Conditions: Major Depressive Disorder
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 501
Healthy volunteers: no

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

Detailed description:

Arms:
arm 1: Levomilnacipran extended release (ER) capsules, orally, 10 milligram per day (mg/day) on Days 1 to 3, 20 mg/day on Days 4 to 7, and 40 mg/day from Week 2 through Week 8 of the Double-blind Treatment Period followed by levomilnacipran ER 40 mg/day on Days 1 and 2, and then 20 mg/day from Day 3 through Day 7 in the Down-taper Period. Based on therapeutic response and tolerability, an additional dose increase to 80 mg/day was permitted at Week 3 of the Double-blind Treatment Period. arm 2: Fluoxetine capsule, orally, 10 mg/day at Week 1, and 20 mg/day from Week 2 through Week 8 of the Double-blind Treatment Period followed by fluoxetine 10 mg/day from Day 1 through Day 7 of the Down-taper Period. arm 3: Matching placebo capsules once daily through 8 weeks in the Double-blind Treatment Period and Days 1 through 7 in the Down-taper Period.

Interventions: intervention 1: Levomilnacipran ER intervention 2: Fluoxetine intervention 3: Placebo
Intervention descriptions: intervention 1: Levomilnacipran extended-release oral capsules intervention 2: Fluoxetine oral capsules intervention 3: Matching placebo oral capsules

Protocol document:
Prot_000.pdf: 
Protocol LVM-MD-14
Allergan Sales, LLC
Page 1
2020
1.0
TITLE PAGE
Allergan Sales, LLC
5 Giralda Farms, Madison, NJ 07940
A Double-blind, Placebo- and Active-controlled Evaluation of the 
Safety and Efficacy of Levomilnacipran ER in Pediatric Patients 7-17 Years
With Major Depressive Disorder 
LVM-MD-14
Original Protocol Date:
02 March 2018
Amendment 1:
12 Feb 2020
Amendment 2:
05 Aug 2020
Confidentiality Statement
This document is the property of Allergan 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 Allergan.
Approval Date: 05-Aug-2020 10:42:17 (GMT)
NCT03569475




Protocol LVM-MD-14
Allergan Sales, LLC
Page 3
2020
Amendment 2 Summary of Changes
The Amendment 1 protocol, dated 12 Feb 2020, has been amended to reflect the 
following changes:
1. During the COVID-19 pandemic, remote study visits are possible to avoid 
missing efficacy data but are not preferred over clinic visits. 
2. Considering the coronavirus disease 2019 (COVID-19) pandemic, the benefit and 
risk to patients participating in this study has been re-evaluated. Based on the 
limited information to date, no additional risk to study participants is anticipated 
with the use of the investigational product.
3. Updated Section 9.7.8 (Interim Analysis) to reflect that the interim futility 
analysis has now been performed, after 62% of randomized patients completed or 
discontinued the study.
Remote Study Visits:
Investigators/appropriately designated study staff will be allowed to perform selected 
study procedures as remote study assessments (eg, conducted via phone, video 
conference) if participants are unable to attend in-person due to the COVID-19 pandemic. 
During these remote study visits, the supplemental Schedule of Visits and Procedures for 
Remote Study Visits below should be followed and documented that the visit was 
conducted remotely due to COVID-19 pandemic issues.
Safety Assessments: 
Safety assessments permitted to be completed remotely include assessment of adverse 
events and concomitant medications. The Columbia-Suicide Severity Rating Scale 
(C-SSRS) may be performed remotely, and any positive results will be reviewed with an 
Investigator-delegated clinician to ensure the participant is not at risk for suicide. Lab 
draws (PK, pregnancy testing and safety labs), ECG, physical exam and vital signs will 
need to be collected by an appropriate healthcare professional from the site or captured as 
a deviation if it is not possible to collect these data.
Efficacy Assessments:
Due to the nature of the participant CDRS-R assessment, the interview may be performed 
remotely provided that the participant has access to a videoconferencing platform where 
the rating clinician can visually see the participant during the discussion. The 
parent/caregiver CDRS-R interview may be conducted via phone or videoconferencing.
Study Medication Dispensation for Remote Study Visits:
If it is necessary to conduct any part of a visit remotely, resulting in Study Medication not 
being able to be dispensed to the patient at the study site, the option to have study 
medication delivered by courier direct-to-patient (DTP) may be possible. Approval by the 
Sponsor for DTP will need to be obtained from the Study Site each time DTP is utilized.
Approval Date: 05-Aug-2020 10:42:17 (GMT)


Protocol LVM-MD-14
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Page 4
2020
Amendment 1 Summary of Changes
The original protocol, dated 02 Mar 2018, has been amended to reflect the following 
changes:
1. Clarification that pharmacokinetic samples will only be collected in patients aged 
7 to 11 years old.
2. Clarification that participants from Study LVM-MD-11 are excluded from 
participating in this study.
3. Updated exclusion item #2 to replace the term “mental retardation” with 
“intellectual disability” per the category in the Diagnostic and Statistical Manual 
of Mental Disorders, 5th Edition.
4. Added interim futility analysis for when approximately 50% of randomized 
patients have either completed or discontinued the study.
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2.0
SYNOPSIS AND SCHEDULE OF EVALUATIONS
CLINICAL STUDY SYNOPSIS: Study LVM-MD-14
Title of Study
A Double-blind, Placebo- and Active-controlled Evaluation of the 
Safety and Efficacy of Levomilnacipran ER in Pediatric Patients
7-17 Years With Major Depressive Disorder 
Study Centers
Approximately 60 study centers
Development Phase
3
Objective
To evaluate the efficacy, safety, and tolerability of levomilnacipran 
compared with placebo in pediatric outpatients (7-17 years) with 
major depressive disorder (MDD). 
In addition, the study is designed to obtain pharmacokinetic (PK) data 
to define the PK profile of levomilnacipran in the pediatric population 
(7-17 years of age).
Methodology
Multicenter, randomized, double-blind, placebo- and active-
controlled, flexible-dose, parallel group study
During the coronavirus disease 2019 (COVID-19) pandemic, remote 
study visits were implemented and will continue to be possible to 
avoid missing efficacy but are not preferred over clinic visits. The 
study center needs to alert the Sponsor, ahead of time when possible, 
that a remote procedure was performed.
Number of Patients
480 planned (160 placebo, 160 levomilnacipran, and 160 fluoxetine) 
Diagnosis and 
Main Criteria for Inclusion
Male and female outpatients, 7 to 17 years of age (inclusive), who 
meet Diagnostic and Statistical Manual of Mental Disorders, 5th
Edition (DSM-5) 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) score ≥ 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
(nontrade), 20 mg, and 40 mg capsules; once-daily oral 
administration, at the same time each day
Duration of Study
!
10 weeks in duration: 1-week screening/washout period, 
followed by an 8-week double-blind treatment period 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 capsules; 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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2020
Safety Measures
Adverse event (AE) recording, clinical laboratory tests, vital sign 
measurements including height and weight, electrocardiograms 
(ECGs), physical examinations, and Columbia–Suicide Severity 
Rating Scale (C-SSRS)
Pharmacokinetic Analysis
The population PK of levomilnacipran will be characterized using 
plasma concentration-time data. The maximum plasma drug 
concentration, area under the curve, time of maximum plasma 
concentration, half-life, apparent oral clearance and/or apparent 
volume of distribution for levomilnacipran ER will be estimated and 
a summary will be reported.
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. 
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.
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. 
Approval Date: 05-Aug-2020 10:42:17 (GMT)


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SCHEDULE OF EVALUATIONS: Study LVM-MD-14
Screening 
Period
Double-blind Treatment Period
Double-blind 
Down-taper 
Period
Visit 1a
Visit 2 
(Baseline) Visit 3
Visit 4
Visit 5
Visit 6
Visit 7 Visit 8/ 
ETb
Visit 9/SFU c
End of Study 
Week
–1
0
1
2
3
4
6
8
9
Informed assent 
(patient) and 
consent 
(parent[s])/LAR) 
X
Informed consent 
(caregiver)d
X
Inclusion and 
exclusion criteria 
X
X
Determination of 
ability to swallow 
capsule
X
Medical history
X
Psychiatric 
history
X
Medication 
history and
nondrug 
psychiatric 
treatment history
X
X
Concomitant 
medications
X
X
X
X
X
X
X
Physical 
examination
Xe
X
Clinical 
laboratory 
determinations
Xe
X
Serum β-hCG 
pregnancy testf
Xe
X
Thyroxine, TSH 
tests
Xe
Urine drug screen
Xe
ECG
Xe
X
X
Vital signs 
(BP, pulse, 
weight)
X
X
X
X
X
X
X
Vital signs 
(BP, pulse, 
weight and 
heightg)
Xe
X
K-SADS-PLh
X
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SCHEDULE OF EVALUATIONS: Study LVM-MD-14
Screening 
Period
Double-blind Treatment Period
Double-blind 
Down-taper 
Period
Visit 1a
Visit 2 
(Baseline) Visit 3
Visit 4
Visit 5
Visit 6
Visit 7 Visit 8/ 
ETb
Visit 9/SFU c
End of Study 
Week
–1
0
1
2
3
4
6
8
9
CDRS-R
X
X
X
X
X
X
X
X
CGI-S
X
X
X
X
X
X
X
X
CGI-I
X
X
X
X
X
X
C-SSRS
X
X
X
X
X
X
X
X
X
PK Samplingi
X
X
X
AEs
X
X
X
X
X
X
X
X
X
IP dispensing
X
X
X
X
X
X
Xj
IP return
X
X
X
X
X
X
Xj
IP compliance
X
X
X
X
X
X
Xj
Note: If necessary, visits may be conducted up to 3 days before or after scheduled visits relative to the Baseline Visit 
(Visit 2). 
a
After assent and consent are obtained, the screening period may be up to 5 weeks in duration, as described in 
Section 9.5.5.
b
Visit 8 assessments to be completed for all randomized patients who complete the study or discontinue before
Week 8.
c
All randomized patients must complete Visit 8/ET and, at the end of the down-taper period, return for 
Visit 9/SFU. Patients who do not enter the down-taper period must return for Visit 9/SFU approximately 1 week 
after Visit 8/ET Visit.
d
If the parent(s), guardian, or legally authorized representative (LAR) is also the patient’s caregiver, he/she will be 
asked to sign both the parent and caregiver consents.
e
May be repeated at the Investigator’s discretion before Visit 2.
f
A pregnancy test will be obtained for female patients of childbearing potential only. 
g
Height will be recorded at Screening (Visit 1) and Visit 8/ET using a stadiometer.
h
K-SADS-PL data will be retained as source documents at the site.
i
PK only collected on participants aged 7-11 years. Sparse PK blood samples will be collected during Visit 5 (at 
predose and 1-4 hour postdose), Visit 6 (4-6 hours postdose), and Visit 7 (6-8 hours postdose). At Visit 5, or at 
any 24-hour period between Visit 5 and Visit 7, inclusive, serial blood samples will be collected from a subset of 
consented 7-11-year-old patients instead of sparse PK samples at the following time points: predose [20-24 hours 
after the most recent dose], and 2, 4, 6, 8, 10-12, and 24-hours postdose. Refer to Section 9.5.3 for additional 
details.
j
For patients entering the double-blind down-taper period.
AE = adverse event; β-hCG = β-human chorionic gonadotropin; BP = blood pressure; CDRS-R = Children’s 
Depression Rating Scale–Revised; CGI-I = Clinical Global Impressions–Improvement (scale); CGI-S = Clinical Global 
Impressions–Severity (scale); C-SSRS = Columbia–Suicide Severity Rating Scale; ECG = electrocardiogram; ET = 
early termination; IP = investigational product; K-SADS-PL = Kiddie Schedule for Affective Disorders and 
Schizophrenia–Present and Lifetime; LAR = legally authorized representative; PK = pharmacokinetic; SFU = Safety 
Follow-up; TSH = thyroid stimulating hormone
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Allergan Sales, LLC
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2.1
SCHEDULE OF EVALUATIONS THAT MAY BE 
PERFORMED REMOTELY
Double-blind Treatment Period
Visit 2 
(Baseline)
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8/ 
ETb
Visit 9/
SFUc
End of Study Week
0
1
2
3
4
6
8
9
Inclusion and exclusion 
criteria 
X
Medication history and 
nondrug psychiatric 
treatment history
X
Concomitant medicationsa
X
X
X
X
X
X
X
Physical examinationa
X
Clinical laboratory 
determinationsa
X
Serum β-hCG pregnancy 
testa
X
ECGa
X
X
Vital signs (BP, pulse, 
weight)a
X
X
X
X
X
X
X
Vital signs (BP, pulse, 
weight and height)a
X
CDRS-Ra
X
X
X
X
X
X
X
CGI-S
X
X
X
X
X
X
X
CGI-I
X
X
X
X
X
X
C-SSRSa
X
X
X
X
X
X
X
X
PK Samplinga
X
X
X
AEsa
X
X
X
X
X
X
X
IP dispensinga
X
X
X
X
X
X
X
IP returna
X
X
X
X
X
X
X
IP compliancea
X
X
X
X
X
X
X
Note: If necessary, visits may be conducted up to 3 days before or after scheduled visits relative to the Baseline Visit 
(Visit 2). 
a
Remote assessments must be performed by an appropriate, qualified health care professional from the 
site. Patient data which are collected via phone, videoconference, or telehealth video should remain 
consistent with either methods for each patient. For remote visits, study drug may be sent to patients via 
preferred courier or curbside pickup.
b
Visit 8 assessments to be completed for all randomized patients who complete the study or discontinue 
before Week 8.
c
All randomized patients must complete Visit 8/ET and, at the end of the down-taper period, return for 
Visit 9/SFU. Patients who do not enter the down-taper period must return for Visit 9/SFU approximately 
1 week after Visit 8/ET Visit.
AE = adverse event; β-hCG = β-human chorionic gonadotropin; BP = blood pressure; CDRS-R = Children’s 
Depression Rating Scale–Revised; CGI-I = Clinical Global Impressions–Improvement (scale); CGI-S = Clinical Global 
Impressions–Severity (scale); C-SSRS = Columbia–Suicide Severity Rating Scale; ECG = electrocardiogram; ET = 
early termination; IP = investigational product; PK = pharmacokinetic; SFU = Safety Follow-up
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3.0
TABLE OF CONTENTS
1.0
Title Page .................................................................................................................1
2.0
Synopsis and Schedule of Evaluations ....................................................................5
2.1
Schedule of Evaluations that May Be Performed Remotely .......................9
3.0
Table of Contents...................................................................................................10
List of Tables .....................................................................................................................14
List of Figures....................................................................................................................14
4.0
List of Abbreviations .............................................................................................15
5.0
Ethical Considerations ...........................................................................................18
5.1
Institutional Review Board and Independent Ethics Committee...............18
5.2
Ethical Conduct of the Study.....................................................................18
5.3
Patient Information and Informed Consent................................................19
5.3.1
Patient Assent Form.......................................................................19
5.3.2
Parent, Legal Guardian, and Legally Authorized Representative 
Informed Consent...........................................................................19
5.3.3
Caregiver Consent..........................................................................20
6.0
Investigators and Study Administrative Structure.................................................21
7.0
Introduction............................................................................................................22
8.0
Study Objectives ....................................................................................................24
9.0
Investigational Plan................................................................................................25
9.1
Overall Study Design and Plan: Description .............................................25
9.1.1
COVID-19 Specific Process ..........................................................27
9.2
Discussion of Study Design, Including the Choice of Control Groups.....28
9.3
Selection of Study Population....................................................................29
9.3.1
Inclusion Criteria ...........................................................................29
9.3.2
Exclusion Criteria ..........................................................................29
9.3.3
Removal of Patients from Therapy or Assessment........................34
9.3.4
Patient Replacement Procedures....................................................34
9.3.5
Demographic Considerations.........................................................35
9.4
Treatments..................................................................................................35
9.4.1
Treatments Administered...............................................................35
9.4.2
Identity of Investigational Products...............................................35
9.4.3
Method of Assigning Patients to Treatment Groups......................36
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9.4.4
Selection of Dosages in the Study .................................................36
9.4.5
Selection and Timing of Dose for Each Patient.............................37
9.4.5.1
Screening Period.............................................................37
9.4.5.2
Double-blind Treatment Period ......................................37
9.4.5.3
Double-Blind Down-Taper Period..................................38
9.4.6
Blinding..........................................................................................39
9.4.7
Unblinding .....................................................................................39
9.4.8
Prior and Concomitant Therapy.....................................................39
9.4.9
Monitoring Treatment Compliance................................................39
9.4.10 Treatment After Discontinuation...................................................39
9.5
Efficacy and Safety Variables....................................................................40
9.5.1
Efficacy Assessments.....................................................................40
9.5.1.1
Primary Efficacy Assessment .........................................40
9.5.1.2
Secondary Efficacy Assessment .....................................40
9.5.1.3
Additional Efficacy Assessment.....................................40
9.5.2
Safety Assessments........................................................................40
9.5.2.1
Adverse Events ...............................................................41
9.5.2.2
Causality Assessment......................................................41
9.5.2.3
Severity Assessment .......................................................42
9.5.2.4
Serious Adverse Events ..................................................43
9.5.2.5
Reporting Adverse Events and Serious Adverse Events 43
9.5.2.6
Immediate Reporting of Serious Adverse Events and 
Events of Special Interest ...............................................44
9.5.2.7
Reporting of Pregnancies Occurring During the Study..45
9.5.2.8
Potential Hy’s Law Cases...............................................46
9.5.2.9
Clinical Laboratory Determinations ...............................46
9.5.2.10 Vital Signs.......................................................................49
9.5.2.11 Electrocardiograms .........................................................49
9.5.2.12 Other Safety Assessments...............................................50
9.5.2.12.1 Physical Examination....................................50
9.5.2.12.2 Columbia–Suicide Severity Rating Scale.....50
9.5.3
Investigational Product Concentration Measurements ..................51
9.5.4
Health Economic and Outcomes Research Assessments...............51
9.5.5
Schedule of Assessments...............................................................51
9.5.5.1
Visit 1 (Screening)..........................................................52
9.5.5.2
Visit 2 (Baseline Visit)....................................................53
9.5.5.3
Visit 3 (End of Week 1)..................................................54
9.5.5.4
Visits 4 (End of Week 2) and 5 (End of Week 3)...........55
9.5.5.5
Visits 6 (End of Week 4) and 7 (End of Week 6)...........55
9.5.5.6
Visit 8 (End of Week 8 or Early Termination Visit) ......56
9.5.5.7
Visit 9 (End of Week 9/Safety Follow-up Visit) ............57
9.6
Data Quality Assurance .............................................................................58
9.6.1
Data Monitoring.............................................................................58
9.6.2
Data Recording and Documentation..............................................59
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9.7
Statistical Methods and Determination of Sample Size.............................59
9.7.1
Patient Populations.........................................................................59
9.7.1.1
Screened Population........................................................59
9.7.1.2
Randomized Population..................................................60
9.7.1.3
Safety Population............................................................60
9.7.1.4
Intent-to-Treat Population...............................................60
9.7.2
Patient Disposition.........................................................................60
9.7.3
Demographics and Other Baseline Characteristics........................61
9.7.4
Extent of Exposure and Treatment Compliance ............................61
9.7.4.1
Extent of Exposure..........................................................61
9.7.4.1.1
Investigational Product .................................61
9.7.4.2
Measurement of Treatment Compliance.........................62
9.7.5
Efficacy Analyses ..........................................................................62
9.7.5.1
Primary Efficacy Parameter............................................63
9.7.5.2
Secondary Efficacy Parameter........................................64
9.7.5.3
Additional Efficacy Parameters ......................................64
9.7.6
Safety Analyses..............................................................................65
9.7.6.1
Adverse Events ...............................................................65
9.7.6.2
Clinical Laboratory Parameters ......................................66
9.7.6.3
Vital Signs.......................................................................66
9.7.6.4
Electrocardiogram...........................................................67
9.7.6.5
Other Safety Parameters .................................................68
9.7.6.5.1
Columbia-Suicide Severity Rating Scale......68
9.7.6.5.2
Growth Evaluation........................................68
9.7.6.6
Investigational Product Plasma Concentration 
Parameters.......................................................................68
9.7.7
Health Economics and Outcomes Research Analyses...................68
9.7.8
Interim Analysis.............................................................................68
9.7.9
Determination of Sample Size .......................................................69
9.7.10 Computer Methods.........................................................................69
9.8
Changes in the Conduct of the Study or Planned Analyses.......................69
9.9
Protocol Deviations and Violations ...........................................................69
9.10
Data Monitoring Committee......................................................................70
10.0
Study Sponsorship .................................................................................................71
10.1
Study Termination .....................................................................................71
10.2
Reporting and Publication..........................................................................71
11.0
Investigator Obligations.........................................................................................72
11.1
Documentation...........................................................................................72
11.2
Performance...............................................................................................72
11.3
Use of Investigational Materials................................................................73
11.4
Case Report Forms.....................................................................................73
11.5
Retention and Review of Records..............................................................73
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11.6
Patient Confidentiality...............................................................................74
12.0
Investigator’s Statement.........................................................................................75
13.0
Appendices.............................................................................................................76
Appendix I.
Elements of Informed Consent ...................................................77
Appendix II.
Contact Information....................................................................79
Appendix III.
Concomitant Medications...........................................................80
Appendix IV.
Pharmacokinetic Blood Sampling and Shipping Instructions 
(only in participants aged 7-11 years)........................................................85
Appendix V.
Children’s Depression Rating Scale–Revised ............................86
Appendix VI.
Clinical Global Impressions–Severity ........................................93
Appendix VII.
Clinical Global Impressions–Improvement ................................94
Appendix VIII. Baseline Columbia–Suicide Severity Rating Scale ....................95
Appendix IX.
Since Last Visit Columbia–Suicide Severity Rating Scale.........99
14.0
Literature Cited....................................................................................................103
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List of Tables
Table 9-1.
Double-blind Dosing Regimen ................................................................. 38
List of Figures
Figure 9-1.
Study Design............................................................................................. 27
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4.0
LIST OF ABBREVIATIONS
5-HT
5-hydroxytryptamine (serotonin)
5-HTP
5-hydroxytryptophan
AGN
Allergan
AE
adverse event
ALT
alanine aminotransferase 
AST
aspartate aminotransferase
AUC
area under the plasma concentration versus time curve
BP
blood pressure
CDRS-R
Children’s Depression Rating Scale-Revised
CFR
Code of Federal Regulations
CGI-I
Clinical Global Impressions-Improvement
CGI-S
Clinical Global Impressions-Severity
COVID-19
coronavirus disease 2019
C-SSRS
Columbia-Suicide Severity Rating Scale
DHEA
dehydroepiandrosterone
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition
DTP
direct-to-patient
ECG
electrocardiogram, electrocardiographic
eCRF
electronic case report form
EDC
electronic data capture
ER
extended release 
ET
early termination
FDA
Food and Drug Administration
FR
Federal Register
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GCP
good clinical practice
GLMM
generalized linear mixed model
β-hCG
β-human chorionic gonadotropin
HIPAA
Health Insurance Portability and Accountability Act of 1996
ICF
informed consent form
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ITT
intent to treat
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 Frederica formula 
(QTcF = QT/[RR]⅓)
RSM
Regional Site Manager
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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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5.0
ETHICAL CONSIDERATIONS
5.1
INSTITUTIONAL REVIEW BOARD AND INDEPENDENT 
ETHICS COMMITTEE
United States
Approval by the Institutional Review Board (IRB) before the start of the study will be the 
responsibility of the Investigator. A copy of the approval letter will be supplied to 
Allergan (AGN [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 study, AGN 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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In the event of a state of emergency due to the COVID-19 pandemic leading to 
difficulties in performing protocol-specified procedures, the Sponsor will engage with 
study site personnel in efforts to ensure the safety of patients, maintain protocol 
compliance, and minimize risks to the integrity of the study while trying to best manage 
patient continuity of care. This may include alternative methods for assessments 
(eg, phone contacts or virtual site visits), and shipping investigational product and/or 
supplies direct to patients to ensure continuity of treatment where allowed. In all cases, 
these alternative measures must be allowed by local regulations and permitted by 
IRB/IEC. Investigators should notify the Sponsor if any urgent safety measures are taken 
to protect the patients against any immediate hazard.
5.3
PATIENT INFORMATION AND INFORMED CONSENT
After being given an explanation of the study and before participating in any study 
procedures, each patient, if developmentally appropriate, must provide written assent, and 
his or her parent(s), legal guardian(s), or legally authorized representative (LAR) 
(hereafter referred to as parent/guardian/LAR) must provide voluntary and written 
informed consent in compliance with 21 CFR, Parts 50 and 312 and give HIPAA 
authorization (or an equivalent of HIPAA authorization in non-US countries). 
The signed documents will be placed in the Investigator’s study files. A unique patient 
identification (PID) number will be assigned.
5.3.1
Patient Assent Form
To participate in the study, the patient will read, assent understanding of, sign the assent 
form, and be made aware they can withdraw from the study at any time. Patients who are 
unable to read the assent form will have the statements read to them. If the patient cannot 
sign the form, a witness will be allowed to provide written verification of oral assent. A 
copy of the signed assent will be given to the patient’s parent/guardian/LAR. 
5.3.2
Parent, Legal Guardian, and Legally Authorized Representative 
Informed Consent
Written informed consent will be obtained from the patient’s parent/guardian/LAR before 
the patient participates in any study-related procedure. To provide consent for the 
patient’s participation in the study, the patient’s parent/guardian/LAR will read, assent to 
an understanding of, and sign an instrument of informed consent or other locally 
applicable regulations and authorization form after having had an opportunity to discuss 
the forms with the Investigator before signing. The parent/guardian/LAR will be made 
aware that the patient may withdraw from the study at any time and will receive a copy of 
the signed ICF. Patients who reach the age of majority (ie, 18 years of age in most 
jurisdictions) during the course of the study, are required to be re-consented.
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5.3.3
Caregiver Consent
A caregiver is a person identified as able and willing to provide safety and efficacy 
information about the patient and oversee the administration of investigational product, 
and may be a different individual than the parent/guardian/LAR. The caregiver must 
commit to accompanying the patient to each study visit. To be eligible for the study, the 
caregiver, whether or not he or she is the parent/guardian/LAR, must read and sign the 
caregiver consent and meet the relevant inclusion/exclusion criteria. If the 
parent/guardian/LAR is the caregiver, he or she will be asked to sign both the parent/legal
guardian permission (ICF) and the caregiver consent. If a caregiver is replaced during the 
study, each caregiver must provide separate ICF/caregiver consents and will be given a 
signed copy of his/her caregiver consent.
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6.0
INVESTIGATORS AND STUDY ADMINISTRATIVE 
STRUCTURE
This study will be performed at approximately 60 study centers.
The Investigator is responsible for ensuring that 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, AGN, 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 staff qualified by education, experience, 
and licensure (in accordance with local regulations) and that the Investigator oversight is 
documented and assessment of their capabilities and performance is 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). During the COVID-19 pandemic, remote monitoring of data may be employed 
if allowed by the local regulatory authority, IRB/IEC, and the study site.
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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 2006). By the ages of 10 to 15, girls appear to be more likely to 
experience depression than boys (Angold 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 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 2006; Vaishnavi 2004). Levomilnacipran exhibits a distinct in vitro profile, 
exhibiting more potent inhibition of NE reuptake than 5-HT reuptake (Auclair 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 pediatric patients 
(7-17 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 compared with placebo in pediatric outpatients (7-17 years) with MDD. 
In addition, the study is designed to obtain pharmacokinetic (PK) data to define the PK 
profile of levomilnacipran in the pediatric population (7-17 years of age).
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9.0
INVESTIGATIONAL PLAN
9.1
OVERALL STUDY DESIGN AND PLAN: DESCRIPTION
Study LVM-MD-14 will be a multicenter, randomized, double-blind, placebo- and 
active-controlled, flexible-dose, parallel group study in pediatric patients, ages 
7-17 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 be generally 1 week (± 3 days) prior to Visit 2
(Baseline), 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 
3 treatment groups: placebo, levomilnacipran, or fluoxetine. 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 randomized 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 480 patients (160 per treatment group) are planned to be randomized in 
the study.
Figure 9-1 provides a schematic of the study design. 
The coronavirus disease 2019 (COVID-19) pandemic developed after this study began,
and this protocol has been amended to account for study procedures that may need to be 
modified in association with adhering to local guidelines or regulations or site flexibility 
to complete study-required procedures.
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During the COVID-19 pandemic, remote study visits, in which data are collected via 
phone or videoconference, were and will continue to be possible when needed. To 
accommodate changes that sites may need to implement during the pandemic, Section 2.0
outlines the conduct of study assessments during on-site clinic visits, which is the 
preferred method of conducting the study, while study assessments for remote visits are 
included in Section 2.1. Sites will need to inform the Sponsor of the need for a remote 
visit in advance whenever possible.
In the event that it is required to perform procedures remotely, every effort should be 
made to perform the remote assessment in a manner as similar as possible to the on-site 
assessment. Patient data collected via phone or video conferencing should remain 
consistent with either method for each patient.
Detailed descriptions of each study visit are provided in Section 9.5.5.




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Visit conduct options will allow remote visits as outlined below:
!
Option 1: In-clinic visits 
This is the preferred option. All study visits are performed as in clinic visits with all 
assessments outlined in the Schedule of Assessments in Section 2.0.
!
Option 2: Remote visits (except screening) 
This option is only to be used if local guidance, regulations, or the needs of the patient
prevent the site or the patient from completing on-site visit procedures. Screening visits 
must take place as an in-clinic visit with all assessments outlined in the schedule of 
assessments in Section 2.0. All other visit procedures (V2-V8) can be completed 
remotely with the assessments outlined in Section 2.1. The study center needs to alert the 
Sponsor, ahead of time when possible, that a remote procedure was performed.
For remote visits, there is an option to have study drug delivered by preferred courier. 
Approval from the Sponsor study team must be obtained from the study center each time 
the preferred courier service is utilized. 
9.2
DISCUSSION OF STUDY DESIGN, INCLUDING THE CHOICE 
OF CONTROL GROUPS
This placebo- and active-controlled, flexible-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 children and 
adolescents meeting Diagnostic and Statistical Manual of Mental Disorders, 5th Edition 
(DSM-5; American Psychiatric Association 2013) 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 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 assay sensitivity in 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.
In the current study, safety and efficacy assessments are included in every visit to 
determine adequacy of response, safety, and tolerability for all patients. 


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9.3
SELECTION OF STUDY POPULATION
9.3.1
Inclusion Criteria
Patients must provide assent to participate and their parent/guardian/LAR and caregiver 
(even if the same as the parent/guardian/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 7 to 17 years of age, inclusive, at Visit 1 
2. Patients must meet DSM-5 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 of childbearing potential must have a negative serum β-human 
chorionic gonadotropin (β-hCG) pregnancy test result at Visit 1
8. No known active COVID-19 infection. Subject must not have signs/symptoms 
associated with COVID-19 infection or known exposure to a confirmed case of 
COVID-19 infection during 14 days prior to Screening.
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-5–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. 
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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 intellectual disability or amnestic or other cognitive disorders 
based on DSM-5 criteria
3. Imminent risk of injuring self or others or causing damage to property as judged by 
the Investigator
4. Suicide risk as determined by meeting either of the following criteria:
o
Any suicide attempt within the past year
o
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)
7. Patients taking any psychoactive drug or psychoactive herbal remedy within 
5 half-lives before Baseline (Visit 2), (St. John’s wort, ginkgo biloba, kava kava, 
SAMe, valerian root, dehydroepiandrosterone (DHEA), tyrosine, tryptophan and 
5-hydroxytryptophan (5-HTP), antidepressants, anxiolytics, monoamine oxidase 
inhibitors, antipsychotics, or anticonvulsants/mood stabilizers, carbamazepine, or 
others). Patients who have ever been treated with a depot antipsychotic must also be 
excluded 
8. Patients who have initiated or terminated psychotherapy or behavior therapy within 
1 month before Visit 1 (Screening), or who plan to initiate or change such therapies 
during the course of the study
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Other Medical criteria
9. A clinically significant disease state that, in the investigator’s opinion, might indicate 
that the patient is unsuitable for the study
10. A history or evidence of malignancy, unless the condition has been stable for 
> 3 years for a malignancy other than excised basal cell carcinoma; excised basal cell 
carcinoma must have been stable for ≥ 1 year
11. 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:
a.
Second-degree (if Mobitz II) or third-degree atrioventricular block
b. Premature ventricular contraction (PVC) associated with clinical symptoms 
and/or any complex PVCs (ie, PVCs that are frequent [> 30/hour] or ≥ 2 beats if 
multifocal or show bigeminy, trigeminy, quadrigeminy, couplets, triplets [salvos], 
or R-on-T phenomenon) 
c.
Atrial fibrillation or flutter that is symptomatic or associated with uncontrolled 
heart rate or hemodynamic instability, requiring anticoagulation, or is of recent 
(< 12 months) or unknown onset
d. Any systolic and/or diastolic blood pressure (BP) and/or manually measured pulse 
rate and/or QTc interval (Frederica corrected) that is symptomatic or clinically 
significant per the opinion of the Investigator
12. Hypo- or hyperthyroidism, unless stabilized on appropriate pharmacotherapy with no 
change in dosage for at least 3 months before Visit 1 (Screening)
13. Any condition that would be expected to affect drug absorption (eg, gastric bypass 
surgery)
14. 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 
15. Liver enzyme tests (aspartate aminotransferase [AST] and/or alanine 
aminotransferase [ALT]) > 2 times the upper limit of normal (ULN)
16. History of conditions that might worsen with SSRI or SNRI treatment (eg, syndrome 
of inappropriate antidiuretic hormone secretion)
17. History of drug or alcohol abuse or dependence within the past year
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18. Positive result from the blood alcohol test or the urine drug screen (UDS) for 
prohibited substance, with the following exceptions: 
a.
Positive blood alcohol test may be allowed if there is a negative repeat test before 
Visit 2 (Baseline)
b. Amphetamines can be allowed if prescribed for treatment of attention deficit 
disorder at a dose that is stable for at least 60 days before Visit 1 (Screening). If 
not stable for at least 60 days before Visit 1 (Screening), the patient should be 
discontinued. However, the patient can be rescreened on a later date 
c.
Patients who have a positive UDS for other prohibited substances (barbiturates, 
benzodiazepines, opiates, cannabinoids, cocaine, methadone, phencyclidine, or 
other prohibited concomitant medications) may be allowed to enroll if (1) the 
substance use is discontinued, and (2) this is documented by a negative UDS 
before Visit 2 (Baseline). If the repeat UDS cannot be performed within 21 days 
of the initial UDS, the patient should be discontinued. The patient can be 
rescreened on a later date if use is discontinued and must have a negative UDS
19. Pregnant, breastfeeding, and/or planning to become pregnant and/or breastfeed during 
the study or within 30 days following the end of study participation
20. For female patients of childbearing potential who are sexually active:
Not practicing a reliable method of contraception that will continue for the duration 
of the study and within 30 days following the end of study participation. Reliable 
contraception is defined as:
a.
surgical sterilization
b. oral contraceptives (consisting of an estrogen-progestin combination or progestin 
alone)
c.
transdermally delivered contraceptives (eg, Ortho-Evra), depot injections 
(eg, Depo-Provera)
d. vaginal contraceptive ring (eg, NuvaRing), contraceptive implants (eg, Implanon, 
Norplant II/Jadelle)
e.
an intrauterine device
f.
diaphragm plus condom (the only acceptable double-barrier method)
g. Other forms of contraceptives (pharmacological and/or non-pharmacological) are 
not accepted
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Use of hormonal contraceptives by females of childbearing potential must have been 
stable for at least 1 month before Visit 1 and must follow that product’s package insert 
instructions concerning additional protection at times when doses might be missed. The 
following are examples of contraception methods that are not acceptable: rhythm, 
withdrawal, single-barrier methods (eg, contraceptive sponge, female condom or male 
condom alone or with spermicide, diaphragm alone or with spermicide), the sole planned 
reliance on emergency contraceptives (eg, Plan B). Patients who are abstinent must agree 
to use one of the acceptable forms of contraception should they become sexually active.
21. For sexually active male patients:
Not agreeing to use contraception as detailed below during the treatment period and 
for at least 30 days after the last dose of investigational product.
A male condom plus partner use of a contraceptive method with a failure rate of < 1% 
per year when having penile-vaginal intercourse with a female partner of childbearing 
potential
Other Criteria
22. Patients who are unable to swallow capsules
23. Participation in Study LVM-MD-11.
24. Treatment with any investigational product within 3 months (or at least 5 half-lives, 
whichever is longer) of Visit 1. Treatment with any investigational product other than 
those provided by AGN during study participation will be a protocol violation, and 
the patient will be terminated from this study
25. Employee or immediate relative of an employee of AGN, any of its affiliates or 
partners, or of the study center
26. Patients or patients whose parent/guardian/LAR and/or caregivers are unable to speak 
and understand English (or their native language if this can be accommodated by the 
site and is approved by the Sponsor) sufficiently to understand the nature of the study, 
to provide informed assent/consent, or to allow the completion of all study 
assessments
27. Unable or unlikely to comply with the study protocol or are unsuitable for any other 
reason, as judged by the Investigator
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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 parent/guardian/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 by subject
!
Adverse event (AE)
!
Lack of efficacy
!
Protocol deviation
!
Non-compliance with study drug
!
Lost to follow-up
!
Study terminated by Sponsor 
!
Site terminated by Sponsor
!
Other
All randomized patients who prematurely discontinue from the study, regardless of cause, 
should be seen for a final assessment at 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.
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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. AGN 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 3 treatment groups: placebo, levomilnacipran, or fluoxetine.
9.4.1
Treatments Administered
At Visit 1 (Screening) and after consent/assent is obtained, patients will be given a 
placebo capsule to swallow to confirm their ability to swallow investigational product.
Investigational product in the form of over-encapsulated capsules will be packaged in 
blister cards and provided by AGN. 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 AGN as capsules containing placebo or 
nontrade levomilnacipran 10 mg capsules, trade levomilnacipran 20 mg capsules, trade 
levomilnacipran 40 mg capsules, fluoxetine 10 mg capsules, or fluoxetine 20 mg capsules 
packaged in blister cards.
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 PID number on the label.
All investigational product will be provided and shipped to the study centers by AGN and 
must be stored in an appropriate secure area (eg, a locked cabinet in a locked room) at 
room temperature (25°C or 77°F, with a permitted range of 15°C-30°C or 59°F-86°F), 
and must be protected from light, heat, and moisture.
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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, parent/guardian/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), 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. This PID number will be used to identify the patient 
throughout the study (ie, at all study phases). 
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.
9.4.4
Selection of Dosages in the Study
Doses of levomilnacipran in pediatric patients (7-17 years of age) were selected based on 
modeling of available PK data submitted with NDA 204,168 from the adult healthy 
volunteers and patients with MDD, as well as adolescent patients (12-17 years of age, 
LVM-MD-11, 2017) with MDD. Based on the results of modeling a common dosing 
scheme for both age groups of 7-11 and 12-17 years is appropriate. While the adolescent 
age group, 12-17 years of age, demonstrates similar plasma concentrations as adults 
administered the same dose of 80 mg/day, for the younger age group, 7-11 years of age, 
data indicate that equivalent concentrations are achieved with approximately a 33% dose 
reduction. Thus, 80 mg/day is expected to show exposure similar to exposures seen for 
the adult population administered 120 mg/day.
Based on the above findings, levomilnacipran 40 mg/day, with an optional increase to 
80 mg/day based on therapeutic response and tolerability, is appropriate for the pediatric 
patient age range (7-17 years of age). The corresponding plasma concentrations of these 
doses in pediatric patients are expected to remain within the plasma concentrations 
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9.4.5
Selection and Timing of Dose for Each Patient
All investigational products should be taken orally as a single dose, once-daily at the 
same time each day. After consent/assent is obtained, patients undergoing screening will 
be required to swallow a placebo capsule to confirm their ability to swallow the 
investigational product, as part of their eligibility assessment.
Patients who meet all eligibility criteria at Visit 1 (Screening) and who continue to meet 
all the eligibility criteria for participation in the study will be assigned a randomization 
number at Visit 2 (Baseline) 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
Screening Period
At Visit 1 (Screening) after consent/assent is obtained, a placebo capsule will be 
administered for the purpose of eligibility determination. Patients will be given a placebo 
capsule to swallow. If a patient is unable to swallow the placebo capsule, the patient will 
be ineligible for study participation.
9.4.5.2
Double-blind Treatment Period
The titration schedule is as follows:
!
Levomilnacipran: Days 1-3, 10 mg/day; Days 4-7, 20 mg/day; Week 2 through 
Week 8, 40 mg/day; Based on therapeutic response and tolerability, an additional 
dose increase to 80 mg/day is permitted at Week 3.
!
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 (Baseline) 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 9-1.
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Table 9-1.
Double-blind Dosing Regimen
Treatment Group
Row
Week
1
2
3-8
Down-Taper
9/ET
Days 1-3
Days 4-7
Days 1-7
Days 1-7
Days 1-2
Days 3-7
Levomilnacipran 
40 mg - 80 mg
A
LVM 
10 mg
LVM 
20 mg
LVM 
40 mg
LVM 
40 mg
LVM 
40 mg
LVM 
20 mg
B
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
A
Optional dose escalation to 80 mg as 
determined by treating physician
LVM 
40 mg
LVM 
40 mg
LVM 
20 mg
B
LVM 
40 mg
Placebo
Placebo
Fluoxetine 20 mg
A
Fluoxetine 
10 mg
Fluoxetine 
10 mg
Fluoxetine 
20 mg
Fluoxetine 
20 mg
Fluoxetine 
10 mg
Fluoxetine 
10 mg
B
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
A
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
B
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
ET = Early termination; LVM = levomilnacipran.
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. If appropriate, as deemed by the investigator, 
patient may resume medication at 40 mg/day or reduce to 40 mg/day (if taking 
80 mg/day). Those unable to tolerate 40 mg/day should be discontinued from the study.
9.4.5.3
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:
!
Levomilnacipran 40 mg/day and 80 mg/day: Days 1-2, 40 mg/day;
Days 3-7, 20 mg/day
!
Fluoxetine 20 mg/day: Days 1-7, 10 mg/day 
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9.4.6
Blinding
A list of patient randomization codes will be generated by Statistical Programming at 
AGN 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
The IWRS will be programmed with blind-breaking instructions. The study blind may be 
broken if, in the opinion of the investigator, it is in the patient’s best interest to know the 
study treatment assignment. The Sponsor must be notified before the blind is broken 
unless identification of the study treatment is required for a medical emergency in which 
the knowledge of the specific blinded study treatment will affect the immediate 
management of the patient’s condition. In this case, the Sponsor must be notified within 
24 hours after breaking the blind. The date and reason that the blind was broken must be 
recorded in the source documentation and eCRF, as applicable.
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 Visit 1 (Screening) in the eCRF. Thereafter, any changes in 
concomitant medications or new medications added will be recorded in the eCRF.
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 AGN. Patients who initiate a new 
treatment for MDD must be discontinued from the study.
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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 AGN 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.
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.” 
9.5.1.3
Additional Efficacy Assessment
The CGI-I is a clinician-rated instrument (Appendix VII). Based on the Investigator’s 
clinical opinion, the total improvement or worsening of the patient’s mental illness is 
rated on a scale from 1 to 7, with 1 being very much improved and 7 being very much 
worse, relative to Visit 2 (Baseline), regardless of whether the Investigator considers the 
worsening to be related to investigational product.
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.
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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
!
All diseases that occur after signing ICF, including any change in severity or 
frequency of preexisting disease
!
Laboratory values that are deemed to be clinically significant by the Investigator
!
Physical exam findings, including vital sign measurements, that are deemed to be 
clinically significant by the Investigator
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:
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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
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
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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.
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.
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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 and caregivers are to be reminded, as described in the ICF and in 
accordance with Section 9.5.2.1, to notify site personnel of any AEs occurring during the 
30-day poststudy period. Any AEs reported by the patient (or patient representative) 
during this period are to be recorded in original source documents. AEs are also to be 
recorded in the eCRF if at least one of the following conditions is met: 1) the event meets
the criteria for an SAE (see Sections 9.5.2.4 and 9.5.2.6), and/or 2) the event is judged by 
the Investigator to be potentially causally related to investigational product.
Any AEs that are ongoing at the time of the final protocol-defined study visit will be 
followed until the condition returns to prestudy status, has resolved or stabilized, or can 
be explained as being unrelated to the investigational product. If a follow-up visit is 
deemed necessary for appropriate safety surveillance, it will take place within 30 days of 
the final protocol-defined study visit.
9.5.2.6
Immediate Reporting of Serious Adverse Events and Events of 
Special Interest
AGN is required to inform worldwide regulatory authorities of SAEs that meet specific 
criteria. Therefore, AGN 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. 
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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. AGN may contact the 
study center to solicit additional information or follow up on the event.
Fax the SAE Form for Clinical Trials to AGN:
SAE fax number: 
Primary: 1-714-796-9504
Back-up: 1-714-246-5295
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. 
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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9.5.2.8
Potential Hy’s Law Cases
Potential Hy’s law criteria are:
!
ALT or AST ≥ 3 × ULN AND 
!
Total bilirubin ≥ 2 × ULN AND 
!
Alkaline phosphatase < 2 × ULN
Study center personnel must report every patient who meets these potential criteria. 
Typically, all 3 analytes will be obtained from the same sample, but they may come from 
multiple samples taken within a 24-hour period. This requirement applies from the time 
he or she signs the ICF for the study until 30 days after the final protocol-defined study 
visit or the last known dose of investigational product (if the final visit does not occur). 
A laboratory alert for potential Hy’s laws cases will be in place and the laboratory must 
notify Investigators and AGN immediately when the above criteria have been met. A 
potential Hy’s law case must be faxed to AGN on an AE of Special Interest Form as soon 
as possible (within 24 hours of learning of the potential Hy’s law case) to the 
SAE/Pregnancy fax number stated in Section 9.5.2.6, even if no AE has occurred. The 
eCRF for potential Hy’s law cases must be completed within 7 calendar days. Every 
effort to determine the cause of the liver enzyme abnormalities must be made, and close 
monitoring should be initiated in conjunction with the Study Physician and in accordance 
with the FDA “Guidance for Industry: Drug Induced Liver Injury- Pre-Marketing 
Clinical Evaluation” July 2009.
9.5.2.9
Clinical Laboratory Determinations
Blood and urine samples for clinical laboratory tests will be collected as detailed in the 
Schedule of Evaluations (Section 2.0). During Screening, the Investigator will assess the 
clinical significance of any values that are outside the reference ranges provided by the 
central laboratory; patients with abnormalities judged to be clinically significant will be 
excluded from the study.
Patients will be instructed to fast overnight (for at least 8 hours) before coming in for 
their appointments when clinical laboratory blood tests are to be drawn. If non-fasting, 
an attempt should be made to draw blood at least 4 hours after a meal.
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A UDS will be conducted for all patients at Visit 1 (Screening). A negative UDS for 
prohibited substances (illegal drugs or prohibited concomitant medications [see 
Appendix III and Exclusion Criterion #18]) is required before Visit 2 (Baseline) for the 
patient to continue in the study. Amphetamines can be allowed if prescribed for treatment 
of attention deficit disorder at a dose that is stable for at least 60 days before Visit 1 
(Screening). If not stable for at least 60 days before Visit 1 (Screening), the patient 
should be discontinued. However, the patient can be rescreened on a later date.
Patients who have a positive UDS at Visit 1 (Screening) for other prohibited substances 
(barbiturates, benzodiazepines, opiates, cannabinoids, cocaine, methadone, 
phencyclidine, or other prohibited concomitant medications) may be allowed to enroll if 
(1) there is no suspicion of drug abuse per the Investigator judgment, (2) the use is 
discontinued and (3) this is documented by a negative UDS before Visit 2 (Baseline). If 
the repeat test cannot be performed within 21 days, the patient should be discontinued 
from the study. The patient can be rescreened on a later date and must have a negative 
UDS to be considered for inclusion in the study.
Alcohol consumption is prohibited during the study. A UDS or blood alcohol test may be 
performed at any time during the study at the discretion of the Investigator. A patient 
with a positive blood alcohol test or a positive UDS for any prohibited substances at any 
postrandomization visit may be allowed to continue in the study if approved by the 
Investigator and by the Study Physician.
Females of childbearing potential will be required to have a serum β-hCG pregnancy test 
at Visit 1 (Screening) and Visit 8/ET. Positive pregnancy test results at Visit 1 will 
exclude female patients from participating in the study. At every study visit, Investigators 
should inquire about the use of acceptable methods of contraception in females of 
childbearing potential who are, or become, sexually active, and perform a urine 
pregnancy test if there is any question of non-compliance with contraception. If the urine 
pregnancy test is negative, a serum β-hCG pregnancy test must be performed to rule out 
pregnancy. Any positive pregnancy test results during the study will result in patient 
termination from the study.
The following clinical laboratory levels will be measured:
Hematology:
Absolute and differential white blood cell count, 
erythrocyte count, hemoglobin, hematocrit, platelet count, 
and red blood cell indices (mean corpuscular volume, mean 
corpuscular hemoglobin, and mean corpuscular hemoglobin 
concentration)
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Chemistry:
Sodium, potassium, calcium, chloride, bicarbonate, 
magnesium, phosphate, glucose, blood urea nitrogen, 
creatinine, total protein, alkaline phosphatase, albumin, 
bilirubin (total; direct; indirect), AST, ALT, total 
cholesterol, low-density lipoprotein, high-density 
lipoprotein, triglycerides
Urinalysis:
Specific gravity, pH, protein, glucose, ketones, nitrite, 
bilirubin, and blood
Thyroid:
Free thyroxine and thyroid stimulating hormone (TSH) 
tests at Visit 1 (Screening)
Hepatitis screening:
Hepatitis-C virus antibody, hepatitis-B surface antigen, 
and hepatitis-B core antibody total will be tested. Reflex 
hepatitis-B core antibody IgM will be performed for 
all hepatitis-B core antibody total positive or reactive 
results. Hepatitis screening will be conducted at Visit 1 
(Screening)
UDS:
Benzoylecgonine (cocaine), barbiturates, amphetamines, 
benzodiazepines, cannabinoids, opiates, methadone, 
phencyclidine. UDS will be performed for all patients at 
Visit 1 (Screening). UDS may be repeated during the study 
at the Investigator’s discretion
Blood alcohol level:
Blood alcohol level will be conducted at Visit 1 
(Screening). May be performed at random during the study 
upon request of the Investigator
Serum β-hCG:
Female patients of childbearing potential only. Will be 
performed at Visit 1 (Screening) and for randomized 
patients at Visit 8/ET. Urine pregnancy tests may be 
performed at the discretion of the Investigator at any visit 
during the double-blind treatment period; if negative, 
perform a serum β-hCG test to rule out pregnancy.
Other laboratory assessments may be repeated at any visit if there was an abnormal 
finding at the most recent, previous evaluation or if additional information is clinically 
necessary to appropriately evaluate the patient’s current condition, follow up and/or 
manage an AE. Fasting for at least 8 hours is recommended before unscheduled visits to 
assess serum chemistry.
A central laboratory will be used to evaluate all urine and blood samples, which will be 
collected, processed, and stored according to the instructions provided by the laboratory. 
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9.5.2.10
Vital Signs
Vital sign measurements, seated radial pulse rate, seated systolic and diastolic BP, and 
body weight, will be documented at every visit. Pulse and BP readings will be taken 
twice after the patient has been sitting for at least 5 minutes. The second measurement 
will be entered in the eCRF. A BP cuff of appropriate size for the patient should be used. 
The same arm and BP cuff should be used for all BP and radial pulse measurements 
throughout the study.
BP may be measured manually or by machine, but the same method of measurement 
should be used for a patient throughout the study. Radial pulse rate should be measured 
manually. All BP and radial pulse measurements will be recorded in the patient’s source 
documents. 
Patients should be instructed not to wear clothing with tight sleeves when they come to 
have their BP measured. Additionally, they should be kept as calm and undisturbed as 
possible while BP and pulse measurements are taken (ie, there should be no talking while 
the BP is being measured).
Height will be measured as accurately as possible using a stadiometer while the patient is 
standing with no shoes on and recorded at Visit 1 (Screening) and Visit 8/ET. Patients 
should wear their usual indoor clothing, but take off their jacket and shoes during weight 
measurements. For each patient, body weight and height should be determined using the 
same equipment during the study after confirming proper calibration.
9.5.2.11
Electrocardiograms
A 12-lead ECG will be performed at Visit 1 (Screening), Visit 5 (Week 3), and at Visit 8 
(Week 8/ET). The paper speed will be standard 25 mm/sec. ECGs will be electronically 
transmitted for analysis according to the instructions provided by the central ECG 
laboratory. Measurements (in msec) will be recorded for the following parameters in 
lead II or lead III: PR interval, QRS duration, and uncorrected QT interval. QTcF 
(Frederica corrected QT interval) and QTcB (Bazett corrected QT interval) will be 
calculated.
The overall interpretation and determination of the clinical relevance of ECG findings 
using the central laboratory ECG interpretation report will be the responsibility of the 
Investigator and will be recorded in the patient’s eCRF.
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9.5.2.12
Other Safety Assessments
9.5.2.12.1
Physical Examination
A complete physical examination will be performed at Visit 1 (Screening) and at Visit 8 
(Week 8/ET) by a professionally trained physician or health professional listed on Form 
FDA 1572 and licensed to perform physical examinations.
9.5.2.12.2
Columbia–Suicide Severity Rating Scale
The Columbia–Suicide Severity Rating Scale (C-SSRS) is an instrument that reports the 
severity of both suicidal ideation and behavior. Suicidal ideation is classified on a 5-item 
scale: 1 (wish to be dead), 2 (nonspecific active suicidal thoughts), 3 (active suicidal 
ideation with any methods [not plan] without intent to act), 4 (active suicidal ideation 
with some intent to act, without specific plan), and 5 (active suicidal ideation with 
specific plan and intent). The C-SSRS also captures information about the intensity of 
ideation, specifically the frequency, duration, controllability, deterrents, and reasons for 
the most severe types of ideation. Suicidal behavior is classified on a 5-item scale: 
0 (no suicidal behavior), 1 (preparatory acts or behavior), 2 (aborted attempt), 
3 (interrupted attempt), and 4 (actual attempt). More than 1 classification can be selected 
provided they represent separate episodes. For actual attempts only, the actual or 
potential lethality is classified for the initial, most lethal, and most recent attempts. 
The paper version of the C-SSRS will be completed at all study visits. At Visit 1
(Screening), the C-SSRS will be completed for the patient’s lifetime history of suicidal 
ideation and behavior (Appendix VIII). At all other visits, the C-SSRS will be completed 
for ideation and behavior since the previous visit (Appendix IX). The C-SSRS will be 
evaluated and signed at each visit by a qualified staff member (ie, the Investigator or 
designee that has extensive professional training and experience in assessing mental 
illness), before the patient leaves the study center.
The patient should not be released from the study center until the results of the C-SSRS 
are reviewed and the patient is not considered to be at risk. If there is doubt about 
whether a patient is at risk, the Investigator must obtain appropriate psychiatric 
consultation. The results of the C-SSRS will be recorded in the eCRF.
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9.5.3
Investigational Product Concentration Measurements
PK blood samples will be collected from assented/consented patients aged 7-11 years 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. 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, and 7, as follows:
!
Visit 5, at predose and at 1-4 hour postdose
!
Visit 6, 4-6 hours postdose
!
Visit 7, 6-8 hours postdose
In case of scheduling constraints and with prior notification of AGN, the sampling times 
above may be collected in a different sequence among 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: predose (20-24 hours after the most recent dose), 
and 2, 4, 6, 8, 10-12, and 24-hours postdose.
To allow for a predose sampling, patients may be instructed to hold their daily dose on 
the sampling day and take it when instructed at the study center.
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 2 doses before the reference dose for each patient who undergoes PK sampling.
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 and Section 2.1. The descriptions of the procedures to be 
performed at each visit are provided below. 
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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).
9.5.5.1
Visit 1 (Screening)
At Visit 1 (Screening), study procedures will be reviewed with the patient, 
parent/guardian/LAR, and caregiver. Documentation of informed assent (from patient), 
parent/guardian/LAR permission and caregiver consent will be obtained 
(See Section 5.3). Then, patients will be assigned a unique PID number 
(see Section 9.4.3). 
The following procedures will be performed:
!
Obtain and record medical, psychiatric history
!
Obtain and record medication history, non-drug psychiatric treatment history, and 
current medication status
!
Administer placebo capsule to confirm patient is able to successfully swallow
!
Administer CDRS-R (caregiver and patient)
!
Administer C-SSRS (Baseline C-SSRS). Results should be evaluated by the 
Investigator or designee before the patient leaves the study center
!
Administer K-SADS-PL (caregiver and patient; all findings recorded in the source 
documents only) 
!
Administer CGI-S
!
Measure vital signs (including height, measured by stadiometer)
!
Complete physical examination
!
Perform ECG
!
Collect blood and urine samples for clinical laboratory determinations, hepatitis 
screening, blood alcohol, thyroid tests 
!
Serum β-hCG pregnancy test (females of childbearing potential only) 
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!
Collect urine samples for UDS
!
Review of all inclusion/exclusion criteria
!
Schedule Visit 2 for approximately 1 week after Visit 1
!
Record AEs after consent/assent during the screening period
9.5.5.2
Visit 2 (Baseline Visit)
The Baseline Visit (Visit 2) will be conducted approximately 1 week (up to a maximum 
of 5 weeks to accommodate prior medication washout) after Visit 1 (Screening) to 
determine whether the patient and caregiver are eligible to continue into the double-blind 
treatment period.
At the Baseline Visit, the following procedures will be performed:
!
Review of all inclusion/exclusion criteria
!
Review and record AEs
!
Review prior medications and non-drug psychiatric treatment history
!
Measure vital signs
!
Complete efficacy evaluations
○
Administer CDRS-R (caregiver and patient)
○
Administer CGI-S
!
Administer C-SSRS (Since-Last-Visit) and have the results evaluated by the 
Investigator or designee before the patient leaves the study center
!
If the patient and caregiver are eligible to continue in the study, a randomization 
number will be assigned to the patient and double-blind investigational product will 
be dispensed per IWRS assignment. Written and verbal instructions for dosing will be 
provided to patient and caregiver. Document that instructions were given in source 
documents 
!
If Visit 2 is done remotely, the study drug may be sent to patients via preferred 
courier or via curbside pickup and must be approved in advance by the Sponsor
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!
Schedule next visit:
o
Visit 3: 1 week (± 3 days) after Visit 2
9.5.5.3
Visit 3 (End of Week 1)
At this visit, the following procedures will be performed:
!
Review and record AEs
!
Review concomitant medications
!
Measure vital signs
!
Complete efficacy evaluations
○
Administer CDRS-R (caregiver and patient)
○
Administer CGI-S
○
Administer CGI-I
!
Administer C-SSRS (Since-Last-Visit). Results should be evaluated by the 
Investigator or designee before the patient leaves the study center 
!
Confirm investigational product return and assess investigational product compliance
!
Dispense double-blind investigational product for the next visit per IWRS assignment 
and provide written and verbal instructions for dosing to patient and caregiver. 
Document that instructions were given in source documents 
!
If Visit 3 is done remotely, the study drug may be sent to patients via preferred 
courier or via curbside pickup must be approved in advance by the Sponsor
!
Schedule next visits
○
Visit 4: 2 weeks (± 3 days) after Visit 2 and
○
Visit 5: 3 weeks (± 3 days) after Visit 2


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9.5.5.4
Visits 4 (End of Week 2) and 5 (End of Week 3)
At these visits, the following procedures will be performed:
!
Review and record AEs
!
Review concomitant medications
!
Measure vital signs
!
Perform ECG (Visit 5 only)
!
Complete efficacy evaluations
○
Administer CDRS-R (caregiver and patient)
○
Administer CGI-S
○
Administer CGI-I
!
Administer C-SSRS (Since-Last-Visit). Results should be evaluated by the 
Investigator or designee before the patient leaves the study center
!
Obtain PK samples (Visit 5 only; see Section 9.5.3 for details) 
!
Confirm investigational product return and assess investigational product compliance
!
Dispense double-blind investigational product for the next visit per IWRS assignment 
and provide written and verbal instructions for dosing to patient and caregiver. 
Document that instructions were given in source documents
!
If Visit 4 and 5 are done remotely, the study drug may be sent to patients via 
preferred courier or via curbside pickup must be approved in advance by the Sponsor
!
Schedule next visits
○
Visit 6: 4 weeks (± 3 days) after Visit 2 and
○
Visit 7: 6 weeks (± 3 days) after Visit 2
9.5.5.5
Visits 6 (End of Week 4) and 7 (End of Week 6)
At these visits, the following procedures will be performed:
!
Review and record AEs
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!
Review concomitant medications
!
Measure vital signs
!
Complete efficacy evaluations
○
Administer CDRS-R (caregiver and patient)
○
Administer CGI-S
○
Administer CGI-I
!
Administer C-SSRS (Since-Last-Visit). Results should be evaluated by the 
Investigator or designee before the patient leaves the study center 
!
Obtain PK samples (if applicable; see Section 9.5.3 for details)
!
Confirm investigational product return and assess investigational product compliance
!
Dispense double-blind investigational product for the next visit per IWRS assignment 
and provide written and verbal instructions for dosing to patient and caregiver. 
Document that instructions were given in source documents 
!
If Visit 6 and Visit 7 are done remotely, the study drug may be sent to patients via 
preferred courier or via curbside pickup must be approved in advance by the Sponsor
!
Schedule next visit
○
Visit 8: 8 weeks (± 3 days) after Visit 2
9.5.5.6
Visit 8 (End of Week 8 or Early Termination Visit)
All randomized patients should be seen for a final assessment at Visit 8/ET. A final 
assessment will be defined as completion of the evaluations scheduled at the end of 
Week 8 or ET Visit. The following procedures will be performed at Visit 8:
!
Review and record AEs
!
Review concomitant medications
!
Measure vital signs (including height, measured by stadiometer)
!
Perform ECG
!
Complete physical examination
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!
Collect blood and urine samples for clinical laboratory determinations
!
Serum β-hCG pregnancy test (females of childbearing potential only)
!
Complete efficacy evaluations
○
Administer CDRS-R (caregiver and patient)
○
Administer CGI-S
○
Administer CGI-I
!
Administer C-SSRS (Since-Last-Visit). Results should be evaluated by the 
Investigator or designee before the patient leaves the study center 
!
Confirm investigational product return and assess investigational product compliance
!
If entering down-taper period: dispense double-blind down-taper investigational 
product for the next visit per IWRS assignment and provide written and verbal 
instructions for dosing to patient and caregiver. Document that instructions were 
given in source documents
!
If Visit 8 is done remotely, the study drug may be sent to patients via preferred 
courier or via curbside pickup must be approved in advance by the Sponsor. All 
attempts must be made to collect safety labs
!
Schedule Visit 9/SFU: 1 week (± 3 days) after Visit 8
Any clinical findings observed during this visit, including clinically significant laboratory 
abnormalities observed at prior visits, 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. 
9.5.5.7
Visit 9 (End of Week 9/Safety Follow-up Visit)
All randomized patients must complete Visit 8/ET Visit and, at the end of the double-
blind down-taper period, return for Visit 9/SFU Visit. Patients who do not enter the 
double-blind down-taper period must return for Visit 9/SFU Visit approximately 1 week 
after Visit 8/ET.
The following procedures will be performed at Visit 9:
!
Review and record AEs
!
Review concomitant medications
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!
Measure vital signs
!
Administer C-SSRS (Since-Last-Visit). Results should be evaluated by the 
Investigator or designee before the patient leaves the study center
!
Confirm investigational product return and assess investigational product compliance
(for patients who enter the double-blind down-taper period)
Any clinical findings observed during this visit, including clinically significant laboratory 
abnormalities observed at prior visits, will be followed until the condition returns to 
pre-study status, has resolved or stabilized, or can be explained as being unrelated to the 
investigational product. If a follow-up visit is necessary, it should take place within 
30 days of investigational product termination.
9.6
DATA QUALITY ASSURANCE
9.6.1
Data Monitoring
Before any patient enters the study, a representative of AGN 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 AGN
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.
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9.6.2
Data Recording and Documentation
Data collection will involve the use of the AGN 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.
Each query will carry identifying information (assigned username, date, and time) to 
assist AGN 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 AGN, 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.
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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.
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. Patients who were impacted by the 
COVID-19 pandemic (ie, had protocol deviations, missing safety assessments, AEs 
[as determined by investigator], or withdrew from the study due to the COVID-19 
pandemic, or whose anxiety appeared to be affected by the pandemic) will also be 
summarized.
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 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
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!
Concomitant medications
These and any additional important protocol deviations will be reviewed and documented 
before database lock and unblinding of treatment codes.
Protocol deviations that occur due to COVID-19 will be summarized and listed 
separately.
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.
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.
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9.7.4.2
Measurement of Treatment Compliance 
Dosing compliance for a specified period will be defined as the total number of capsules 
actually taken by a patient during that period divided by the number of capsules 
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. 
The total number of capsules actually taken during a specific time period is calculated 
based on the study medication record. The number of capsules 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 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. 
In the MMRM analysis, if the model fails to converge based on the unstructured 
covariance matrix, then structures of Heterogenous Toeplitz, Toeplitz, and Compound 
symmetry will be applied, only if necessary, in the specified order until the model 
converges.
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 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.
A sensitivity analysis will also be performed using the LOCF approach as described in 
Section 9.7.5.1.
9.7.5.3
Additional Efficacy Parameters
The additional efficacy parameters will include the following at each postbaseline visit:
!
CGI-I score
!
Change from baseline in CGI-S score
!
CDRS-R response (≥ 40% reduction in CDRS-R from baseline) rate
!
CDRS-R remission (CDRS-R ≤ 28) rate
CGI-I score and the change in CGI-S will be analyzed using the MMRM and LOCF 
approaches similar to those used for the primary efficacy parameter. For CGI-I score, the 
baseline CGI-S score will be used as the baseline variable.
The CDRS-R response rate and CDRS-R remission rate will be analyzed using a 
generalized linear mixed model (GLMM), based on logit link function, with random 
intercept and flexible terms of treatment group, visit, treatment-by-visit interaction, and 
baseline score. If the GLMM does not converge, a logistic regression model with 
treatment group and the baseline score as explanatory variables will be used. For the 
logistic regression analysis, the postbaseline missing data will be imputed using the 
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9.7.6
Safety Analyses
The safety analysis will be performed for the double-blind treatment period and 
double-blind down-taper period separately using the Safety Population. The safety 
parameters will include AEs, clinical laboratory parameters, vital sign measurements, 
ECG parameters, C-SSRS, and growth evaluations. For each safety parameter, the last 
assessment made before the first dose of double-blind investigational product will be 
used as the baseline for all analyses of that safety parameter. 
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.
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.
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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 SAEs, AEs leading to discontinuation, and death (if any).
9.7.6.2
Clinical Laboratory Parameters
Descriptive statistics for clinical laboratory values (in SI units) and changes from the 
baseline values at each assessment time point will be presented by treatment group for 
each clinical laboratory parameter.
The number and percentage of patients with potentially clinically significant (PCS) 
postbaseline clinical laboratory values will be tabulated by treatment group. The criteria 
for PCS laboratory values will be detailed in the Statistical Analysis Plan. The 
percentages will be calculated relative to the number of patients with available non-PCS 
baseline values and at least 1 postbaseline assessment. The numerator will be the total 
number of patients with available non-PCS baseline values and at least 1 PCS 
postbaseline value. A supportive listing of patients with PCS postbaseline values will be 
provided, including the PID number, study center number, and baseline and postbaseline 
values. 
9.7.6.3
Vital Signs
Descriptive statistics for vital signs (ie, pulse rate, systolic and diastolic BP, and body 
weight) and changes from baseline values at each visit and at end of study will be 
presented by treatment group. In addition, height and weight z-scores will be calculated 
based on growth charts (see Section 9.7.6.5.2).
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Vital sign values will be PCS if they meet both the observed-value criteria and the change 
from baseline–value criteria. The criteria for PCS vital sign values will be detailed in the 
Statistical Analysis Plan. The percentages will be calculated relative to the number of 
patients with baseline values and at least 1 postbaseline assessment. The numerator will 
be the total number of patients with available baseline values and at least 1 PCS 
postbaseline value. A supportive listing of patients with PCS postbaseline values will be 
provided, including the PID number, study center number, and baseline and postbaseline 
values. 
9.7.6.4
Electrocardiogram
Descriptive statistics for ECG parameters (ie, ventricular heart rate, RR interval, 
PR interval, QRS interval, QT interval, and QTc interval) and changes from baseline 
values at each assessment time point will be presented by treatment group. The QTc 
interval is calculated using the Bazett and Frederica corrections.
The number and percentage of patients with PCS postbaseline ECG values will be 
tabulated by treatment group. The criteria for PCS ECG values will be detailed in the 
Statistical Analysis Plan. The percentages will be calculated relative to the number of 
patients with available non-PCS baseline values and at least 1 postbaseline assessment. 
The numerator will be the total number of patients with available non-PCS baseline 
values and at least 1 PCS postbaseline value. A supportive listing of patients with 
PCS postbaseline values will be provided, including the PID number, study center 
number, and baseline and postbaseline values. 
A listing of patients with postbaseline clinically significant ECG abnormalities, as 
reported by the Investigator or by the central cardiologist, will also be provided.
The number and percentage of patients with an increase > 30 msec but ≤ 60 msec, and 
with an increase > 60 msec in QTcF will be tabulated. A supportive listing of patients 
with postbaseline QTcF increases > 30 msec will be provided, including the PID number, 
study center, and all QTcF values (including changes from baseline). A listing of all AEs 
for patients with postbaseline QTcF increases > 30 msec will also be provided.
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9.7.6.5
Other Safety Parameters
9.7.6.5.1
Columbia-Suicide Severity Rating Scale
For the C-SSRS, the number and percentage of patients with suicidal ideation or suicidal 
behavior as recorded on the C-SSRS scale will be presented by treatment group. The 
distribution of responses for most severe suicidal ideation and suicidal behavior during 
the lifetime history, the double-blind treatment period and the down-taper period will also 
be presented by treatment group for the Safety Population. Supportive listings will be 
provided and will include the PID number, treatment group, visit number, lifetime 
history, and postbaseline values for each patient. Intensity of ideation, suicidal behavior 
type, and lethality of suicidal behavior will also be included in these listings.
9.7.6.5.2
Growth Evaluation
Weight and height will be presented as standardized z-scores adjusted for gender and age, 
using the lambda-mu-sigma method (Cole TJ 1990). To assess the impact of treatment on 
growth, the change from baseline in the age and gender adjusted height will be analyzed 
using an analysis of variance model with treatment as factor. A non-parametric 
(Wilcoxon) test will also be performed.
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.
9.7.8
Interim Analysis
The interim analysis was conducted to identify early signs of futility after 62% of 
randomized patients had either completed or discontinued the study. The futility 
assessment of the primary efficacy parameter (CDRS-R total score) on ITT population 
was based on the conditional power as described in Lan et al. 1999. In calculating the 
conditional power, it was assumed that the future patients to be enrolled into the Study
will have similar efficacy as those of the existing patients of the same treatment group. 
The non-binding futility criteria was set when the conditional power for detecting a 
statistically significant treatment difference between the levomilnacipran treatment group 


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(40-80 mg/day) and placebo at the final analysis was 0.2 (20%) or lower given the 
interim analysis results. After the futility analysis results were reviewed by a data 
monitoring committee member, it was determined that this study will continue until the 
planned study end.
9.7.9
Determination of Sample Size
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. A sample size of 480 patients (160 per treatment group) 
will be needed to provide 85% power for primary analysis (levomilnacipran 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.
9.7.10
Computer Methods
Statistical analyses will be performed using version 9. 3 (or newer) of SAS on a 
LINUX operating system.
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 AGN. 
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 AGN. 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. 
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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 AGN. Protocol 
deviations, including those that may be due to the COVID-19 pandemic, should be 
reported to AGN (either verbally or electronically) in a timely manner from the date of 
discovery. 
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 AGN 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 (FDA 2006).
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10.0
STUDY SPONSORSHIP
This study is sponsored by AGN.
10.1
STUDY TERMINATION
AGN 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 AGN. 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 AGN and will follow the AGN’s Standard Operating Procedure on 
publications. 
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11.0
INVESTIGATOR OBLIGATIONS
11.1
DOCUMENTATION
The Investigator must provide the following to AGN 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 AGN 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 AGN 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 AGN will inventory the investigational products at the 
site. The Investigator must maintain adequate records documenting the receipt and 
disposition of all study supplies. AGN 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 AGN. It is the 
Investigator’s responsibility to ensure that patients return their investigational product.
If a subject is unable to come to the study site to pick up their study drug due to 
COVID-19, a DTP study drug shipment can be made from the study site to the subject if 
allowed by local regulations. 
11.4
CASE REPORT FORMS
All patient data relating to the study will be recorded on eCRFs to be provided by AGN
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 AGN. 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 AGN. 
No study records shall be destroyed without notifying AGN and providing AGN the 
opportunity to arrange long-term storage for such study records or authorizing in writing 
the destruction of records after the required retention period.
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The Investigator must permit access to any documentation relating to the study upon 
request of AGN 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. AGN must be notified 
in writing of the name and address of the new custodian in advance of the transfer.
11.6
PATIENT CONFIDENTIALITY
All patient records will only be identified by PID number. Patients’ names are not to be 
transmitted to AGN. 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 (Protocol LVM-MD-14) 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
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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; 
AGN; 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
!
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
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!
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 AGN personnel will be provided in the study reference binder.


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APPENDIX III.
CONCOMITANT MEDICATIONS
Drugs Allowed (Y) and Drugs Not Allowed (N) as Concomitant Medications
Drug Name or Class
Episodic Use
(PRN)
Chronic Use
Restrictions
ADHD Medications
N
Y
Oral or transdermal methylphenidate, 
amphetamine products or prodrugs, 
pseudoephedrine, modafinil (Provigil), and 
armodafinil (Nuvigil) are allowed if the 
patient has been stable on the same dose for 
at least 2 months prior to Screening and the 
patient is to remain on the same dose 
throughout the double-blind treatment period. 
Catapres (clonidine), Strattera (atomoxetine), 
Tenex (guanfacine), and Intuniv (guanfacine 
extended-release) are not allowed.
Analgesics
Y
Y
•
Non-narcotic analgesics are allowed. 
•
Tramadol, pregabalin, and indomethacin 
are not allowed. 
•
Clinically appropriate episodic use of 
narcotic analgesics for acute medical 
indications limited to 3 days for an 
episode is allowed, except on days of 
efficacy evaluations.
Anesthetics, local
Y
N
Anorexics/appetite 
suppressants/anti-absorption 
agents
N
N
Antacids
Y
Y
Anti-acne agents
Y
Y
Isotretinoin (Accutane) is not allowed.
Antianginal agents
N
N
Antiarrhythmics
N
N
Anti-asthma agents
Y
Y
•
Systemic corticosteroids are not allowed.
•
Inhaled steroids at approved dosages and 
other asthma medications are allowed.
Antibiotics (antibacterial)
Y
N
•
Chronic use of topical antibiotics for 
acne is allowed.
•
Linezolid (Zyvox), and monoamine 
oxidase inhibitors [MAOI]) and isoniazid 
are not allowed.
•
Erythromycin, clarithromycin, 
telithromycin, chloramphenicol, 
rifampicin, and rifabutin are not allowed.
•
Azithromycin is recommended if a 
macrolide antibiotic is needed.
Anticonvulsants
N
N
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Drugs Allowed (Y) and Drugs Not Allowed (N) as Concomitant Medications
Drug Name or Class
Episodic Use
(PRN)
Chronic Use
Restrictions
Antidiarrheal preparations
Y
N
Only loperamide HCl (Imodium), bismuth 
subsalicylate (Pepto-Bismol), and kaolin 
preparations are allowed.
Antiemetics/antinauseants
Y
N
•
Antidopaminergic agents (such as 
metoclopramide, domperidone, and 
phenothiazines), scopolamine, 5-HT3 
receptor antagonists (eg, ondansetron) 
and sedating (H1) antihistamines are not 
allowed. 
•
Phosphoric acid preparations (Emetrol, 
Emecheck), bismuth subsalicylate (Pepto 
Bismol), and cola syrup are allowed.
Antifungals, systemic
N
N
Antifungals, topical
Y
Y
Antihistamines
Y
Y
•
Sedating antihistamines are not allowed.
•
Only fexofenadine (Allegra), loratadine 
(Claritin), desloratadine (Clarinex), 
cetirizine (Zyrtec), and levocetirizine 
(Xyzal) are allowed for episodic or 
chronic use. 
•
See cough and cold preparations for 
combination products.
Antihypertensives
N
Ya
The medication and dosage should be stable 
for 1 month before screening (for diuretics, 
the patient should have been treated with the 
diuretic for at least 3 months, with at least 
1 month on the current dose).
Anti-inflammatory drugs
Y
Yb
•
Chronic use is allowed if dosage is stable 
for 1 month before screening.
•
Indomethacin (Indocin) and systemic 
corticosteroids are not allowed.
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Drugs Allowed (Y) and Drugs Not Allowed (N) as Concomitant Medications
Drug Name or Class
Episodic Use
(PRN)
Chronic Use
Restrictions
Antimigraine
Y
Y
•
Triptans should be used with some 
caution. Note that cases of serotonin 
syndrome have been reported with the 
concomitant use of triptans and 
serotonergic reuptake inhibitors.
•
Ergotamine or ergot derivatives, 
antidepressants, and anticonvulsants are 
not allowed for migraine treatment or 
prophylaxis.
Antineoplastics
N
N
Antiobesity agents
N
N
Antipsoriatic treatments
Y
Y
Acitretin (Soriatane) is not allowed.
Antipsychotics
N
N
Antismoking medications
N
N
•
Varenicline (Chantix) and bupropion 
(Zyban) are not allowed.
•
Nicotine replacement therapies are 
allowed.
Antiviral agents
Y
Y
•
Only acyclovir, famciclovir, 
valacyclovir, penciclovir, docosanol, 
trifluridine, and vidarabine are allowed.
•
Amantadine and rimantadine are 
permitted for influenza prophylaxis, but 
use is limited to a 7- to 14-day course. 
•
Interferons are not allowed. 
Anxiolytics
N
N
Cough and cold preparations
Y
N
•
Cough/cold preparations containing 
dextromethorphan or narcotics are not 
allowed. 
•
Decongestant preparations containing 
pseudoephedrine or 
phenylpropanolamine are not allowed.
•
Phenylephrine nasal sprays are allowed 
for brief clinically appropriate use, for up 
to 5 days. 
•
Combination products containing the 
word “Nighttime” or some synonym 
routinely include a sedating 
antihistamine and are not allowed. 
•
Combination products ending in “D” 
routinely contain a stimulant such as 
pseudoephedrine or 
phenylpropanolamine and are not 
allowed (also see antihistamines).


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Drugs Allowed (Y) and Drugs Not Allowed (N) as Concomitant Medications
Drug Name or Class
Episodic Use
(PRN)
Chronic Use
Restrictions
Strong CYP3A4 Inhibitors
N
N
Following are examples of strong
CYP3A4 inhibitors which are prohibited:
Indinavir, nelfinavir, ritonavir,
saquinavir, itraconazole, ketoconazole,
clarithromycin, telithromycin,
nefazodone, and suboxone. Refer to the
following website for the most up to date
list of strong CYP3A4 inhibitors:
http://medicine.iupui.edu/clinpharm/DDIs/tab
le.aspx
H2 blockers/proton pump 
inhibitors
Y
Ya
Tagamet (cimetidine) is not allowed; all 
others acceptable.
Hormones, non-reproductive
N
N
Thyroid replacement is allowed if not for 
depression and condition and dose stable for 
1 month.
Hormones: reproductive
N
Y
Hormonal contraception such as oral 
contraceptives (estrogen-progestin 
combination or progestin alone), 
transdermally delivered contraceptives 
(eg, Ortho Evra), depot injections 
(eg, Depo-Provera), vaginal contraceptive 
ring (eg, NuvaRing), and contraceptive 
implant (eg, Implanon, Norplant) are 
allowed.
Hormone suppressants
N
N
Hypoglycemic agents
Y
Y
Hypolipidemics
N
Ya
Statins are allowed. 
Laxatives
Y
Yb
•
Episodic and chronic use of bulk 
laxatives and emollient laxatives are 
allowed.
•
Episodic use of stimulant laxatives 
containing senna, bisacodyl, and 
anthraquinone derivatives is allowed.
•
Episodic use of osmotic laxatives such as 
oral magnesium hydroxide (milk of 
magnesia), oral sodium citrate, and 
sodium biphosphate is allowed.
•
Hyperosmotic laxatives such as sorbitol, 
lactulose, and polyethylene glycol 
(eg, Miralax) are not allowed.
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Drugs Allowed (Y) and Drugs Not Allowed (N) as Concomitant Medications
Drug Name or Class
Episodic Use
(PRN)
Chronic Use
Restrictions
Muscle relaxants
N
N
Psychotropic drugs not 
otherwise specified 
(including herbal products)
N
N
No drugs with psychomotor effects or with 
anxiolytic, antidepressant, stimulant, 
antipsychotic, or sedative properties are 
allowed except as stipulated by the protocol. 
Herbal/dietary products and supplements 
with potential psychoactive actions, including 
St. John’s wort, ginkgo biloba, kava, SAMe, 
valerian root, DHEA, tyrosine, tryptophan 
and 5-HTP are not allowed. Omega-3 
supplements are allowed if the dose of EPA 
is ≤1000 mg/day, and the patient has been 
taking same for at least 1 month.
Sedatives/Hypnotics
Y
N
Only zolpidem (Ambien up to 5 mg/day and 
Ambien CR up to 6.25 mg/day), zaleplon 
(Sonata) up to 10 mg/day, and eszopiclone 
(Lunesta) up to 3 mg/day and melatonin are 
permitted up to 3 times a week, if required 
for sleep. Sedatives/hypnotics may not be 
used in the 8 hours preceding any behavioral 
assessments.
Corticosteroids, systemic
N
N
Corticosteroids, topical
Y
Y
Corticosteroids, inhalant
Y
Y
Corticosteroids, intra-
articular
Y
NA
Vaccines
Y
NA
a
If being taken for at least 3 months before study and dose is stabilized.
b
If being taken before admission to the study.
ADHD = attention deficit hyperactivity disorder; MAOI = monoamine oxidase inhibitor; NA = not applicable; N = no; 
PRN = pro re nata (as needed); Y = yes.
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APPENDIX IV.
PHARMACOKINETIC BLOOD SAMPLING AND 
SHIPPING INSTRUCTIONS (ONLY IN PARTICIPANTS 
AGED 7-11 YEARS)
Specimen Tube Collection Preparation
!
Adhere the provided label to a 3-mLVacutainer K2EDTA containing tube 
!
Prechill (eg, in an ice bath or refrigerator) the labeled Vacutainer tube and a 
polypropylene tube 
Plasma Collection Procedure
!
Collect blood into the prechilled Vacutainer tube; invert the tube gently 8-10 times to 
mix the blood and anticoagulant. Place the tube in an ice-water bath (use crushed ice).
!
Centrifuge the tube (within 30 minutes from the time the blood is drawn) at 2500 rpm 
to 3750 rpm for 10 minutes at approximately 4°C (ie, refrigerated centrifuge). In 
absence of a refrigerated centrifuge, the blood tubes should be chilled in ice for at 
least 10 minutes prior to centrifuging. Blood samples should still be centrifuged 
within 30 minutes of blood collection.
!
After centrifugation, transfer harvested plasma immediately into a prechilled, labeled, 
polypropylene tube provided by the central laboratory. Ensure the tube has the 
appropriate label marked with study number, patient identification number, date, and 
time of collection. 
!
The tube must then be immediately placed in the freezer and should be stored at 
approximately –70°C (or up to 6 weeks at –20°C).
!
Enter the actual time that the blood sample was collected on the appropriate form of 
the eCRF.
!
Send the frozen sample to the central laboratory according to the central laboratory 
sample shipment guide.
Shipping Guide from the Study Center to the Central Laboratory
Samples will be shipped from the study center to the central laboratory on the 
first available appropriate date after sample collection, and can be batch-shipped but no 
later than 6 weeks after sample collection. The central laboratory will provide packaging, 
labeling, and shipping instructions to the study center. Plasma samples will be shipped on 
sufficient dry ice to keep them frozen for at least 96 hours.
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APPENDIX V.
CHILDREN’S DEPRESSION RATING SCALE–REVISED
1. 
IMPAIRED SCHOOLWORK
Performance is consistent with ability
1
2
Decrease in school performance and/or ability to concentrate
3
4
Major interference with performance in most subjects
5
6
No motivation to perform
7
Comment:
2. 
DIFFICULTY HAVING FUN
Interest and activities realistically appropriate for age, 
personality, and social environment. No appreciable change 
from usual behavior during at least the past 2 weeks. Any 
feelings of boredom are seen as transient
1
2
Describes some activities as enjoyable that are 
realistically available several times a week but not on a 
daily basis. Shows interest but not enthusiasm.
3
4
Is easily bored. Complains of “nothing to do” as 
characteristic of daily experience. Participates in 
structured activities with a “going through the motions” 
attitude. May express interest primarily in activities that 
are (realistically) unavailable on a daily or weekly basis.
5
6
Has no initiative to become involved in any activities. 
Describes himself/herself as primarily passive. Watches 
others play or watches TV but shows little interest. 
Requires coaxing and/or pushing to get involved in 
activity. Shows no enthusiasm or real interest. Has 
difficulty naming activities.
7
Comment:
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3. 
SOCIAL WITHDRAWAL
Enjoys friendships with peers at school and at home. 
1
2
Does not actively seek out friendships but waits instead for 
others to initiate a relationship. Occasionally rejects 
opportunities to play, without having a describable 
alternative.
3
4
Frequently avoids or refuses opportunities for desirable 
interaction with others and/or sets up situations where 
rejection is inevitable.
5
6
Does not currently relate to other children. States that he/she 
has “no friends” or actively rejects new or former friends.
7
Comment:
4. 
SLEEP DISTURBANCE
No difficulty or occasional difficulty that is situationally 
explainable.
1
2
Frequently has mild difficulty with sleep.
3
4
Has difficulty with sleep nearly every night.
5
Supplemental information (not scored)
Indicate when sleep disturbance occurs (check all applicable items):
____
Upon first going to bed
____
In the middle of the night
____
Early in the morning
Comment:
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5. 
APPETITE DISTURBANCE
No problems or changes in eating pattern.
1
2
Mild but notable change from usual eating habits.
2
3
Avoids eating and/or is not hungry most of the time OR 
describes a noteworthy increase in appetite and/or 
excessive food intake.
5
Supplemental information (not scored)
If applicable, indicate type of appetite disturbance:
____
Increased appetite
____
Decreased appetite
Comment:
6. 
EXCESSIVE FATIGUE
No unusual complaints of “feeling tired” during the day.
1
2
Complains of fatigue seem somewhat excessive and are not 
related to boredom or increased activity levels.
3
4
Daily complaints of feeling tired.
5
6
Complains of feeling tired most of the day. May voluntarily 
take long naps without feeling refreshed. Degree of fatigue 
interferes with play activities.
7
Comment:
7. 
PHYSICAL COMPLAINTS
Occasional complaints that do not appear to be excessive.
1
2
Complaints appear mildly excessive.
3
4
Complains daily of aches and pains. These occasionally 
interfere with his/her ability to function.
5
6
Preoccupied with aches and pains. These regularly interfere 
with play activities.
7
Comment:
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8. 
IRRITABILITY
Rarely irritable.
1
2
Easily irritable. Periods of irritability occur several times a 
week, but do not last long.
3
4
Frequently irritable. Extended periods of irritability occur 
several times a week and are difficult to break out of.
5
6
Constant experience of irritability. Nothing changes this 
mood.
7
Comment:
9.
EXCESSIVE GUILT
Does not express any undue feelings of guilt. Reported guilt 
appears appropriate to precipitating event.
1
2
Exaggerates guilt and/or shame out of proportion to the event 
described.
3
4
Feels guilty over things not under his/her control. These 
feelings interfere with everyday functioning.
5
6
Severe delusions of guilt.
7
Comment:
10. 
LOW SELF-ESTEEM
Describes himself/herself in primarily positive terms.
1
2
Describes one important or prominent area where he/she feels 
there is a deficit.
3
4
Describes himself/herself in predominantly negative terms or 
gives bland answers to questions asked.
5
6
Refers to himself/herself in derogatory terms. Reports that other 
children frequently refer to him/her by using derogatory 
nicknames. Puts himself/herself down.
7
Comment:
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11. 
DEPRESSED FEELINGS
Occasionally feelings of unhappiness that quickly disappear.
1
2
Describes sustained periods of unhappiness that appear excessive 
for events described.
3
4
Feels unhappy most of the time without a major precipitating 
cause.
5
6
Feels unhappy all of the time; characterized by a sense of psychic 
pain (eg, “I can’t stand it”).
7
Comment:
12.
MORBID IDEATION
No morbid thinking reported.
1
Strongly denies morbid thoughts.
2
Discusses morbid thoughts that relate to a real event but seem excessive. 3
4
Describes preoccupation with morbid thoughts several times a week. 
These morbid thoughts extend beyond external reality.
5
6
Preoccupied on a daily basis with death themes or morbid thoughts that
are elaborate, extensive, or bizarre.
7
Comment:
13. 
SUICIDAL IDEATION
Understands the word suicide, but does not apply the term to 
himself/herself.
1
Sharp denial of suicidal thoughts.
2
Has thoughts about suicide, or of hurting himself/herself (if 
he/she does not understand the concept of suicide), usually when 
angry.
3
4
Has recurrent thoughts of suicide.
5
6
Has made a suicide attempt within the last month or is actively 
suicidal.
7
Comment:
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14. 
EXCESSIVE WEEPING
Report appears normal for age.
1
Suggestive statements that he/she cries, or feels like crying, more 
frequently than peers.
2
Cries more often than peers, occasionally without clear 
precipitant.
3
4
Cries or feels like crying frequently (several times a week). 
Admits to crying without knowing the reason why.
5
6
Cries nearly every day.
7
Comment:
15. 
DEPRESSED FACIAL AFFECT
Facial expression and voice animated during the interview. No 
sign of depressed affect.
1
Mild suppression of affect. Some loss of spontaneity.
2
Overall loss of spontaneity. Looks unhappy during parts of the 
interview (eg, sullen face, lowered eyes, lack of animation in face). 
Is capable of smiling, however, and does not avoid eye contact 
when discussing non-threatening areas.
3
4
Moderate restriction of affect throughout most of the interview. 
Has longer and frequent periods of looking distinctly unhappy. 
Nothing seems to enliven him/her.
5
6
Severe restriction of affect. Looks distinctly sad and withdrawn. 
Minimal verbal interaction throughout the interview. Cries or 
may appear tearful.
7
Comment:
16. 
LISTLESS SPEECH
Quality of speech seems situationally sensitive without any 
noteworthy deviations.
1
Slowed tempo, monotone, or overly soft speech.
2
Slowed tempo with many pauses where he/she appears to drift. 
Hesitations include sighing. Voice qualities are distinctly monotonic 
and unanimated, and convey a sense of distress and psychic 
discomfort.
3
4
Extreme sense of psychic distress exhibited in voice or by a profound 
sense of hollowness or emptiness. Has difficulty conducting the 
interview.
5
Comment:
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17.
HYPOACTIVITY
Bodily movements are animated. (Note that a hyperactive, agitated 
child is not distinguished here from what would be seen as normal 
nondistracting behavior; hyperactivity should be noted).
1
2
Bodily movements appear somewhat restricted and/or slowed.
3
4
Definite restriction in bodily movements and an overall sense of 
motor retardation.
5
6
Severe sense of motor retardation with catatonic-like qualities.
7
Comment:
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APPENDIX VI.
CLINICAL GLOBAL IMPRESSIONS–SEVERITY
SEVERITY OF ILLNESS
Considering your total clinical experience with this population, how mentally ill is the 
patient at this time? (Check one)
1 
Normal, not at all ill
2 
Borderline ill
3 
Mildly ill
4 
Moderately ill
5 
Markedly ill
6 
Severely ill
7 
Among the most extremely ill patients
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APPENDIX VII.
CLINICAL GLOBAL IMPRESSIONS–IMPROVEMENT
GLOBAL IMPROVEMENT
Rate total improvement whether or not, in your judgment, it is due entirely to drug 
treatment.
Compared to his/her condition at BASELINE, how much has the patient changed? 
(Check one)
1
Very much improved
2 
Much improved
3 
Minimally improved
4 
No change
5 
Minimally worse
6 
Much worse
7 
Very much worse
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APPENDIX VIII.
BASELINE COLUMBIA–SUICIDE SEVERITY RATING 
SCALE


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APPENDIX IX.
SINCE LAST VISIT COLUMBIA–SUICIDE SEVERITY 
RATING SCALE


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14.0
LITERATURE CITED
American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 
5th Edition. Washington, DC: American Psychiatric Association; 2013.
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.
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.
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.
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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 flexible 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.
Lan, K.K.G. and Trost D.C. 1999. The use of conditional power in interim analysis. 
Pfizer Technical Report 99-006.
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 
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Child Adolesc Psychiatr Clin N Am 15:827-41, vii, 2006.

SAP_001.pdf: 
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Levomilnacipran
LVM-MD-14 Statistical Analysis Plan Amendment 1                                                                 April 21, 2021
1.0
TITLE PAGE
LVM-MD-14
A Double-blind, Placebo- and Active-controlled Evaluation of the Safety and 
Efficacy of Levomilnacipran ER in Pediatric Patients 7-17 Years with Major 
Depressive Disorder
STATISTICAL ANALYSIS PLAN
Final: 15 July 2019
Amendment #1: 21 April 2021
Confidentiality Statement
This document is the property of Allergan Sales, LLC and may not!in full or part!be 
passed on, reproduced, published, distributed to any person, or submitted to any 
regulatory authority without the express written permission of Allergan Sales, LLC.
NCT03569475


Allergan PLC
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Levomilnacipran
LVM-MD-14 Statistical Analysis Plan Amendment 1                                                                 April 21, 2021
2.0
TABLE OF CONTENTS
1.0
TITLE PAGE....................................................................................................................................1
2.0
TABLE OF CONTENTS..................................................................................................................2
2.1
LIST OF TABLES..............................................................................................................3
2.2
LIST OF FIGURES ............................................................................................................3
3.0
LIST OF ABBREVIATIONS...........................................................................................................4
4.0
INTRODUCTION ............................................................................................................................6
5.0
OBJECTIVES.................................................................................................................................10
6.0
PATIENT POPULATIONS............................................................................................................11
6.1
Screened population..........................................................................................................11
6.2
Randomized population....................................................................................................11
6.3
Safety Population..............................................................................................................11
6.4
Intent-to-treat population..................................................................................................11
7.0
PATIENT DISPOSITION ..............................................................................................................12
8.0
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS........................................13
9.0
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE................................................14
9.1
Extent of Exposure ...........................................................................................................14
9.2
Measurement of Treatment Compliance...........................................................................14
10.0
EFFICACY ANALYSES ...............................................................................................................15
10.1
Primary Efficacy Parameter(s)..........................................................................................15
10.2
Secondary Efficacy Parameter(s)......................................................................................17
10.3
Additional Efficacy parameter(s)......................................................................................17
11.0
SAFETY ANALYSES....................................................................................................................19
11.1
Adverse Events .................................................................................................................19
11.2
Clinical Laboratory Parameters ........................................................................................20
11.3
Vital Signs ........................................................................................................................23
11.4
Electrocardiogram.............................................................................................................24
11.5
Other Safety Parameters ...................................................................................................25
11.5.1
Columbia-Suicide Severity Rating Scale............................................................26
11.5.2
Growth Evaluation..............................................................................................26
12.0
HEALTH OUTCOMES ANALYSES............................................................................................27
13.0
INTERIM ANALYSIS ...................................................................................................................28
14.0
DETERMINATION OF SAMPLE SIZE .......................................................................................29
15.0
STATISTICAL SOFTWARE.........................................................................................................30


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16.0
DATA HANDLING CONVENTIONS ..........................................................................................31
16.1
Visit Time Windows.........................................................................................................31
16.2
Derived efficacy Variables ...............................................................................................32
16.3
AGE-AND-GENDER-CORRELATED VALUES FOR WEIGHT AND HEIGHT........32
16.4
Repeated or Unscheduled Assessments of Safety Parameters..........................................33
16.5
Missing Date of the Last Dose of Investigational product................................................33
16.6
Missing Severity Assessment for Adverse Events............................................................33
16.7
Missing Causal Relationship to stuyd drug for Adverse Events.......................................33
16.8
Missing Date Information for Adverse Events .................................................................34
16.9
Missing Date Information for Prior or Concomitant Medications....................................35
16.9.1
Incomplete Start Date.........................................................................................35
16.9.2
Incomplete Stop Date .........................................................................................36
16.10
Character Values of Clinical Laboratory Parameters........................................................37
17.0
COVID-19 RELATED ANALYSIS...............................................................................................39
17.1
Efficacy Evaluation ..........................................................................................................39
17.2
Safety and Other Evaluation.............................................................................................39
18.0
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL..........................................................41
19.0
REFERENCES ...............................................................................................................................42
20.0
APPENDICES ................................................................................................................................43
APPENDIX I.
PATTERN-MIXTURE MODEL DETAILS......................................................43
APPENDIX II.
REPORTING SELECTED LABORATORY PARAMETERS IN 
CONVENTIONAL UNIT..................................................................................48
APPENDIX III. STATISTICAL ANALYSIS LIST FOR FUTILITY ANALYSIS ....................49
APPENDIX IV. CONDITIONAL POWER CALCULATION ....................................................50
APPENDIX V.
SUMMARY OF CHANGES FOR AMENDMENT #1.....................................51
2.1
LIST OF TABLES
Table 4–1.
Double-blind Daily Dosing Regimen ......................................................... 7
Table 4–2.
Schedule of Evaluations: Study LVM-MD-14 ........................................... 8
Table 11–1
Criteria for Potentially Clinically Significant Laboratory Values ............ 22
Table 11–2.
Criteria for Potentially Clinically Significant Vital Signs........................ 24
Table 11–3.
Criteria for Potentially Clinically Significant Electrocardiograms........... 25
Table 16–1.
Visit Time Windows for Double-Blind Treatment Period ....................... 31
Table 16–2.
Visit Time Windows for the Double-Blind Down-Taper period.............. 31
Table 16–3.
Examples of Coding Special Character Values for Clinical Laboratory 
Parameters................................................................................................. 38
Table 20–1.
List of Selected Parameters to be Reported in Conventional Units.......... 48
Table 20–2
List of Statistical Analysis for Futility Analysis....................................... 49
2.2
LIST OF FIGURES
Figure 4–1.
Study Design............................................................................................... 7


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3.0
LIST OF ABBREVIATIONS
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
ANCOVA
Analysis of covariance
ANTE(1)
First-order antedependence
AR(1)
First-order autoregressive
AST
Aspartate Aminotransferase
CDRS-R 
Children’s Depression Rating Scale–Revised
CS
Compound symmetry
COVID-19
Coronavirus disease 2019
C-SSRS
Columbia-Suicide Severity Rating Scale
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition
ECG
Electrocardiogram, electrocardiographic
eCRF
Electronic case report forms
ITT
Intent-to-treat
LOCF
Last observation carried forward
MDD
Major Depressive Disorder
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed-effects model for repeated measures
OC
Observed cases
PCS
Potentially clinically significant
PID
Patient identification
QTc
QT interval corrected for heart rate
QTcB
QT interval corrected for heart rate using the Bazett formula 
(QTcB = QT/(RR)½)


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QTcF
QT interval corrected for heart rate using the Fridericia formula 
(QTcF = QT/(RR)⅓)
SAE
Serious adverse event
SAP
Statistical analysis plan
SD
Standard deviation
SI
Le Système International d’Unités (International System of Units)
TBL
Total bilirubin
TEAE
Treatment-emergent adverse event
TOEP
Toeplitz
TESAE
Treatment-emergent serious adverse event
ULN
Upper limit of normal 


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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 specified in the 
protocol amendment #2 of Study LVM-MD-14 (dated 06 August 2020). Specifications of 
tables, figures, and data listings are contained in a separate document. The Modeling and 
Simulation Analysis Plan for pharmacokinetic will be prepared separately.
Study LVM-MD-14 is a Phase 3, multicenter, randomized, double-blind, placebo- and 
active-controlled, flexible-dose, parallel-group study in pediatric patients, ages 7-17 
years, who have been diagnosed with major depressive disorder (MDD) using Diagnostic 
and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) diagnostic criteria. The 
severity of MDD will be assessed based on Children’s Depression Rating Scale –
Revised (CDRS-R) scores, ranging in this study from 40 to 113. 
The length of this study will be 10 weeks, including a 1-week screening/washout period, 
followed by an 8-week double-blind treatment period and a 1-week double-blind down-
taper period. Signed informed consent from the patient or the patient’s legally authorized 
representative and caregiver will be obtained before any study-related procedures are 
begun. All patients will be assigned a screening number. At the end of Visit 2 (Baseline), 
patients meeting the inclusion criteria will be randomized in 1:1:1 ratio to treatment 
groups of placebo, levomilnacipran, fluoxetine, respectively. A total of 480 patients 
(160 per treatment group) are planned to be randomized. Patients randomized to the 
levomilnacipran 40 – 80 mg/day group will receive 10 mg/day on Days 1-3, 20 mg/day 
on Days 4-7, and 40 mg/day during Weeks 2 through 8. Based on therapeutic response 
and tolerability, an additional dose increase to 80 mg/day is permitted at Week 3. During 
the down-taper period, patients will take levomilnacipran 40 mg/day for 2 days, and then 
levomilnacipran 20mg/day for 5 days. Patients randomized to the fluoxetine 20 mg/day 
group will receive fluoxetine 10 mg/day on Days 1-7, and then 20 mg/day during Weeks 
2 through Week 8. During the down-taper period, patients will take fluoxetine 10 mg/day 
for 7 days. The dosing regimen and schedule for this study are presented in Table 4–1. 
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 when 
considered clinically appropriate by the investigator. Figure 4–1 provides a schematic of
the study design. 
Efficacy and safety assessments will be conducted at the clinic at the ends of Weeks 1, 2, 
3, 4, 6, and 8 of double-blind treatment. Patients prematurely discontinuing from the 
study, regardless of cause, will be seen for a final evaluation. The schedule of evaluations 
for Study LVM-MD-14 is presented in Table 4–2.


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Table 4–1.
Double-blind Daily Dosing Regimen
ET = Early termination; LVM = levomilnacipran
Figure 4–1.
Study Design
Treatment Group
Row
Week
1
2
3-8
Down-Taper
9/ET
Days 1-3
Days 4-7
Days 1-7
Days 1-7
Days 1-2
Days 3-7
Levomilnacipran
40 mg – 80 mg
A
LVM
10 mg
LVM
20 mg
LVM
40 mg
LVM
40 mg
LVM
40 mg
LVM
20 mg
B
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
A
Optional dose escalation to 80 mg as 
determined by treating physician
LVM
40 mg
LVM
40 mg
LVM
20 mg
B
LVM
40 mg
Placebo
Placebo
Fluoxetine
20 mg
A
Fluoxetine
10 mg
Fluoxetine
10 mg
Fluoxetine
20 mg
Fluoxetine
20 mg
Fluoxetine
10 mg
Fluoxetine
10 mg
B
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
A
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
B
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo


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Table 4–2.
Schedule of Evaluations: Study LVM-MD-14
Screening 
Period
Double-blind Treatment Period
Double-blind 
Down-Taper 
Period
Visit 1a
Visit 2 
(Baseline)
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8/ 
ETb
Visit 9/SFU c
End of Study Week
–1
0
1
2
3
4
6
8
9
Informed assent 
(patient) and 
consent (parent[s]
/legally authorized 
representative) 
X
Informed consent 
(caregiver)d
X
Inclusion and 
exclusion criteria 
X
X
Determination of 
ability to swallow 
capsule
X
Medical history
X
Psychiatric history
X
Medication history 
and non-drug 
psychiatric 
treatment history
X
X
Concomitant 
medications
X
X
X
X
X
X
X
Physical 
examination
Xe
X
Clinical laboratory 
determinations
Xe
X
Serum β-hCG 
pregnancy testf
Xe
X
Thyroxine, TSH 
tests
Xe
Urine drug screen
Xe
ECG
Xe
X
X
Vital signs 
(BP, pulse, weight)
X
X
X
X
X
X
X
Vital signs 
(BP, pulse, weight 
and heightg)
Xe
X
K-SADS-PLh
X
CDRS-R
X
X
X
X
X
X
X
X
CGI-S
X
X
X
X
X
X
X
X
CGI-I
X
X
X
X
X
X
C-SSRS
X
X
X
X
X
X
X
X
X
PK samplingi
X
X
X
AEs
X
X
X
X
X
X
X
X
X
IP dispensing
X
X
X
X
X
X
Xj
IP return
X
X
X
X
X
X
Xj
IP compliance
X
X
X
X
X
X
Xj
Note:
If necessary, visits may be conducted up to 3 days before or after scheduled visits relative to the Baseline 
Visit (Visit 2). 
a
After assent and consent are obtained, the screening period may be up to 5 weeks in duration.


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b
Visit 8 assessments to be completed for all randomized patients who complete the study or discontinue before
Week 8.
c
All randomized patients must complete Visit 8/ET and, at the end of the down-taper period, return for 
Visit 9/SFU. Patients who do not enter the down-taper period must return for Visit 9/SFU approximately 1 week 
after Visit 8/ET Visit.
d
If the parent(s), guardian, or legally authorized representative (LAR) is also the patient’s caregiver, he/she will be 
asked to sign both the parent and caregiver consents.
e
May be repeated at the Investigator’s discretion before Visit 2.
f
A pregnancy test will be obtained for female patients of childbearing potential only. 
g
Height will be recorded at Screening (Visit 1) and Visit 8/ET using a stadiometer.
h
K-SADS-PL data will be retained as source documents at the site.
i
PK only collected on patients aged 7-11 years. Sparse PK blood samples will be collected during Visit 5 (at 
predose and 1-4 hour postdose), Visit 6 (4-6 hours postdose), and Visit 7 (6-8 hours postdose). At Visit 5, or at 
any 24-hour period between Visit 5 and Visit 7, inclusive, serial blood samples will be collected from a subset of 
consented 7-11-year-old patients instead of sparse PK samples at the following time points: predose [20-24 hours 
after the most recent dose], and 2, 4, 6, 8, 10-12, and 24-hours postdose.
j
For patients entering the double-blind down-taper period.
AE = adverse event; β-hCG = β-human chorionic gonadotropin; BP = blood pressure; CDRS-R = Children’s 
Depression Rating Scale–Revised; CGI-I = Clinical Global Impressions–Improvement (scale); CGI-S = Clinical Global 
Impressions–Severity (scale); C-SSRS = Columbia–Suicide Severity Rating Scale; ECG = electrocardiogram; 
ET = early termination; IP = investigational product; K-SADS-PL = Kiddie Schedule for Affective Disorders and 
Schizophrenia–Present and Lifetime; LAR = legally authorized representative; PK = pharmacokinetic; SFU = Safety 
Follow-up; TSH = thyroid stimulating hormone


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5.0
OBJECTIVES
The objective of this study is to evaluate the efficacy, safety, and tolerability of 
levomilnacipran compared with placebo in pediatric outpatients (7-17 years) with MDD. 
In addition, the study is designed to obtain pharmacokinetic (PK) data to define the PK
profile of levomilnacipran in the pediatric population (7-17 years of age).


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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 and
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 
received at least 1 dose of double-blind investigational product.
6.4
INTENT-TO-TREAT POPULATION
The Intent-to-Treat (ITT) Population will consist of all patients in the Safety Population
who had the baseline and at least 1 postbaseline assessment of the CDRS-R total score.


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7.0
PATIENT DISPOSITION
The number and percentage 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 all the screened patients. 
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.


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8.0
DEMOGRAPHICS AND OTHER BASELINE 
CHARACTERISTICS
Demographic parameters (age; age group [7-11 and 12-17]; sex; race; ethnicity), and 
baseline characteristics (weight; height; and body mass index (BMI)) 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, 
Q1, Q3, minimum, and maximum values. Categorical variables will be summarized by 
number and percentage of patients.
Abnormalities in patients’ medical and surgical histories will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA), version 22.0 or newer. The number and 
percentage of patients with abnormalities in medical and surgical histories in each system 
organ class and preferred term will be summarized by treatment group for the Safety 
Population. MDD history and nondrug psychiatric treatment history will also be 
summarized by treatment group for the Safety Population.
The World Health Organization Drug Dictionary, version March 2017 or newer, will be 
used to classify prior and concomitant medications by therapeutic class and drug name. 
Prior medication is defined as any 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 for the coded drug name or therapeutic class.
Summaries of 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. 


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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 period, inclusive. Descriptive 
statistics (number of patients, mean, SD, median, Q1, Q3, 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 the double-blind investigational product in 
years (excluding the double-blind down-taper period), will be summarized by treatment 
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.


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10.0
EFFICACY ANALYSES
The efficacy analyses will be based on the ITT Population. Baseline for efficacy is 
defined as the last non-missing efficacy assessment recorded at or prior to first dose of 
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, 
hich 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.
10.1
PRIMARY EFFICACY PARAMETER(S)
The primary efficacy parameter will be the change from baseline in CDRS-R total score
at Week 8. The primary analysis for comparing levomilnacipran vs. placebo for the 
primary efficacy parameter will be performed using an MMRM with treatment group, 


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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. In the event of non-
convergence of the model using unstructured covariance matrix, a structured covariance 
matrix will be used in combination with empirical variance estimate (i.e. sandwich 
estimator) to address the potential mis-specified situation. The following sequence of 
alternative covariance structures (First-order antedependence [ANTE (1)], Toeplitz 
[TOEP], First-order autoregressive [AR(1)] and compound symmetry[CS]) will be 
considered in the MMRM until convergence.
To control the overall type I error rate for the multiple comparisons across the primary 
and the secondary hypotheses, a fixed sequence procedure will be applied. Details are 
provided in Section 10.2.
In addition, two sensitivity analyses, LOCF and pattern-mixture model approaches, will 
be performed on the primary efficacy parameter. 
The LOCF approach is based on an analysis-of-covariance (ANCOVA) model including 
treatment group and pooled study center as factors and baseline CDRS-R total score as a 
covariate. 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 pattern for the pattern-mixture model will be defined by the 
patient’s last visit with an observed value. The observed CSRS-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 (e.g., the models for the pattern-specific identifiable densities 
and the unidentified conditional distributions, the shift parameter Δ, and the multiple 
imputation algorithm) are provided in Appendix I to this SAP.
Graphical display of treatment difference vs. placebo (mean difference ± SE) in primary
efficacy parameter will be provided by pooled study center to examine the consistency of 
the primary efficacy results across study centers.


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The site 0070 ceased operations on October 31, 2020, due to the damage caused by 
Hurricanes Laura and Delta, which made landfall on August 27, 2020 and October 10, 
2020, respectively. One more sensitivity analysis excluding all data from this site 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 0070. 
10.2
SECONDARY EFFICACY PARAMETER(S)
The secondary efficacy parameter is the change from baseline to Week 8 in CGI-S score, 
which will be analyzed using the MMRM approach similar to the one used for the 
primary efficacy parameter. A sensitivity analysis will also be performed using the LOCF 
approach as described in Section 10.1. 
To control the overall family-wise type I error rate for multiple comparisons across the 
primary and the secondary efficacy parameters, the fixed sequence testing procedure will
be implemented, i.e., the efficacy analysis of the secondary efficacy parameter will be 
carried out inferentially only if the null hypothesis for the primary efficacy parameter is 
rejected. 
10.3
ADDITIONAL EFFICACY PARAMETER(S)
The additional efficacy parameters will include the following at each postbaseline visit:
∀CGI-I score
∀Change from baseline in CGI-S score
∀CDRS-R response (≥40% reduction in CDRS-R from baseline) rate
∀CDRS-R remission (CDRS-R ≤ 28) rate
The CGI-I score and change from baseline in CGI-S score will be analyzed using the 
MMRM and the LOCF approaches similar to the ones used for the primary efficacy 
parameter. For the analysis of CGI-I score, the baseline CGI-S score will be used as the 
baseline variable.
The CDRS-R response rate and CDRS-R remission rate will be analyzed using a 
generalized linear mixed model (GLMM), based on a logit link function, with a random 
intercept and fixed effect terms of treatment group, visit, treatment-by-visit interaction, 
and baseline score. If the GLMM does not converge, a logistic regression model with 
treatment group and baseline score as explanatory variables will be used. For the logistic 
regression analysis, postbaseline missing data will be imputed using the LOCF approach. 


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In addition, plots of changes from baseline in CDRS-R total score will be presented 
across study visits by treatment group. 


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11.0
SAFETY ANALYSES
The safety analysis will be performed for the double-blind treatment period and the 
double-blind down-taper period (only for safety parameters collected during the double-
blind down-taper period), separately, using the Safety Population unless stated otherwise. 
The safety parameters will include adverse events (AEs) and clinical laboratory
parameters, vital sign measurements, electrocardiographic (ECG) parameters, suicide risk 
assessment using the Columbia-Suicide Severity Rating Scale (C-SSRS), and growth 
evaluation. For each safety parameter, the last nonmissing safety assessment before the
first dose of investigational product will be used as the baseline for all analyses of that 
safety parameter. Continuous variables will be summarized by number of patients and 
mean, SD, median, Q1, Q3, minimum, and maximum values. Categorical variables will 
be summarized by number and percentage of patients.
For patients who take the double-blind down-taper investigational product, the double-
blind treatment period starts with the first dose of double-blind investigational product 
and ends with the last assessment date up to the first dose of the double-blind down-taper 
investigational product. The double-blind down-taper period starts one day after the end 
of the double-blind treatment period and ends with the latter of the last dose of the 
double-blind down-taper investigational product and the last assessment date.
For patients who do not take the double-blind down-taper investigational product, the
double-blind treatment period starts with the first dose of double-blind investigational
product and ends with the latter of the last dose of the double-blind investigational 
product and the last assessment date.
11.1
ADVERSE EVENTS
Adverse events will be coded by system organ class and preferred term using the 
MedDRA, version 22.0 or newer.
An AE will be considered a treatment-emergent adverse event (TEAE) if the AE began or 
worsened (increased in severity or became serious) on or after the date of the first dose of 
investigational product. However, an AE that occurs more than 30 days after the last dose 
of study intervention will not be counted as a TEAE. Per eCRF instructions, a new AE 
record will be created with a new AE onset date for any AE that worsens. Therefore,
TEAEs can simply be identified as those AEs with recorded onset date on or after the 
date of the first dose of investigational product and within 30 days after the last dose of 
investigational product. If more than 1 AE was reported before the date of the first dose 
of 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.


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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 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.
An AE will be considered a treatment-emergent serious adverse event (TESAE) if it is a 
TEAE that additionally meets any serious adverse event (SAE) criterion. 
The number and percentage of patients who have TESAEs will be summarized by 
preferred term and treatment group and will be sorted by decreasing frequency for the
levomilnacipran treatment groups. 
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.
11.2
CLINICAL LABORATORY PARAMETERS
Descriptive statistics for clinical laboratory values (in SI units) and changes from the 
baseline values at each assessment time point (including the end of the double-blind 
treatment period) will be presented by treatment group for the following laboratory 
parameters:


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Hematology: Absolute and differential white blood cell count, erythrocyte count, 
hemoglobin, hematocrit, platelet count, and red blood cell indices (mean corpuscular 
volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration)
Chemistry: Sodium, potassium, calcium, chloride, bicarbonate, glucose, blood urea 
nitrogen, creatinine, total protein, alkaline phosphatase, albumin, total bilirubin, direct 
bilirubin, indirect bilirubin, AST, ALT, Free T3, free T4, TSH, lactate dehydrogenase, 
creatine phosphokinase, γ-glutamyl transpeptidase, uric acid, phosphate, lipid panel (total 
cholesterol, triglycerides, low density lipoproteins, high density lipoproteins), prolactin, 
insulin, and magnesium
Urinalysis: Specific gravity, pH, protein, glucose
In addition, descriptive statistics for values and changes from the baseline values in 
conventional units at each assessment time point will be presented for selected clinical 
laboratory parameters listed in Appendix II.
Clinical laboratory test values will be considered potentially clinically significant (PCS)
if they meet either the lower-limit or higher-limit PCS criteria listed in Table 11–1. The
number and percentage of patients who have PCS postbaseline clinical laboratory values
will be tabulated by treatment group. The percentages will be calculated relative to the
number of patients with available non-PCS baseline values and at least 1 postbaseline
assessment. The numerator will be the total number of patients with available non-PCS
baseline values and at least 1 PCS postbaseline value. A supportive listing of patients
with PCS postbaseline values will be provided, including the patient identification (PID)
number, and baseline and all postbaseline (including non-PCS) values. In addition, a 
listing of all AEs that occurred in patients who had PCS postbaseline clinical laboratory 
values will be provided. 


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Table 11–1
Criteria for Potentially Clinically Significant Laboratory Values
Parameter
SI Unit
Lower Limit
Higher Limit
HEMATOLOGY
Basophils 
%
—
> 6
Eosinophils 
%
—
> 10
Hematocrit 
ratio
< 0.9 × LLN
—
Hemoglobin 
g/L
< 0.9 × LLN
—
Lymphocytes 
%
< 10
> 60
Monocytes 
%
—
> 20
Neutrophils 
%
< 30
> 90
Platelet count 
× 109/L
≤ 75
≥ 700
White blood cell count 
× 109/L
≤ 2.5
≥ 15
CHEMISTRY 
Albumin 
g/L
< 0.9 × LLN
> 1.1 × ULN
Alkaline phosphatase 
U/L
—
≥ 3 × ULN
Alanine aminotransferase 
U/L
—
≥ 3 × ULN
Aspartate aminotransferase 
U/L
—
≥ 3 × ULN
Bicarbonate
mmol/L
< 0.9 × LLN
> 1.1 × ULN
Blood urea nitrogen
mmol/L
—
> 1.2 × ULN
Calcium 
mmol/L
< 0.9 × LLN
> 1.1 × ULN
Chloride 
mmol/L
< 0.9 × LLN
> 1.1 × ULN
Cholesterol, total 
mmol/L
—
> 1.3 × ULN
Creatinine 
μmol/L
—
> 1.3 × ULN
Glucose 
mmol/L
< 0.8 × LLN
> 1.4 × ULN
High-density lipoprotein
mmol/L
< 0.8 × LLN
—
Low-density lipoprotein
mmol/L
—
> 2.0 × ULN
Magnesium
mmol/L
< 0.9 × LLN
> 1.1 × ULN
Phosphate
mmol/L
< 0.9 × LLN
> 1.1 × ULN
Potassium 
mmol/L
< 1.0 × LLN
> 1.0 × ULN
Sodium 
mmol/L
< 1.0 × LLN
> 1.0 × ULN
Total bilirubin 
μmol/L
—
> 1.5 × ULN
Total protein 
g/L
< 0.9 × LLN
> 1.1 × ULN
Triglyceride
mmol/L
—
> 3.0 × ULN
URINALYSIS
Protein 
mg/dL
—
at least 2 +
Glucose 
mmol/L
—
at least 2 +
ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatine phosphokinase; 
LLN = lower limit of normal value provided by the laboratory; PCS = potentially clinically significant; 
SI = Le Système International d'Unités (International System of Units); ULN = upper limit of normal 
value provided by the laboratory.
Shift tables from baseline to end of double-blind treatment period for clinical laboratory 
parameters will be presented by treatment group for the following categories: low, 
normal, and high.


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Potential Hy’s Law criteria is defined by a postbaseline elevation of alanine
aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 3x ULN (ULN = upper
limit of normal laboratory reference range), along with total bilirubin (TBL) ≥ 2x ULN
and a non-elevated alkaline phosphatase (ALP) < 2x ULN, all based on blood draws
collected within a 24-hour period. The number and percentage of patients who meet the
following criteria of clinical interest during the double-blind treatment period will be
tabulated by treatment group. A supportive list will also be provided.
∀ALT: ≥ 3x ULN, ≥ 5x ULN, ≥ 10x ULN, ≥ 20x ULN
∀AST: ≥ 3x ULN, ≥ 5x ULN, ≥ 10x ULN, ≥ 20x ULN
∀ALT or AST: ≥ 3x ULN, ≥ 5x ULN, ≥ 10x ULN, ≥ 20x ULN
∀TBL: ≥ 2x ULN
∀ALP: ≥ 1.5x ULN
∀Concurrent elevations: ALT or AST ≥ 3x ULN with TBL ≥ 1.5x ULN; ALT or 
AST ≥ 3x ULN with TBL ≥ 2x ULN; ALT or AST ≥ 3x ULN with TBL ≥ 2x 
ULN and ALP < 2x ULN.
11.3
VITAL SIGNS
Descriptive statistics for vital signs (sitting radial pulse rate, sitting systolic and diastolic 
blood pressure, body weight and height) and changes from baseline values at each visit,
and at the end of double-blind treatment period, and at the end of double-blind down-
taper period will be presented by treatment group. Only patients with available baseline 
and at least 1 postbaseline assessment will be included in the summary. Vital sign values 
will be considered PCS if they meet both the observed-value criteria and the change-
from-baseline criteria listed in Table 11–2. The number and percentage of patients with 
PCS postbaseline values will be tabulated by treatment group separately for the double-
blind treatment period and the double-blind down-taper period. The percentages will be 
calculated relative to the number of patients with available baseline and at least 1 
postbaseline assessment. The numerator will be the total number of patients with 
available baseline values and at least 1 PCS postbaseline value. A supportive listing of 
patients with PCS postbaseline values will be provided, including the PID number, and 
baseline and all postbaseline (including non-PCS) values. 
In addition, a listing of all AEs that occurred in patients who had PCS postbaseline vital 
sign values will be provided. 


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Table 11–2.
Criteria for Potentially Clinically Significant Vital Signs
Parameter
Flag
Criteriaa
Observed Value
Change From Baseline
Sitting systolic blood 
pressure, mm Hg
High
≥140
Increase of ≥ 20
Low
≤80
Decrease of ≥ 20
Sitting diastolic blood 
pressure, mm Hg
High
≥ 100
Increase of ≥ 15
Low
≤ 50
Decrease of ≥ 15
Sitting pulse rate, bpm
High
≥ 130
Increase of ≥ 15
Low
≤ 45
Decrease of ≥ 15
Weight, kg
High
—
Increase of ≥ 7%
Low
—
Decrease of ≥7%
a
A postbaseline value is considered potentially clinically significant if it meets both the observed-value and the 
change-from-baseline criteria.
bpm = beats per minute.
11.4
ELECTROCARDIOGRAM
Descriptive statistics for ECG parameters (heart rate, RR interval, PR interval, QRS 
interval, QT interval, and QTc) at baseline and changes from baseline values at each 
assessment time point (including the end of the double-blind treatment period) will be 
presented by treatment group. The QTc will be calculated using both the Bazett and 
Fridericia corrections. Only patients with available baseline and at least 1 postbaseline 
assessment will be included in the summary. 
Electrocardiographic parameter values are considered PCS if they meet or exceed the 
higher-limit PCS criteria listed in Table 11–3. The number and percentage of patients 
with PCS postbaseline ECG values will be tabulated by treatment group for the double-
blind treatment period. The percentages will be calculated relative to the number of 
patients with available non-PCS baseline values and at least 1 postbaseline assessment for 
the double-blind treatment period. The numerator is the total number of patients with 
available non-PCS baseline values and at least 1 PCS postbaseline value for the 
double-blind treatment period. A supportive tabular display of patients with PCS 
postbaseline values will be provided, including the PID number, baseline, all postbaseline
(including non-PCS) values, and change from baseline.
In addition, a listing of all AEs that occurred in patients who had postbaseline PCS ECG 
values will be provided.


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Table 11–3.
Criteria for Potentially Clinically Significant Electrocardiograms
Parameter
Unit
Higher Limit
QRS interval
msec
≥ 150
PR interval
msec
≥ 250
QTcB
msec
>500 
QTcF
msec
> 500
QTcB = QT interval corrected for heart rate using the Bazett formula (QTcB=QT/(RR)1/2); QTcF = QT interval 
corrected for heart rate using the Fridericia formula (QTcF=QT/(RR)1/2)
A listing of patients with postbaseline clinically significant ECG abnormalities as 
reported by the central laboratory and the Investigators will be provided. 
The number and percentage of patients with an increase > 30 msec but ≤ 60 msec, and 
with an increase > 60 msec in QTcB or QTcF will be tabulated. A supportive listing of 
patients with postbaseline QTcB or QTcF increases > 30 msec will be provided, 
including the PID number, and all QTcB and QTcF values (including changes from 
baseline). A listing of all AEs for patients with postbaseline QTcB or QTcF increases 
> 30 msec will also be provided. 
A shift table from baseline to the end of double-blind treatment period in the 
Investigator’s overall interpretation of the ECG will be presented by treatment group for 
the following categories: normal; abnormal, not clinically significant; abnormal, 
clinically significant.
11.5
OTHER SAFETY PARAMETERS
Other safety parameters include Columbia-Suicide Severity Rating Scale (C-SSRS) and 
growth.


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11.5.1
Columbia-Suicide Severity Rating Scale
For the C-SSRS, the number and percentage of patients with any suicidal ideation or
suicidal behavior at Baseline (lifetime history), and during the double-blind treatment 
period and during double-blind down-taper period will be summarized by treatment 
group for the Safety population. The distribution of responses for the most severe suicidal 
ideation and the most severe suicidal behavior will also be summarized by treatment 
group, separately for the lifetime history, the double-blind treatment period, and the 
double-blind down-taper period. Supportive listings will be provided and will include the 
PID number, treatment group, visit number, lifetime history, and postbaseline values for 
each patient. Intensity of ideation, suicidal behavior type, and lethality of suicidal 
behavior will also be included in these listings. A listing of all AEs occurring in patients 
who have suicidal ideation or suicidal behavior will also be provided. 
11.5.2
Growth Evaluation
Weight and height will be presented as standardized z-scores adjusted for gender and age, 
using the LMS method (Cole T.J., 1990). 
To assess the impact of treatment on growth, the change from baseline to Week 8 in the 
age-and-gender-adjusted height and weight will be analyzed using an ANOVA model 
with treatment as factor. A non-parametric (Wilcoxon) test will also be performed. 


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12.0
HEALTH OUTCOMES ANALYSES
Not applicable. 


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13.0
INTERIM ANALYSIS
The interim analysis will be conducted when at least 50% of randomized patients have 
either completed or discontinued the study. A futility analysis and safety analysis will be 
included in the interim analysis listed in the Appendix III. The general data derivation
and preparation will follow the specification in the SAP and the amendment. 
The futility assessment of the primary efficacy parameter (CDRS-R total score) on ITT 
population will be based on the conditional power as described in Lan et al. (1988) and 
Proschan et al. (2006). In calculating the conditional power, it is assumed that the future 
patients to be enrolled into the Study will have similar efficacy as those of the existing 
patients of the same treatment group. The non-binding futility criteria will be met when 
the conditional power for detecting a statistically significant treatment difference between 
the levomilnacipran treatment group (40-80 mg/day) and placebo at the final analysis 
given the interim analysis results is 0.2 (20%) or lower. Further details of the calculation 
of conditional power are provided in Appendix IV. 
The safety analysis will be performed on the Safety Population, including the summary of 
TEAE, SAE, death, and TEAE leading to study discontinuation; the incidence of 
common TEAEs (≥ 2%); PCS for laboratory parameters, vital signs, and ECGs; and the 
summary of C-SSRS during the double-blind treatment period. 
Data will be presented in an unblinded fashion. A separate, independent, fire-walled 
Statistical Analysis Group and Data Review Committee will be established to conduct the 
unblinded interim analysis, review the unblinded results and make recommendations 
regarding the continuation of the study. To maintain the scientific reliability of statistical 
analyses after the final database lock, preserve the integrity of study conduct, and guard 
from introducing any potential bias into the conduct of the study and/or analysis of its 
results, individuals in these two groups will not be involved in any operational aspects of 
the trial.


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14.0
DETERMINATION OF SAMPLE SIZE
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. A sample size of 480 patients (160 per treatment group) 
will be needed to provide 85% power for primary analysis (levomilnacipran 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. 


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15.0
STATISTICAL SOFTWARE
Statistical analyses will be performed using version 9.4 (or newer) of SAS on a Linux
operating system.


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16.0
DATA HANDLING CONVENTIONS
16.1
VISIT TIME WINDOWS
Table 16–1 and Table 16–2 present the visits assigned for efficacy and safety analyses 
and the corresponding range of treatment days (window) during which an actual visit 
may occur.
Table 16–1.
Visit Time Windows for Double-Blind Treatment Period
Derived Visit
Scheduled Visit Daya
Window
Baseline
Week 0 (Day 1)
Days ≤ 1
Week 1
End of Week 1 (Day 8)
Days [2, 11]
Week 2
End of Week 2 (Day 15)
Days [12, 18]
Week 3
End of Week 3 (Day 22)
Days [19, 25]
Week 4
End of Week 4 (Day 29)
Days [26, 35]
Week 6
End of Week 6 (Day 43)
Days [36, 49]
Week 8
End of Week 8 (Day 57)
Days ≥ 50 days and within double-blind 
treatment period
End of double-blind 
treatment periodb
Final or Termination Visit during the double-blind treatment period
a
Relative to the date of the first dose of double-blind investigational product. Day 1 = the date of the first dose of 
double-blind investigational product. There is no Day 0 or Week 0.
b
Presented in analysis tables for safety parameters, including but not limited to electrocardiograms, clinical 
laboratory values, and vital signs, and C-SSRS. If repeat assessments occur at the end of double-blind treatment 
period visit, the algorithm in Section 16.4 will be used to determine which values are used in the analysis. 
Table 16–2.
Visit Time Windows for the Double-Blind Down-Taper period
Derived Visit
Scheduled Visit
Window
Week 9
End of Week 9
Within the double-blind down-taper period 
(from 1 day after the end of double-blind 
treatment period to the end of the double-
blind down-taper period)
End of double-blind 
down-taper perioda
Final of termination visit during the double-blind down-taper period. 
a
Presented in analysis tables for safety parameters collected during the double-blind-down-taper period. If any 
assessments are repeated at the end-of-double-blind-down-taper-period visit, the algorithm in Section 16.4 will be 
used to determine which values are used in the analysis.


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If the visit date is on or after the date of the first dose of double-blind investigational 
product, the study day is calculated by visit date – date of the first dose of double-blind 
investigational product +1. If the visit date is before the date of the firs dose of double-
blind investigational product, the study day is calculated by visit date – date of the first 
dose of double-blind investigational product. Therefore, a negative day indicates a day 
before the start of the double-blind investigational product. 
If a patient has 2 or more visits within the same window, the last visit with a nonmissing 
value will be used for analysis. 
16.2
DERIVED EFFICACY VARIABLES
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.
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 (e.g. weight and height) and L, M and S are the 
values from the appropriate table corresponding to the age in months (or length/stature) 
and sex (1 = male; 2 = female). X must be in metric measurements (kilograms or meters). 
This is called LMS method (Cole TJ, 1990), and parameters L, M, and S are the Box-Cox 
transformation power, median, and standard deviation, respectively, in the reference data, 
which again are provided in the reference data tables.


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16.4
REPEATED OR UNSCHEDULED ASSESSMENTS OF SAFETY 
PARAMETERS
If a patient has repeated assessments before the date of first dose of double-blind
treatment period 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 after all efforts are made it is 
still missing, the last available dosing record date will be used as the last dose date.
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 STUYD DRUG 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 investigational product, a causality of yes will be 
assigned. The imputed values for causal relationship to investigational product will be 
used for the incidence summary; the values will be shown as missing in the data listings.


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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 
study 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
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:


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∀
If the stop date is after the date of the first dose of double-blind investigational 
product, the date of the first dose of 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 and then the 
stop date will be imputed. If the imputed started date is after the imputed stop date, the 
imputed stop date will be adjusted by imputed start date. 
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 and the 
imputed start date is after the stop date, the start date will be imputed using the stop date.
Missing month and day
∀
If the year of the incomplete start date is the same as the year of the first dose of 
double-blind investigational product, the month and day of the first dose of 
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


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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 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, impute it as descripted in Section 16.4. 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.
Missing month and day
∀
If the year of the incomplete stop date is the same as the year of the last dose of 
investigational product during double-blind treatment period, the month and day 
of the last dose of investigational product will be assigned to the missing fields
∀
If the year of the incomplete stop date is before the year of the last dose of 
investigational product during double-blind treatment period, 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 
investigational product during double-blind treatment period, 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


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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 investigational product during double-blind treatment 
period, the day of the last dose of 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 investigational product during double-blind treatment period 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 investigational product during double-blind 
treatment period, 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 investigational product during double-blind treatment period 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 investigational product during double-blind treatment 
period, the first day of the month will be assigned to the missing day
16.10
CHARACTER VALUES OF CLINICAL LABORATORY 
PARAMETERS
If the reported value of a clinical laboratory parameter cannot be used in a statistical 
summary table because, for example, a character string is reported for a parameter of the 
numeric type, a coded value must be appropriately determined for use in the statistical 
analyses. The actual values, however, as reported in the database will be presented in the 
data listings.
Table 16–3 shows examples of how some possible laboratory results should be coded for 
the analysis.


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Table 16–3.
Examples of Coding Special Character Values for Clinical
Laboratory Parameters
Laboratory Test,
SI Unit
Possible Laboratory Results
Coded Value for Analysis
CHEMISTRY
ALT, U/L
< 5
5
AST, U/L
< 5
5
Bilirubin, total, μmol/L
< 2
2
URINALYSIS
Glucose, mmol/L
< 2.775, Negative
0
[2.775, 5.55)
1+
[5.55, 13.875)
2+
[13.875, 27.75)
3+
[27.75, 55.5)
4+
≥55.5
5+
Ketones, mmol/L
> 0.444, ≥ 0.444, > 0, Trace
Positive
≤ 0, Negative
Negative
pH
> 8.0, ≥8.0
8.0
≥8.5
8.5
Protein g/L
< 0, Negative
Negative
[0, 0.15), Trace
0
[0.15, 0.3)
1+
[0.3, 1.0)
2+
[1.0, 5.0)
3+
≥ 5.0
4+
ALT = alanine aminotransferase; AST = aspartate aminotransferase; SI = Le Système International d’Unités
(International System of Units).


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17.0
COVID-19 RELATED ANALYSIS
To eliminate immediate potential hazards to patients and study staff due to the 
COVID-19 pandemic while ensuring patients safety and maintaining data integrity, the
protocol amendment #2 has been sent to sites to allow remote visits. 
This section specifies analyses for evaluating the impact of COVID-19. 
17.1
EFFICACY EVALUATION
Due to the nature of the patient CDRS-R assessment, the interview may be performed 
remotely provided that the patient has access to a videoconferencing platform where the 
rating clinician can visually see the patient during the discussion. Minimal disruption is 
expected for this endpoint. 
17.2
SAFETY AND OTHER EVALUATION
This section specifies analyses related to the COVID-19 pandemic from the following 
aspects:
∀
Disposition
∀
Study visit (missing entire visit due to COVID-19 or missing assessments due to 
COVID-19)
∀
Protocol deviation
∀
Study drug disruption due to COVID-19
∀
TEAEs related to COVID-19
The Safety Population will be used for the planned analyses described above. 
The number of patients impacted by COVID-19 during the study will be summarized by 
treatment group and overall. In addition, the number of patients impacted by COVID-19 
and their corresponding disposition status in the double-blind treatment period, down-
taper period, and follow-up period will be summarized, respectively. 
The number of patients who missed at least one entire visit due to COVID-19 will be 
summarized by treatment group and overall. Furthermore, the number of patients who 
missed at least one assessment due to COVID-19 will be summarized by assessment 
category (laboratory, C-SSRS, vital signs, and ECG) and overall. Similar summarized 
will by provided by visit.


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The protocol deviations that occur due to COVID-19 will be summarized and listed 
separately. 
The number of patients with study drug disruption due to COVID-19 will be provided as
well. The number of patients with TEAEs related to corona virus infection or coronavirus 
test positive will be provided. Supporting listings for the described analyses above will be 
provided.


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18.0
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL
None.


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19.0
REFERENCES
Cole TJ., The LMS method for constructing normalized growth standards. Eur J Clin 
Nutr., 44: 45-60, 1990.
Kenward MG, Molenberghs G, Thijs H., Pattern-mixture models with proper time 
dependence. Biometrika, 2003; 90:53-71.
Kenward MG, Roger JH., Small sample inference for fixed effects from restricted 
maximum likelihood. Biometrics, 1997;53:983-997.
Lu K., Sample size calculations with multiplicity adjustment for longitudinal clinical 
trials with missing data. Stat Med 2012; 31:19-28.
Lan, K.K.G. and Trost D.C. 1999. The use of conditional power in interim analysis. 
Pfizer Technical Report 99-006.
Proschan, M., Lan, K.K.G., Wittes, J.T. 2006. Statistical Monitoring of Clinical Trials. 
Springer. New York. Chang, Mark. 2008. Classical and Adaptive Clinical Trial Designs. 
John Wiley & Sons. Hoboken, New Jersey.


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20.0
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 at. (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)


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


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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 3.0.
Note that per recommendation in Wang and Daniels (2011), only the observed data 
within pattern is assumed to be multivariate normal. The observed data distribution can 
be expressed in terms of the marginal distribution of baseline measurement and the 
conditional distributions of postbaseline measurements given earlier measurements. 
Assuming that these distributions are normal, the linear regression of each observation on 
prior observations will yield least-squares estimates of model parameters that can be 
utilized for independent posterior draws of model parameters for observed data. Multiple 
imputation approach will be used to estimate the overall mean at the final time point.


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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. 


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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 a 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.


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APPENDIX II.
REPORTING SELECTED LABORATORY PARAMETERS IN 
CONVENTIONAL UNIT
All clinical laboratory parameters will be reported in the International System (SI) units 
as standard practice. In addition, descriptive statistics for values and changes from 
baseline in conventional units at all assessed visits will be reported for selected laboratory 
parameters as listed in Table 20–1 below. 
Table 20–1.
List of Selected Parameters to be Reported in Conventional Units
Number
Laboratory Parameter
Conventional Unit
1
Alanine Aminotransferase (SGPT)
U/L
2
Albumin
G/dL
3
Alkaline Phosphatase
U/L
4
Aspartate Aminotransferase (SGOT)
U/L
5
Bilirubin, Direct (Conjugated)
mg/dL
6
Bilirubin, Indirect (Unconjugated)
mg/dL
7
Bilirubin, Total
mg/dL
8
Blood Urea Nitrogen
mg/dL
9
Calcium
mg/dL
10
Cholesterol, HDL
mg/dL
11
Cholesterol, LDL
mg/dL
12
Cholesterol, LDL direct and calculated (combined)
(This lab parameter could be the same as #11) 
mg/dL
13
Cholesterol, Total
mg/dL
14
Creatine Kinase
U/L
15
Creatinine
mg/dL
16
Glucose
mg/dL
17
Insulin
uIU/mL
18
Triglycerides
mg/dL
19
Uric Acid
mg/dL
20
Hemoglobin
G/dL


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APPENDIX III.
STATISTICAL ANALYSIS LIST FOR FUTILITY 
ANALYSIS
Table 20–2
List of Statistical Analysis for Futility Analysis
Table ID
Title
Analysis Population
14.1-1.1
Disposition of Participants
Screened Population
14.1-4.1.1A
Demographics
Safety Population
14.1-4.1.3
Baseline Characteristics and Efficacy Variables
Intent-to-Treat Population
14.2-1.1
CDRS-R Total Score: Summary of Baseline, Post-
baseline and Analysis of Change from Baseline -
MMRM
Intent-to-Treat Population
14.2-2.1
CGI-S Score: Summary of Baseline, Post-baseline 
and Analysis of Change from Baseline - MMRM
Intent-to-Treat Population
14.3-1.1
Extent of Exposure
Safety Population
14.3-2.1.A
Adverse Events: Overall Number (%) of
Participants with Adverse Events During the 
Double-Blind Treatment Period
Safety Population
14.3-2.2.A
Treatment-Emergent Adverse Events: Number (%) 
of Participants with Treatment-Emergent Adverse 
Events During the Double-Blind Treatment Period 
by Treatment Group, System Organ Class and 
Preferred Term
Safety Population
14.3-2.3.A
Common (≥2%) Treatment-Emergent Adverse 
Events: Number (%) of Participants by Preferred 
Term During the Double-blind Treatment Period
Safety Population
14.3-4.1
Laboratory Parameters: Number (%) of 
Participants with Post-baseline Potentially 
Clinically Significant Values During the Double-
blind Treatment Period
Safety Population
14.3-5.1
Vital Sign Parameters: Number (%) of Participants 
with Post-baseline Potentially Clinically 
Significant Values During the Double-blind
Treatment Period
Safety Population
14.3-6.1
ECG Parameters: Number (%) of Participants with 
Post-baseline Potentially Clinically Significant 
Values
Safety Population
14.3-7.2.A
C-SSRS: Number (%) of Patients with Suicidal 
Ideation or Suicidal Behavior During the Double-
blind Treatment Period
Safety Population
* Table IDs are based on the Study SAP TFL shell document.


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APPENDIX IV.
CONDITIONAL POWER CALCULATION
Conditional power is defined as the probability of rejecting H0 at the end of the trial when
total information is obtained, conditional on the partial information accumulated up to
that point. 
Suppose that the final analysis is a Z test based on a total of N observations, denoted as
ZN and we compare it with the critical value 1.96 that is for the significance level of 0.025 
of a one-sided Z test at the end of trial. 
At the interim stage, suppose there are N1 observations; z1 is the Z statistics; 
is the 
observed treatment different; I1 is the information at the interim analysis; u2 is the final 
efficacy boundary value (u2 =1.96 for futility interim); I2 is the total maximum 
information. The conditional power at hypothesized 
is as following,
The way we calculate the I1 and I2 in conditional power follows the EAST method, using 
the estimated standard error se1
at the interim look. Let 
denote the estimated 
standard deviation at the interim, then
, and then we have
and
.


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APPENDIX V.
SUMMARY OF CHANGES FOR AMENDMENT #1
Amendment #1 specifies the following changes to the Statistical Analysis Plan for 
LVM-MD-14 dated in 15 July 2019.
1. Add the sensitivity analysis in Section 10.1 for the site 0070.
2. Update the Section 13.0 Interim Analysis to add the futility analysis
3. Update the Section 17.0 to COVID-19 related analysis
4. Add the Appendix III to statistical analysis list for futility analysis
5. Add the Appendix IV to conditional power calculation
The details related to content changes are provided below. Minor editorial and document 
formatting revisions have not been summarized.
Section 10.1 Primary Efficacy Parameter(s)
The site 0070 ceased operations on October 31, 2020, due to the damage caused by 
Hurricanes Laura and Delta, which made landfall on August 27, 2020 and October 10, 
2020, respectively. One more sensitivity analysis excluding all data from this site 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 0070. 
Section 13.0 Interim Analysis
No interim analysis is planned for this study.
Revised text reads as follows:
The interim analysis will be conducted when at least 50% of randomized patients have 
either completed or discontinued the study. A futility analysis and safety analysis will be 
included in the interim analysis listed in the Appendix III. The general data derivation 
and preparation will follow the specification in the SAP and the amendment. 


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The futility assessment of the primary efficacy parameter (CDRS-R total score) on ITT 
population will be based on the conditional power as described in Lan et al. (1988) and 
Proschan et al. (2006). In calculating the conditional power, it is assumed that the future 
patients to be enrolled into the Study will have similar efficacy as those of the existing 
patients of the same treatment group. The non-binding futility criteria will be met when 
the conditional power for detecting a statistically significant treatment difference between 
the levomilnacipran treatment group (40-80 mg/day) and placebo at the final analysis 
given the interim analysis results is 0.2 (20%) or lower. Further details of the calculation 
of conditional power are provided in Appendix IV.
The safety analysis will be performed on the Safety Population, including the summary of 
TEAE, SAE, death, and TEAE leading to study discontinuation; the incidence of 
common TEAEs (≥ 2%); PCS for laboratory parameters, vital signs, and ECGs; and the 
summary of C-SSRS during the double-blind treatment period. 
Data will be presented in an unblinded fashion. A separate, independent, fire-walled 
Statistical Analysis Group and Data Review Committee will be established to conduct the 
unblinded interim analysis, review the unblinded results and make recommendations 
regarding the continuation of the study. To maintain the scientific reliability of statistical 
analyses after the final database lock, preserve the integrity of study conduct, and guard 
from introducing any potential bias into the conduct of the study and/or analysis of its 
results, individuals in these two groups will not be involved in any operational aspects of 
the trial.
Section 17.0 COVID-19 Related Analysis
To eliminate immediate potential hazards to patients and study staff due to the 
COVID-19 pandemic while ensuring patients safety and maintaining data integrity, a 
protocol amendment was sent to sites to allow remote visits. 
This section specifies analyses for evaluating the impact of COVID-19. 
Section 17.1 Efficacy Evaluation
Due to the nature of the patient CDRS-R assessment, the interview may be performed 
remotely provided that the patient has access to a videoconferencing platform where the 
rating clinician can visually see the patient during the discussion. Minimal disruption is 
expected for this endpoint.
Section 17.2 Safety and Other Evaluation
This section specifies analyses related to the COVID-19 pandemic from the following 
aspects:
∀
Disposition


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∀
Study visit (missing entire visit due to COVID-19 or missing assessments due to 
COVID-19)
∀
Protocol deviation
∀
Study drug disruption due to COVID-19
∀
TEAEs related to COVID-19
The Safety Population will be used for the planned analyses described above. 
The number of patients impacted by COVID-19 during the study will be summarized 
by treatment group and overall. In addition, the number of patients impacted by 
COVID-19 and their corresponding disposition status in the double-blind treatment 
period, down-taper period, and follow-up period will be summarized, respectively. 
The number of patients who missed at least one entire visit due to COVID-19 will be 
summarized by treatment group and overall. Furthermore, the number of patients who 
missed at least one assessment due to COVID-19 will be summarized by assessment 
category (laboratory, C-SSRS, vital signs, and ECG) and overall. Similar summarized 
will by provided by visit.
Appendix III. Statistical Analysis List for Futility Analysis
Table 20-2.
List of Statistical Analysis for Futility Analysis
Table ID
Title
Analysis Population
14.1-1.1
Disposition of Patients
Screened Population
14.1-
4.1.1A
Demographics 
Safety Population
14.1-4.1.3
Baseline Characteristics and Efficacy 
Variables
Intent-to-Treat 
Population
14.2-1.1
CDRS-R Total Score: Summary of Baseline, 
Post-baseline and Analysis of Change from 
Baseline - MMRM
Intent-to-Treat 
Population
14.2-2.1
CGI-S Score: Summary of Baseline, Post-
baseline and Analysis of Change from 
Baseline - MMRM
Intent-to-Treat 
Population
14.3-1.1
Extent of Exposure
Safety Population
14.3-2.1.A
Adverse Events: Overall Number (%) of
Patients with Adverse Events During the 
Double-Blind Treatment Period
Safety Population


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14.3-2.2.A
Treatment-Emergent Adverse Events: Number 
(%) of Patients with Treatment-Emergent 
Adverse Events During the Double-Blind 
Treatment Period by Treatment Group, System 
Organ Class and Preferred Term
Safety Population
14.3-2.3.A
Common (≥2%) Treatment-Emergent Adverse 
Events: Number (%) of Patients by Preferred 
Term During the Double-blind Treatment 
Period
Safety Population
14.3-4.1
Laboratory Parameters: Number (%) of 
Patients with Post-baseline Potentially 
Clinically Significant Values During the 
Double-blind Treatment Period
Safety Population
14.3-5.1
Vital Sign Parameters: Number (%) of Patients 
with Post-baseline Potentially Clinically 
Significant Values During the Double-blind
Treatment Period
Safety Population
14.3-6.1
ECG Parameters: Number (%) of Patients with 
Post-baseline Potentially Clinically Significant 
Values
Safety Population
14.3-7.2.A
C-SSRS: Number (%) of Patients with Suicidal 
Ideation or Suicidal Behavior During the 
Double-blind Treatment Period
Safety Population
* Table IDs are based on the Study SAP TFL shell document.
Appendix IV. Conditional Power Calculation 
Conditional power is defined as the probability of rejecting H0 at the end of the trial 
when total information is obtained, conditional on the partial information accumulated up 
to that point. 
Suppose that the final analysis is a Z test based on a total of N observations, denoted as
ZN and we compare it with the critical value 1.96 that is for the significance level of 
0.025 of a one-sided Z test at the end of trial. 
At the interim stage, suppose there are N1 observations; z1 is the Z statistics; 
is the 
observed treatment different; I1 is the information at the interim analysis; u2 is the final 
efficacy boundary value (u2 =1.96 for futility interim); I2 is the total maximum 
information. The conditional power at hypothesized 
is as following,


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The way we calculate the I1 and I2 in conditional power follows the EAST method, using 
the estimated standard error se1
at the interim look. Let 
denote the estimated 
standard deviation at the interim, then
, and then we have
and
.