility criteria at Screening (Visit 1) and who continue to meet 
all the eligibility criteria for participation in the study will be assigned a randomization 
number at Baseline (Visit 2) and dispensed the corresponding blister card containing 
capsules of double-blind investigational product for Week 1. Patients will begin dosing 
with double-blind capsules on the next day. Patients will be instructed to take 2 capsules 
orally as a single dose, once daily at approximately the same time each day 
(morning dosing recommended), with or without food. 
Dosing may be switched from the morning to another time of day if a patient prefers or if 
tolerability issues arise. However, any switch must allow at least 20 hours between 
2 consecutive doses. 
9.4.5.1
Double-blind Treatment Period
The titration schedule is as follows:

Levomilnacipran 40 mg/day treatment group: Days 1-2, 10 mg/day; Days 3-7,
20 mg/day; Week 2 through Week 8, 40 mg/day

Levomilnacipran 80 mg/day treatment group: Days 1-2, 10 mg/day; Days 3-4,
20 mg/day; Days 5-7, 40 mg/day; Week 2 through Week 8, 80 mg/day
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
Fluoxetine 20 mg/day (active comparator): Week 1, 10 mg/day; Week 2 through
Week 8, 20 mg/day
Patients will be assigned a randomization number at Visit 2 and dispensed the 
corresponding blister card containing capsules of double-blind investigational product for 
Week 1. Patients will begin dosing with double-blind capsules on the next morning. 
Patients will be instructed to take 2 capsules from each column (1 each from Row A and
Row B) as a single dose daily each morning with or without food. The double-blind 
dosing regimen is presented in Table 9.4.5.1–1.
Patients will be instructed to return the blister card with any remaining investigational 
product, and to return it even if it is empty, preferably at the next study visit. Additional 
investigational product will be dispensed as per the schedule shown in Section 2.0.
If a patient experiences an AE, the investigational product may be stopped for up to a 
maximum of 4 consecutive days. The date and reason for missed doses must be recorded 
on the appropriate page of the eCRF. 
9.4.5.2
Double-Blind Down-Taper Period
All randomized patients who complete the 8-week double-blind treatment period and
patients who prematurely discontinue from the study before completing 8 weeks of 
double-blind treatment should enter the 1-week, double-blind down-taper period unless it 
is considered not clinically appropriate by the Investigator. The double-blind down-
titration regimen is as follows:
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
Levomilnacipran 40 mg/day and 80 mg/day treatment groups: Days 1-2, 40 mg/day;
Days 3-7, 20 mg/day

Fluoxetine 20 mg/day: Days 1-7, 10 mg/day 
9.4.6
Blinding
A list of patient randomization codes will be generated by Statistical Programming at FRI
and implemented by the IWRS vendor (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 
(see 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 Global Drug Safety at FRI 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. 
In an emergency, the Investigator can obtain the treatment assignment of any patient at 
his/her study center through the IWRS. In an emergency, the Investigator should access 
the IWRS to break the blind.
9.4.8
Prior and Concomitant Therapy
A list of concomitant medications that are allowed and not allowed for either episodic or 
chronic use is provided in Appendix III. Medication history (psychotropic medication 
history during the previous 5 years and all other medications during the past 12 months) 
will be recorded at Screening (Visit 1) in the eCRF. Thereafter, any changes in 
concomitant medications or new medications added will be recorded in the eCRF.
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9.4.9
Monitoring Treatment Compliance
Investigational product compliance during any treatment period will be closely monitored 
by counting the number of capsules dispensed and returned. Before new investigational 
product is dispensed at each visit, every effort will be made to collect all unused 
investigational product. Patients who do not take investigational product for 5 or more 
consecutive days, or consistently demonstrate poor compliance (< 80% or > 120% in 
2 consecutive visit intervals, measured by capsule count) should be considered for study 
discontinuation.  Investigators should consult with the Study Physician before 
discontinuing a patient due to poor compliance.
9.4.10
Treatment After Discontinuation
Patients whose MDD symptoms worsen or are determined by the Investigator to be 
inadequately controlled before completing the double-blind treatment period are allowed 
to discontinue investigational product and start appropriate treatment at the Investigator’s 
discretion. This new treatment will not be provided by FRI. Patients who initiate a new 
treatment for MDD must be discontinued from the study.
9.5
EFFICACY AND SAFETY VARIABLES
9.5.1
Efficacy Assessments
The efficacy assessments will include the CDRS-R, CGI-S, and Clinician Global 
Impressions-Improvement (CGI-I). Efficacy assessments are not to be administered if the 
patient is not accompanied by his/her consented caregiver. The K-SADS-PL and all 
efficacy assessments will be conducted by experienced clinicians meeting training 
requirements and qualifications standards established by FRI and rater training vendor.
9.5.1.1
Primary Efficacy Assessment
The CDRS-R (Appendix V; Poznanski and Mokros, 1996) is a semi-structured, 
clinician-rated instrument designed for use with children and adolescents between the 
ages of 6-17 years and contains 17 ordinally-scaled items that evaluate the presence and 
severity of symptoms commonly associated with childhood depression. The CDRS-R 
total score ranges from 17 to 113. 
The CDRS-R will be administered separately to the patient and to the caregiver. For each 
item, the clinician administering the interviews will select the rating that provides the best 
description of the patient and will then determine the total score. 
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9.5.1.2
Secondary Efficacy Assessment
The CGI-S (Appendix VI; Guy, 1976) is a clinician-rated scale used to rate the severity 
of the patient’s current state of mental illness compared with an MDD patient population. 
The patient will be rated on a scale from 1 to 7, with 1 indicating a “normal, not at all ill” 
and 7 indicating “among the most extremely ill patients.” 
9
3
 
 
 
 
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. Scheduled safety assessments 
are not to be administered if the patient is not accompanied by his/her consented 
caregiver.
9.5.2.1
Adverse Events
An AE is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment. An AE can therefore be 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 data collection for this study, any untoward event that was reported 
from the time the patient signed the ICF until 30 days after the last dose of treatment 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
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
All diseases that occur after signing ICF, 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
Please note that 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 that the investigational product caused the event?
Yes:
There is evidence to suggest a causal relationship between the investigational 
product and AE, ie:
o
There is a reasonable temporal relationship between the investigational product 
and the event, and/or 
o
The event is unlikely to be attributed to underlying/concurrent disease, other 
investigational products, or other factors, and/or
o
Positive dechallenge and/or rechallenge exist
No:
There is no evidence to suggest a causal relationship between the 
investigational product and AE, ie:
o
There is no reasonable temporal relationship between the investigational product 
and the event, or
o
The patient did not take the investigational product, or
o
The event is likely to be attributed to underlying/concurrent disease, other 
investigational products, or other factors, or
o
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. Severity,
which is a description of the intensity of manifestation of the AE, is distinct from 
seriousness, which implies a patient outcome or AE-required treatment measure 
associated with a threat to life or functionality (Section 9.5.2.4). Severity will be assessed 
according to the following scale:
Mild:
A type of AE that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally 
interfere with usual activities of daily living
Moderate:
A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, 
causing discomfort but poses no significant or permanent risk of harm to 
the research participant
Severe:
A type of AE that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention
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. 
In addition, any SAEs reported by the patient (or patient representative) or otherwise 
identified by the Investigator after the study period (ie, after 30 days post last dose) 
should be documented and reported.
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 
post-study period. Any AEs reported by the patient (or patient representative) during this 
period are to be recorded in original source documents. AEs are also to be recorded in the 
eCRF if at least 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. FRI may contact the 
study center to solicit additional information or follow up on the event.
9.5.2.7
Reporting of Pregnancies Occurring During the Study
Study center personnel must report every pregnancy from the time the patient signs the 
ICF until 30 days after the last dose of investigational product. Within 24 hours of 
learning of a pregnancy, the study center personnel must report the event to 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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The pregnancy 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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9.5.3
Investigational Product Concentration Measurements
For patients enrolled under protocol amendment #3, no PK sampling will be 
conducted.  For patients enrolled prior to protocol amendment #3, the following 
procedures should be followed:
PK blood samples will be collected from assented/consented patients to determine plasma 
concentrations of levomilnacipran. The blood sample will be processed, stored, and 
shipped as indicated in Appendix IV. The population PK of levomilnacipran will be 
characterized using serial and sparse plasma concentration-time data. Non-compartmental 
analysis using the serial concentration-time data will also be performed. The plasma 
concentration-time data collected will provide estimates of PK parameters, eg, area under 
the curve (AUC), half-life, maximum plasma drug concentration, and time of maximum 
plasma concentration.
Sparse PK blood samples will be collected during Visits 5, 6, 7, and 8, or ET as follows:

Visit 5, a pre-dose and at 1-4 hours post-dose

Visit 6, 4-6 hours post-dose

Visit 7, 6-8 hours post-dose

Visit 8, random post-dose sample 
In case of scheduling constraints, the sampling times above may be collected in a 
different sequence among the specified visits. 
From a subset of consented patients, instead of sparse PK samples, 7 serial PK blood 
samples will be collected at Visit 5 (or at any 24-hour period between Visit 5 and Visit 7, 
inclusive) at the following time points: pre-dose (20-24 hours after the most recent dose), 
and 2, 4, 6, 8, 10-12, and 24-hours post-dose.
To allow for a pre-dose sampling, patients who take their daily dose in the morning will 
be instructed to hold their daily dose on the sampling day and take it when instructed at 
the study center. Patients who take their dose in the evening will be instructed to not take 
their dose on the evening before the pre-dose sampling visit and to bring the daily dose to 
the site.
PK samples will not be obtained from patients who missed investigational product dosing
for 2 or more consecutive days before the sampling date.
The actual date and clock times of the reference dose (the last dose taken before the 
PK sample) and all blood draws will be recorded in the eCRF along with the date and 
time of the dose before the reference dose for each patient who undergoes PK sampling.
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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. 
The screening period should be 1 week (± 3 days) before Visit 2, but may be extended up 
to a total of 5 weeks to accommodate prior medication washout or to repeat assessments. 
The reason for the extended screening will be recorded in the source documents.
If necessary, visits may be conducted up to 3 days before or after the indicated 
postbaseline weeks relative to Visit 2 (Baseline).
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9.6
DATA QUALITY ASSURANCE
9.6.1
Data Monitoring
Before any patient enters the study, a representative of FRI will meet with the 
Investigator and the study center staff to review the procedures to be followed during the 
study. Electronic data capture (EDC) functionality training is provided via 
computer-based training to train Investigators and authorized designees on recording the 
data in the eCRFs using the EDC system. After the first patient is enrolled, the FRI
representative, a Regional Site Manager (RSM) or designee, will periodically monitor the 
progress of the study by conducting on-site visits. This RSM or designee will review 
query statuses remotely, possibly warranting more frequent communication and/or site 
visits with the Investigator and the study center staff. The Investigator will make 
available to the RSM or designee source documents (written notes and electronic medical 
records, if used), signed consent forms, and all other study-related documents. The 
Investigator and the study center staff will be responsible for data entry of patient data 
into the eCRFs via the EDC system, resolving data queries generated via the EDC 
system, and providing missing or corrected data. The Investigator or designee will be 
responsible for approving all changes performed on the data, and endorsing the patient 
data within the EDC system. This approval method will include applying an electronic 
signature linked to a uniquely assigned username and password that together will 
represent a traditional handwritten signature used in the past.
9.6.2
Data Recording and Documentation
Data collection will involve the use of the FRI EDC system, to which only authorized 
personnel will have access. Patient’s data are to be entered into the EDC system by the 
Investigator or designee using their assigned EDC user account. After data entry into the 
EDC system by the Investigator or designee, a combination of manual and programmatic 
edit checks will be used to review the data for completeness, logic, and adherence to 
study protocol. As a result of these edits checks, data monitoring, and reviews, queries 
may be electronically issued to the site and should be answered electronically via the 
EDC system.
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Each query will carry identifying information (assigned username, date, and time) to 
assist FRI and the Investigator on the origin of the data clarification request and the 
response provided by the Investigator. All data changes made to the patient’s data via a 
data query will be approved by the Investigator before the final database lock.
After all data have been reviewed and all issues have been resolved, the database will be 
locked.
All data collected in the context of this study will be stored and evaluated per regulatory 
requirements and applicable guidance for electronic records. Also, data will be stored and 
evaluated in such a way as to guarantee patient confidentiality in accordance with the 
legal stipulations applying to confidentiality of data. Study records (eg, copies of eCRFs, 
laboratory reports, patient diaries, regulatory documents) will be retained at the site, 
along with adequate source documentation, according to FDA and ICH requirements. All 
study records must be available for inspection by FRI, its authorized representatives, and 
the FDA or other health authorities.
9.7
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE
9.7.1
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 and 
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 the 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 the 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 (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 disposition
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.
The number and percentage of patients with important protocol deviations will be 
summarized overall and by treatment group for the Safety Population. Deviations related 
to the following categories will be included:

Inclusion or exclusion criteria

Withdrawal criteria

Treatment or dose

Concomitant medications
These and any additional important protocol deviations will be reviewed and documented 
before database lock and unblinding of treatment codes.
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.
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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.
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 recorded medication taken on or after the date of the first dose of double-blind 
investigational product. 
Both prior and concomitant medication use will be summarized by the number and 
proportion of patients in each treatment group receiving each medication within each 
therapeutic class for the Safety Population. Multiple medication use by a patient will only 
be counted once. Any recorded medications started after last dose of double-blind 
investigational product will not be summarized but will be included in listings.
9.7.4
Extent of Exposure and Treatment Compliance
9.7.4.1
Extent of Exposure 
9.7.4.1.1
Investigational Product
Exposure to double-blind investigational product for the Safety Population during the 
double-blind treatment period will be summarized for treatment duration, calculated as 
the number of days from the date of the first dose of double-blind investigational product 
taken to the date of the last dose taken, inclusive. Descriptive statistics (n, mean, SD, 
minimum, median, and maximum) will be presented by treatment group.
In addition, weekly and overall mean daily dose of investigational product will be 
summarized by treatment group for the Safety Population.
9.7.4.2
Measurement of Treatment Compliance 
Dosing compliance for a specified period will be defined as the total number of capsules 
or tablets actually taken by a patient during that period divided by the number of 
capsules or tablets prescribed to be taken for the same period multiplied by 100. This 
information will be obtained from the investigational product record of the patient’s 
eCRF. 
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The total number of capsules or tablets actually taken during a specific time period is 
calculated based on the study medication record. The number of capsules or tablets 
prescribed to be taken for a specific treatment period will be calculated by multiplying 
the number of days in that period by the number of capsules or tablets to be taken per 
day.
Descriptive statistics for investigational product compliance will be presented by 
treatment group for each period between 2 consecutive visits, as well as for the entire 
double-blind treatment period.
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 Visit 2. All
statistical tests will be 2-sided hypothesis tests performed at the 5% level of significance. 
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 less than 2 patients in at least 1 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 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 more than 1 smallest pseudo center, the pseudo center with the 
smallest center code will be selected. In case 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.
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.
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In addition, by-visit analyses using the last-observation-carried-forward (LOCF) 
approach will be presented for all continuous 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.
9.7.5.1
Primary Efficacy Parameter
The primary efficacy parameter is the change from baseline to end of Week 8 in the 
CDRS-R total score. The primary analysis will be performed using an MMRM with 
treatment group, 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. 
The multiple comparison issues will be addressed using the matched parallel gatekeeping 
procedure (Chen et al, 2005). 
In addition, 2 sensitivity analyses, LOCF and pattern-mixture model, will be performed 
on the primary efficacy parameter. For the LOCF approach, the between-treatment group 
comparison will be performed by means of an analysis-of-covariance model with 
treatment group and pooled study center as factors and the baseline CDRS-R total score 
as the covariate. The LOCF approach will be used to impute missing postbaseline values, 
provided that at least 1 postbaseline assessment is available. Missing values between the 
baseline and the first nonmissing postbaseline will be imputed with the baseline value. If 
all the postbaseline values are missing, baseline value will not be carried forward. Only 
the total score of a parameter will be imputed using the LOCF approach; individual item 
scores will not be carried forward.
In the other sensitivity analysis, a pattern-mixture model 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 missingness assumption. The non-future dependent missing value restriction 
states that the probability of drop-out at a specific visit can only depend on the observed 
value and the possibly missing value up to that visit, but not future values beyond that 
visit. The details of this sensitivity analyses are as follows:
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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 dataset with 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 the same model as the primary analysis 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. 
9.7.5.2
Secondary Efficacy Parameter
The secondary efficacy parameter is the change from baseline to the end of Week 8 in 
CGI-S score. This parameter will be analyzed similarly to the primary efficacy parameter.
To control the overall type I error rate for multiple comparisons across the primary and 
the secondary efficacy parameters, the matched parallel gatekeeping procedure 
(Chen et al, 2005) will be implemented.
A sensitivity analysis will also be performed using the LOCF approach as described in 
Section 9.7.5.1.
 
 
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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 treatment 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 was 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.
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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 and will be sorted by decreasing frequency for the test treatment. In 
addition, the incidence of fatal on-therapy SAEs (ie, events that caused death) will be 
summarized separately by treatment group and preferred term. An SAE will be defined as 
an on-therapy SAE if it occurred on or after the date of the first dose of double-blind 
investigational product and within 30 days of the date of the last dose of double-blind 
investigational product.
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 
discontinuation, and patients who die (if any). 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.
 
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9.7.6.6
Investigational Product Plasma Concentration Parameters
Plasma samples will be analyzed for the concentrations of levomilnacipran using 
validated bioanalytical methods. Population PK parameters will be estimated using 
nonlinear mixed-effects modeling methods. The study will be prospectively powered to 
target a 95% confidence interval within 60% and 140% of the geometric mean estimates 
of clearance and volume of distribution for levomilnacipran ER, with at least 80% power.  
9.7.7
Health Economics and Outcomes Research Analyses
Not applicable.
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9.7.8
Blinded Interim Analysis
A blinded interim analysis will be conducted when approximately 75% of randomized 
patients have either completed or discontinued the study. The blinded interim analysis is 
to obtain an estimate of the pooled SD on change from baseline to Week 8 in the 
CDRS-R total score. If the estimated pooled SD is larger than the assumed pooled SD
specified in the sample size estimation (Determination of Sample Size, Section 9.7.9), 
sample sizes 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 800 (200 per treatment group).
In addition, an interim PK analysis will be performed by updating the adult population 
PK model with PK data from this adolescent pediatric study to establish the doses to be 
used in future studies.
9.7.9
Determination of Sample Size
Original sample size calculation: The effect size (treatment group difference relative to 
pooled SD) of 0.36 for both levomilnacipran and fluoxetine is based on a treatment 
difference of 4 units with a common pooled SD of 11.1 for the primary efficacy 
parameter, change from baseline to Week 8 in CDRS-R total score. Adjusting for 
multiple comparisons of 2 levomilnacipran groups with placebo across the primary and 
secondary endpoints by using the matched parallel gatekeeping procedure, a sample size
of 660 patients (165 per treatment group) will be needed to provide 85% power for 
primary analysis (levomilnacipran vs placebo) and for assay sensitivity analysis 
(fluoxetine vs placebo) 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 data in pediatric patients. Following discussions with 
FDA, the study will be deemed to be successful if at least 1 of 2 levomilnacipran doses 
(40 mg/day and 80 mg/day) is shown to be statistically significant versus placebo based 
on the primary efficacy endpoint. Therefore, the study will be powered at 85% based on 
at least one of the two dose levels achieving statistical significance, which yields a 
resultant sample size of 520 patients using the same assumptions.
Sample size recalculation: Following a blinded interim analysis, the sample size has 
been re-estimated. The MMRM model is used to estimate the pooled variance for change 
from baseline in CDRS-R total score at Week 8; it includes pooled study site and week as 
factors, and baseline CDRS-R total score and baseline value-by-week interaction as 
covariates.
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A total of 421 subjects were included in the ITT analysis. Of these 421 patients, 
347 (82.4%) patients have observed data at Week 8, so the estimated dropout rate at 
Week 8 is 17.6%. Based on the MMRM model, the variance estimate for the change from 
baseline in CDRS-R total score at Week 8 is 129.53, and the estimated pooled standard 
deviation is 11.38.  Thus, the estimated effect size is 0.35 based on a treatment difference 
of 4 units and a pooled standard deviation of 11.38.
Assuming an effect size of 0.35, a common dropout rate of 17.6%, and a correlation of 
0.7 between the repeated measures, an estimated total sample size of 544 patients 
(136 per group) will be needed to maintain the 85% power to detect the treatment 
difference of 4 units in at least 1 of the 2 doses of levomilnacipran versus placebo.
9.7.10
COMPUTER METHODS
Statistical analyses will be performed using version 
 
.
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. 
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 patient 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. 
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Protocol deviations that may impact a 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
(http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm127073.pdf).
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10.0
STUDY SPONSORSHIP
This study is sponsored by FRI.
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 the FRI’s Standard Operating Procedure on 
publications. 
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11.0
INVESTIGATOR OBLIGATIONS
11.1
DOCUMENTATION
The Investigator must provide the following to FRI before the start of the study:

A completed and signed Form FDA 1572. If, during the course of the study, any 
changes are made that are not reflected on Form FDA 1572, a new Form FDA 1572 
must be completed and returned to FRI for submission to the FDA

A fully executed contract

The curricula vitae for the Investigator and all Subinvestigators listed on 
Form FDA 1572, including a copy of each physician’s license

A copy of the original IRB/IEC approval for conducting the study. If the study is 
ongoing, renewals must be submitted at yearly intervals. All subsequent 
modifications must be submitted and approved by the IRB/IEC, as stated in 
Section 5.1

A copy of the IRB/IEC-approved ICF

A copy of the HIPAA authorization form, or other local privacy applicable forms

A list of the IRB/IEC members or the US Department of Health and Human Services
general assurance number

A copy of the laboratory certifications and reference ranges

The Investigator’s Statement page in this protocol signed and dated by the 
Investigator 

Financial disclosure agreement completed and signed by the Investigator and all 
Subinvestigators listed on Form FDA 1572. The Investigator and all Subinvestigators 
will provide an updated financial disclosure agreement to FRI 1 year after the 
completion of the study
11.2
PERFORMANCE
The Investigator must demonstrate reasonable efforts to obtain qualified patients for the 
study.
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11.3
USE OF INVESTIGATIONAL MATERIALS
The Investigator will acknowledge that the investigational product supplies are 
investigational and as such must be used strictly in accordance with the protocol and only 
under the supervision of the Investigator or Subinvestigators listed on Form FDA 1572. 
The investigational products must be stored and locked in a secured location. At study 
initiation, a representative from FRI will inventory the investigational products at the site. 
The Investigator must maintain adequate records documenting the receipt and disposition 
of all study supplies. FRI will supply forms on which to record the date the 
investigational products were received and a dispensing record in which to record 
each patient’s use. All unused investigational products must be returned to FRI. It is the 
Investigator’s responsibility to ensure that patients return their investigational product.
11.4
CASE REPORT FORMS
All patient data relating to the study will be recorded on eCRFs to be provided by FRI 
through the EDC system. The Investigator is responsible for verifying that all data entries 
in the eCRFs are accurate and correct by electronically signing the completed eCRF 
casebook submitted to FRI. The Investigator must maintain and retain accurate 
documentation that supports the information entered into the EDC system for source 
document verification and possible regulatory inspection.
11.5
RETENTION AND REVIEW OF RECORDS
Records and documents pertaining to the conduct of this study, including case report 
forms, 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 (Protocol 
LVM-MD-11, Amendment #3) dated 25 Mar 2019 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 from each patient participating in a clinical research study or from the patient’s 
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/IEC; or an authorized contract research organization may inspect the 
records

For research involving more than minimal risk, an explanation of whether any 
medical treatment is available if injury occurs and, if so, what it consists of or where 
further information may be obtained

An explanation of whom to contact, including the relevant telephone number, for 
answers to pertinent questions about the research and the research patient’s rights and 
whom to contact in the event of a research-related injury to the patient. (Note: In 
some cases, it may be necessary to identify a person other than the Investigator as the 
contact. The guidance of the IRB/IEC may be required)

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 consent (eg, “I agree to participate . . .”)

A place for the patient’s signature and date of signing

A statement indicating that information about this study has been, or will be, entered 
into a databank that is publicly accessible at www.ClinicalTrials.gov.
A copy of the signed consent form must be given to the patient.
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APPENDIX II.
CONTACT INFORMATION 
Contact information for FRI personnel will be provided in the study reference binder.
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14.0
LITERATURE CITED
American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 
Fourth Edition, Text Revision. Washington, DC: American Psychiatric Association; 
2000.
Angold A, Costello EJ, Worthman CM. Puberty and depression: the roles of age, pubertal 
status and pubertal timing. Psychol Med 1998;28:51-61. 
Auclair AL, Martel JC, Assié MB, et al. Levomilnacipran (F2695), a norepinephrine-
preferring SNRI: Profile in vitro and in models of depression and anxiety.
Neuropharmacology 2013;70:338-347.
Centers for Disease Control, Injury Center: Violence Prevention. 
http://www.cdc.gov/violenceprevention/pub/youth_suicide.html. Last review 09 Jan 2014. 
Accessed 11 Nov 2014.
Chen X, Luo X, Capizzi T. The application of enhanced parallel gatekeeping strategies. 
Statistics in Medicine 2005;24:1385-1397.
Citrome L. Levomilnacipran for major depressive disorder: a systematic review of the 
efficacy and safety profile for this newly approved antidepressant—what is the number 
needed to treat, number needed to harm, and likelihood to be helped or harmed? 
2013 Nov;67(11):1089-104.
Cole TJ. The LMS method for constructing normalized growth standards. Eur J Clin 
Nutr. 1990;44:45-60.
Deecher DC, Beyer CE, Johnston G, et al. Desvenlafaxine succinate: a new serotonin and 
norepinephrine reuptake inhibitor. J Pharm Experimental Therapeutics 2006; 
318(2):657-69.
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: E10, Choice of Control Group and Related Issues in 
Clinical Trials, May 2001.
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.
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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.
Kenward MG, Molenberghs G, Thijs H. Pattern-mixture models with proper time 
dependence. Biometrika 2003; 90(1):53-71.
Kenward MG and 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.
Lu K. Sample size calculations with multiplicity adjustment for longitudinal clinical trials 
with missing data. Stat Med 2012;31:19-28.
Montgomery S and Briley M. Noradrenergic symptom cluster in depression. 
Neuropsychiatr Dis Treat. 2011;7(Suppl 1):1-2.
Poznanski EO and Mokros HB. Children’s Depression rating Scale Revised (CDRS R), 
Western Psychological Services, Los Angeles, 1996.
Vaishnavi SN, Nemeroff CB, Plott SJ et al. Milnacipran: a comparative analysis of 
human monoamine uptake and transporter binding affinity. Bio Psychiatry 2004; 
44:320-22.
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_000.pdf: 
NCT02431806 
 
Study ID: LVM-MD-11 
 
 
 
Title: A Double-blind, Placebo- and Active-Controlled Evaluation of the Safety and Efficacy of 
Levomilnacipran ER in Adolescent Patients With Major Depressive Disorder 
 
Statistical Analysis Plan Amendment 2 Date: 3 Oct 2019 
 
 


1.0 
TITLE PAGE 
 
Forest Research Institute, Inc. 
Harborside Financial Center, Plaza V 
Jersey City, NJ 07311 
LVM-MD-11 
A Double-blind, Placebo- and Active-Controlled Evaluation of the Safety and 
Efficacy of Levomilnacipran ER in Adolescent Patients with Major Depressive 
Disorder 
STATISTICAL ANALYSIS PLAN 
Original SAP Date: 06 Mar 2015 
Amendment #1:       16 July 2015 
Amendment #2:       3 October 2019 
 
 
 
 
 
 
 
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, Inc. 


2 
 
2.0 
TABLE OF CONTENTS 
1.0 
TITLE PAGE .................................................................................................................................... 1 
2.0 
TABLE OF CONTENTS .................................................................................................................. 2 
3.0 
LIST OF ABBREVIATIONS ........................................................................................................... 4 
4.0 
INTRODUCTION ............................................................................................................................ 6 
5.0 
OBJECTIVES ................................................................................................................................. 11 
6.0 
PATIENT POPULATIONS ............................................................................................................ 12 
6.1 
SCREENED POPULATION ............................................................................................ 12 
6.2 
RANDOMIZED POPULATION ..................................................................................... 12 
6.3 
SAFETY POPULATION ................................................................................................. 12 
6.4 
INTENT-TO-TREAT POPULATION ............................................................................. 12 
7.0 
PATIENT DISPOSITION .............................................................................................................. 13 
8.0 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ........................................ 14 
9.0 
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE ................................................ 15 
9.1 
EXTENT OF EXPOSURE ............................................................................................... 15 
9.2 
MEASUREMENT OF TREATMENT COMPLIANCE .................................................. 15 
10.0 
EFFICACY ANALYSES ............................................................................................................... 16 
10.1 
PRIMARY EFFICACY PARAMETER ........................................................................... 17 
10.2 
SECONDARY EFFICACY PARAMETER ..................................................................... 18 
 
 
 
 
11.1 
ADVERSE EVENTS ........................................................................................................ 20 
 
 
 
 
 
 
 
 
 
 
 
 
12.0 
HEALTH OUTCOMES ANALYSES ............................................................................................ 28 
13.0 
BLINDED INTERIM ANALYSIS ................................................................................................. 29 
14.0 
DETERMINATION OF SAMPLE SIZE ....................................................................................... 30 
15.0 
STATISTICAL SOFTWARE ......................................................................................................... 31 
16.0 
DATA HANDLING CONVENTIONS .......................................................................................... 32 
 
 


3 
 
16.2 
DERIVED EFFICACY VARIABLES ............................................................................. 33 
16.3 
AGE-AND-GENDER-CORRELATED VALUES FOR WEIGHT AND HEIGHT ........ 33 
16.4 
REPEATED OR UNSCHEDULED ASSESSMENTS OF SAFETY PARAMETERS ... 34 
16.5 
MISSING DATE OF THE LAST DOSE OF INVESTIGATIONAL PRODUCT ........... 34 
16.6 
MISSING SEVERITY ASSESSMENT FOR ADVERSE EVENTS ............................... 35 
16.7 
MISSING CAUSAL RELATIONSHIP TO INVESTIGATIONAL PRODUCT FOR 
ADVERSE EVENTS ........................................................................................................ 35 
16.8 
MISSING DATE INFORMATION FOR ADVERSE EVENTS ..................................... 35 
16.9 
MISSING DATE INFORMATION FOR PRIOR OR CONCOMITANT 
MEDICATIONS ............................................................................................................... 36 
16.9.1 
Incomplete Start Date ......................................................................................... 36 
16.9.2 
Incomplete Stop Date ......................................................................................... 37 
 
 
17.0 
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL .......................................................... 40 
18.0 
REFERENCES ............................................................................................................................... 41 
19.0 
APPENDICES ................................................................................................................................ 42 
APPENDIX I 
PATTERN-MIXTURE MODEL DETAILS ...................................................... 42 
     
 
 
APPENDIX III     SAP AMENDMENT #2 SUMMARY .............................................................. 49 
 


4 
 
3.0 
LIST OF ABBREVIATIONS  
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ANCOVA 
analysis of covariance 
BP 
blood pressure 
CDRS-R 
Children’s Depression Rating Scale-Revised 
CGI-I 
Clinical Global Impression - Improvement 
CGI-S 
Clinical Global Impression - Severity 
 
 
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 
MAR 
missing at random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed-effects model for repeated measures 
MNAR 
missing not at random 


5 
 
NEAE 
newly emergent adverse event 
NFD 
non-future dependence 
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 


6 
 
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 LVM-MD-11. Specifications of tables, figures, and data listings are 
contained in a separate document. The statistical analysis for pharmacokinetic parameters 
will be specified in a separate document. 
Study LVM-MD-11 is a multicenter, randomized, double-blind, placebo- and active-
controlled, parallel-group, fixed-dose study in adolescent patients, ages 12 - 17 years, 
who have been diagnosed with major depressive disorder (MDD) using Diagnostic and 
Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) 
diagnostic criteria. This study includes 4 treatment groups: placebo, levomilnacipran 
40 mg/day, levomilnacipran 80 mg/day, and fluoxetine 20 mg/day. A total of 544 patients 
(136 per treatment group) are planned to be randomized. 
The length of this study will be 10 weeks, starting with a 1-week screening period, 
followed by 8-week of double-blind treatment period, and 1-week of double-blind 
down-taper period. Patients must provide assent to participation and their legally 
authorized representative (LAR) and caregiver must provide written informed consent 
prior to the conduct of any study-specific procedures. At the end of Visit 2 (Baseline), 
patients meeting eligibility criteria will be randomized in 1:1:1:1 ratio to treatment groups 
of placebo, levomilnacipran 40 mg, levomilnacipran 80 mg, and fluoxetine 20 mg, 
respectively. Patients randomized to the levomilnacipran 40 mg/day group will receive 
10 mg/day for Days 1 to 2 (2 days), 20 mg/day for Days 3 to 7 (5 days), and 40 mg/day 
for Weeks 2 through Week 8; patients randomized to the levomilnacipran 80 mg/day 
group will receive 10 mg/day for Days 1 to 2 (2 days), 20 mg/day for Days 3 to 4 
(2 days), 40 mg/day for Days 5 to 7, and 80 mg/day for Weeks 2 through Week 8; 
Patients randomized to fluoxetine 20 mg/day group will receive 10 mg/day for Week 1, 
and 20 mg/day for Weeks 2 through 8. (Table 4–1). 


7 
 


8 
 


9 
 


10 
 


11 
 
5.0 
OBJECTIVES 
The objective of this study is to evaluate the efficacy, safety, and tolerability of 
levomilnacipran relative to placebo in adolescent outpatients (12 - 17 years) with MDD. 
In addition, the study is designed to obtain pharmacokinetic (PK) data to guide the dose 
selection for future levomilnacipran pediatric studies. 


12 
 
6.0 
PATIENT POPULATIONS 
Four populations will be considered in the statistical analysis of the study as specified 
below. 
6.1 
SCREENED POPULATION 
The Screened Population will consist of all patients who underwent a Screening Visit, 
received a screening number, and for whom 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 took 
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 the baseline and at least 1 postbaseline assessment of the CDRS-R total score. 


13 
 
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 double-blind down-taper period and of 
patients who complete the double-blind 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 (eCRF) will be 
summarized (number and percentage) by treatment group for the Safety Population. 
Percentage of premature discontinuations will be provided for overall and for each 
discontinuation reason. All patients who prematurely discontinue during the double-blind 
treatment period will be listed by discontinuation reason for the Safety Population. 


14 
 
8.0 
DEMOGRAPHICS AND OTHER BASELINE 
CHARACTERISTICS 
Demographic parameters (age, sex, race, and 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. 
Medical and surgical history/physical findings will be classified by system organ class 
and preferred term using the Medical Dictionary for Regulatory Activities, version 16.1 
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 MDD and nondrug 
psychiatric treatment history will also be summarized by treatment group for the Safety 
Population. 
The World Health Organization Drug Dictionary, version March 2013 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.  
Summaries for concomitant medication use will be presented for the double-blind 
treatment period and the double-blind down-taper period, separately. Any concomitant 
medications started 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. 


15 
 
9.0 
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE 
9.1 
EXTENT OF EXPOSURE 
Exposure to the 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 double-blind down-taper period), will be summarized by treatment group 
for the Safety Population. 
In addition, weekly and overall mean 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 
Dosing compliance for a specified period is defined as the number of capsules actually 
taken by a patient during that period divided by the number of capsules prescribed for the 
same period multiplied by 100. The total number of capsules actually taken during a 
specific time period will be calculated from the study medication records. The number of 
capsules expected to be taken for a specific treatment period will be calculated by 
multiplying the number of days in that period by the number of capsules prescribed to be 
taken per day. 
Descriptive statistics for investigational product compliance during the double-blind 
treatment period will be presented by treatment group for each period between 
2 consecutive visits, as well as for the whole double-blind treatment period, for the Safety 
Population. 


16 
 
10.0 
EFFICACY ANALYSES 
The efficacy analyses will be based on the ITT Population. Baseline for each efficacy 
parameter is defined as the last nonmissing assessment 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 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. 


17 
 
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 levomilnacipran 40 mg vs. placebo, and 
levomilnacipran 80 mg vs. placebo for the primary efficacy parameter will be performed 
using an MMRM with treatment group, pooled study center, visit, and treatment 
group-by-visit interaction as fixed effects and the baseline value and baseline value-by-
visit interaction as 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, the matched parallel gatekeeping procedure 
(Chen et al.,2005) will be applied. Details are provided in Section 10.2. 
Graphical display of treatment difference vs. placebo (mean difference ± SE) in primary 
efficacy parameter will be provided by study center. 
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. The pattern-mixture model approach is based on the non-future dependent 
missing value restrictions (Kenward et al., 2003) and is 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 Δ. The dataset with all 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 Δ is selected as 0 to 6 based on 
experience with historical data. Technical details of the proposed pattern-mixture model 
approach (eg, 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. 


18 
 
Since the investigator of Site 054 didn’t conduct the study in accordance with signed 
statement, one more sensitivity analysis excluding all data from Site 054 will be 
performed on the primary efficacy parameter. The same MMRM would be applied on all 
OC of change from baseline to Week 8 in CDRS-R total score except all values of Site 
054.  
10.2 
SECONDARY EFFICACY PARAMETER 
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 type I error rate for multiple comparisons across the primary and 
the secondary efficacy parameters and multiple doses, the matched parallel gatekeeping 
procedure (Chen et al., 2005) will be implemented. The primary hypotheses family, F1, 
consists of 2 null hypotheses H11 and H12 which are for comparisons of levomilnacipran 
40 mg and 80 mg, respectively, with placebo in regard to the primary efficacy parameter, 
change from baseline to Week 8 in CDRS-R total score. Similarly for the secondary 
efficacy parameter, change from baseline to Week 8 in CGI-S score, we have the 
corresponding hypotheses family F2 = {H21, H22}. Family F1 will serve as the parallel 
gatekeeper for F2. Then the matched gatekeeper procedure utilizes the special logical 
relationship between the primary and the secondary parameters to enhance the power of 
statistical testing, i.e., primary and secondary hypotheses are matched on dose. The 
secondary efficacy parameter will be tested at a specific dose only if the corresponding 
primary efficacy parameter is statistically significant. Weighted Simes test will be 
performed to derive the local p-values for the intersection hypotheses. Assignment of 
weight for all 24 - 1 = 15 intersection hypotheses is shown in Table 10.2–1. 
Table 10.2–1. 
Weights for Intersection Tests in the Matched Parallel Gatekeeping Procedure 
Intersection hypothesis 
Weight 
H11 
H12 
H21 
H22 
H11∩H12∩H21∩H22 
0.5 
0.5 
0 
0 
H11∩H12∩H21 
0.5 
0.5 
0 
0 
H11∩H12∩H22 
0.5 
0.5 
0 
0 
H11∩H12 
0.5 
0.5 
0 
0 
H11∩H21∩H22 
0.5 
0 
0 
0.5 
H11∩H21 
1 
0 
0 
0 
H11∩H22 
0.5 
0 
0 
0.5 
H11 
1 
0 
0 
0 
H12∩H21∩H22 
0 
0.5 
0.5 
0 


19 
 
H12∩H21 
0 
0.5 
0.5 
0 
H12∩H22 
0 
1 
0 
0 
H12 
0 
1 
0 
0 
H21∩H22 
0 
0 
0.5 
0.5 
H21 
0 
0 
1 
0 
H22 
0 
0 
0 
1 
 
The adjusted p-values for the four elementary hypotheses will be calculated from the 
local p-values based on the closed testing principle. Statistical significance is determined 
by comparing the adjusted p-values to α = 0.05. The multiplicity method controls the 
family-wise type I error rate since the Simes inequality holds for multivariate normal 
distributions with nonnegative correlations (Sarkar, 2008). The large sample size of this 
study ensures asymptotic normality while nonnegative correlations are well-known 
among different active versus placebo comparisons and are expected to exist across 
different time points and between the CDRS-R and CGI-S endpoints based on historical 
data. 


20 
 
11.1 
ADVERSE EVENTS 
Adverse events will be coded by system organ class and preferred term using the Medical 
Dictionary for Regulatory Activities, version 16.1 or newer. 


21 
 
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 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 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 in the study will not be counted as a TEAE but will 
be included in the listings. 
An AE occurring during the double-blind down-taper period will be considered a newly 
emergent AE (NEAE) 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 NEAEs during the 
double-blind down-taper period will be summarized by body system, preferred term, and 
treatment group for all patients who enter the double-blind down-taper period. 
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. Common TEAE during the double-blind 
treatment period is defined 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 levomilnacipran treatment group (first levomilnacipran 80 mg/day, then 
levomilnacipran 40 mg/day). 
A serious adverse event (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, inclusive, will be considered an on-therapy SAE.  


22 
 
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 
levomilnacipran treatment groups. In addition, the incidence of on-therapy SAEs that led 
to death will be summarized separately by treatment group and preferred term. 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 
levomilnacipran treatment group. 
Listings will be presented for patients with SAEs, patients with AEs leading to 
discontinuation, and patients who died (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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


23 
 


24 
 


25 
 


26 
 


27 
 


28 
 
12.0 
HEALTH OUTCOMES ANALYSES 
Not applicable. 


29 
 
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 800 (200 per treatment group). 
Detailed specification of the blinded interim analysis will be provided in the blinded 
interim analysis plan, a separate document. 


30 
 
14.0 
DETERMINATION OF SAMPLE SIZE 
Original sample size calculation: the effect size (treatment group difference relative to 
pooled standard deviation) of 0.36 for both levomilnacipran and fluoxetine is based on a 
treatment difference of 4 units with a common pooled standard deviation of 11.1 for the 
primary efficacy parameter, change from baseline to Week 8 in CDRS-R total score. 
Adjusting for multiple comparisons of two levomilnacipran groups with placebo across 
the primary and secondary endpoints by using the matched parallel gatekeeping 
procedure, a sample size of 660 patients (165 per treatment group) will provide 85% 
power for the primary analysis (levomilnacipran vs. placebo) and for assay sensitivity 
analysis (fluoxetine vs. placebo) 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 data in pediatric patients. 
Sample size recalculation based on discussion with FDA: following the discussion 
with FDA, the study will be deemed as successful if statistical significance is achieved in 
at least one of two levomilnacipran doses (40 mg/day and 80 mg/day) versus placebo 
based on the primary efficacy endpoint. Therefore, resultant sample size is 520 patients 
(130 per treatment group) as required by 85% power based upon statistical significance in 
at least one of the two dose levels with the same effect size assumption.  
Sample size recalculation based on interim analysis: following a blinded interim 
analysis, the sample size has been re-estimated. The MMRM model to estimate the 
pooled variance for change from baseline in CDRS-R total score at Week 8 includes 
pooled study site and week as factors and baseline CDRS-R total score and baseline 
value-by-week interaction as covariates, where week is included as a class variable. A 
total of 421 patients were included in the ITT analysis. Of these 421 patients, 347 
(82.4%) patients have observed data at Week 8, so the estimated drop-out rate at Week 8 
is 17.6%. Based on the MMRM model, the variance estimate for the change from 
baseline in CDRS-R total score at Week 8 is 129.53, and the estimated pooled standard 
deviation is 11.38.  Thus the estimated effect size is 0.35 based on a treatment difference 
of 4 units and a pooled standard deviation of 11.38. Assuming an effect size of 0.35, a 
common dropout rate of 17.6%, and a correlation of 0.7 between the repeated measures, 
an estimated total sample size of 544 patients (136 per treatment group) will be needed to 
maintain the 85% power to detect the treatment difference of 4 units for at least one 
levomilnacipran group versus placebo and for fluoxetine versus placebo. 


31 
 
15.0 
STATISTICAL SOFTWARE 
Statistical analyses will be performed using
 
 


32 
 
16.0 
DATA HANDLING CONVENTIONS 


33 
 
 
 
 
 
 
 
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 


34 
 
The z-score is calculated as below 
SL
M
X
z
L
1
)
/
(
−
=
, if L ≠ 0 and 
S
M
X
z
)
/
ln(
=
, if 
0
=
L
, 
where X is the physical measurement (eg 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 visit date will be used as the last dose date. 


35 
 
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). 
Missing month and day 
• If the year of the incomplete start date is the same as the year of the first dose of 
double-blind investigational product, the month and day of the first dose of 
double-blind investigational product will be assigned to the missing fields 
• If the year of the incomplete start date is before the year of the first dose of 
double-blind investigational product, December 31 will be assigned to the missing 
fields 
• If the year of the incomplete start date is after the year of the first dose of 
double-blind investigational product, January 1 will be assigned to the missing fields 
Missing month only 
• If only the month is missing, the day will be treated as missing and both the month 
and the day will be replaced according to the above procedure 


36 
 
Missing day only 
• If the month and year of the incomplete start date are the same as the month and year 
of the first dose of double-blind investigational product, the day of the first dose of 
double-blind investigational product will be assigned to the missing day 
• If either the year of the incomplete start date is before the year of the date of the first 
dose of double-blind investigational product or if both years are the same but the 
month of the incomplete start date is before the month of the date of the first dose of 
double-blind investigational product, the last day of the month will be assigned to the 
missing day 
• If either the year of the incomplete start date is after the year of the date of the first 
dose of double-blind investigational product or if both years are the same but the 
month of the incomplete start date is after the month of the date of the first dose of 
double-blind investigational product, the first day of the month will be assigned to the 
missing day 
If the stop date is complete and the imputed start date as above is after the stop date, the 
start date will be imputed by the stop date. 
If the start date is completely missing and the stop date is complete, the following 
algorithm will be used to impute the start date: 
• If the stop date is after the date of the first dose of double-blind investigational 
product, the date of the first dose of double-blind investigational product will be 
assigned to the missing start date 
• If the stop date is before the date of the first dose of double-blind investigational 
product, the stop date will be assigned to the missing start date 
16.9 
MISSING DATE INFORMATION FOR PRIOR OR 
CONCOMITANT MEDICATIONS 
For prior or concomitant medications, including rescue medications, incomplete 
(i.e., partly missing) start dates and/or stop dates will be imputed. When the start date and 
the stop date are both incomplete for a patient, the start date will be imputed first. 
16.9.1 
Incomplete Start Date 
The following rules will be applied to impute the missing numeric fields for an 
incomplete prior or concomitant medication start date. If the stop date is complete (or 
imputed) and the imputed start date is after the stop date, the start date will be imputed 
using the stop date. 


37 
 
Missing month and day 
• If the year of the incomplete start date is the same as the year of the first dose of 
double-blind investigational product, the month and day of the first dose of 
double-blind investigational product will be assigned to the missing fields 
• If the year of the incomplete start date is before the year of the first dose of 
double-blind investigational product, December 31 will be assigned to the missing 
fields 
• If the year of the incomplete start date is after the year of the first dose of 
double-blind investigational product, January 1 will be assigned to the missing fields 
Missing month only 
• If only the month is missing, the day will be treated as missing and both the month 
and the day will be replaced according to the above procedure 
Missing day only 
• If the month and year of the incomplete start date are the same as the month and year 
of the first dose of double-blind investigational product, the day of the first dose of 
double-blind investigational product will be assigned to the missing day 
• If either the year of the incomplete start date is before the year of the date of the first 
dose of double-blind investigational product or if both years are the same but the 
month of the incomplete start date is before the month of the date of the first dose of 
double-blind investigational product, the last day of the month will be assigned to the 
missing day 
• If either the year of the incomplete start date is after the year of the date of the first 
dose of double-blind investigational product or if both years are the same but the 
month of the incomplete start date is after the month of the date of the first dose of 
double-blind investigational product, the first day of the month will be assigned to the 
missing day 
16.9.2 
Incomplete Stop Date 
The following rules will be applied to impute the missing numeric fields for an 
incomplete prior or concomitant medication stop date. If the date of the last dose of 
double-blind investigational product is missing, replace it with the last visit date in the 
imputations described below. If the imputed stop date is before the start date (imputed or 
non-imputed start date), the imputed stop date will be equal to the start date. 


38 
 
Missing month and day 
• If the year of the incomplete stop date is the same as the year of the last dose of 
double-blind investigational product, the month and day of the last dose of 
double-blind investigational product in the study will be assigned to the missing fields 
• If the year of the incomplete stop date is before the year of the last dose of 
double-blind investigational product, December 31 will be assigned to the 
missing fields 
• If the year of the incomplete stop date is after the year of the last dose of double-blind 
investigational product, January 1 will be assigned to the missing fields 
Missing month only 
• If only the month is missing, the day will be treated as missing and both the month 
and the day will be replaced according to the above procedure 
Missing day only 
• If the month and year of the incomplete stop date are the same as the month and year 
of the last dose of double-blind investigational product, the day of the last dose of 
double-blind investigational product will be assigned to the missing day 
• If either the year of the incomplete stop date is before the year of the date of the last 
dose of double-blind investigational product or if both years are the same but the 
month of the incomplete stop date is before the month of the date of the last dose of 
double-blind investigational product, the last day of the month will be assigned to the 
missing day 
• If either the year of the incomplete stop date is after the year of the date of the last 
dose of double-blind investigational product or if both years are the same but the 
month of the incomplete stop date is after the month of the date of the last dose of 
double-blind investigational product, the first day of the month will be assigned to the 
missing day 
 
 
 
 
 
 
 
 


39 
 


40 
 
17.0 
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL 
The major change to the analyses specified in the Protocol Amendment #3, dated 25 
March 2019, is as follows: 
• Delete the Fisher exact test to compare the percentage of premature discontinuation of 
levomilnacipran with placebo (specified in Section 9.7.2 of the protocol amendment 
#3) to reflect the current sponsor standards.  
• Delete the comparability analysis with placebo for continuous variables and 
categorical variables (specified in Section 9.7.3 of the protocol amendment #3) to 
reflect the current sponsor standards.  


41 
 
18.0 
REFERENCES 
Chen X, Luo X, Capizzi, T. The application of enhanced parallel gatekeeping strategies. 
Statistics in Medicine, 2005;24:1385-1397. 
Cole TJ. The LMS method for constructing normalized growth standards. Eur J Clin 
Nutr., 44: 45-60, 1990. 
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. 
Sarkar SK. On the Simes inequality and its generalization. IMS Collections, Beyond 
Parametrics in Interdisciplinary Research: Festschrift in Honor of Professor Pranab K. 
Sen, 2008; 1: 231-242. 


42 
 
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 (NFD) missing 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) 


43 
 
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
. 


44 
 
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. 
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. 


45 
 
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.  


46 
 
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. 


47 
 


48 
 


49 
 
APPENDIX III     SAP AMENDMENT #2 SUMMARY 
Title: A Double-blind, Placebo- and Active-Controlled Evaluation of the Safety and 
Efficacy of Levomilnacipran ER in Adolescent Patients with Major Depressive Disorder 
Study LVM-MD-11 SAP Amendment #2 
Date of Amendment #2: 3 October 2019 
Amendment Summary 
This summary includes changes made to SAP LVM-MD-11 Amendment #1 (16 July 
2015). 
Minor editorial and document formatting revisions have not been summarized. The 
following is a summary of the major changes that were made to each section of the SAP, 
and a brief rational for these changes.  
Section 
Major Revision 
Rationale 
Section 7.0 
Delete the Fisher exact test to compare the 
percentage of premature discontinuation 
of levomilnacipran with placebo. 
To reflect current sponsor 
standards. 
 
Section 8.0 
Delete the comparability analysis with 
placebo for continuous variables and 
categorical variables. 
To reflect current sponsor 
standards. 
 
Section 10.1 
Add a sensitivity analysis on primary 
efficacy parameter to exclude the data 
from Site 054.   
Investigator of Site 054 
didn’t conduct in 
accordance with signed 
statement. Operational 
concerns to add this 
sensitivity analysis. 
 
 
 
 
 
 
Section 14.0 
Update the determination of sample size.  
To reflect the discussion 
with FDA and blinded 
interim analysis.