Clinical trial NCT03586427
Conditions: Depressive Disorder, Major
Sponsor: Syndeio Biosciences, Inc
Start date: 2018-06-13; Completion date: 2019-08-21
Enrollment: 251 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy at 1 day post initial oral dose of AGN-241751 compared with placebo in participants with Major Depressive Disorder (MDD).

Detailed description:

Arms: arm 1: AGN-241751 Dose 1 administered as 1 tablet taken orally every day arm 2: AGN-241751 Dose 2 administered as 1 tablet taken orally every day arm 3: AGN-241751 Dose 3 administered as 1 tablet taken orally every day arm 4: AGN-241751 Dose 4 administered as 1 tablet taken orally every day arm 5: Placebo administered as 1 tablet taken orally every day
Interventions: intervention 1: AGN-241751 intervention 2: Placebo
Intervention descriptions: intervention 1: AGN-241751 administered orally as a single tablet intervention 2: Placebo administered orally as a single tablet

Protocol documents:
Prot_000.pdf: 
 
 
Protocol:  A double-blind, placebo-controlled, fixed dose study of AGN-241751 in adult participants with 
major depressive disorder, Amendment 2 
 
NCT 03586427 
 
Document date:  May 1, 2019 


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AGN-241751
Protocol 3125-201-002
1
Title Page
Protocol Title: A Double-Blind, Placebo-Controlled, Fixed-Dose Study of AGN-241751 in 
Adult Participants with Major Depressive Disorder
Brief Protocol Title: AGN-241751 in the treatment of major depressive disorder 
Product: AGN-241751
Sponsor Name and Legal Registered Address: Naurex, Inc., an indirect subsidiary of Allergan 
plc, 5 Giralda Farms Madison, NJ 07940 USA
Regulatory Agency Identifying Number: IND 129,495
Emergency Telephone Number: Refer to the study contacts page
SAE Reporting Fax Number/Email: 
Business Unit
Email
Fax
Allergan
IR-Clinical-SAE@allergan.com
+1-714-796-9504 
Backup fax: 
+1-714-246-5295
Sponsor Signatory:
Armin Szegedi, MD, PhD
Vice President and Therapeutic Area Head, Clinical Development CNS


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AGN-241751
Protocol 3125-201-002
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Protocol Amendment Summary of Changes Table
DOCUMENT HISTORY
Document
Date
Amendment 2
01 May 2019
Amendment 1
08 Jun 2018
Original Protocol
02 Mar 2018
Protocol Amendment 2: May 2019
Overall Rationale for the Amendment:
The protocol was amended to incorporate regulatory agency feedback on statistical analysis.
Section No. and Name
Description of Change
Brief Rationale
1 Synopsis
Added that framework for estimands will be 
discussed in Section 10.1
Based on 
updated 
regulatory 
requirements 
for statistical 
analysis that 
requires 
inclusion of 
estimands.
4. Objectives and 
Endpoints
This section was updated to clarify endpoints for 
the additional analysis to include all days where 
MADRS, CGI-S, etc were evaluated that were not 
part of primary or secondary analysis
Clarification to 
the protocol
10.1 Estimands 
Framework
This section was added, including subsections, and 
provides an estimand framework for the primary 
and secondary endpoints
As above
10.4.1 Efficacy 
Analysis
Removed LOCF calculations and changed small 
center will be defined as a center with fewer than 2 
participants (instead of 5 participants) in the mITT 
Population
As above and to 
align with other 
studies in the 
program
10.4.1.1 Primary and 
Secondary Endpoint
Added reference to estimands
As above
10.4.1.2 Primary and 
Secondary Analysis
Updated statistical methods, including removal of 
LOCF and ANCOVA from analysis and replaced 
with a sensitivity analysis using the MI approach 
under MNAR assumptions 
As above
10.4.2.2 Clinical 
Laboratory 
Clarified language regarding non-PCS baseline 
values
Clarification


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AGN-241751
Protocol 3125-201-002
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Section No. and Name
Description of Change
Brief Rationale
Assessments
10.4.2.3 Vital Signs
Clarified language regarding non-PCS baseline 
values
Clarification
12.1 Appendix 1
Updated abbreviations based on changes to body
To align with 
other changes in 
the protocol
12.5 Appendix 5
Removed bilateral tubal ligation as the type of 
surgical sterilization for female partners of male 
study subjects.
To align with 
other studies in 
the program.


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AGN-241751
Protocol 3125-201-002
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Table of Contents
Title Page ........................................................................................................................................1
Table of Contents...........................................................................................................................4
List of Figures.................................................................................................................................7
1.
Synopsis............................................................................................................................8
2.
Schedule of Activities (SoA).........................................................................................11
3.
Introduction...................................................................................................................14
3.1.
Study Rationale...............................................................................................................17
3.2.
Background.....................................................................................................................18
3.3.
Benefit/Risk Assessment ................................................................................................18
4.
Objectives and Endpoints ............................................................................................19
5.
Study Design..................................................................................................................21
5.1.
Overall Design ................................................................................................................21
5.2.
Participant and Study Completion ..................................................................................23
5.3.
End of Study Definition..................................................................................................23
5.4.
Scientific Rationale for Study Design ............................................................................23
5.5.
Justification for Dose......................................................................................................23
6.
Study Population...........................................................................................................25
6.1.
Inclusion Criteria ............................................................................................................25
6.2.
Exclusion Criteria ...........................................................................................................26
6.3.
Lifestyle Restrictions ......................................................................................................31
6.3.1.
Meals and Dietary Restrictions.......................................................................................31
6.3.2.
Caffeine, Alcohol, and Tobacco .....................................................................................31
6.3.3.
Activity ...........................................................................................................................31
6.4.
Screen Failures................................................................................................................31
7.
Treatments.....................................................................................................................32
7.1.
Treatments Administered................................................................................................32
7.2.
Dose Modification ..........................................................................................................33
7.3.
Method of Treatment Assignment ..................................................................................33
7.4.
Blinding/Masking ...........................................................................................................33
7.5.
Preparation/Handling/Storage/Accountability................................................................34
7.6.
Treatment Compliance....................................................................................................34
7.7.
Concomitant Therapy .....................................................................................................35
7.7.1.
Prohibited Treatments.....................................................................................................35
7.7.2.
Permitted Treatments......................................................................................................35
7.8.
Treatment after the End of the Study..............................................................................36
8.
Discontinuation/Withdrawal Criteria.........................................................................37
8.1.
Discontinuation of Study Treatment...............................................................................37
8.2.
Withdrawal from the Study.............................................................................................38


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8.3.
Lost to Follow Up...........................................................................................................38
9.
Study Assessments and Procedures.............................................................................40
9.1.
Efficacy Assessments .....................................................................................................41
9.1.1.
The Montgomery-Åsberg Depression Rating Scale .......................................................41
9.1.2.
The Clinical Global Impressions-Severity......................................................................41
9.2.
Adverse Events ...............................................................................................................42
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information .....................................................................................................................42
9.2.2.
Method of Detecting AEs and SAEs ..............................................................................43
9.2.3.
Follow-up of AEs and SAEs...........................................................................................43
9.2.4.
Regulatory Reporting Requirements for SAEs...............................................................43
9.2.5.
Pregnancy........................................................................................................................43
9.2.6.
Potential Hy’s Law .........................................................................................................44
9.2.7.
Medication Errors ...........................................................................................................44
9.3.
Treatment of Overdose ...................................................................................................45
9.4.
Safety Assessments.........................................................................................................45
9.4.1.
Physical Examinations....................................................................................................45
9.4.2.
Vital Signs.......................................................................................................................45
9.4.3.
Electrocardiograms .........................................................................................................45
9.4.4.
Clinical Safety Laboratory Assessments ........................................................................46
9.4.5.
Columbia-Suicide Severity Rating Scale........................................................................46
9.4.6.
Brief Psychiatric Rating Scale—Positive Symptoms Subscale......................................47
9.4.7.
Clinician Administered Dissociative States Scale ..........................................................47
9.4.8.
Symbol Digit Coding ......................................................................................................47
9.5.
Pharmacokinetics............................................................................................................48
9.6.
Pharmacodynamics .........................................................................................................48
9.7.
Genetics ..........................................................................................................................48
9.8.
Biomarkers......................................................................................................................48
9.9.
Medical Resource Utilization and Health Economics ....................................................48
10.
Statistical Considerations ............................................................................................49
10.1.
Estimands Framework ....................................................................................................49
10.1.1.
Population .......................................................................................................................49
10.1.2.
Variables .........................................................................................................................49
10.1.3.
Intercurrent Events and Their Handling Rules ...............................................................49
10.1.4.
Population-Level Summary ............................................................................................50
10.2.
Sample Size Determination ............................................................................................50
10.3.
Populations for Analyses ................................................................................................50
10.4.
Statistical Analyses .........................................................................................................50
10.4.1.
Efficacy Analyses ...........................................................................................................50
10.4.2.
Safety Analyses...............................................................................................................52
10.4.3.
Interim Analyses .............................................................................................................55
11.
References......................................................................................................................56


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AGN-241751
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12.
Appendices.....................................................................................................................59
12.1.
Appendix 1: Abbreviations and Trademarks..................................................................59
12.2.
Appendix 2: Clinical Laboratory Tests ..........................................................................61
12.3.
Appendix 3: Study Governance Considerations.............................................................64
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting.........................................................67
12.5.
Appendix 5: Contraceptive Guidance and Collection of 
Pregnancy Information ...................................................................................................72
12.6.
Appendix 6: Concomitant Medications ..........................................................................75
12.7.
Appendix 7: Standard Discontinuation Criteria..............................................................80
12.8.
Appendix 8: Montgomery-Åsberg Depression Rating Scale .........................................81
12.9.
Appendix 9: Clinical Global Impressions–Severity .......................................................85
12.10.
Appendix 10: Brief Psychiatric Rating Scale – Positive 
Symptoms Subscale ........................................................................................................86
12.11.
Appendix 11: Clinician Administered Dissociative States Scale ...................................87
12.12.
Appendix 12: Columbia-Suicide Severity Rating Scale –
Baseline/Screening..........................................................................................................92
12.13.
Appendix 13: Columbia–Suicide Severity Rating Scale - Since 
Last Visit.........................................................................................................................95
12.14.
Appendix 14: Protocol Amendment 1 ............................................................................99


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AGN-241751
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List of Figures
Figure 5–1
Study Design Diagram ...................................................................................... 22
Figure 10-1
Graphical Procedure for Primary and Key Secondary Hypotheses .................. 52


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AGN-241751
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1.
Synopsis
Protocol Title: A Double-Blind, Placebo-Controlled, Fixed-Dose Study of AGN-241751 in 
Adult Participants with Major Depressive Disorder
Protocol Number: 3125-201-002
Brief Title: AGN-241751 in the treatment of major depressive disorder 
Study Phase: 2a
Study Rationale:
AGN-241751 is a functional modulator of the N-methyl D-aspartate receptor (NMDAR) with 
partial agonist properties. In rodent models of depression, AGN-241751 elicited potent, rapid, 
and long-lasting antidepressant activity without adverse central nervous system (CNS) effects. 
AGN-241751 is an orally bioavailable small molecule with NMDAR partial co-agonist 
pharmacology. Thus, it represents a novel pharmacology that may address a significant unmet 
need with minimal side effects and the feasibility of an oral dosage form. This is a 
proof-of-concept study of AGN-241751 monotherapy in the treatment of major depressive 
disorder (MDD).
Objectives and Endpoints:
The primary objective is to evaluate the efficacy, as measured by improvement in Montgomery-
Åsberg Depression Rating Scale (MADRS) total score, at 1 day post initial oral dose of 
AGN-241751 compared with placebo in participants with MDD. The key secondary objective is 
to evaluate the efficacy at Week 3 of AGN-241751 administered orally once a week compared 
with placebo in participants with MDD.
Objectives
Endpoints
Primary

To evaluate the efficacy at 1 day post initial 
oral dose of AGN-241751 compared with 
placebo in participants with MDD

Change from baseline in MADRS total score at 
1 day after first dose
Key Secondary

To evaluate the efficacy at Week 3 of 
AGN-241751 administered orally once a 
week compared with placebo in participants 
with MDD

Change from baseline in MADRS total score at 
Week 3


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AGN-241751
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The framework of estimands for this study is presented in Section 10.1
Overall Study Design:
This study is a multicenter, randomized, double-blind (with a single-blind placebo lead-in), 
placebo-controlled, parallel-group, fixed-dose, 3-week study in participants with MDD. The 
study will include a total of 10 visits and will be approximately 5 weeks in duration: 
•
Up to 1-week screening period 
•
3-week double-blind treatment period 
•
1-week safety follow-up period 
After providing written consent, participants will enter a single-blind placebo lead-in screening 
period of up to 7 days. Screening procedures may be conducted on up to 2 separate dates 
where necessary to accommodate participant and site schedule; however, every effort 
should be made to conduct all procedures as early as possible in the screening period and 
the rater-administered MADRS and computer-administered MADRS must be collected on 
the same date. Participants will receive single-blind placebo during the screening period. 
Participants meeting the eligibility criteria at the end of Visit 2 (Baseline) will be assigned a 
treatment by the interactive web response system (IWRS) and enter the double-blind treatment 
period.
Approximately 250 participants are planned for enrollment in the double-blind treatment period 
(50 participants each in the AGN-241751 and placebo groups). Participants will be randomized 
in a ratio of 1:1:1:1:1 to 1 of 5 treatment groups: 0.25-mg, 1-mg, 3-mg, 10-mg dose 
AGN-241751 and placebo. 
Aside from the single-blind screening period and double-blind treatment period, there is an 
additional single-blind element to this study (blinded to the participant). AGN-241751 is being 
developed for once-weekly dosing; however, in order to minimize participant’s expectations and 
control for placebo response, treatment will be presented to participants as oral daily dosing. 
Each treatment kit (dispensed once weekly) in the double-blind treatment period will contain 
2 bottles: Bottle 1 will contain a single dose of double-blind study treatment and Bottle 2 will 
contain multiple doses of single-blind placebo tablets (blinded to the participant). At Visit 2 
(Day 1), Visit 5 (Day 8), and Visit 8 (Day 15), site staff will give the participant the single dose 
of double-blind study treatment from Bottle 1 to take by oral ingestion in the clinic (ie, the first 
dose of study treatment for that week). Site staff will give Bottle 2, which contains the 
single-blind placebo tablets, to the participant with the instruction to take 1 tablet daily by oral 
ingestion for the remainder of that week. To maintain consistency, study treatment at Visit 1 
(single-blind placebo lead-in) will be dispensed in the same manner; the single dose of 
single-blind study treatment from Bottle 1 will be given to the participant for oral ingestion in the 
clinic, and then, Bottle 2 containing single-blind placebo tablets will be dispensed for the 
participant to take 1 tablet daily by oral ingestion through the remainder of the week.
During the first 2 weeks of the double-blind treatment period, participants will have 3 study 
visits per week. The visits will occur in the following pattern: in-clinic treatment day, 1 day 


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AGN-241751
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following the in-clinic treatment day, 4 days following the in-clinic treatment day, and 7 days 
following the in-clinic treatment day (which is the next in-clinic treatment day). If necessary, 
study visits may be conducted up to 2 days before or after the scheduled visits with the exception 
of visits that are 1 day apart (ie, Visits 2 and 3 must be conducted 1 day apart; and Visits 5 and 6 
must be conducted 1 day apart). Visit 8 will be conducted 7 days following the second in-clinic 
treatment day. All participants who receive study treatment must complete Visit 9/Early 
Termination (ET) Visit. Participants will enter a 1-week safety follow-up period and return for 
Visit 10. Participants who prematurely discontinue from the study before completing 3 weeks of 
double-blind treatment should enter the 1-week safety follow-up period. Additional follow-up 
visits may be scheduled within 30 days, if necessary for safety reasons.
Number of Participants:
Approximately 250 participants who meet eligibility criteria at Visit 2 (Baseline) will be 
randomly assigned to study treatment such that approximately 50 participants per arm will be 
allocated in a 1:1:1:1:1 ratio.
Treatment Groups and Study Duration:
Treatment Groups: AGN-241751 0.25 mg, 1 mg, 3 mg, and 10 mg, and placebo
Study Duration: approximately 5 weeks
Dosage Regimen: 
During the lead-in screening period of up to 7 days, participants will take 1 single-blind placebo 
tablet by oral ingestion once daily; the first dose will be administered in the clinic.
During the 3-week double-blind treatment period, a single tablet of double-blind study treatment 
(placebo, AGN-241751 0.25 mg, 1 mg, 3 mg, or 10 mg) will be administered orally once weekly 
in the clinic. A bottle of single-blind placebo tablets (blinded to the participant) will be dispensed 
for the participant to take 1 tablet once daily by oral ingestion through the remainder of that 
corresponding week.
Number of Sites:
Approximately 20 sites in the United States


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AGN-241751
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2.
Schedule of Activities (SoA)
Single-blind 
Placebo Run-In 
Period
Double-blind Treatment Period
Safety 
Follow-up 
Period
Visit
1
(Screening)
2
(Baseline)
2a
3
4
5
6
7
8
9/ETa
10
Study Day
up to -7 days
1
4 hrs 
post dose 
2
(1 day 
post dose)
5
8
9
12
15
22
29
Informed consent
x
Medical (surgical, neurologic) and 
psychiatric histories
x
Prior medication history
x
Inclusion/exclusion
x
x
Randomization assessment
x
Clinical laboratory determinationsb
x
x
Urine drug screen
x
x
Serum pregnancy test
x
x
Vital signsc
x
x
x
x
x
x
x
x
x
x
x
ECG
x
x
Physical examination
x
x
DxV
x
SCID
x
MADRS
x
x
x
x
x
x
x
x
x
x
CGI-S
x
x
x
x
x
x
x
x
x
x
BPRS+
x
x
x
x
CADSS
x
x
x
x
C-SSRS
x
x
x
x
x
x
x
x
x
x
x
SDC 
x
x
C-VISA
x


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AGN-241751
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Single-blind 
Placebo Run-In 
Period
Double-blind Treatment Period
Safety 
Follow-up 
Period
Visit
1
(Screening)
2
(Baseline)
2a
3
4
5
6
7
8
9/ETa
10
Study Day
up to -7 days
1
4 hrs 
post dose 
2
(1 day 
post dose)
5
8
9
12
15
22
29
AEs
x
x
x
x
x
x
x
x
x
x
Concomitant medications
x
x
x
x
x
x
x
x
x
x
x
PK samplingd
x
(1 hr, 2 hrs, and 4 hrs 
post dose)
x
1 sample 
(15 min
to 3 hrs
post dose)
Study treatment administration in the 
clinic
x
(single-blind 
placebo)
x
x
x
Study treatment compliance
x
x
x
x
x
x
x
x
Screening procedures may be conducted on up to 2 separate dates where necessary to accommodate participant and site schedule; however, every effort 
should be made to conduct all procedures as early as possible in the screening period. The rater-administered MADRS and computer-administered 
MADRS must be collected on the same date. At Visit 1 (Screening), the computer-administered MADRS will be conducted prior to the 
rater-administered MADRS. At all other visits, the rater-administered MADRS will be conducted first.
If necessary, study visits may be conducted up to 2 days before or after the scheduled visits except for visits that are 1 day apart (ie, Visits 2 and 3 must 
be conducted 1 day apart, and Visits 5 and 6 must be conducted 1 day apart). 
AE = adverse event; BPRS+ = Brief Psychiatric Rating Scale - Positive Symptoms Subscale; CADSS = Clinician Administered Dissociative States Scale; 
CGI-S = Clinical Global Impressions-Severity; C-SSRS = Columbia–Suicide Severity Rating Scale; C-VISA = Clinical Validation Inventory for Study 
Admission; DSM = Diagnostic and Statistical Manual of Mental Disorders; DxV = Diagnostic Validation; ECG = electrocardiogram; ET = Early Termination; 
MADRS = Montgomery-Åsberg Depression Rating Scale; PK = pharmacokinetic; SCID = Structured Clinical Interview for DSM disorders; SDC = Symbol 
Digit Coding
a
Performed for all participants, including those prematurely discontinued after randomization. Clinically significant findings upon termination should be 
followed until the condition returns to prestudy status or can be explained as unrelated to study treatment. If necessary, additional follow-up visits can be 
scheduled. 
b
Participants will be requested to fast overnight or for at least 8 hours before arriving at the study center for appointments involving the collection of clinical 


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laboratory blood tests. Clinical laboratory tests can be done at any visit for safety reasons at the discretion of the investigator.
c
Height will only be measured at Visit 1 (Screening); pulse rate, blood pressure, temperature, and body weight will be assessed at every visit. Blood pressure 
and pulse will be assessed while the participant is supine and standing.
d
PK sampling is optional. For participants who consent to participate, samples will be collected at Visit 2/2a (Day 1) at 1 hour (± 15 minutes), 2 hours 
(± 15 minutes), and 4 hours (± 15 minutes) post dose. At Visit 5 (Day 8), a single sample will be collected any time from 15 minutes to 3 hours post dose; 
site staff should record the time of the prior meal taken by the participant before the PK sample collection, whenever possible.


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AGN-241751
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3.
Introduction
Disease Burden of Major Depressive Disorder
Major depressive disorder (MDD) is a highly disabling, serious condition which is associated 
with significant morbidity and mortality. MDD manifests as a major depressive episode (which 
may be singular or recurrent) in which the affected individual experiences 1) depressed mood, or 
2) loss of interest or pleasure (as well as other symptoms) for most of the day, nearly every day, 
for at least 2 weeks. MDD affects approximately 14.8 million American adults, or about 6.7% of 
the US population 18 years of age and older, in a given year (Kessler 2005). Worldwide, about 
15% of the adult population is at lifetime risk of developing MDD (Kessler 1994).
Depression may cause serious, long-lasting symptoms and often disrupts a person’s ability to 
perform routine tasks. In 2000, unipolar depressive disorders were by far the leading cause 
(11.9%) of worldwide years of life lived with disability (World Health Organization, 2001), and 
the total economic burden of treating depression in the United States was $83.1 billion, with 
workplace costs, including missed days and lack of productivity due to illness, accounting for 
most of the total economic burden (62%). Other economic burdens in 2000 included 
$26.1 billion (31%) for treatment costs and $5.4 billion (7%) for suicide-related costs 
(Greenberg 2003).
MDD is a leading cause of disability in the United States (Murray 2013). Moreover, MDD is 
known to be a significant risk factor for suicide and ischemic heart disease, as it accounted for 
16 million of the disability adjusted life years (DALYs) associated with suicide and 4 million of 
the DALYs associated with ischemic heart disease. Research has shown that untreated 
depression has both a functional (social and work role) as well as a neuroanatomical 
(hippocampal shrinkage) effect on the patient (Videbech and Ravnkilde 2004). Given the disease 
burden and link to suicidality as well as increased mortality with other comorbid conditions, 
MDD is a serious and life-threatening condition which is a leading cause of disability in the 
world.
Selective Serotonin Reuptake Inhibitors and Selective Serotonin and Norepinephrine Reuptake 
Inhibitors in Major Depressive Disorder
Selective serotonin reuptake inhibitors (SSRIs) and selective serotonin and norepinephrine 
reuptake inhibitors (SNRIs) currently represent the first line of treatment of depression in the 
United States. Unfortunately, a large number of patients do not experience therapeutic benefit 
from these first-line agents (Rosenzweig-Lipson 2007). Lack of sufficient response to adequate 
treatment remains a critical problem in the management of patients with MDD. Up to two-thirds 
of patients treated with first-line antidepressant monotherapy do not reach full remission, and as 
many as a third become treatment resistant (Fava and Davidson 1996; Trivedi 2006). Not 
achieving remission has been shown to be predictive of poorer psychosocial functioning, higher 
rates of relapse, and higher rates of rehospitalization (McIntyre and O’Donovan 2004).


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The results of the STAR*D study suggest that with successive failures of treatment, patients are 
less and less likely to respond to subsequent treatment, and those who do respond are more likely 
to relapse (Rush 2006). Present strategies available to treat patients who do not respond to 
first-line antidepressant monotherapy include switching of antidepressant (either within or 
between classes); combination therapy in which multiple antidepressants are used 
simultaneously; augmentation of ongoing antidepressant monotherapy with adjunctive use of 
drugs such as mood stabilizers or atypical antipsychotics (Boland and Keller 2006); and 
nonpharmacologic treatments including psychotherapy and phototherapy, vagus nerve 
stimulation, transcranial magnetic stimulation, and electroconvulsive therapy (ECT). Clearly, 
there remains a critically important unmet medical need for this patient population.
Existing antidepressants have a number of limitations, leading to considerable unmet medical 
need in the effective treatment of MDD, with up to 50% of patients with MDD having an 
inadequate response or failing current antidepressant therapy (ADT). Currently available 
first-line antidepressants (SSRIs, SNRIs) typically take 3 to 4 weeks or more of continuous daily 
dosing to relieve symptoms of MDD and are associated with side effects related to their 
pharmacological mechanisms of action (sexual dysfunction, weight gain, jitteriness, sleep 
disturbances), which are further associated with poor patient compliance 
(Masand 2003, Ashton 2005). Patients often experience undesirable side effects before they 
experience an improvement in depressive symptoms, which could lead to premature 
discontinuation of therapy. Taken together, these factors define significant areas for 
improvement of ADT.
Patients vary greatly in their response to antidepressants and it is not possible to reliably predict 
whether an individual patient will respond to a given antidepressant. This leads to clinicians 
often using a trial-and-error approach to identify an effective antidepressant. Due to the slow 
onset of the development of the full therapeutic effect of currently available treatments, each 
antidepressant needs to be administered for 4 weeks or longer to determine the individual 
therapeutic benefit, making the process of finding an effective antidepressant a lengthy process 
for patients who are often severely depressed and at a high risk for suicide. Clearly a drug that 
could induce a rapid antidepressant effect would represent a major advancement for these 
patients.
While inhibition of serotonin reuptake improves the management of patients with depression, 
these agents suffer two severe limitations: 1) they require several weeks of continued dosing 
until a patient can experience the full therapeutic benefit, and during this time patients continue 
to be affected by the symptoms of depression and the risk of self-harm, and 2) a large number of 
patients do not experience therapeutic benefit (Rosenzweig-Lipson 2007). Intravenous ketamine, 
an NMDAR antagonist, provides rapid relief of depressive symptoms, unlike the SSRIs and 
SNRIs; however, this beneficial effect is accompanied by classic NMDAR antagonist effects, 
including psychotomimetic activity, confusion, and dissociation. In addition, ketamine is 
approved as an anesthetic agent, and not approved for use as an antidepressant. Psychiatric use of 
ketamine may be limited by the need for repeated infusions to maintain a treatment response, its 
safety profile, and its abuse potential, being a Schedule III controlled substance. Based upon the 


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available evidence of ketamine, modulation of the NMDAR is being pursued as a therapeutic 
target for MDD treatment.
Recently, rapastinel has emerged as a representative of a potentially new class of antidepressants 
that positively modulate the NMDAR function and have the potential to provide rapid and 
significant antidepressant activity without many of the adverse side effects of NMDAR
antagonists like ketamine. Rapastinel has demonstrated rapid and long-lasting antidepressant 
effects in rodent models of depression as well as in MDD patients, with a favorable side-effect 
profile (Burgdorf 2013; Preskorn 2015). Rapastinel’s unique mechanism of action may explain 
its lack of ketamine-like side effects. Rapastinel is believed to activate a cascade of biochemical 
and physiological processes like long-term potentiation (LTP)-based synaptic plasticity. 
Rapastinel potentiates LTP following acute treatment (unlike ketamine) and does not impair 
cognition in a variety of animal models of cognition (unlike ketamine and other NMDAR 
antagonists like PCP and MK-801) (Blanke 2009; Nicholson 2009; Skolnick 2009). Early 
Phase 2 clinical trial experience suggests that the rapastinel pharmacology lacks the negative 
symptomatic effects of NMDAR antagonists. Compared with ketamine and other NMDAR 
antagonists, rapastinel exhibits a significantly improved central nervous system (CNS) 
tolerability profile.
Like rapastinel, AGN-241751 is a novel NMDAR modulator with partial agonist properties. 
AGN-241751 has appropriate oral bioavailability and blood brain barrier penetration. 
In support of AGN-241751 investigation in human subjects, a series of nonclinical 
pharmacology studies have been performed. These studies were designed to characterize 
AGN-241751 in terms of its potential to a) potentiate NMDAR activity; b) strengthen 
NMDAR-dependent LTP; and c) produce antidepressant-like effects in rat models. Additional 
safety and tolerability studies were carried out to evaluate AGN-241751’s side effect profile, 
including potential ataxic/sedative and pro-convulsive effects. Besides displaying potent partial 
agonist activity at NMDAR, AGN-241751 increased NMDAR-dependent synaptic plasticity in 
rat hippocampus and medial prefrontal cortex in vitro and ex vivo. AGN-241751 was active in 
several models of depression, and has demonstrated rapid onset of action in rat models of 
depression without causing CNS side effects. AGN-241751 had no appreciable affinity for over 
60 neurotransmitter-receptors and ion channels in a CEREP screen indicating a lack of potential 
off-target effects. Central nervous system safety and tolerability profile of AGN-241751 was 
favorable at substantially higher doses relative to its antidepressant doses. Although transient 
lowering of blood pressure in conscious telemetered dogs was observed in cardiovascular safety 
studies, there were no findings that preclude its use for further development. In other safety 
pharmacology studies, AGN-241751 was not associated with any adverse effects. In summary, 
the safety profile of AGN-241751 supports the proposed clinical doses in Phase 2a (0.25 mg to 
10 mg).
Following oral administration, mean oral bioavailability of AGN-241751 in rats and dogs was 
approximately 100% and 99%, respectively. There was no accumulation after repeat 
administration and AGN-241751 was rapidly distributed to the target tissue (brain) with time to 


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AGN-241751
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reach maximum concentration (Tmax) at 1 hour post dose in rats. Brain to plasma and 
cerebrospinal fluid (CSF) to plasma area under the concentration-time curve (AUC) ratios were 
0.16 and 0.3, respectively. 
Acute dosing in rats showed no effects on the central or peripheral nervous system. Drug-related 
findings after oral dosing in rats for 28 days were limited to mild increases in absolute and 
relative (to brain and body) liver weights that correlated with minimal hepatocellular 
hypertrophy, minimal to mild pigmented material in bile ducts, and minimal periductal 
mononuclear cell infiltrates at ≥ 300 mg/kg/day. The no-observed-adverse-effect level (NOAEL)
in this study was 600 mg/kg/day. Oral dosing in dogs was not tolerated at ≥ 40 mg/kg/day. 
Drug-related findings in dogs included decreases in body weight and alterations in serum 
chemistry (only males) at 20 mg/kg/day, reversible increases in hepatic enzymes and brown 
pigmented material in hepatic sinusoids at ≥ 10 mg/kg/day and minimal to moderate Kupffer cell 
hypertrophy/hyperplasia and minimal to mild increased incidence of mononuclear cell infiltrates 
at all doses. Increases in liver enzymes correlated with microscopic findings of hepatotoxicity at 
20 mg/kg/day. The NOAEL was 10 mg/kg/day; however, the more conservative dose of 
3 mg/kg/day is used for the calculation of safety margins due to moderate liver enzymes 
increases observed at 10 mg/kg/day. A dose of 3 mg/kg/day in dogs (the most sensitive species) 
results in a systemic exposure (AUC; Day 1) that is 3.5 times the exposure at the highest dose 
(50 mg) evaluated in the single ascending dose study.
Preliminary data from ongoing clinical studies, a single ascending dose study (3125-101-009) 
and multiple ascending dose study (3125-102-009) in healthy male and female volunteers, have 
demonstrated an acceptable safety and tolerability profile up to doses of 50 mg administered 
once, or 25 mg administered daily for consecutive 10 days. Based upon preliminary PK data in 
healthy volunteers, systemic exposures of AGN-241751 demonstrate rapid absorption, rapid 
clearance, and dose-related increases in exposures in plasma and CSF. Female subjects 
demonstrated similar PK exposures to male counterparts receiving a 1.0 mg dose of 
AGN-241751 under fasted conditions, hence sex does not appear to significantly influence the 
overall exposures of AGN-241751. After multiple doses of AGN-241751, no apparent systemic 
accumulation was observed up to 25 mg. Although the systemic exposures of AGN-241751 were 
slightly delayed when dosed in the fed state (approximate 40% reduction in Cmax, and 1-hour 
delay in Tmax), the overall exposures were similar for the plasma (AUC), and CSF profiles.
Hence, administration of AGN-241751 can be in the fed or fasted state.
3.1.
Study Rationale
AGN-241751 is a functional modulator of the NMDAR with partial agonist properties. In rodent 
models of depression, AGN-241751 elicited potent, rapid, and long-lasting antidepressant 
activity without adverse CNS effects. AGN-241751 is an orally bioavailable small molecule with 
NMDAR partial co-agonist pharmacology. Thus, it represents a novel pharmacology that may 
address a significant unmet need with minimal side effects and the feasibility of an oral dosage 
form. This is a proof-of-concept study of AGN 241751 monotherapy in the treatment of MDD.


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3.2.
Background
AGN-241751 is a novel NMDAR modulator with partial agonist properties and high oral 
bioavailability. Unlike the NMDAR antagonist, ketamine, AGN-241751 potentiates NMDAR 
function (Study BIO-16-1126, Study DMP-2015-003). AGN-241751 has the potential to provide 
rapid and significant antidepressant activity, unlike SSRIs and SNRIs that require several weeks 
of continued dosing to experience full therapeutic benefit. The compound is being developed for 
the treatment of MDD.
3.3.
Benefit/Risk Assessment
The expected benefits of AGN-241751 are potentially a rapid-onset, and long-acting, oral 
treatment for depression. The compound has the potential to have lower side effects than what is 
currently on the market. 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of AGN-241751 can be found in the investigator’s brochure.


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4.
Objectives and Endpoints
The primary objective is to evaluate the efficacy, as measured by improvement in MADRS total 
score, at 1 day post initial oral dose of AGN-241751 compared with placebo in participants with 
MDD. The key secondary objective is to evaluate the efficacy at Week 3 of AGN-241751 
administered orally once a week compared with placebo in participants with MDD.
Objectives
Endpoints
Primary

To evaluate the efficacy at 1 day post initial 
oral dose of AGN-241751 compared with 
placebo in participants with MDD

Change from baseline in MADRS total 
score at 1 day after first dose
Key Secondary

To evaluate the efficacy at Week 3 of 
AGN-241751 administered orally once a 
week compared with placebo in 
participants with MDD

Change from baseline in MADRS total 
score at Week 3
Additional

Additional endpoints to be explored to 
determine differences between 
AGN-241751 vs. placebo

Change from baseline in MADRS total 
score at 4 hours post dose, and on Study 
Days 5, 8, 9, 12, and 15 

Change from baseline in Clinical Global 
Impressions-Severity (CGI-S) at 4 hours
post dose, and on Study Days 2, 5, 8, 9, 12, 
15, and 22

Rate of sustained responders during 
treatment

Rate of responders at 4 hours post dose, 
and on Study Days 2, 5, 8, 9, 12, 15, and 22 

Rate of sustained remitters during 
treatment

Rate of remitters at 4 hours post dose, and 
on Study Days 2, 5, 8, 9, 12, 15, and 22

Time to first response

Time to first sustained response

Time to first remission

Time to first sustained remission


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Objectives
Endpoints
Safety Measures

Adverse event (AE) recording, clinical 
laboratory measures, vital sign parameters, 
electrocardiograms (ECGs), and physical 
examinations

Measure of psychotomimetic effects: Brief 
Psychiatric Rating Scale Positive 
Symptoms subscale (BPRS+) 

Measure of dissociative effects: Clinician 
Administered Dissociative States Scale 
(CADSS)

Measure of suicidality: Columbia-Suicide 
Severity Rating Scale (C-SSRS)

Measure of cognition/psychomotor 
function: Symbol Digit Coding (SDC)
Clinical Hypotheses
Once-weekly administration of AGN-241751 will result in greater improvement of symptoms in 
participants with MDD compared with placebo, as measured by the MADRS total score.


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5.
Study Design
5.1.
Overall Design
This study is a multicenter, randomized, double-blind (with a single-blind placebo lead-in), 
placebo-controlled, parallel-group, fixed-dose, 3-week study in participants with MDD. The 
study will include a total of 10 visits and will be approximately 5 weeks in duration: 

Up to 1-week screening period 

3-week double-blind treatment period 

1-week safety follow-up period 
After providing written consent, participants will enter a single-blind placebo lead-in screening 
period of up to 7 days. Screening procedures may be conducted on up to 2 separate dates 
where necessary to accommodate participant and site schedule; however, every effort 
should be made to conduct all procedures as early as possible in the screening period and 
the rater-administered MADRS and computer-administered MADRS must be collected on 
the same date. Participants will receive single-blind placebo during the screening period. 
Participants meeting the eligibility criteria at the end of Visit 2 (Baseline) will be assigned a 
treatment by the interactive web response system (IWRS) and enter the double-blind treatment 
period.
Approximately 250 participants are planned for enrollment in the double-blind treatment period 
(50 participants each in the AGN-241751 and placebo groups). Participants will be randomized 
in a ratio of 1:1:1:1:1 to 1 of 5 treatment groups: 0.25 mg, 1 mg, 3 mg, 10 mg dose AGN-241751 
and placebo. 
Aside from the single-blind screening period and double-blind treatment period, there is an 
additional single-blind element to this study (blinded to the participant). AGN-241751 is being 
developed for once-weekly dosing; however, in order to minimize participant’s expectations and 
control for placebo response, treatment will be presented to participants as oral daily dosing. 
Each treatment kit (dispensed once weekly) in the double-blind treatment period will contain 
2 bottles: Bottle 1 will contain a single dose of double-blind study treatment and Bottle 2 will 
contain multiple doses single-blind placebo tablets (blinded to the participant). At Visit 2 
(Day 1), Visit 5 (Day 8), and Visit 8 (Day 15), site staff will give the participant the single dose 
of double-blind study treatment from Bottle 1 to take by oral ingestion in the clinic (ie, the first
dose of study treatment for that week). Site staff will give Bottle 2, which contains the 
single-blind placebo tablets, to the participant with the instruction to take 1 tablet daily by oral 
ingestion for the remainder of that week. To maintain consistency, study treatment at Visit 1 
(single-blind placebo lead-in) will be dispensed in the same manner; the single dose of 
single-blind study treatment from Bottle 1 will be given to the participant for oral ingestion in the 
clinic, and then, Bottle 2 containing single-blind placebo tablets will be dispensed for the 
participant to take 1 tablet daily by oral ingestion through the remainder of the week.


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During the first 2 weeks of the double-blind treatment period, participants will have 3 study 
visits per week. The visits will occur in the following pattern: in-clinic treatment day, 1 day 
following the in-clinic treatment day, 4 days following the in-clinic treatment day, and 7 days 
following the in-clinic treatment day (which is the next in-clinic treatment day). If necessary, 
study visits may be conducted up to 2 days before or after the scheduled visits with the exception 
of visits that are 1 day apart (ie, Visits 2 and 3 must be conducted 1 day apart; and Visits 5 and 6 
must be conducted 1 day apart). Visit 8 will be conducted 7 days following the second in-clinic 
treatment day. All participants who receive study treatment must complete Visit 9/ET. 
Participants will enter a 1-week safety follow-up period and return for Visit 10. Participants who 
prematurely discontinue from the study before completing 3 weeks of double-blind treatment 
should enter the 1-week safety follow-up period. Additional follow-up visits may be scheduled 
within 30 days, if necessary for safety reasons.
Figure 5–1
Study Design Diagram
   All study treatment will be administered orally


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5.2.
Participant and Study Completion
Approximately 250 participants who meet eligibility criteria at Visit 2 (Baseline) will be 
randomly assigned to study treatment such that approximately 50 participants per arm will be 
allocated in a 1:1:1:1:1 ratio.
5.3.
End of Study Definition
The end of the study is defined as the completion of enrollment and completion of all periods of 
the study. 
A participant is considered to have completed the study if he/she has completed the double-blind 
treatment period of the study.
5.4.
Scientific Rationale for Study Design
The double-blind study design was adopted to minimize systematic bias resulting from the 
investigator or the participant knowing the treatment being administered. Randomization is 
expected to minimize participant selection bias and increase baseline comparability among the 
treatment groups. A placebo treatment group is included in the study to comply with worldwide 
regulatory preferences (Laughren 2001; Gispen-de Wied 2012), since placebo-controlled 
superiority trials have been shown to be conducive to higher quality studies and to provide more 
reliable outcomes (Feifel 2008; Laughren 2001; Gispen-de Wied 2012). Additionally, 
randomized double-blind comparisons versus placebo are needed to permit adequate evaluation 
of efficacy. Comparison to a placebo treatment is also of value for distinguishing disease 
manifestations from adverse reactions to the study treatment (EMA guidance 2013). The use of 
placebo in place of the 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) (FDA Guidance for Industry: E10, May 2001).
5.5.
Justification for Dose
The doses and regimen of AGN-241751 (0.25 mg, 1 mg, 3 mg, and 10 mg) were selected based 
on summation of in vitro, nonclinical pharmacology and safety studies, and clinical studies in 
healthy volunteers.

Based upon scaling of preclinical and in vitro data, these doses are expected to provide 
similar clinical exposures that demonstrated potentiation of NMDAR activity; 
strengthening NMDAR-dependent LTP; and producing lasting antidepressant-like effects 
in rat models.

Given the similar mechanism of activity with rapastinel and ketamine (ie, NMDA 
modulation), single-dose administration of AGN-241751 is expected to result in lasting 
improvements within MADRS scores, and therefore, justifying the weekly interval 
between dosing.


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
Within healthy volunteers, there was evidence from multiple pharmacodynamic tests that 
AGN-241751 had beneficial effects on electroencephalographic parameters, such as 
activation and increasing dominant frequency at doses up to 25 mg.

Compared to the available preclinical toxicology studies, the proposed top dose of 10 mg 
is expected to result in substantial margins below the 28-day study NOAELs designated 
in the rat (575-fold) and dog (10-fold).
AGN-241751 demonstrated acceptable safety and tolerability when administered in doses of 
50 mg administered once or 25 mg administered daily for 10 consecutive days in healthy male 
and female volunteers. Hence, it is expected that the proposed top dose of 10 mg, administered 
weekly, will be well tolerated.


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6.
Study Population
6.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
1. Written informed consent from the participant has been obtained prior to any study-related 
procedures (as described in Appendix 3). 
2. Male or female participants must be 18 to 65 years of age, inclusive, at the time of signing 
the informed consent. 
3. Meet Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) 
criteria for MDD (based on confirmation from the modified Structured Clinical Interview 
for DSM disorders [SCID]), with a current major depressive episode of at least 8 weeks 
and not exceeding 18 months in duration at Visit 1. 
4. Have a minimum score of 26 on the rater-administered MADRS and a minimum score of 
24 on the computer-administered MADRS at both Visit 1 (Screening) and Visit 2 
(Baseline).
5. Have a difference of no greater than 7 points between the rater-administered MADRS and 
computer-administered MADRS at both Visit 1 (Screening) and Visit 2 (Baseline).
6. Have a CGI-S score ≥ 4 at both Visit 1 (Screening) and Visit 2 (Baseline).
7. Have a negative serum β-human chorionic gonadotropin (β-hCG) pregnancy test if a 
woman of childbearing potential (WOCBP).
8. Female participants willing to minimize the risk of becoming pregnancy for the duration 
of the clinical study and follow-up period. A female participant is eligible to participate if 
she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
a.
Not a WOCBP
OR
b. A WOCBP who agrees to follow the contraceptive guidance in Appendix 5 during the 
treatment period and for at least 5 terminal half-lives after the last dose of study 
treatment.


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9. Male participants willing to minimize the risk of inducing pregnancy for the duration of 
the clinical study and follow-up period. A male participant must agree to use contraception 
as detailed in Appendix 5 of this protocol during the treatment period and for at least 
5 terminal half-lives after the last dose of study treatment and refrain from donating sperm 
during this period. 
10. Able, as assessed by the investigator, and willing to follow study instructions and likely to 
complete all required study visits.
11. Normal physical-examination findings, clinical-laboratory test results, and ECG results 
from Visit 1 (Screening) or abnormal results that are determined to be not clinically 
significant by the investigator.
12. Body mass index (BMI) within the range 18 and 40 kg/m2 (inclusive).
13. Eligibility confirmed through a formal adjudication process (see Section 9 
Diagnostic Assessments).
6.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Psychiatric and Treatment-Related Criteria
1. DSM-5–based diagnosis of any disorder other than MDD that was the primary focus of 
treatment within 6 months before Visit 1. Comorbid generalized anxiety disorder, social 
anxiety disorder, or specific phobias are acceptable provided they play a secondary role in 
the balance of symptoms and are not the primary driver of treatment decisions.
2. Lifetime history of meeting DSM-5 criteria for:
a.
Schizophrenia spectrum or other psychotic disorder
b. Bipolar or related disorder
c.
Major neurocognitive disorder 
d. Neurodevelopmental disorder of greater than mild severity or of a 
severity that impacts the participant’s ability to consent, follow study 
directions, or otherwise safely participate in the study
e.
Dissociative disorder


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f.
Posttraumatic stress disorder
g. MDD with psychotic features
3. History of meeting DSM-5 criteria for alcohol or substance use disorder (other than 
nicotine or caffeine) within the 6 months before Visit 1.
4. DSM-5–based diagnosis of any personality disorder of sufficient severity to interfere with 
participation in this study in the opinion of the investigator. 
5. History (based on participant report and/or medical records, and investigator judgment) 
of:
a.
Inadequate response to ECT, a monoamine oxidase inhibitor, ketamine, 
or adjunctive treatment with an antipsychotic 
b. Treatment with clozapine or any depot antipsychotic
c.
ECT, vagus nerve stimulation, transcranial magnetic stimulation, or any 
experimental central nervous system treatment during the current 
episode or in the 6 months before Visit 1 (whichever is longer)
d. Tardive dyskinesia, serotonin syndrome, or neuroleptic malignant 
syndrome
6. Having received:
a.
Anticonvulsant/mood stabilizer, within 1 year prior to Visit 1
b. Antipsychotic in the current episode, with the exception of quetiapine 
given for insomnia ≤ 50 mg/day provided it can be safely discontinued 
prior to Visit 2
c.
Combination therapy of 2 or more ADTs in the current episode if given 
for depression at adequate dose and duration
d. ADT augmentation agent in the current episode
7. Lifetime history of nonresponse to ≥2 antidepressants after adequate trials (adequate 
treatment is defined as at least 6 weeks at an adequate dose(s) based on approved package 
insert recommendations).
8. Positive result at Visit 1 from the urine drug screen (UDS) test for any prohibited 
medication. Exception: participants with a positive UDS at Visit 1 for opiates, 
cannabinoids, or episodic use of benzodiazepines may be allowed in the study provided:


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a.
The drug was used for a legitimate medical purpose; 
b. The drug can be discontinued prior to participation in the study (except 
for episodic use of benzodiazepines which may be continued); and
c.
A repeat UDS is negative for these substances prior to enrollment 
(except for episodic use of benzodiazepines which may be continued)
9. Suicide risk, as determined by meeting any of the following criteria:
a.
A suicide attempt within the past year
b. Significant risk, as judged by the investigator, based on the psychiatric 
interview or information collected in the C-SSRS at Visit 1 (Screening) 
or Visit 2 (Baseline)
c.
MADRS Item 10 score ≥ 5 at Visit 1 (Screening) or Visit 2 (Baseline) 
on the MADRS
10. At imminent risk of injuring self or others or causing significant damage to property, as 
judged by the investigator.
11. Requiring concomitant treatment with any of the prohibited medications, supplements, or 
herbal products listed in Appendix 6, including any psychotropic drug or any drug with 
psychotropic activity, except as described in Section 7.7.2.
12. Prior participation in any investigational study of AGN-241751.
13. Initiation or termination of psychotherapy for depression within the 3 months preceding 
Visit 1, or plans to initiate, terminate, or change such therapy during the course of the 
study. (Support meetings or counseling [eg, marital counseling] are allowed provided they 
are no more frequent than weekly and do not have treatment of depression as their 
objective).
14. Ongoing treatment with phototherapy, or termination of phototherapy within 1 month of 
Visit 1.
15. Known allergy or sensitivity to the study medication or its components.
Other Medical Criteria
16. BMI < 18 kg/m2 or > 40 kg/m2 at screening. 
17. Females who are pregnant, breastfeeding, or planning to become pregnant or breastfeed 
during the study.


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18. WOCBP and male partners of WOCBP, not using a reliable means of contraception 
(Appendix 5).
19. Participant has a condition or is in a situation which, in the investigator's opinion, may put 
the participant at significant risk, may confound the study results, or may interfere 
significantly with the participant’s participation in the study.
20. Any cardiovascular disease that is clinically significant, unstable, or decompensated.
21. Heart rate (supine) of ≤ 45 bpm or ≥ 120 bpm, or any heart rate that is clinically 
symptomatic at Visit 1 or Visit 2 based upon vital signs.
22. Any systolic and/or diastolic blood pressure (BP) that is symptomatic or clinically 
significant in the opinion of the investigator.
23. History of congenital QTc prolongation or QTc prolongation (screening ECG with QTcF 
≥450 msec for men and QTcF ≥ 470 msec for women).
24. Hypothyroidism or hyperthyroidism, unless stabilized on appropriate pharmacotherapy 
with no change in dosage for at least 1 month before Visit 1.
25. History of seizure disorder, stroke, significant head injury, tumor of the central nervous 
system, or any other condition that predisposes to seizure.
26. Known human immunodeficiency virus (HIV) infection.
27. Positive hepatitis C antibody on screening, with the exception of participants for whom 
the reflex HCV RNA test is negative.
28. Positive test for hepatitis B surface antigen and/or hepatitis B core antibody 
immunoglobulin M.
29. Screening liver enzyme test (aspartate aminotransferase [AST] and/or alanine 
aminotransferase [ALT]) results > 2 times the upper limit of normal (ULN).
Other Criteria
30. Current enrollment in an investigational drug or device study or participation in such a 
study within 6 months of entry into this study.
31. Employee, or immediate relative of an employee, of the sponsor, any of its affiliates or 
partners, or the study center. 


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32. Inability to speak, read, and understand the English language sufficiently to understand 
the nature of the study, to provide written informed consent, or to allow the completion of 
all study assessments.


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6.3.
Lifestyle Restrictions
6.3.1.
Meals and Dietary Restrictions
None
6.3.2.
Caffeine, Alcohol, and Tobacco
Participants should not be abusing alcohol before or throughout the duration of the study.
6.3.3.
Activity
None
6.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to treatment in the study. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any serious adverse event (SAE).


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7.
Treatments
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo, or 
medical device(s) intended to be administered to a study participant according to the study 
protocol.
7.1.
Treatments Administered
During the lead-in screening period, all participants will receive single-blind placebo tablets 
(participants will be blinded to lead-in treatment; site personnel will be aware that the lead-in 
treatment is placebo). At Visit 1 (Screening), a single dose of single-blind placebo from Bottle 
1 will be given to the participant for oral ingestion in the clinic. Bottle 2, containing single-blind 
placebo tablets, will be dispensed for the participant to take 1 tablet daily by oral ingestion 
through the remainder of the week.
Study treatment kits for the double-blind treatment period will be assigned at Visit 2 (Day 1), 
Visit 5 (Day 8), and Visit 8 (Day 15). Each treatment kit will contain 2 bottles: Bottle 1 will 
contain a single dose of double-blind study treatment and Bottle 2 will contain multiple doses of 
single-blind placebo tablets (blinded to the participant). At Visit 2 (Day 1), Visit 5 (Day 8), and 
Visit 8 (Day 15), site staff will give the participant the single dose of double-blind study 
treatment from Bottle 1 to take by oral ingestion in the clinic (ie, the first dose of study treatment 
for that week). Site staff will give Bottle 2, which contains the single-blind placebo tablets, to the 
participant with the instruction to take 1 tablet daily by oral ingestion for the remainder of that
week.
Study Treatment Name
AGN-241751
Placebo
Dosage Formulation
Tablet
Tablet
Unit Dose Strengths
0.25 mg
1 mg
3 mg
10 mg
-
Route of Administration
Oral
Oral


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Study Treatment Name
AGN-241751
Placebo
Dosing Instructions
First dose from Bottle 1 given by 
site staff to the participant for oral
ingestion in the clinic; Bottle 2 will 
be given to participant to take home 
with instructions to take 1 tablet 
orally every day for the rest of the 
week
Note: study treatment will be 
dispensed once a week for a total of 
3 weeks (at Visits 2, 5, and 8)
First dose from Bottle 1 given by 
site staff to the participant for oral 
ingestion in the clinic; Bottle 2 will 
be given to participant to take home 
with instructions to take 1 tablet 
orally every day for the rest of the 
week
Note: study treatment will be 
dispensed once a week for a total of 
3 weeks (at Visits 2, 5, and 8)
Packaging and Labeling
Allergan will provide study 
treatment in the form of identically 
appearing tablets containing 
AGN-241751 doses of 0.25 mg, 
1 mg, 3 mg, 10 mg, or placebo. 
All participants will receive 
single-blind placebo tablets for the 
run-in period.
Allergan will provide study 
treatment in the form of identically 
appearing placebo tablets. 
All participants will receive 
single-blind placebo tablets for the 
run-in period.
Manufacturer
Allergan, Inc.
Allergan, Inc.
7.2.
Dose Modification
Dose modification is not allowed.
7.3.
Method of Treatment Assignment
All participants will be centrally assigned to randomized study treatment using an IWRS. Before 
the study is initiated, the log-in information and directions for the IWRS will be provided to each 
site.
Study treatment will be dispensed at the study visits summarized in the schedule of activities
(Section 2). 
Returned study treatment should not be re-dispensed to the participants.
7.4.
Blinding/Masking
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 participant’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 participant’s 
condition (eg, antidote is available). In this case, the sponsor must be notified within 24 hours 


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after breaking the blind. The date and reason that the blind was broken must be recorded in the 
source documentation and electronic case report form (eCRF), as applicable.
7.5.
Preparation/Handling/Storage/Accountability
1. All study treatment will be provided and shipped to the study centers by Allergan Inc., and 
must be stored in an appropriate secure area (eg, a locked cabinet in a locked room) at 
refrigerate conditions (5°C with a permitted range of 2°C-8°C) and must be protected from 
heat and moisture.
2. The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported 
and resolved before use of the study treatment.
3. Only participants enrolled in the study may receive study treatment, and only authorized site 
staff may supply or administer study treatment. All study treatments must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in accordance 
with the labeled storage conditions with access limited to the investigator and authorized site 
staff.
4. The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (ie,
receipt, reconciliation, and final disposition records).
5. Further guidance and information for the final disposition of unused study treatment are 
provided in the study reference manual.
7.6.
Treatment Compliance
Compliance with administration of double-blind study treatment in the clinic at Visits 2, 5, and 8 
will be monitored by capturing the date that the participant ingested the double-blind study 
treatment at each of these visits. If a scheduled ingestion does not occur, the sponsor must be 
notified and the reason captured in the eCRF.
Compliance with study treatment dosing by the participant outside of the clinic will be monitored 
by counting the number of tablets dispensed and returned. Before dispensing new study 
treatment, study center personnel will make every effort to collect all unused study treatment and 
empty bottles. If a participant demonstrates poor compliance at any time during the study (< 80% 
or > 120% measured by pill counts), the investigator should evaluate whether the participant
should be discontinued from the study. 
The study centers will keep an accurate drug disposition record that specifies the amount of 
study treatment administered to each participant and the date of administration. 


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7.7.
Concomitant Therapy
The use of any concomitant medication, prescription or over-the-counter, is to be recorded on the 
participant’s eCRF at each visit along with the reason the medication is taken.
7.7.1.
Prohibited Treatments 
Participants must discontinue any of the medications listed below for the specified period prior to 
baseline. These medications are prohibited for the duration of the study. Other medications being 
used at screening may be continued.
The following medications are prohibited: 
•
Antipsychotics
•
Antidepressants 
•
Stimulants
•
Anticonvulsants/mood stabilizers
•
Dopamine-releasing drugs or dopamine agonists
•
Psychotropic drugs not otherwise specified (including herbal products, such as St. John’s 
Wort, and certain nutritional supplements)
See Appendix 6 Concomitant Medications for a comprehensive list of prohibited medications 
and allowed medication usage. Appropriate washout of prohibited medications is to be 
conducted at the discretion of the investigator and should begin as soon as practical following 
consent and screening.
The decision to administer a prohibited medication/treatment during the study period is done 
with the safety of the study participant as the primary consideration. When possible, the sponsor
is to be notified before the prohibited medication/treatment is administered.
7.7.2.
Permitted Treatments
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or receives 
during the study must be recorded along with:

Indication

Dates of administration including start and end dates

Dosage information including dose and frequency
Therapy considered necessary for the participant’s welfare may be given at the discretion of the 
investigator. If the permissibility of a specific medication/treatment is in question, please contact 
the sponsor.
The sponsor or designee should be contacted if there are any questions regarding concomitant or 
prior therapy.


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For Insomnia
Eszopiclone, zolpidem, zolpidem extended-release, zopiclone or zaleplon for insomnia may be 
continued provided the medication has been used in a consistent manner for 4 weeks prior to 
enrollment. Following enrollment, these medications may also be introduced in participants not 
previously treated as necessitated by insomnia that emerges or worsens during the study. In these 
participants, the medications will be permitted up to 3 times a week at the following doses (not 
permitted within 8 hours of efficacy measures):

Zolpidem (maximum of 10 mg/day)

Zolpidem extended release (maximum of 12.5 mg/day)

Zaleplon (maximum of 20 mg/day)

Eszopiclone (maximum of 3 mg/day)

Zopiclone (maximum of 7.5 mg/day)

Suvorexant (maximum of 10 mg/day)
These medications must be administered before bedtime as recommended in their prescribing 
information. The medication must be documented on the concomitant medications page of the 
eCRF. No such medication is permitted within 8 hours of psychiatric or neurological 
assessments.
For Anxiety or Agitation
Episodic use of benzodiazepines up to approximately 2 mg/day lorazepam equivalent dose and 
for up to 3 consecutive days at a time may be given for anxiety-related conditions and agitation 
(not permitted within 8 hours of efficacy assessments).
7.8.
Treatment after the End of the Study
Participants whose MDD symptoms worsen or are determined by the investigator not to be 
adequately controlled prior to completing the double-blind treatment period will be allowed to 
discontinue the study and start appropriate treatment at the investigator’s discretion. This new 
treatment will not be provided by the sponsor. 


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8.
Discontinuation/Withdrawal Criteria
Notification of early participant discontinuation from the study and the reason for 
discontinuation will be made to the sponsor and will be clearly documented on the appropriate 
case report form.
Reasons for discontinuation from the study treatment and/or the study may include the 
following:

Adverse event

Lack of efficacy

Lost to follow-up

Non-compliance with study drug

Other

Pregnancy

Protocol deviation

Screen failure

Site terminated by sponsor

Study terminated by sponsor

Withdrawal by subject (withdrawal of consent to participate in the study)
8.1.
Discontinuation of Study Treatment
All randomized participants who prematurely discontinue from the study, regardless of cause, 
should be seen for a final assessment at an ET Visit. A final assessment will be defined as 
completion of the evaluations scheduled for all participants at Visit 9/ET Visit. Participants who
prematurely discontinue from the study before completing 3 weeks of double-blind treatment 
should enter the 1-week safety follow-up period. 
Any participant may be withdrawn due to AE at the discretion of the investigator.
Any participant who meets any of the following criteria at any point during the study must be 
withdrawn from participation, due to AE(s) related to suicide:
a) A suicide attempt
b) Significant risk, as judged by the investigator, based on the psychiatric interview or 
information collected in the C-SSRS
c) MADRS Item 10 score ≥ 5


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In the event that a participant is withdrawn for a suicide-related AE, the participant should be 
referred for additional treatment or hospitalization, as clinically indicated, in addition to 
withdrawing the participant from the study.
Discontinuation of study treatment for abnormal liver function (criteria for potential Hy’s law 
described in Section 9.2.6) should be considered by the investigator if the investigator believes 
that it is in best interest of the participant.
If a clinically significant finding is identified after enrollment, the investigator or qualified 
designee will determine if the participant can continue in the study and if any change in 
participant management is needed. Any new clinically relevant finding should be reported as an 
AE.
See the schedule of activities (Section 2) for data to be collected at the early termination visit and 
the safety follow-up visit.
8.2.
Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, compliance, 
or administrative reasons.

If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.

If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must document this in the site study records.

See the schedule of activities for data to be collected at the time of study discontinuation and 
follow-up and for any further evaluations that need to be completed.
8.3.
Lost to Follow Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in the 
study.


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
Before a participant is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 2 telephone calls, and if 
necessary, a certified letter to the participant’s last known mailing address or local equivalent 
methods). These contact attempts should be documented in the participant’s medical record.

Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 


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9.
Study Assessments and Procedures

Study procedures and their timing are summarized in the schedule of activities (Section 2).

Protocol waivers or exemptions are not allowed.

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue study 
treatment.

Adherence to the study design requirements, including those specified in the schedule of 
activities, is essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.

Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilized for screening or baseline 
purposes provided the procedure met the protocol-specified criteria and were performed 
within the time frame defined in the schedule of activities.

Repeat or unscheduled blood samples may be taken for safety reasons or for technical issues 
with the samples.
Diagnostic Assessments
The SCID will be administered during the screening interviews by a psychiatrist, doctoral-level 
clinical psychologist, or other clinician who has extensive professional training and experience in 
the diagnosis of mental illness and who meets the training requirements and qualification 
standards set by the sponsor and rater training vendor. 
Participants will complete a computer-administered Diagnostic Validation (DxV) assessment at 
Visit 1 (Screening) prior to the rater-administered SCID, on a tablet computer provided to the 
study center. The DxV will collect data about the participants’ history relative to lifelong history 
of MDD. The participant’s diagnostic information, based on the responses to the computerized 
interview, will be reviewed by the independent clinical reviewers team appointed by the sponsor, 
and any uncertainty raised by the participant’s responses on the diagnostic interview will be 
discussed with the investigator/study center clinician in order to establish confidence in the 
diagnosis. Participants for whom diagnostic agreement between the investigator/study center 
clinician and the rater vendor clinician cannot be reached, may not be appropriate for study 
participation.
Eligibility of potential participants will be confirmed by agreement with external clinical 
reviewer (Bracket), in which screening data will be obtained to evaluate psychiatric status 
(including MADRS, CGI-S, and SCID). Investigators will complete the Clinical Validation 
Inventory for Study Admission (C-VISA) worksheet as part of the adjudication process. The 


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SCID and MADRS will be audio recorded at the Visit 1 (Screening). The C-VISA worksheet and 
SCID and MADRS recordings will be reviewed by a team of independent clinical reviewers 
appointed by the sponsor.
9.1.
Efficacy Assessments
The efficacy assessments (MADRS and CGI-S) will be administered by a psychiatrist, 
doctoral-level clinical psychologist, or other clinician who has extensive professional training 
and experience in the diagnosis of mental illness and who meets the training requirements and 
qualifications standards set by the sponsor and rater training vendor.
9.1.1.
The Montgomery-Åsberg Depression Rating Scale
The MADRS (Montgomery and Åsberg 1979) is a clinician-rated scale (Appendix 8). The 
MADRS will be used to assess depressive symptomatology. Participants are rated on 10 items to
assess feelings of sadness, lassitude, pessimism, inner tension, suicidality, reduced sleep or 
appetite, difficulty concentrating, and lack of interest. Each item will be scored on a 7-point 
scale. A score of 0 indicates the absence of symptoms, and a score of 6 indicates symptoms of 
maximum severity. 
A qualified rater (ie, who meets the training requirements and qualifications set by the rater 
training vendor [Bracket]) at each investigational center will conduct the MADRS assessment.
The rater-administered MADRS will be used for the primary and secondary efficacy 
analyses. In addition to MADRS administration by a qualified rater, each participant will 
complete an interactive, computer-administered MADRS interview on the dedicated study 
device. Data from the computer-administered interview will be compared with data derived from 
the rater-administered interview on an ongoing basis as part of a remote quality assurance 
program conducted by an independent vendor appointed by the sponsor. 
At each visit with a MADRS assessment, the rater-administered MADRS interview will be audio 
recorded. The computer-administered interview (conducted by participant alone) will involve a 
series of probe and follow-up questions with multiple-choice response options. At Visit 1 
(Screening), the computer administered MADRS will be conducted prior to the 
rater-administered MADRS. At all other visits, the rater-administered MADRS will be 
conducted first. At Visit 1 (Screening) and Visit 2 (Baseline), the MADRS will be administered 
with a look-back timeframe of 1 week. At all other evaluations, the MADRS will be 
administered with a look-back timeframe of “since last evaluation”.
9.1.2.
The Clinical Global Impressions-Severity
The CGI-S (Guy 1976) is a clinician-rated scale used to rate the severity of the patient’s current 
state of mental illness compared with a patient population with MDD (Appendix 9). The patient 
will be rated on a scale from 1 to 7 with 1 indicating a “normal, not at all ill” and 7 indicating 


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“among the most extremely ill patients”. The CGI-S will be administered by the investigator or a 
sub-investigator with extensive professional training and experience in assessing mental illness 
and qualification standards set by the sponsor and rater training vendor. At Visit 1 (Screening) 
and Visit 2 (Baseline), the CGI-S will be administered with a look-back timeframe of 1 week. At 
all other evaluations, the CGI-S will be administered with a look-back timeframe of “since last 
evaluation”.
9.2.
Adverse Events
The definitions of an AE or SAE can be found in Appendix 4.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant’s legally authorized representative).
The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE. 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 study treatment. 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.
9.2.1.
Time Period and Frequency for Collecting AE and SAE Information
All SAEs from the signing of the ICF will be collected at the timepoints specified in the schedule 
of activities (Section 2), and as observed or reported spontaneously by study participants, until 
30 days from the last dose of study treatment.
All AEs from the signing of the ICF will be collected at the timepoints specified in the schedule 
of activities (Section 2), and as observed or reported spontaneously by study participants, until 
30 days from the last dose of study treatment.
Medical occurrences that begin before the start of study treatment but after obtaining informed 
consent will be recorded on the AE section of the eCRF.
All SAEs will be recorded and reported to the sponsor or designee within 24 hours, as indicated 
in Appendix 4. The investigator will submit any updated SAE data to the sponsor within 
24 hours of it being available.
Investigators are not obligated to actively seek AE or SAE information in former study 
participants. However, if the investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and he/she considers the event to be reasonably 
related to the study treatment or study participation, the investigator must promptly notify the 
sponsor.
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 4.


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9.2.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
9.2.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All AEs/SAEs will be followed until resolution, stabilization, until 
the event is otherwise explained, or the participant is lost to follow-up (as defined in Section 8.3).
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may include 
additional laboratory tests or investigations, histopathological examinations, or consultation with 
other health care professionals.
If a participant dies during participation in the study or during a recognized follow-up period, the 
investigator will make every effort to provide the sponsor with a copy of any postmortem 
findings including histopathology. 
New or updated information will be recorded in the originally completed eCRF.
The investigator will submit any updated SAE data to the sponsor within 24 hours of receipt of 
the information.
9.2.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study treatment under clinical investigation are met. 

The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study treatment under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, institutional review boards (IRBs)/independent ethics 
committees (IECs), and investigators.

An investigator who receives an investigator safety report describing a SAE or other specific 
safety information (eg, summary or listing of SAEs) from the sponsor will review and then 
file it along with the investigator’s brochure and will notify the IRB/IEC, if appropriate 
according to local requirements.
9.2.5.
Pregnancy

Site personnel must report every pregnancy in female participants, and female partners of 
male participants, from the time the participant signs the ICF until 30 days after the last dose 
of study treatment.


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
Within 24 hours of learning of the pregnancy, the investigator must report the event to the 
sponsor on the Clinical Trial Pregnancy Form and fax or e-mail it to the SAE reporting fax 
number or e-mail provided on the title page of this protocol, even if no AE has occurred.
The investigator should follow the procedures outlined in Appendix 5.

Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs.
9.2.6.
Potential Hy’s Law
Criteria for potential Hy’s law cases are as follows: 

ALT or AST ≥ 3 × ULN AND 

Total bilirubin ≥ 2 × ULN AND 

Alkaline phosphatase < 2 × ULN
Study site personnel must report every participant 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 the participant signs the 
ICF for the study until 30 days after the final protocol-defined study visit or the last known dose 
of study treatment (if the final visit does not occur). 
A laboratory alert for potential Hy’s laws cases will be in place, and must notify investigators 
and the sponsor immediately when the above criteria have been met. A potential Hy’s law case 
must be faxed or e-mailed to the sponsor on an adverse event of interest form, as soon as 
possible (within 24 hours of learning of the potential Hy’s law case) to the SAE fax number or 
e-mail shown on the title page of this protocol, 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 medical monitor and in accordance with the FDA Guidance for Industry, 
Drug-Induced Liver Injury: Premarketing Clinical Evaluation, July 2009.
9.2.7.
Medication Errors
Medication error refers to any unintended error in the dosing and/or administration of the study 
treatment as per instructions in the protocol. Medication errors generally fall into 4 categories as 
follows:

Wrong study drug

Wrong dose (including dosing regimen, strength, form, concentration, amount)

Wrong route of administration

Wrong participant (ie, not administered to the intended participant)
Medication errors include occurrences of overdose and underdose of the study treatment.


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9.3.
Treatment of Overdose
Treatment of an overdose is not applicable for this study because only 1 dose of double-blind 
study treatment is provided per kit and that dose is administered to the participant once weekly in 
the clinic. AGN-241751 has a short half-life, hence, even in the event of an overdosage, the 
likelihood of lasting high exposures would be minimal.
9.4.
Safety Assessments
Planned timepoints for all safety assessments are provided in the schedule of activities
(Section 2).
9.4.1.
Physical Examinations
A complete physical examination will be done at Visit 1 (Screening) and at Visit 9/ET by a 
professionally trained physician or health professional listed on Form FDA 1572 and licensed to 
perform physical examinations.
9.4.2.
Vital Signs
Vital signs (pulse rate, systolic and diastolic blood pressure, oral or tympanic temperature, and 
body weight) will be assessed at every visit. Height will be assessed at Visit 1 (Screening).
Blood pressure and radial pulse rate will be measured in the supine position followed by the 
standing position. The standing measurements should be assessed after a sufficient amount of 
time (approximately 1-3 minutes) has been elapsed to allow the BP to equilibrate in the standing 
state. 
Radial pulse rate should be measured after blood pressure measurements. Blood pressure may be 
measured manually or by machine, but radial pulse rate should only be measured manually and 
for a sufficient time to acquire an accurate measurement.
Participants should be instructed not to wear clothing with tight sleeves when they come for 
clinic visits. Additionally, participants should be kept as calm and undisturbed as possible while 
blood pressure and pulse rate measurements are taken (eg, there should be no talking while the 
blood pressure is being measured). The same arm and blood pressure cuff (appropriate to the arm 
circumference) should be used for all blood pressure measurements. 
Whenever possible, the participant’s weight will be measured at the same time of day; 
participants should wear their usual indoor clothing, but take off their jacket and shoes. For each 
participant, body weight should be determined using the same equipment during the study after 
ensuring its proper calibration.
9.4.3.
Electrocardiograms
A 12-lead ECG will be performed at Visit 1 (Screening) and Visit 9/ET. ECGs will be performed 
and electronically transmitted to a central ECG laboratory for analysis according to the 
instructions provided by the central ECG laboratory. Measurements (in msec) will be recorded 


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for the following parameters: PR interval, QRS duration, and uncorrected QT interval. QTcB 
(Bazett corrected QT interval) and QTcF (Fridericia corrected QT interval) will be calculated. 
The overall interpretation and determination of the clinical relevance of ECG findings using the 
central ECG interpretation laboratory report will be the responsibility of the investigator and will 
be recorded in the participant’s eCRF. 
Throughout the study, the investigator will review the central ECG reports and indicate the 
clinical significance of all abnormal values, and then sign and file the report in the participant’s 
study file.
9.4.4.
Clinical Safety Laboratory Assessments

See Appendix 2 for the list of clinical laboratory tests to be performed and the schedule of 
activities (Section 2) for the timing and frequency. 

The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study that are considered Adverse Events per 
the judgment of the investigator in the AE section of the eCRF. The laboratory reports must 
be filed with the source documents. Clinically significant abnormal laboratory findings are 
those which are not associated with the underlying disease, unless judged by the investigator 
to be more severe than expected for the participant’s condition.

All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or after the last dose of study treatment should be repeated until the 
values return to normal or baseline or are no longer considered clinically significant by the 
investigator.
o
If such values do not return to normal/baseline within a period of time judged reasonable 
by the investigator, the etiology should be identified and the sponsor notified.
o
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the schedule of activities.
o
If laboratory values from non-protocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the eCRF.
9.4.5.
Columbia-Suicide Severity Rating Scale
The C-SSRS is an instrument that reports the severity of both suicidal ideation and behavior
(Appendix 12 and Appendix 13). 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), 


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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 C-SSRS will be completed at all study visits. At Visit 1 (Screening), the C-SSRS will be 
completed for the participant’s lifetime history of suicidal ideation and behavior. At all other 
visits, the C-SSRS will be completed for ideation and behavior since the previous visit. The 
C-SSRS will be evaluated and signed at each visit by a qualified staff member (ie, the 
investigator or designee who has extensive professional training and experience in assessing 
mental illness), before the participant leaves the study center.
9.4.6.
Brief Psychiatric Rating Scale—Positive Symptoms Subscale
The BPRS is an 18-item evaluation that assesses psychiatric symptoms and unusual behavior 
(Overall and Gorham 1962). The BPRS+ is a subset of the BPRS that assesses 4 components of 
the BPRS related to the degree of psychosis: Conceptual Disorganization, Suspiciousness, 
Hallucinatory Behavior, and Unusual Thought Content (Appendix 10). Only the 4 items of 
BPRS + subscale will be collected and analyzed. The BPRS+ will be administered by the 
investigator or designee with extensive professional training and experience in assessing mental 
illness. At Visit 1 (Screening) and Visit 2 (Baseline) the BPRS+ will be administered with a 
look-back timeframe of 1 week. At all other evaluations, the BPRS+ with a look-back timeframe 
of “since last evaluation”.
9.4.7.
Clinician Administered Dissociative States Scale
The CADSS is a 28-item clinician-administered measure of perceptual, behavioral, and 
attentional alterations occurring during active dissociative experiences composed of 
23 subjective self-reported and 5 objective observer-reported ratings, each scored from 0 (not at 
all) to 4 (extremely) (Appendix 11). Only the 23 subjective items will be collected and analyzed. 
The CADSS provides a validated assessment of dissociative states sensitive to change over time 
and amenable to repeated measures (Bremner 1998). The CADSS will be administered by the 
investigator or designee with extensive professional training and experience in assessing mental 
illness. At Visit 1 (Screening) and Visit 2 (Baseline) the CADSS will be administered with a 
look-back timeframe of 1 week. At all other evaluations, the CADSS will be administered with a 
look-back timeframe of “since last evaluation”.
9.4.8.
Symbol Digit Coding
The Central Nervous System Vital Signs Symbol Digital Coding (SDC; Gualtieri and Johnson 
2006), a version of the Symbol Digit Modalities Test (SDMT) (Smith and Jones 1982), is a 
variant of the Wechsler Digit Symbol Substitution Test (DSST), but the position of symbols and 
digits is reversed. The clinical and psychometric properties of the SDMT are similar to those of 
the DSST. The patient is given a training session to learn how to link numbers to digits. The test 
itself consists of serial presentations of screens, each of which contains a bank of 8 symbols 
above and 8 empty boxes below. The patient types in the number that corresponds to the symbol 
that is highlighted. Only the digits from 2 through 9 are used; this to avoid the confusion between 


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“1” and “I” on the keyboard. The test lasts for 120 seconds. The goal is to type in as many 
correct numbers as one can in 120 seconds.
9.5.
Pharmacokinetics
For participants who consent to the optional PK sampling, whole blood samples of 
approximately 4 mL will be collected for measurement of plasma concentrations of 
AGN-241751 as specified in the schedule of activities (Section 2). Samples will be collected at 
Visit 2/2a (Day 1) at 1 hour (± 15 minutes), 2 hours (± 15 minutes), and 4 hours (± 15 minutes) 
post dose. At Visit 5 (Day 8), a single sample will be collected any time from 15 minutes to 
3 hours post dose; site staff should record the time of the prior meal taken by the participant 
before the PK sample collection, whenever possible.
Instructions for the collection and handling of biological samples will be provided by the 
sponsor. The date and time of the administered dose of study treatment and the date and time of 
each sample collection will be recorded.
Samples will be used to evaluate the pharmacokinetics of AGN-241751. Each plasma sample 
will be divided into 2 aliquots (1 each for PK, and other analyses/backup). Samples collected for 
analyses of AGN-241751 plasma concentration may also be used to evaluate safety, efficacy, or 
exploratory biomarker aspects related to concerns arising during or after the study.
9.6.
Pharmacodynamics
Pharmacodynamic samples are not being collected within this study.
9.7.
Genetics
Genetics are not evaluated in this study.
9.8.
Biomarkers
Biomarker samples are not being collected within this study.
9.9.
Medical Resource Utilization and Health Economics
Medical resource utilization and health economics parameters are not evaluated in this study.


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10.
Statistical Considerations 
10.1.
Estimands Framework
This estimand framework is being proposed for the primary and secondary endpoints.
10.1.1.
Population
The target study population is the participants with MDD satisfying the inclusion and exclusion 
criteria as specified in Sections 6.1 and 6.2. 
The analysis population is defined as all randomized participants who received at least 
1 administration of study treatment and had a baseline MADRS total score and at least 
1 postbaseline assessment for the MADRS total score during the double-blind treatment period.
10.1.2.
Variables
The variable is the same as the primary efficacy endpoint defined in Section 10.4.1.1, which is 
the change from baseline in MADRS total score at 1 day after first dose of double-blind 
treatment; and the secondary efficacy endpoint of the change from baseline in MADRS total 
score at Week 3. 
10.1.3.
Intercurrent Events and Their Handling Rules
The intercurrent events involve all discontinuations of study due to any reason. Participants who 
discontinue study will be considered adhered to the study treatment by 1 day after the first dose 
for the primary endpoint and assumed adhered to the study treatment by Week 3 for the 
secondary endpoint.
For Day 1 primary analysis, the first dose of the study drug is administered to the participants at Baseline 
(Visit 2) in the clinic, and the study analysis population is defined as all randomized participants who 
received at least 1 administration of study treatment and had a baseline MADRS total score and at least 
1 postbaseline assessment of MADRS total score. Therefore, all participants will adhere to the study 
treatment by Day 1.
For Week 3 secondary analysis, per the study protocol all study treatment doses including at Week 3 are
administered in the clinic. Given the very short treatment period, very small (at most 5%) proportion of 
participants are expected not to receive the treatments at Weeks 2 or 3. Therefore assuming those 
discontinued treatments at Weeks 2 or 3 to adhere to study treatment will have a minimum impact on the 
overall analysis. 
Also, this is a Phase 2 study with an important objective to inform the doses for the Phase 3 studies. 
Given at least 95% study participants will adhere to study treatment for the secondary endpoint and the 
objective of the study being dose finding, we consider a hypothetical estimand defined as all participants 
in the study population adhere to study treatment as an appropriate estimand.


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10.1.4.
Population-Level Summary
The population-level summary for the primary endpoint is the difference in primary variable 
means between each AGN-241751 dose and placebo.
Similarly, the population-level summary for the secondary endpoint is the difference in 
secondary variable means between each AGN-241751 dose and placebo.
10.2.
Sample Size Determination
The sample size of approximately 50 randomized participants in each of the 5 treatment groups 
is not based on statistical power consideration due to the lack of information of AGN-241751 for 
the variability of change from baseline to 1 day after first dose in MADRS total score. 
10.3.
Populations for Analyses
The analysis populations will consist of participants as defined below:

The modified intent-to-treat (mITT) population includes all randomized participants who 
received at least 1 administration of study treatment, and have a baseline MADRS total 
score and at least 1 postbaseline assessment for the MADRS total score during the
double-blind treatment period. Participants will be summarized according to the 
randomized study treatment.

The safety population includes all participants who received ≥ 1 administration of study 
treatment. Participants will be summarized according to the study treatment they actually 
received.
10.4.
Statistical Analyses
The study statistical analysis plan (SAP) will be developed and finalized before database lock 
and will describe in detail the participant populations to be included in the analyses, the safety 
and efficacy analysis, and the procedures for accounting for missing or unscheduled data. This 
section is a summary of the planned statistical analyses of the primary and secondary endpoints. 
10.4.1.
Efficacy Analyses
The efficacy analyses will be based on the mITT population. Baseline for efficacy is defined as 
the last nonmissing efficacy assessment before the first dose of study treatment. 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 participants in the mITT Population. All the small centers will be pooled to 
form a pseudo-center. If the pseudo-center is still a small center, it will be pooled with the 
smallest non-small center. If there is more than one smallest non-small center, the small 
pseudo-center will be pooled with the smallest non-small center that has the largest center 
number.


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10.4.1.1.
Primary and Secondary Endpoint
To perform the analysis based on the estimands framework, the primary and secondary efficacy 
endpoints are listed below and analyses will be defined in the following sections. All analyses for 
other efficacy endpoints listed below will be defined in the SAP.
Primary efficacy endpoint:

Change from baseline in MADRS total score at 1 day after first dose 
Secondary efficacy endpoint:

Change from baseline in MADRS total score at Week 3
10.4.1.2.
Primary and Secondary Analyses
The primary analysis for the primary and secondary endpoints will be performed using an
MMRM with treatment group, visit, pooled study center, and treatment group-by-visit interaction 
as fixed effects and the baseline value and baseline value-by-visit as covariates. An unstructured 
covariance matrix will be used to model the covariance of within-participant scores. If the model 
fails to converge based on the unstructured covariance matrix, then structures of Heterogenous 
Toeplitz, Toeplitz, and Compound Symmetry will be applied, in the specified order, until the 
model converges. The Kenward-Roger approximation will be used to estimate denominator 
degrees of freedom (Kenward and Roger 1997). These analyses will be performed based on all 
postbaseline scores using only the OCs without imputation of missing values.
In addition, a sensitivity analysis using the multiple imputation (MI) approach under missing not 
at random (MNAR) assumptions will be performed on the primary and secondary efficacy 
parameters. 
Detailed methods and procedures for the above outlined missing data-derived sensitivity 
analyses will be documented in the final SAP prior to the study database lock.
10.4.1.3.
Multiple Comparisons Procedure
Let H11, H21, H31, H41 represent the comparisons of AGN-241751 0.25 mg, 1 mg, 3 mg, and 
10 mg, respectively with placebo in regarding to the primary efficacy parameter; and let H12, 
H22, H32, and H42 represent the comparisons of AGN-241751 0.25 mg, 1 mg, 3 mg, and 10 mg, 
respectively with placebo in regarding to the key secondary efficacy parameter, the graphical 
procedure as displayed in Figure 10-1 will be employed to controlled the overall familywise 
error rate (FWER) at α = 0.05. The e in the figure represents a small positive number less than 
0.0001.


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Figure 10-1
Graphical Procedure for Primary and Key Secondary Hypotheses
10.4.2.
Safety Analyses
The safety analysis will be performed using the safety population for the double-blind treatment 
period and for the safety follow-up period, if applicable, and will be fully defined in the SAP. 
The safety parameters will include AEs, clinical laboratory including potential Hy’s law cases, 
vital signs, ECG, C-SSRS, BPRS+, CADSS, and SDC parameters. For each safety parameter, 
the last nonmissing safety assessment before the first dose of study intervention will be used as 
the baseline for all analyses of that safety parameter.
10.4.2.1.
Adverse Event
An AE will be considered a treatment-emergent adverse event (TEAE) if:

The AE began on or after the date of the first dose of study treatment; or

The AE was present before the date of the first dose of study treatment, but increased in 
severity or became serious on or after the date of the first dose of study treatment
If more than 1 AE is reported before the first dose of study treatment and is coded to the same 
preferred term, the AE with the greatest severity will be used as the benchmark for comparison 
with the AEs that were also coded to that preferred term and that occurred during the period. An 
AE that occurs more than 30 days after the last dose of study treatment will not be counted as a 
TEAE.
An AE will be considered a treatment-emergent serious adverse event (TESAE) if it is a TEAE 
that additionally meets any SAE criteria


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The number and percentage of participants reporting TEAEs in each study treatment will be 
tabulated as follows:
•
By system organ class and preferred term
•
By system organ class, preferred term, and severity.
The number and percentage of participants reporting treatment related TEAEs in each study 
treatment will be tabulated by system organ class and preferred term.
If more than 1 AE is coded to the same preferred term for the same participant, the participant 
will be counted only once for that preferred term using the most severe and most related 
occurrence for the summarization by severity and by relationship to study treatment.
Summary tables will be provided for participants with TESAEs and participants with TEAEs 
leading to discontinuation if 2 or more participants reported such events. Listings of all AEs, 
SAEs, and AEs leading to discontinuation by participant will be presented.
The definitions of an AE and SAE can be found in Appendix 4.
10.4.2.2.
Clinical Laboratory Assessments
Descriptive statistics of actual values and change from baseline for clinical laboratory values (in 
SI units) will be presented at each assessment timepoint by treatment. In addition, descriptive 
statistics for values and changes from the baseline values in conventional units at each 
assessment timepoint will be presented for selected clinical laboratory parameters listed in the 
SAP.
The criteria for potentially clinically significant (PCS) laboratory values will be detailed in the 
SAP. The number and percentage of participants who have PCS postbaseline clinical laboratory 
values will be tabulated by study treatment at each assessment. The percentages will be 
calculated relative to the number of participants who have available non-PCS baseline values and 
at least 1 postbaseline assessment. The numerator will be the total number of participants with
available non-PCS baseline values and at least 1 PCS postbaseline value. A supportive listing of 
participants with PCS postbaseline values will be provided.
10.4.2.3.
Vital Signs
Descriptive statistics of actual values and change from baseline for vital signs (systolic and 
diastolic BP, pulse rate, weight, and temperature) will be presented at each assessment timepoint 
by treatment.
Vital sign values will be considered to be PCS if they meet both the observed value criterion and 
the change from baseline value criterion that will be detailed in the SAP. The number and 
percentage of participants who have PCS postbaseline vital sign values will be tabulated by study 
treatment for each assessment. The percentages will be calculated relative to the number of 
participants who have available baseline values and at least 1 postbaseline assessment. The 
numerator will be the total number of participants with at least 1 PCS postbaseline value. A 
supportive listing of participants with PCS postbaseline values will be provided.


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10.4.2.4.
Electrocardiograms
Descriptive statistics of actual values and change from baseline for ECG parameters (ie, heart 
rate, PR interval, QRS interval, QT interval, and QTc interval) will be presented at each 
assessment timepoint by treatment.
The number and percentage of participants with PCS postbaseline values will be tabulated by 
study treatment. The criteria for PCS ECG values will be detailed in the SAP. The percentages 
will be calculated relative to the number of participants with an available non-PCS baseline value 
and at least one postbaseline assessment. The numerator will be the total number of participants 
with an available non-PCS baseline value and at least one PCS postbaseline ECG value. A 
supportive listing of participants with PCS postbaseline values will be provided and will include 
the participant number and the baseline and postbaseline values. A listing of all AEs for 
participants with PCS ECG values will also be provided.
A shift table from baseline to the end of study 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. A tabular display of participants with 
postbaseline clinically significant ECG abnormalities according to the investigator’s overall 
interpretation will be provided.
The number and percentage of participants with a change from baseline QTc > 30 msec but not 
exceeding 60 msec and of participants with an increase > 60 msec will be tabulated by treatment 
group. A supportive listing that includes the participant identification number, all QTc values 
(including change from baseline values), and all AEs will be provided for all participants who 
have postbaseline QTc changes > 30 msec.
10.4.2.5.
Other Safety Parameters
Other safety parameters include the BPRS+, CADSS, C-SSRS, and SDC.
Descriptive statistics of actual values and change from baseline for BPRS+ total score will be 
presented at each assessment timepoint by treatment.
Descriptive statistics of actual values and change from baseline for CADSS total score will be 
presented at each assessment timepoint by treatment. The CADSS total score is defined as the 
sum of scores for 23 subjective items.
The number and percentage of participants with suicidal ideation or suicidal behavior as 
recorded on the C-SSRS will be summarized by treatment. The distribution of responses for most 
severe suicidal ideation and most severe suicidal behavior during the participant’s lifetime, 
during the double-blind treatment period, and during the safety follow-up period will also be 
presented by treatment. Supportive listings will be provided and will include the participant 
number, lifetime history, and postbaseline values. Intensity of suicidal ideation, suicidal behavior 
type, and lethality of suicidal behavior will also be included in these listings. A listing of all AEs 
occurring in participants who have suicidal ideation or suicidal behavior will also be provided.
Descriptive statistics will be presented at each assessment timepoint by treatment for the SDC 
parameters including the number of symbols completed, the rate of completion (number of 


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symbols completed/time of trial), the number of corrected responses (symbols completed 
correctly), and the number of errors (symbols completed incorrectly).
10.4.3.
Interim Analyses 
No interim analysis planned.


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11.
References
American Psychiatric Association (2013). Diagnostic and statistical manual of mental disorders, 
5th edition: DSM-5. Washington, DC: American Psychiatric Association
Ashton AK, Jamerson BD, Weinstein W, et al. Antidepressant-related adverse effects impacting 
treatment compliance: Results of a patient survey. Current Therapeutic Research, Clinical and 
Experimental 2005;66(2):96-106.doi:10.1016/j.curtheres.2005.04.006.
Blanke ML, VanDongen AMJ. Activation Mechanisms of the NMDA Receptor. In: Van Dongen 
AM, editor. Biology of the NMDA Receptor. Boca Raton, Florida: CRC Press/Taylor & Francis; 
2009. Chapter 13. Available from: http://www.ncbi.nlm.gov/books/NBK5274.
Boland RJ, Keller MB. Treatment of depression. In: Schatzberg AF, Nemeroff CB, editors. 
Essentials of clinical psychopharmacology. 2nd ed. Arlington, VA: American Psychiatric 
Publishing, Inc.; 2006. p 465-78.
Bremner JD, Krystal JH, Putnam FW, et al. Measurement of dissociative states with the 
Clinician Administered Dissociative States Scale (CADSS). J Trauma Stress 1998;11:125–36.
Burgdorf J, Zhang X, Nicholson K, Balster R, Leander J, Stanton P, et al. GLYX-13, a NMDA 
receptor glycine-site functional partial agonist, induces antidepressant-like effects without 
ketamine-like side effects. Neuropsychopharm. 2013;38:729–742.
EMA/CHMP/185423/2010 Rev. 2 previously (CPMP/EWP/518/97, Rev. 1) Committee for 
Medicinal Products for Human Use (CHMP) 30 May 2013 Guideline on clinical investigation of 
medicinal products in the treatment of depression.
Fava M, Davidson KG. Definition and epidemiology of treatment-resistant depression. Psychiatr 
Clin North Am. 1996 Jun;19(2):179-200.
FDA Guidance for Industry: Drug Induced Liver Injury- Pre-Marketing Clinical Evaluation, July 
2009.
FDA Guidance for Industry: E10, Choice of Control Group and Related Issues in Clinical Trials, 
May 2001.
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
Gualtieri CT, Johnson LG. Reliability and validity of a computerized neurocognitive test battery, 
CNS Vital Signs. Arch Clin Neuropsychol. 2006 Oct;21(7):623-43.
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)
Greenberg PE, Kessler RC, Birnbaum HG, et al. The economic burden of depression in the 
United States: how did it change between 1990 and 2000? J Clin Psychiatry 2003;64(12):
1465-75.


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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, Roger JH. Small sample inference for fixed effects from restricted maximum 
likelihood. Biometrics 1997; 53:983-97
Kessler RC, McGonagle KA, Zhao S, et al. Lifetime and 12-month prevalence of DSM-III-R 
psychiatric disorders in the United States: results from the National Comorbidity Study. Arch 
Gen Psychiatry 1994;51:8-19.
Kessler RC, Chiu WJ, Demler O, et al. Prevalence, severity, and comorbidity of 12-month 
DSM-IV disorders in the National Comorbidity Survey. Arch Gen Psychiatry 2005;62(6): 
617-27.
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
Masand PS. Tolerability and adherence issues in antidepressant therapy. Clin Ther 
2003;25(8):2289-304.
McIntyre RS and O’Donovan C. The human cost of not achieving full remission in depression. 
Can J Psychiatry 2004;49(suppl 1):10S-16S.
Montgomery SA, Åsberg M. A new depression scale designed to be sensitive to change. 
Br J Psychiatry 1979; 134:382-9
Murray CJ, Atkinson C, Bhalla K, Birbeck C, Burstein R, Chou D, et al. The state of US health, 
1990-2010: burden of diseases, injuries, and risk factors. JAMA 2013;310(6):591-608.
Nicholson KL, Balster RL. The discriminative stimulus effects of N-methyl-D-aspartate 
glycine-site ligands in NMDA antagonist-trained rats. Psychophar. 2009;203(2):441–451.
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1962;10:799-812.
Preskorn S, Macaluso M, Mehra DO, Zammit G, Moskal JR, Burch RM. GLYX-13 Clinical 
Study Group. Randomized proof of concept trial of GLYX-13, an N-methyl-D-aspartate receptor 
glycine site partial agonist, in major depressive disorder nonresponsive to a previous 
antidepressant agent. J Psychiatr Pract. 2015;21:140–149.
Rosenzweig-Lipson S, Beyer CG, Hughes ZA, et al. Differentiating antidepressants of the future: 
efficacy and safety. Pharmacol Ther 2007;113(1):134-53.
Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed 
outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry 
2006;163:1905-17.


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Skolnick P, Popik P, Trullas R. Glutamate-based antidepressants: 20 years on. Trends Pharmacol 
Sci. 2009;30:563–569.
Smith DW and Jones KL (1982). Recognizable Patterns of Human Malformation. (3 ed.) 
Philadelphia: Saunders.
Trivedi MH, Fava M, Wisniewski SR, et al. Medication augmentations after the failure of SSRIs 
for depression. N Engl J Med 2006;354(12):1243-52.
Videbech P and Ravnkilde B. Hippocampal volume and depression: a meta-analysis of MRI 
studies. Am J Psychiatry 2004;161:1957-66.
World Health Organization. Mental health: new understanding, new hope. World Health Report 
2001


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12.
Appendices
12.1.
Appendix 1: Abbreviations and Trademarks
ADT
antidepressant therapy
AE
adverse event
ALT
alanine aminotransferase 
AESI
adverse event of special interest 
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
BMI
body mass index
BPRS+
Brief Psychiatric Rating Scale - Positive Symptoms Subscale
CADSS
Clinician Administered Dissociative States Scale
CFR
Code of Federal Regulations
CGI-S
Clinical Global Impressions-Severity
Cmax
maximum concentration
CNS
central nervous system
CSF
cerebrospinal fluid
C–SSRS
Columbia–Suicide Severity Rating Scale
C-VISA
Clinical Validation Inventory for Study Admission 
DALY
disability adjusted life years
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition
DSST
Digit Symbol Substitution Test 
DxV
Diagnostic Validation 
ECT
electroconvulsive therapy
ECG
electrocardiogram, electrocardiographic
eCRF
electronic case report form
ET
early termination
FDA
Food and Drug Administration
FSH
follicle stimulating hormone
GCP
good clinical practice
β-hCG 
β-human chorionic gonadotropin
HIPAA
Health Insurance Portability and Accountability Act 
HIV
human immunodeficiency virus 
HRT
hormonal replacement therapy
ICF
informed consent form
ICH
International Council for Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use
IEC
independent ethics committee


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IRB
Institutional Review Board
ITT
Intent-to-Treat
IWRS
Interactive Web Response System
LTP
long-term potentiation
MADRS
Montgomery- Åsberg Depression Rating Scale
MDD
major depressive disorder
mITT
modified intent-to-treat
MI
multiple imputation
MMRM
mixed-effect model for repeated measures
MNAR
missing not at random
NMDA 
N-methyl-D-aspartate
NMDAR 
N-methyl-D-aspartate receptor
NOAEL
no-observed-adverse-effect level
PCS
potentially clinically significant
QTc
QT interval corrected for heart rate
QTcB
QT interval corrected for heart rate using the Bazett formula (QTcB = QT/[RR]½)
QTcF
QT interval corrected for heart rate using the Fridericia formula (QTcF = QT/[RR]⅓)
SAE
serious adverse event
SAP
Statistical Analysis Plan
SCID
Structured Clinical Interview for DSM disorders
SDC
Symbol Digit Coding
SDMT
Symbol Digit Modalities Test
SNRI
selective serotonin and norepinephrine reuptake inhibitor
SSRI
selective serotonin reuptake inhibitor
TEAE
treatment-emergent adverse event
TESAE
treatment-emergent serious adverse event
Tmax
time to reach maximum concentration 
UDS
urine drug screen
ULN
upper limit of normal
WOCBP
woman of childbearing potential


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12.2.
Appendix 2: Clinical Laboratory Tests 
Blood and urine samples for clinical laboratory tests will be collected as listed in the schedule of 
activities (Section 2). 
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
During screening, the investigator will assess the clinical significance of any values that are 
outside the reference ranges provided by the central laboratory; participants with abnormalities 
judged to be clinically significant will be excluded from the study.
Participants will be asked to fast overnight or for at least 8 hours before arriving at the study 
center for appointments involving the collection of clinical laboratory blood tests. 
The following clinical laboratory levels will be measured at Visit 1 (Screening) only:
Clinical laboratory 
screening tests:
Hemoglobin A1c (HbA1c), fasting insulin, 
thyroid-stimulating hormone (TSH), triiodothyronine (T3), and 
free thyroxine (free T4)
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. Positive test results will 
be sent for confirmation testing. 


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The following clinical laboratory levels will be measured at Visit 1 (Screening) and Visit 9/ET:
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, magnesium, 
gamma glutamyl transferase, phosphate, glucose, blood urea 
nitrogen, creatinine, creatine phosphokinase, total protein, 
alkaline phosphatase, albumin, bilirubin (total; direct; indirect), 
ALT, AST, total cholesterol, low-density lipoprotein, 
high-density lipoprotein, triglycerides
Urinalysis:
Specific gravity, pH, protein, glucose, ketones, and blood
UDS:
Benzoylecgonine (cocaine), barbiturates, amphetamines, 
benzodiazepines, cannabinoids, opiates, methadone, 
phencyclidine
Pregnancy screening and 
Visit 9/ET:
Serum β-hCG 
Clinical laboratory tests may be performed under special circumstances (and at investigator’s 
discretion).
A negative UDS for cocaine, phencyclidine, barbiturates, and methadone is required at Visit 1 
(Screening) for the participant to continue in the study. Participants with a positive screening 
UDS for opiates (other than methadone), cannabinoids, or episodic use of benzodiazepines may 
continue in the study provided the drug was prescribed for a legitimate medical purpose and can 
be discontinued prior to study participation and a repeat UDS is negative for these substances 
prior to enrollment. An exception is made for episodic use of benzodiazepines, which may be 
continued as described in Section 7.7.2.
A UDS may be performed at any time during the study at the discretion of the investigator. A 
participant with a positive UDS for benzodiazepines or opiates at any postrandomization visit 
may be allowed to continue in the study provided the participant has been prescribed the 
medication and it is being used for legitimate medical purpose in the investigator’s judgment.
Serum pregnancy tests will be conducted at Visit 1 (Screening) and Visit 9/ET as specified in the 
schedule of activities (Section 2) and at investigator’s discretion at any time during the study. 
Positive results on the pregnancy test at Visit 1 (Screening) will exclude participants from 
participating in the study. Investigators should inquire at every study visit about the continued 
use of acceptable methods of contraception in women of childbearing potential. If there is any 
question of noncompliance with contraception or if there is any reason to suspect pregnancy, the 
following should be performed:


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
Urine pregnancy test
o
If the urine pregnancy test is positive, the participant must be discontinued from the 
study immediately
o
If the urine pregnancy test is negative, a serum β-hCG pregnancy test must be 
performed for confirmation.
Positive pregnancy test results during the study will result in participant termination from the 
study.
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 participant’s current condition, follow up, and/or manage an adverse 
experience. 


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12.3.
Appendix 3: Study Governance Considerations
Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the Declaration 
of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) 
international ethical guidelines

Applicable ICH Good Clinical Practice (GCP) guidelines

Applicable laws and regulations
The protocol, protocol amendments, ICF, investigator’s brochure, and other relevant documents 
(eg, advertisements) must be submitted to an IRB/IEC by the investigator and reviewed and 
approved by the IRB/IEC before the study is initiated.
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.

The investigator will be responsible for the following:
o
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC
o
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures
o
Providing oversight of the overall conduct of the study at the site and adherence to 
requirements of applicable local regulations, for example 21 CFR, ICH guidelines, 
the IRB/IEC, and European regulation 536/2014 for clinical studies (if applicable) 
Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to the 
participant and answer all questions regarding the study. 

Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 50, 
local regulations, ICH guidelines, Health Insurance Portability and Accountability Act 
(HIPAA) requirements, where applicable, and the IRB/IEC or study center. 


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
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was obtained. 
The authorized person obtaining the informed consent must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 

A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative. 
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant names 
or any information which would make the participant identifiable will not be transferred. 

The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 

The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
Publication Policy

Allergan as the sponsor has proprietary interest in this study. An integrated clinical and 
statistical report will be prepared at the completion of the study.

The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data.

Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements and will follow the sponsor’s standard 
operating procedure on publications.
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic CRFs
unless transmitted to the sponsor or designee electronically (eg, laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 

The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 

The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 


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
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 

Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 

Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period or otherwise notified in writing by the 
sponsor. No records may be destroyed during the retention period without the written 
approval of the sponsor. No records may be transferred to another location or party without 
written notification to the sponsor. 
Source Documents

Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
Study and Site Closure
The sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor’s procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study treatment development


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12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study treatment, whether or not considered related to 
the study treatment.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study treatment.
AE of Special Interest (AESI)
An adverse event of special interest (serious or nonserious) is one of scientific and medical 
concern specific to the sponsor’s study drug/device or program, which warrants ongoing 
monitoring and rapid communication by the investigator to the sponsor. Such an event might 
warrant further investigation in order to characterize and understand it.
Nonserious AESIs should be reported to the sponsor within 72 hours and serious AESIs should 
be reported to the sponsor within 24 hours.

The AESI should be reported to the SAE reporting fax number (provided on the title page
of this protocol).

The Adverse Event of Special Interest form, along with a targeted questionnaire, if 
applicable, should be used for reporting the AESI, even if a serious outcome may not 
apply.


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Events Meeting the AE Definition 

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (eg, ECGs, radiological scans, vital signs measurements), including those 
that worsen from baseline, considered clinically significant in the medical and scientific 
judgment of the investigator (ie, not related to progression of underlying disease)

Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition

New condition detected or diagnosed after study treatment administration even though it 
may have been present before the start of the study

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study treatment 
or a concomitant medication. Overdose per se will not be reported as an AE/SAE unless it is 
an intentional overdose taken with possible suicidal/self-harming intent. Such intentional 
overdoses should be reported regardless of sequelae.

Lack of efficacy or failure of expected pharmacological action per se will not be reported as 
an AE or SAE. Such instances will be captured in the efficacy assessments. However, the 
signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be reported as 
AEs or SAEs if they fulfil the definition of an AE or SAE.
Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition

The disease/disorder being studied or expected progression, signs, or symptoms (clearly 
defined) of the disease/disorder being studied, unless more severe than expected for the 
participant’s condition

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital)

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen


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Definition of SAE
SAEs must meet both the AE criteria described above and the seriousness criteria listed below.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life threatening
The term life threatening in the definition of serious refers to an event in which the participant
was at risk of death at the time of the event. It does not refer to an event, which hypothetically 
might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or treatment that
would not have been appropriate in the physician’s office or outpatient setting. Complications 
that occur during hospitalization are AEs. If a complication prolongs hospitalization or fulfills 
any other serious criteria, the event is serious. When in doubt as to whether hospitalization 
occurred or was necessary, the AE should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (eg, sprained ankle) which may interfere with or prevent everyday life 
functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be immediately 
life threatening or result in death or hospitalization but may jeopardize the participant or 
may require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definition. These events should usually be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that 
do not result in hospitalization, or development of drug dependency or drug abuse.


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Recording an AE and/or SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event.

The investigator will then record all relevant AE/SAE information in the eCRF.

It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the sponsor in lieu of completion of the AE/SAE eCRF page.

There may be instances when copies of medical records for certain cases are requested by 
the sponsor. In this case, all participant identifiers, with the exception of the participant
number, will be redacted on the copies of the medical records before submission to the 
sponsor.

The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
MILD
A type of adverse event 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 adverse event that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research 
participant.
SEVERE
A type of adverse event that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention.
An event is defined as serious when it meets at least 1 of the predefined outcomes as described in 
the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and each 
occurrence of each AE/SAE.

A reasonable possibility of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.


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
The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study treatment administration 
will be considered and investigated.

The investigator will also consult the investigator’s brochure (IB) and/or product 
information, for marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the sponsor

The investigator may change his/her opinion of causality in light of follow-up information
and send an SAE follow-up report with the updated causality assessment.

The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.
Reporting of SAEs
SAE Reporting to the Sponsor via Fax or Email

Facsimile transmission is the preferred method to transmit SAE information. 
The fax number is +1-714-796-9504 (backup number is +1-714-246-5295). 

Email of the SAE information is also acceptable. The email address is
IR-Clinical-SAE@allergan.com.

In rare circumstances and in the absence of facsimile equipment, notification by telephone is 
acceptable with a copy of the SAE form, sent by overnight mail or courier service.

Initial notification via telephone does not replace the need for the investigator to complete 
and sign the SAE form within the designated reporting time frames.

Contacts for SAE reporting can be found on the protocol title page.


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12.5.
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below).
Women in the following categories are not considered WOCBP
1. Premenarchal
2. Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s: review of the participant’s medical 
records, medical examination, or medical history interview.
3. Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be 
used to confirm a postmenopausal state in women not using hormonal contraception or 
hormonal replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, 
a single FSH measurement is insufficient. 

Females on HRT and whose menopausal status is in doubt will be required to use one of the 
acceptable non-hormonal contraception methods if they wish to continue their HRT during 
the study. Otherwise, they must discontinue HRT to allow confirmation of postmenopausal 
status before study enrollment.
Contraception Guidance
Male Participants

Male participants with female partners of childbearing potential are eligible to participate if 
they agree to ONE of the following during the study:
o
Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent
o
Vasectomy


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o
Female partners of male study subjects reliably use one of the following;
o
Hormonal contraceptives (ie, oral, patch, injection, implant)
o
Vaginal contraceptive ring 
o
Intrauterine device
o
Bilateral tubal ligation
o
Essure placement with correct placement verified by hysterosalpingogram
o
Surgical sterilization 
o
Male or female condom with spermicide 
o
Cap, diaphragm, or sponge with spermicide

Men with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile-vaginal intercourse or use a male condom during each episode of penile penetration 
during the study.

Refrain from donating sperm for the duration of the study and for 10 weeks following the end 
of study.

Refrain from attempting pregnancy with female for 10 weeks following the end of study.
Female Participants
Female participants of childbearing potential are eligible to participate if they agree to use an 
acceptable method of contraception consistently and correctly, as listed below.
o
Hormonal contraceptives (ie, oral, patch, injection, implant) 
o
Vaginal contraceptive ring 
o
Intrauterine device
o
Bilateral tubal ligation
o
Essure placement with correct placement verified by hysterosalpingogram
o
Surgical sterilization (bilateral tubal ligation) 
o
Male or female condom with spermicide 
o
Cap, diaphragm, or sponge with spermicide
o
Abstinence (as described above)
o
Male partner has vasectomy
Refrain from attempting pregnancy for 4 – 5 weeks following the end of study.
Pregnancy Testing

WOCBP should only be included after a confirmed menstrual period and a negative highly 
sensitive serum pregnancy test.

Additional pregnancy testing during the treatment period can be performed any time at the 
Investigator’s discretion and after the last dose of study treatment.
Pregnancy testing will be performed whenever a menstrual cycle is missed or when pregnancy is 
otherwise suspected 


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Collection of Pregnancy Information 
Male Participants with Partners Who Become Pregnant 

The investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This 
applies only to male participants who receive study treatment.

After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the investigator will record pregnancy information on the appropriate form and 
submit it to the sponsor within 24 hours of learning of the partner’s pregnancy. The female 
partner will also be followed to determine the outcome of the pregnancy. Information on the 
status of the mother and child will be forwarded to the sponsor. Generally, the follow-up 
will be no longer than 6 to 8 weeks following the estimated delivery date. Any termination 
of the pregnancy will be reported regardless of fetal status (presence or absence of 
anomalies) or indication for the procedure.
Female Participants Who Become Pregnant 

The investigator will collect pregnancy information on any female participant who becomes 
pregnant while participating in this study. Information will be recorded on the appropriate 
form and submitted to the sponsor within 24 hours of learning of a participant’s pregnancy. 

The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate and the 
information will be forwarded to the sponsor. Generally, follow-up will not be required for 
longer than 6 to 8 weeks beyond the estimated delivery date. Any termination of pregnancy 
will be reported, regardless of fetal status (presence or absence of anomalies) or indication 
for the procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication 
or elective termination of a pregnancy will be reported as an AE or SAE. A spontaneous 
abortion is always considered to be an SAE and will be reported as such. Any poststudy 
pregnancy related SAE considered reasonably related to the study treatment by the 
investigator will be reported to the sponsor as described in Section 9.2. While the 
investigator is not obligated to actively seek this information in former study participants, he 
or she may learn of an SAE through spontaneous reporting.

Any female participant who becomes pregnant while participating in the study will be 
withdrawn from the study.


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12.6.
Appendix 6: Concomitant Medications
Therapy considered necessary for the participant's welfare may be given at the discretion of the 
investigator. If the permissibility of a specific medication/treatment is in question, please contact 
the sponsor.
Medications Allowed (Y) and Medications Not Allowed (N) as Concomitant Medications
Drug Class
Frequency of Use
Restrictions/Exceptions/Clarifications
Episodic 
(PRN)
Chronic
Attention deficit hyperactivity 
disorder medications/stimulants
N
N
Analgesics
Y
Y
Nonnarcotic analgesics are allowed. Pregabalin and 
indomethacin are not allowed. Medically appropriate 
episodic use of narcotic analgesics including tramadol 
for acute medical indications limited to 3 days for an 
episode is allowed. 
Anesthetics - general
N
N
If procedures requiring general anesthesia are to 
occur/have occurred, please contact the Study 
Physician to report the medical condition(s).
Anesthetics - local
Y
N
Topical anesthetics for venipuncture (eg, EMLA 
cream) are allowed. 
Anorectics
N
N
Antacids
Y
Y
Antiacne agents 
Y
Y
Topical agents only, including topical antibiotics. 
Isotretinoin (Accutane) is not allowed.
Antianginal agents
Y
Y
Antiarrhythmics
N
Y
Only class II agents (eg, esmolol), class IV agents (eg, 
diltiazem, verapamil), and digoxin are allowed. 
Dosage must be stable for 1 month before screening. 
For participants on digoxin, there should be a digoxin 
level obtained within 2 months prior to screening. 
Adenosine, parasympatholytics (atropine), and 
sympathomimetics (epinephrine, dopamine) are not 
allowed. Propranolol (Inderal) is not allowed.
Anti-asthma agents
Y
Y
Systemic corticosteroids are not allowed. Inhaled 
steroids at approved dosages are allowed.
Antibiotics
Y
Y
Anticoagulants
N
N
Please see under antiplatelet below.
Anticonvulsants
N
N
Antidepressants
N
N
Antidiarrheal preparations
Y
N
Only Imodium (loperamide HCl), Pepto-Bismol, and 
kaolin preparations are allowed.


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Medications Allowed (Y) and Medications Not Allowed (N) as Concomitant Medications
Drug Class
Frequency of Use
Restrictions/Exceptions/Clarifications
Episodic 
(PRN)
Chronic
Antifungal agents
Systemic
Topical
N
Y
N
Y
Antihistamines
Y
Y
Sedating antihistamines are not allowed. Only 
fexofenadine (Allegra), loratadine (Claritin), 
desloratadine (Clarinex), cetirizine (Zyrtec), and 
levcetirizine (Xyzal) are allowed for episodic or 
chronic use. Terfenadine is not allowed. See Cough 
and Cold Preparations for combination products.
Antihypertensives
N
Y
Reserpine (Diupres), clonidine (Catapres), guanabenz 
(Wytensin), guanfacine (Tenex and Intuniv), 
guanethidine (Ismelin), methyldopa (Aldomet), direct 
vasodilators (hydralazine, minoxidil), nitroglycerin, 
sodium nitroprusside, and diazoxide are not allowed. 
Propranolol (Inderal) is not allowed. For all others 
(α1-blockers, β-blockers, calcium channel blockers, 
ACE inhibitors, etc), the medication and dosage 
should be stable for 1 month before Screening (for 
diuretics, the participant 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
Y
Chronic use is allowed if dosage is stable for 1 month 
prior to Screening. Indomethacin (Indocin) and 
systemic corticosteroids are not allowed.
Antinauseants/antiemetics
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. 
Antineoplastics
N
N
Antiobesity agents/appetite 
suppressants
N
N
Over-the-counter Alli (Xenical) is not allowed.
Sibutramine (Meridia), phenylpropanolamine, and 
phentermine (Adipex-P, others) are not allowed.
Antiplatelet agents
N
Y
Aspirin (maximum dosage of 325 mg/day) and 
clopidogrel (Plavix) are allowed. Medication dosage 
must be stable for 1 month prior to screening.


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Medications Allowed (Y) and Medications Not Allowed (N) as Concomitant Medications
Drug Class
Frequency of Use
Restrictions/Exceptions/Clarifications
Episodic 
(PRN)
Chronic
Antipsoriatic treatments
Y
Y
Only topical treatments are allowed (vitamin D 
analogs, anthralin, topical retinoids); 1 month stability 
is required. Oral medications, such as oral retinoids 
(eg acitretin), methotrexate, azathiaprine, cycloprorin, 
and immunomodulator drugs are not allowed.
Antipsychotics
N
N
Antismoking medications
N
N
Varenicline (Chantix) and bupropion (Zyban) are not 
allowed. However, nicotine replacement therapies are 
allowed.
Antiviral agents
Y
Y
Only oral or topical agents are allowed. Acyclovir, 
famciclovir, valacyclovir, penciclovir, docosanal, 
trifluridine, and vidarabine are allowed. 
Interferons are not allowed. 
Anti-HIV drugs are not allowed.
Contact the medical monitor if participant is taking 
anti-Hepatitis C medications.
Anxiolytics
Y
N
Episodic use of benzodiazepines up to approximately 
2 mg/day lorazepam equivalent dose and for up to 
3 consecutive days at a time can be given for 
anxiety-related conditions and agitation (not permitted 
within 8 hours of efficacy assessments).
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 medically 
appropriate use, for up to 5 days. Combination
products containing the word “Nighttime” or some 
synonym routinely include a sedating antihistamine 
are not allowed. Combination products ending in “D” 
routinely contain a stimulant such as pseudoephedrine 
or phenylpropanolamine and are not allowed (also see 
Antihistamines).
H2 blockers/proton pump 
inhibitors/prokinetic agents
Y
Y
Tagamet (cimetidine) is not allowed. 
Metoclopramide and cisapride are not allowed.
Hormones (nonreproductive)
N
Y
Thyroid hormone replacement is allowed. Therapeutic 
use in psychiatric disorders (eg, T3 augmentation 
therapy) is not allowed. Dosage of thyroid medication 
must be stable for 1 month prior to screening. 


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Medications Allowed (Y) and Medications Not Allowed (N) as Concomitant Medications
Drug Class
Frequency of Use
Restrictions/Exceptions/Clarifications
Episodic 
(PRN)
Chronic
Hormones (reproductive)
Y
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. Must 
follow package inserts for hormonal contraception, 
regarding time must be taking same before they are 
effective (eg, often 1 cycle). Refer to Section 12.5 for 
specifics of allowed contraception.
Hormone suppressants
N
Y
Only Proscar (finasteride) and Avodart (dutasteride) 
are allowed. Dosage must be stable for 1 month prior 
to screening.
Hypoglycemic agents
N
Y
Oral hypoglycemic agents are allowed, except 
pioglitazone and troglitazone are not allowed. Chronic 
use of insulin is allowed. Dosage must be stable for 1 
month prior to screening.
Hypolipidemics
N
Y
Niacin and niacinamide are allowed if dosage has 
been stable for 3 months prior to screening. Statins 
(lovastatin, pravastatin, simvastatin, atorvastatin, 
fluvastatin, rosuvastatin), fibrates (gemfibrozil, 
fenofibrate), and ezetimibe are allowed. Dosage must 
be stable for 1 month prior to screening. Bile 
sequestrants are not allowed.
Laxatives
Y
Y
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 are not 
allowed.
Migraine medications
Y
N
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 
are not allowed. 
Muscle relaxants
N
N


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Medications Allowed (Y) and Medications Not Allowed (N) as Concomitant Medications
Drug Class
Frequency of Use
Restrictions/Exceptions/Clarifications
Episodic 
(PRN)
Chronic
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 participant has 
been taking same for at least 1 month.
Sedatives/hypnotics
Y
N
Only zolpidem (Ambien up to 10 mg/day and Ambien 
CR up to 12.5 mg/day), zaleplon (Sonata) up to 
20 mg/day, eszopiclone (Lunesta) up to 7.5 mg/day, 
zopiclone up to 7.5 mg/day, and suvorexant 
(Belsomra) up to 10 mg/day are permitted, up to 
3 times a week, if required for sleep. 
Sedatives/hypnotics may not be used in the 8 hours 
before any behavioral assessments.
Steroids, inhalant
Y
Y
Steroids, intra-articular
Y
N
Steroids, systemic
N
N
Steroids, topical
Y
Y
Vaccines
Y
N
N = not allowed; PRN = as needed; Y = yes, allowed.


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12.7.
Appendix 7: Standard Discontinuation Criteria
CDISC Submission Value
CDISC Definition
Adverse event
Any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and 
which does not necessarily have a causal relationship with this 
treatment. An adverse event (AE) can therefore be any unintended 
sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal 
(investigational) product. For further information, see the ICH 
Guideline for Clinical Safety Data Management: Definitions and 
Standards for Expedited Reporting. [Modified from ICH E2A] 
Synonyms: side effect, adverse experience. See also serious adverse 
event, serious adverse experience. (CDISC glossary)
Completed
To possess every necessary or normal part or component or step; 
having come or been brought to a conclusion (NCI)
Lack of efficacy
The lack of expected or desired effect related to a therapy (NCI)
Lost to follow-up
The loss or lack of continuation of a subject to follow-up
Non-compliance with study drug
An indication that a subject has not agreed with or followed the 
instructions related to the study medication (NCI)
Other
Different than the one(s) previously specified or mentioned (NCI)
Pregnancy
Pregnancy is the state or condition of having a developing embryo or 
fetus in the body (uterus), after union of an ovum and spermatozoon, 
during the period from conception to birth. (NCI)
Protocol deviation
An event or decision that stands in contrast to the guidelines set out 
by the protocol (NCI)
Screen failure
The potential subject who does not meet one or more criteria 
required for participation in a trial
Site terminated by sponsor
An indication that a clinical study was stopped at a particular site by 
its sponsor (NCI)
Study terminated by sponsor
An indication that a clinical study was stopped by its sponsor (NCI)
Withdrawal by subject
An indication that a study participant has removed itself from the 
study (NCI)


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12.8.
Appendix 8: Montgomery-Åsberg Depression Rating Scale
1. APPARENT SADNESS—Representing despondency, gloom and despair (more than just 
ordinary transient low spirits) reflected in speech, facial expression, and posture. Rate by 
depth and inability to brighten up.
0
No sadness.
1
2
Looks dispirited but does brighten up without difficulty.
3
4
Appears sad and unhappy most of the time.
5
6
Looks miserable all the time. Extremely despondent.
2. REPORTED SADNESS—Representing reports of depressed mood, regardless of whether it 
is reflected in appearance or not. Includes low spirits, despondency, or the feeling of being 
beyond help and without hope. Rate according to intensity, duration and the extent to which 
the mood is reported to be influenced by events.
0
Occasional sadness in keeping with the circumstances.
1
2
Sad or low but brightens up without difficulty.
3
4
Pervasive feelings of sadness or gloominess. The mood is still influenced by external 
circumstances.
5
6
Continuous or unvarying sadness, misery or despondency.
3
INNER TENSION—Representing feelings of ill-defined discomfort, edginess, inner 
turmoil, mental tension mounting to either panic, dread, or anguish. Rate according to 
intensity, frequency, duration, and the extent of reassurance called for.
0
Placid. Only fleeting inner tension.
1
2
Occasional feelings of edginess and ill-defined discomfort.
3
4
Continuous feelings of inner tension or intermittent panic which the patient can only 
master with some difficulty.
5
6
Unrelenting dread or anguish. Overwhelming panic.


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4. REDUCED SLEEP—Representing the experience of reduced duration or depth of sleep 
compared to the patient’s own normal pattern when well.
0
Sleeps as usual.
1
2
Slight difficulty dropping off to sleep or slightly reduced, light, or fitful sleep.
3
4
Sleep reduced or broken by at least 2 hours.
5
6
Less than 2or 3 hours sleep.
5. REDUCED APPETITE—Representing the feeling of a loss of appetite compared with 
when well. Rate by loss of desire for food or the need to force oneself to eat.
0
Normal or increased appetite.
1
2
Slightly reduced appetite.
3
4
No appetite. Food is tasteless.
5
6
Needs persuasion to eat at all.
6. CONCENTRATION DIFFICULTIES—Representing difficulties in collecting one’s 
thoughts mounting to incapacitating lack of concentration. Rate according to intensity, 
frequency, and degree of incapacity produced.
0
No difficulties in concentrating.
1
2
Occasional difficulties in collecting one’s thoughts.
3
4
Difficulties in concentrating and sustaining thought which reduces ability to read or hold 
a conversation.
5
6
Unable to read or converse without great difficulty.


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7. LASSITUDE—Representing a difficulty getting started or slowness initiating and 
performing everyday activities.
0
Hardly any difficulty getting started. No sluggishness.
1
2
Difficulties in starting activities.
3
4
Difficulties in starting simple routine activities which are carried out with effort.
5
6
Complete lassitude. Unable to do anything without help.
8. INABILITY TO FEEL—Representing the subjective experience of reduced interest in the 
surroundings, or activities that normally give pleasure. The ability to react with adequate 
emotion to circumstances or people is reduced.
0
Normal interest in the surroundings and in other people.
1
2
Reduced ability to enjoy usual interests.
3
4
Loss of interest in the surroundings. Loss of feelings for friends and acquaintances.
5
6
The experience of being emotionally paralyzed, inability to feel anger, grief or pleasure 
and a complete or even painful failure to feel for close relatives or friends.
9. PESSIMISTIC THOUGHTS—Representing thoughts of guilt, inferiority, self-reproach, 
sinfulness, remorse and ruin.
0
No pessimistic thoughts.
1
2
Fluctuating ideas of failure, self-reproach or self-deprecation.
3
4
Persistent self-accusations, or definite but still rational ideas of guilt or sin. Increasingly 
pessimistic about the future.
5
6
Delusions of ruin, remorse, or unredeemable sin. Self-accusations which are absurd and 
unshakable.


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10. SUICIDAL THOUGHTS—Representing the feeling that life is not worth living, that a 
natural death would be welcome, suicidal thoughts, and preparations for suicide. Suicidal 
attempts should not in themselves influence the rating.
0
Enjoys life or takes it as it comes.
1
2
Weary of life. Only fleeting suicidal thoughts.
3
4
Probably better off dead. Suicidal thoughts are common, and suicide is considered as a 
possible solution, but without specific plans or intention.
5
6
Explicit plans for suicide when there is an opportunity. Active preparations for suicide.


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12.9.
Appendix 9: 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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12.10.
Appendix 10: Brief Psychiatric Rating Scale – Positive Symptoms 
Subscale


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12.11.
Appendix 11: Clinician Administered Dissociative States Scale


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12.12.
Appendix 12: Columbia-Suicide Severity Rating Scale –
Baseline/Screening


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12.13.
Appendix 13: Columbia–Suicide Severity Rating Scale - Since Last 
Visit
COLUMBIA-SUICIDE SEVERITY
RATING SCALE
(C-SSRS)
Since Last Visit
Version 1/14/09
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; Zelazny, J.; 
Burke, A.; Oquendo, M.; Mann, J.
Disclaimer: 
This scale is intended for use by trained clinicians. The questions contained in the Columbia-Suicide Severity 
Rating Scale are suggested probes. Ultimately, the determination of the presence of suicidality depends on 
clinical judgment. 
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia Suicide 
History Form, developed by John Mann, MD and Maria Oquendo, MD, Conte Center for the Neuroscience of 
Mental Disorders (CCNMD), New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY 10032. 
(Oquendo M. A., Halberstam B. & Mann J. J., Risk factors for suicidal behavior: utility and limitations of 
research instruments. In M.B. First [Ed.] Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.) 
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, 1051 Riverside 
Drive, New York, New York, 10032; inquiries and training requirements contact 
posnerk@childpsych.columbia.edu
© 2008 The Research Foundation for Mental Hygiene, Inc.
SUICIDAL IDEATION
Ask questions 1 and 2. If both are negative, proceed to “Suicidal Behavior” section. If the answer to 
question 2 is “yes”, ask questions 3, 4, and 5. If the answer to question 1 and/or 2 is “yes”, complete 
“Intensity of Ideation” section below.
Since Last 
Visit
1. Wish to be Dead
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up. 
Have you wished you were dead or wished you could go to sleep and not wake up? 
If yes, describe:
Yes No
□ □
2. Non-Specific Active Suicidal Thoughts
General, non-specific thoughts of wanting to end one’s life/commit suicide (e.g., “I’ve thought about killing myself”) without 
thoughts of ways to kill oneself/associated methods, intent, or plan during the assessment period. 
Have you actually had any thoughts of killing yourself?
If yes, describe:
Yes No
□ □


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3. Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act
Subject endorses thoughts of suicide and has thought of at least one method during the assessment period. This is different than a 
specific plan with time, place, or method details worked out (e.g., thought of method to kill self but not a specific plan). Includes 
person who would say, “I thought about taking an overdose but I never made a specific plan as to when, where, or how I would 
actually do it…and I would never go through with it.”
Have you been thinking about how you might do this?
If yes, describe:
Yes No
□ □
4. Active Suicidal Ideation with Some Intent to Act, without Specific Plan
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, as opposed to “I have the 
thoughts but I definitely will not do anything about them.”
Have you had these thoughts and had some intention of acting on them?
If yes, describe:
Yes No
□ □
5. Active Suicidal Ideation with Specific Plan and Intent
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to carry it out.
Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out this plan? 
If yes, describe:
Yes No
□ □
INTENSITY OF IDEATION
The following features should be rated with respect to the most severe type of ideation (i.e., 1-5 from above, with 1 
being the least severe and 5 being the most severe). 
Most Severe Ideation: ______________________________________________________
Type # (1-5) Description of Ideation
Most 
Severe
Frequency
How many times have you had these thoughts?
(1) Less than once a week (2) Once a week (3) 2-5 times in week (4) Daily or almost daily (5) Many times each day
____
Duration
When you have the thoughts, how long do they last?
(1) Fleeting - few seconds or minutes 
(4) 4-8 hours/most of day
(2) Less than 1 hour/some of the time 
(5) More than 8 hours/persistent or continuous
(3) 1-4 hours/a lot of time 
____
Controllability
Could/can you stop thinking about killing yourself or wanting to die if you want to?
(1) Easily able to control thoughts 
(4) Can control thoughts with a lot of difficulty
(2) Can control thoughts with little difficulty 
(5) Unable to control thoughts
(3) Can control thoughts with some difficulty (0) Does not attempt to control thoughts
____
Deterrents
Are there things - anyone or anything (e.g., family, religion, pain of death) - that stopped you from wanting to die 
or acting on thoughts of committing suicide?
(1) Deterrents definitely stopped you from attempting suicide 
(4) Deterrents most likely did not stop you 
(2) Deterrents probably stopped you 
(5) Deterrents definitely did not stop you 
(3) Uncertain that deterrents stopped you 
(0) Does not apply
____
Reasons for Ideation
What sort of reasons did you have for thinking about wanting to die or killing yourself? Was it to end the pain or 
stop the way you were feeling (in other words, you couldn’t go on living with this pain or how you were feeling) 
or was it to get attention, revenge ,or a reaction from others? Or both?
(1) Completely to get attention, revenge or a reaction from others 
(5) Completely to end or stop the pain (you 
(2) Mostly to get attention, revenge or a reaction from others living
couldn’t go on living with the pain or how 
(3) Equally to get attention, revenge or a reaction from others
you were feeling)
and to end/stop the pain
(4) Mostly to end or stop the pain (you couldn’t go on living
(0) Does not apply
with the pain or how you were feeling).
____


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SUICIDAL BEHAVIOR
(Check all that apply, so long as these are separate events; must ask about all types)
Since Last 
Visit
Actual Attempt:
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part thought of as 
method to kill oneself. Intent does not have to be 100%. If there is any intent/desire to die associated with the act, then it can be 
considered an actual suicide attempt. There does not have to be any injury or harm, just the potential for injury or harm. If person 
pulls trigger while gun is in mouth but gun is broken so no injury results, this is considered an attempt. 
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or circumstances. 
For example, a highly lethal act that is clearly not an accident so no other intent but suicide can be inferred (e.g., gunshot to head, 
jumping from window of a high floor/story). Also, if someone denies intent to die, but they thought that what they did could be 
lethal, intent may be inferred. 
Have you made a suicide attempt?
Have you done anything to harm yourself?
Have you done anything dangerous where you could have died?
What did you do?
Did you______ as a way to end your life? 
Did you want to die (even a little) when you_____? 
Were you trying to end your life when you _____?
Or did you think it was possible you could have died from_____?
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to relieve stress, feel 
better, get sympathy, or get something else to happen)? (Self-Injurious Behavior without suicidal intent)
If yes, describe:
Has subject engaged in Non-Suicidal Self-Injurious Behavior?
Yes No
□ □
Total # of
Attempts
______
Yes No
□ □
Interrupted Attempt:
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act (if not for that, actual 
attempt would have occurred).
Overdose: Person has pills in hand but is stopped from ingesting. Once they ingest any pills, this becomes an attempt rather than an 
interrupted attempt. Shooting: Person has gun pointed toward self, gun is taken away by someone else, or is somehow prevented 
from pulling trigger. Once they pull the trigger, even if the gun fails to fire, it is an attempt. Jumping: Person is poised to jump, is 
grabbed, and taken down from ledge. Hanging: Person has noose around neck but has not yet started to hang - is stopped from 
doing so.
Has there been a time when you started to do something to end your life but someone or something stopped you 
before you actually did anything?
If yes, describe:
Yes No
□ □
Total # of 
interrupted
______
Aborted Attempt: 
When person begins to take steps toward making a suicide attempt, but stops themselves before they actually have engaged in any 
self-destructive behavior. Examples are similar to interrupted attempts, except that the individual stops him/herself, instead of 
being stopped by something else.
Has there been a time when you started to do something to try to end your life but you stopped yourself before 
you actually did anything?
If yes, describe:
Yes No
□ □
Total # of
aborted
______
____
Preparatory Acts or Behavior:
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a verbalization or thought,
such as assembling a specific method (e.g., buying pills, purchasing a gun) or preparing for one’s death by suicide (e.g., giving 
things away, writing a suicide note). 
Have you taken any steps towards making a suicide attempt or preparing to kill yourself (such as collecting pills, 
getting a gun, giving valuables away, or writing a suicide note)?
If yes, describe:
Yes No
□ □
Suicidal Behavior:
Suicidal behavior was present during the assessment period?
Yes No
□ □
Completed Suicide:
Yes No


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□ □
Answer for Actual Attempts Only
Most Lethal 
Attempt
Date:
Actual Lethality/Medical Damage: 
0. No physical damage or very minor physical damage (e.g., surface scratches).
1. Minor physical damage (e.g., lethargic speech; first-degree burns; mild bleeding; sprains).
2. Moderate physical damage; medical attention needed (e.g., conscious but sleepy, somewhat responsive; second-degree burns; 
bleeding of major vessel).
3. Moderately severe physical damage; medical hospitalization and likely intensive care required (e.g., comatose with reflexes 
intact; third-degree burns less than 20% of body; extensive blood loss but can recover; major fractures).
4. Severe physical damage; medical hospitalization with intensive care required (e.g., comatose without reflexes; third-degree 
burns over 20% of body; extensive blood loss with unstable vital signs; major damage to a vital area).
5. Death
Enter Code
______
Potential Lethality: Only Answer if Actual Lethality = 0
Likely lethality of actual attempt if no medical damage (the following examples, while having no actual medical damage, had 
potential for very serious lethality: put gun in mouth and pulled the trigger but gun fails to fire so no medical damage; laying on 
train tracks with oncoming train but pulled away before run over).
0 = Behavior not likely to result in injury
1 = Behavior likely to result in injury but not likely to cause death
2 = Behavior likely to result in death despite available medical care 
Enter Code
______


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12.14.
Appendix 14: Protocol Amendment 1
Protocol Amendment 1: June 2018
Overall Rationale for the Amendment:
The protocol was amended to provide clarification of the exclusion criteria and of Appendix 5. 
Section No. and Name
Description of Change
Brief Rationale
Section 6.2 Exclusion 
Criteria 
Revised Exclusion Criterion 7 to state: “Lifetime 
history of nonresponse to ≥ 2 antidepressants after 
adequate trials (adequate treatment is defined as at 
least 6 weeks at an adequate dose(s) based on 
approved package insert recommendations).”
For clarity
Section 12.5: 
Appendix 5 
Contraceptive 
Guidance and 
Collection of 
Pregnancy 
Information
Clarified description of acceptable contraceptive 
methods.
For clarity

SAP_001.pdf: 
 
 
Statistical Analysis Plan:  A double-blind, placebo-controlled, fixed dose study of AGN-241751 in adult 
participants with major depressive disorder, Amendment 2 
 
NCT 03586427 
 
Document date:  August 3, 2018 


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Title Page
STATISTICAL ANALYSIS PLAN
A Double-Blind, Placebo-Controlled, Fixed-Dose Study of AGN-241751 in Adult 
Participants with Major Depressive Disorder
Final SAP Date: 03 Aug 2018
Protocol Number:
3125-201-002
Development Phase:
2a
Product Name:
AGN-241751
Study Statistician:
Ludmyla Rekeda, PhD
Sponsor Name and Legal Registered 
Address:
Naurex, Inc., an indirect subsidiary of Allergan
plc, 5 Giralda Farms Madison, NJ 07940 USA
This document is the property of Naurex, Inc., an indirect subsidiary of Allergan plc, 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 Naurex, Inc., an indirect 
subsidiary of Allergan plc.


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Table of Contents
1
Title Page ................................................................................................................................. 1
2
Table of Contents..................................................................................................................... 2
2.1
List of Tables.................................................................................................................. 3
2.2
List of Figures ................................................................................................................ 3
3
List of Abbreviations and Definition of Terms ........................................................................ 4
4
Introduction.............................................................................................................................. 5
5
Study Objectives...................................................................................................................... 7
6
Analysis Populations ..............................................................................................................11
7
Patient Disposition..................................................................................................................11
8
Demographic and Other Baseline Characteristics ..................................................................11
9
Extent of Exposure and Treatment Compliance .................................................................... 13
9.1
Extent of Exposure....................................................................................................... 13
9.2
Measurement of Treatment Compliance ...................................................................... 13
10
Efficacy Analyses .................................................................................................................. 13
10.1 Primary and Key Secondary Efficacy Endpoints......................................................... 14
10.2 Multiple Comparisons Procedure................................................................................. 14
10.3 Additional Efficacy Endpoints..................................................................................... 15
11
Safety Analyses...................................................................................................................... 16
11.1 Adverse Events............................................................................................................. 17
11.2 Clinical Laboratory Assessments ................................................................................. 18
11.3 Vital Signs .................................................................................................................... 20
11.4 Electrocardiograms ...................................................................................................... 21
11.5 Other Safety Parameters............................................................................................... 22
11.5.1 Brief Psychiatric Rating Scale—Positive Symptoms Subscale ....................... 22
11.5.2 Clinician Administered Dissociative States Scale............................................ 23
11.5.3 Symbol Digit Coding ....................................................................................... 23
11.5.4 Columbia-Suicide Severity Rating Scale ......................................................... 23
12
Health Outcome Analyses...................................................................................................... 23
13
Interim Analysis..................................................................................................................... 23
14
Determination of Sample Size............................................................................................... 23


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15
Statistical Software ................................................................................................................ 23
16
Data Handling Convention .................................................................................................... 24
16.1 Visit Time windows...................................................................................................... 24
16.2 Repeated or Unscheduled Assessments of Safety Parameters ..................................... 24
16.3 Missing Date of the Last Dose of Study treatment ...................................................... 24
16.4 Missing Severity Assessment for Adverse Events ....................................................... 25
16.5 Missing Causal Relationship to Study treatment for Adverse Events.......................... 25
16.6 Missing Date Information for Adverse Events ............................................................ 25
16.7 Missing Date Information for Prior or Concomitant Medications............................... 26
16.7.1 Incomplete Start Date....................................................................................... 26
16.7.2 Incomplete Stop Date....................................................................................... 27
16.8 Character Values of Clinical Laboratory Parameters ................................................... 28
17
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL ................................................. 29
18
REFERENCES ...................................................................................................................... 30
2.1 List of Tables
Table 3-1
Abbreviations and Definitions of Terms ................................................................. 4
Table 5-1
Schedule of Activities (SoA) .................................................................................. 8
Table 11-1
List of Selected Parameters Reported in Conventional Unit ................................ 18
Table 11-2
Criteria for Potentially Clinically Significant Laboratory Values......................... 19
Table 11-3
Criteria for Potentially Clinically Significant Vital Signs .................................... 21
Table 11-4
Criteria for Potentially Clinically Significant Electrocardiograms....................... 22
Table 16-1
Efficacy and Safety Analysis Visit Definitions..................................................... 24
2.2 List of Figures
Figure 4-1
Study Design........................................................................................................... 6
Figure 10-1
Graphical Procedure for Primary and Key Secondary Hypotheses ...................... 15


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3
List of Abbreviations and Definition of Terms
Table 3-1
Abbreviations and Definitions of Terms
Abbreviation/Term
Definition
AE
adverse event
ANCOVA
analysis of covariance
CFB
change from baseline
CGI-S
Clinical Global Impressions–Severity
C-SSRS
Columbia–Suicide Severity Rating Scale
eCRF
electronic case report form
ECG
electrocardiogram, electrocardiographic
ET
early termination
mITT
modified intent-to-treat
LOCF
last observation carried forward
LS
least squares
MADRS
MDD
Montgomery-Åsberg Depression Rating Scale
major depressive disorder
MedDRA
Medication Dictionary for Regulatory Activities
MMRM
mixed-effects model for repeated measures
PCS
potentially clinically significant
PK
pharmacokinetic
PID
participant identification
PT
preferred term
QTc
QT interval corrected for heart rate
QTcB
QT interval corrected for heart rate using the Bazett formula (QTcB = QT/(RR)½)
QTcF
QT interval corrected for heart rate using the Fridericia formula (QTcF = QT/(RR)⅓)
SAE
serious adverse event
SAP
statistical analysis plan
SI
Le Système International d’Unités (International System of Units)
SOC
system organ class
TEAE
treatment-emergent adverse event
WHO
World Health Organization


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4
Introduction
This statistical analysis plan (SAP) details comprehensive, technical specifications of the 
statistical analyses of the efficacy and safety data outlined and/or specified in the final protocol 
of Study 3125-201-002 (version dated 02 March 2018) and the most recent amendment 
(version #1 dated on 08 Jun 2018). Specifications of tables, figures, and data listings are 
contained in a separate document. 
This study is a multicenter, randomized, double-blind (with a single-blind placebo lead-in), 
placebo-controlled, parallel-group, fixed-dose, 3-week study in participants with major 
depressive disorder (MDD). The study will include a total of 10 visits and will be 
approximately 5 weeks in duration:

Up to 1-week screening period

3-week double-blind treatment period

1-week safety follow-up period
Approximately 250 participants are planned for enrollment in the double-blind treatment 
period (50 participants each in the AGN-241751 and placebo groups). Participants will be 
randomized in a ratio of 1:1:1:1:1 to 1 of 5 treatment groups: 0.25 mg, 1 mg, 3 mg, 10 mg dose 
AGN-241751, and placebo.
Aside from the single-blind screening period and double-blind treatment period, there is an 
additional single-blind element to this study (blinded to the participant). AGN-241751 is being 
developed for once-weekly dosing; however, in order to minimize participant’s expectations 
and control for placebo response, treatment will be presented to participants as oral daily 
dosing. Each treatment kit (dispensed once weekly) in the double-blind treatment period will 
contain 2 bottles: Bottle 1 will contain a single dose of double-blind study treatment and Bottle 
2 will contain multiple doses single-blind placebo tablets (blinded to the participant). At Visit 2 
(Day 1), Visit 5 (Day 8), and Visit 8 (Day 15), site staff will give the participant the single dose 
of double-blind study treatment from Bottle 1 to take by oral ingestion in the clinic (ie, the first 
dose of study treatment for that week). Site staff will give Bottle 2, which contains the single-
blind placebo tablets, to the participant with the instruction to take 1 tablet daily by oral 
ingestion for the remainder of that week. To maintain consistency, study treatment at Visit 1 
(single-blind placebo lead-in) will be dispensed in the same manner; the single dose of single-
blind study treatment from Bottle 1 will be given to the participant for oral ingestion in the 
clinic, and then, Bottle 2 containing single-blind placebo tablets will be dispensed for the 
participant to take 1 tablet daily by oral ingestion through the remainder of the week.


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During the first 2 weeks of the double-blind treatment period, participants will have 3 study 
visits per week. The visits will occur in the following pattern: in-clinic treatment day, 1 day 
following the in-clinic treatment day, 4 days following the in-clinic treatment day, and 7 days 
following the in-clinic treatment day (which is the next in-clinic treatment day). If necessary, 
study visits may be conducted up to 2 days before or after the scheduled visits with the 
exception of visits that are 1 day apart (ie, Visits 2 and 3 must be conducted 1 day apart; and 
Visits 5 and 6 must be conducted 1 day apart). Visit 8 will be conducted 7 days following the 
second in-clinic treatment day. All participants who receive study treatment must complete 
Visit 9/ET.  Participants will enter a 1-week safety follow-up period and return for Visit 10. 
Participants who prematurely discontinue from the study before completing 3 weeks of double-
blind treatment should enter the 1-week safety follow-up period. Additional follow-up visits 
may be scheduled within 30 days, if necessary for safety reasons.
Figure 4-1
Study Design


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5
Study Objectives
The primary objective is to evaluate the efficacy, as measured by improvement in MADRS total 
score, at 1 day post initial oral dose of AGN-241751 compared with placebo in participants with 
MDD. The key secondary objective is to evaluate the efficacy at Week 3 of AGN-241751 
administered orally once a week compared with placebo in participants with MDD.


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Table 5-1
Schedule of Activities (SoA)
Single-blind 
Placebo Run-In 
Period
Double-blind Treatment Period
Safety 
Follow-up 
Period
Visit
1 
(Screening)
2 
(Baseline)
2a
3
4
5
6
7
8
9/ETa
10
Study Day
up to -7 days
1
4 hrs 
post dose
2
(1 day 
post dose)
5
8
9
12
15
22
29
Informed consent
x
Medical (surgical, neurologic) and 
psychiatric histories
x
Prior medication history
x
Inclusion/exclusion
x
x
Randomization assessment
x
Clinical laboratory determinationsb
x
x
Urine drug screen
x
x
Serum pregnancy test
x
x
Vital signsc
x
x
x
x
x
x
x
x
x
x
x
ECG
x
x
Physical examination
x
x
DxV
x
SCID
x
MADRS
x
x
x
x
x
x
x
x
x
x
CGI-S
x
x
x
x
x
x
x
x
x
x
BPRS+
x
x
x
x
CADSS
x
x
x
x
C-SSRS
x
x
x
x
x
x
x
x
x
x
x
SDC
x
x
C-VISA
x
9


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Single-blind
Placebo Run-In
Period
Double-blind Treatment Period
Safety 
Follow-up 
Period
Visit
1
(Screening)
2
(Baseline)
2a
3
4
5
6
7
8
9/ETa
10
Study Day
up to -7 days
1
4 hrs 
post dose
2
(1 day 
post dose)
5
8
9
12
15
22
29
AEs
x
x
x
x
x
x
x
x
x
x
Concomitant medications
x
x
x
x
x
x
x
x
x
x
x
PK sampling
x
(1 hr, 2 hrs, and 4 hrs 
post dose)
x
1 sample 
(15 min 
to 3 hrs
post dose)
Study treatment administration in the 
clinic
x
(single-blind 
placebo)
x
x
x
Study treatment compliance
x
x
x
x
x
x
x
x
Screening procedures may be conducted on up to 2 separate dates where necessary to accommodateparticipant and site schedule; however, every effort 
should be made to conduct all procedures as early as possible in the screening period. The rater-administered MADRS and computer-administered MADRS
must be collected on the same date.At Visit 1 (Screening), the computer-administered MADRS will be conducted prior to the rater- administered MADRS.
At all other visits, the rater-administered MADRS will be conducted first.
If necessary, study visits may be conducted up to 2 days before or after the scheduled visits except for visits that are 1 day apart (ie, Visits 2 and 3 must be 
conducted 1 day apart, and Visits 5 and 6 must be conducted 1 day apart).
AE = adverse event; BPRS+ = Brief Psychiatric Rating Scale - Positive Symptoms Subscale; CADSS = Clinician Administered Dissociative States Scale; CGI-
S = Clinical Global Impressions-Severity; C-SSRS = Columbia–Suicide Severity Rating Scale; C-VISA = Clinical Validation Inventory for Study Admission;
DSM = Diagnostic and Statistical Manual of Mental Disorders; DxV = Diagnostic Validation; ECG = electrocardiogram; ET = Early Termination; MADRS =
Montgomery-Åsberg Depression Rating Scale; PK = pharmacokinetic; SCID = Structured Clinical Interview for DSM disorders; SDC = Symbol Digit Coding
a        Performed for all participants, including those prematurely discontinued after randomization.Clinically significant findings upon termination should be 
       followed until the condition returns to prestudy status or can be explained as unrelated to study treatment. If necessary, additional follow-up visits can be 
       scheduled.
b        Participants will be requested to fast overnight or for at least 8 hours before arriving at the study center for appointments involving the collection of clinical


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         laboratory blood tests. Clinical laboratory tests can be done at any visit for safety reasons at the discretion of the investigator.
c        Height will only be measured at Visit 1 (Screening); pulse rate, blood pressure, temperature, and body weight will be assessed at every visit. Blood
      pressure and pulse will be assessed while the participant is supine and standing.
d        PK sampling is optional. For participants who consent to participate, samples will be collected at Visit 2/2a (Day 1) at 1 hour (± 15 minutes), 2 hours
(± 15 minutes), and 4 hours (± 15 minutes) post dose. At Visit 5 (Day 8), a single sample will be collected any time from 15 minutes to 3 hours post dose;
site staff should record the time of the prior meal taken by the participant before the PK sample collection, whenever possible.


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6
Analysis Populations
The analysis populations will consist of participants as defined below:
The modified intent-to-treat (mITT) population includes all randomized participants 
who received at least 1 administration of study treatment, and have a baseline MADRS 
total score and at least 1 postbaseline assessment for the MADRS total score during the
double-blind treatment period. Participants will be summarized according to the
randomized study treatment.
The safety population includes all participants who received ≥ 1 administration of study
treatment. Participants will be summarized according to the study treatment they actually
received.
7
Patient Disposition
The number and percentage of participants in Safety and mITT Populations will be summarized 
by treatment group and study center; the number of participants screened will be summarized 
overall only by study center.
Screen-failure participants (ie, participants screened but not randomized) and the associated 
reasons for failure to randomize will be tabulated overall for the all screened participants. The 
number and percentage of participants who enter the double-blind treatment period, complete the 
double-blind treatment period and of participants who prematurely discontinue during the same 
period will be presented for each treatment group and pooled across treatment groups. A 
participant is considered to have completed the study if he/she has completed the double-blind 
treatment period of the study. The reasons for premature discontinuation from the double-blind 
treatment period as recorded on the termination pages of the electronic case report forms will be 
summarized (number and percentage) by treatment group. The percentage is relevant to the total 
number of randomized participants. Similar disposition information to the double-blind treatment 
period will be presented for the safety follow-up period.  All randomized participants who 
prematurely discontinue during the double-blind treatment period or the safety follow-up period 
will be listed by discontinuation reason.  
8
Demographic and Other Baseline Characteristics
Demographic parameters (age; age group (<20, 20-29, 30-39, 40-49, 50-59, and >=60); race; 
ethnicity; sex), baseline characteristics (weight; height; and body mass index, calculated as 
weight [kg]/(height [m])2 will be summarized descriptively by treatment group for the Safety and 


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mITT populations. Continuous variables will be summarized by number of participants and 
mean, SD, median, minimum, and maximum values. Categorical variables will be summarized 
by number and percentage of participants.
Medical and surgical history, psychiatric history, non-drug psychiatric treatment history, and 
other psychiatric history will also be summarized by double-blind treatment group for the Safety 
Population. 
Prior medication is defined as any medication taken before the first dose of double-blind study 
treatment. Concomitant medication is defined as any medication taken on or after the date of the 
first dose of the double-blind study treatment.  Any medications started after the last visit of 
double-blind treatment period will not be summarized but will be included in listings.
Both prior and concomitant medication use will be summarized by the number and proportion of 
participants in each treatment group receiving each medication within each therapeutic class for 
the double-blind treatment period for the Safety Population. If a participant took a specific 
medication multiple times or took multiple medications within a specific therapeutic class, that 
participant would be counted only once for the coded drug name or therapeutic class. Any prior 
and concomitant medications will be included in listings. 
The World Health Organization (WHO) Drug Dictionary Enhanced, March 2017 or newer, will 
be used to classify prior and concomitant medications by therapeutic class and drug name.
The number and percentage of participants with important protocol deviations will be 
summarized by treatment group for randomized participants. Deviations related to the following 
categories will be included:
•
Inclusion or exclusion criteria
•
Withdrawal criteria
•
Treatment or dose
•
Concomitant medications
These and any additional important protocol deviations will be reviewed and documented before 
database lock and unblinding of treatment codes.   


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9
Extent of Exposure and Treatment Compliance
9.1 Extent of Exposure
The number and percent of participants who received 1, 2, and 3 double-blind study treatment 
(tablet) will be summarized by treatment group for the Safety Population.
9.2 Measurement of Treatment Compliance
Dosing compliance for double-blind study medication for a specified period is defined as the 
total number of double-blind study medications actually taken by a participant during that period 
divided by the number of double-blind study medications that were expected to be taken during 
the same period multiplied by 100. Descriptive statistics for double-blind study medication 
dosing compliance will be presented by treatment group for each week, as well as for the whole 
double-blind treatment period of the study for the Safety Population.
Dosing compliance for placebo tablet during a specified period is defined as the doses actually 
taken by a participant during that period divided by the doses expected to be taken during the 
same period multiplied by 100. Descriptive statistics for placebo dose compliance during the 
double-blind treatment period will be presented by treatment group for the Safety Population.
10 Efficacy Analyses
The efficacy analyses will be based on the mITT population. The last-observation-carried-
forward (LOCF) approach will be used to impute missing postbaseline values. Baseline for 
efficacy is defined as the last nonmissing efficacy assessment before the first dose of study 
treatment. 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 5 participants in the mITT Population. All the small centers will be pooled to 
form a pseudo-center. If the pseudo-center is still a small center, it will be pooled with the 
smallest non-small center. If there is more than one smallest non-small center, the small pseudo-
center will be pooled with the smallest non-small center that has the largest center number.
The rater-administered MADRS will be used for the efficacy analyses.


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10.1 Primary and Key Secondary Efficacy Endpoints
Primary efficacy endpoint:

Change from baseline in MADRS total score at 1 day after first dose
Key secondary efficacy endpoint:

Change from baseline in MADRS total score at Week 3
The primary analysis for the primary and key secondary endpoints will be performed using a 
mixed-effects model for repeated measures (MMRM) with treatment group, visit, pooled study 
center, and treatment group-by-visit interaction as fixed effects and the baseline value and 
baseline value-by-visit as covariates. An unstructured covariance matrix will be used to model 
the covariance of within-participant scores. The Kenward-Roger approximation will be used to 
estimate denominator degrees of freedom (Kenward and Roger 1997). These analyses will be 
performed based on all postbaseline scores using only the OCs without imputation of missing 
values.
In addition, a sensitivity analysis using the LOCF approach will be performed on the primary
efficacy and key secondary parameters. The between-treatment group comparisons will be 
performed by means of an analysis-of-covariance (ANCOVA) model with treatment group and 
study center as factors and the baseline MADRS 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, 
the 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.
10.2 Multiple Comparisons Procedure
Let H11, H21, H31, H41 represent the comparisons of AGN-241751 0.25 mg, 1 mg, 3 mg, and
10 mg, respectively with placebo in regarding to the primary efficacy parameter; and let H12,
H22, H32, and H42 represent the comparisons of AGN-241751 0.25 mg, 1 mg, 3 mg, and 10 mg,
respectively with placebo in regarding to the key secondary efficacy parameter, the graphical
procedure as displayed in Figure 10-1 will be employed to control the overall familywise error 
rate (FWER) at α = 0.05. The ϵ in the figure represents a small positive number less than 0.0001.


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Figure 10-1
Graphical Procedure for Primary and Key Secondary Hypotheses
10.3 Additional Efficacy Endpoints
Additional efficacy endpoints: 

Change from baseline in MADRS total score at 7 days after first dose of treatment

Change from baseline in Clinical Global Impressions-Severity (CGI-S) at 1 day 
and 7 days after first dose of double-blind study treatment, and end of double-
blind study treatment period (end of Week 3)

Rate of MADRS sustained responders during treatment

Rate of MADRS and CGI-S responders at 1 day and 7 days after first dose of 
double-blind study treatment, and end of double-blind study treatment period (end 
of Week 3)

Rate of MADRS sustained remitters during treatment

Rate of MADRS remitters at 1 day and 7 days after first dose of double-blind 
study treatment, and end of double-blind study treatment period (end of Week 3)

Time to first response

Time to first sustained response

Time to first remission

Time to first sustained remission
CGI-S responder is defined as patients achieving a score of ≤ 2 on the CGI-S of Illness scale.
During the randomized treatment period, 4 types of events for MADRS total score will be 
defined based on the following criteria:


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
Responder: ≥ 50% reduction from baseline MADRS total score

Sustained responder: meet responder criteria at ≥ 2 consecutive visits and 
continued through to final assessment

Remitter: MADRS total score ≤ 10

Sustained remitter: meet remitter criteria at ≥ 2 consecutive visits and continued
through to final assessment
MADRS total score is the sum of the 10 items from the MADRS. If more than 2 items of 
MADRS are missing, then the total score will be set to missing.
Additional quantitative efficacy parameters will be analyzed in the following way:
Analysis of change from baseline in MADRS total score and CGI-S score will be performed 
using a similar MMRM for the primary and key secondary endpoints. Baseline CGI-S score will 
be used as a covariate for the analysis of CGI-S score. In addition, these parameters will be 
analyzed using ANCOVA (with LOCF imputation) as used for the analysis of primary efficacy 
parameters.
Additional categorical efficacy parameters will be analyzed in the following way:
Rates for categorical parameters (response and remission) will be reported by treatment group 
and by visit; logistic regression model (with LOCF imputation) will be used to model the 
probability of a response or the probability of a remission as a function of a treatment group and 
the corresponding baseline score as explanatory variables.
Additional time to event efficacy parameters will be analyzed in the following way:
For the time to event type of endpoints, the log-rank test will be performed to compare the 
treatment arms. Kaplan-Meier curves will be plotted for each treatment arm.
11 Safety Analyses
The safety analysis will be performed using the Safety Population. The safety parameters will 
include adverse events (AEs), clinical laboratory, vital sign, electrocardiographic (ECG), 
BPRS+, CADSS, C-SSRS, and SDC parameters. For each safety parameters, except AEs, the last 
nonmissing safety assessment before the first dose of double-blind study treatment will be used 
as the baseline for all analyses of that safety parameter. Continuous variables will be summarized 
by number of participants and mean, SD, median, minimum, and maximum values. Categorical 
variables will be summarized by number and percentage of participants.


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11.1 Adverse Events
Adverse events will be coded by system organ class and preferred term using the Medical 
Dictionary for Regulatory Activities (MedDRA), version 21.0 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 
double-blind study treatment.  However, an AE that occurs more than 30 days after the last dose 
of double-blind study treatment will not be counted as a TEAE.  Per case report form 
instructions, a new AE record will be created for any AE that worsens; therefore TEAEs can be 
identified as those AEs with recorded onset date on or after the date of the first dose of double-
blind study treatment and within 30 days after the last dose of double-blind study treatment. For 
participants who enter the double-blind treatment period, but did not enter the safety follow-up 
period, any AE that occurred up to 30 days after the date of the last dose of double-blind study 
treatment, is considered as TEAEs for the double-blind treatment period. For participants who 
entered the safety follow-up period, AEs that occurred on or after the date of Visit 9/ET will be 
considered as TEAEs for the safety follow-up period.  
An AE will be considered a treatment-emergent serious AE (TESAE) if it is a TEAE that 
additionally meets any SAE criteria.
Summaries of TEAEs/AEs will be presented separately for the double-blind treatment period and 
safety follow-up period.
The number and percentage of participants reporting TEAEs in each treatment group will be 
tabulated by system organ class and preferred term. In addition, the number and percentage of 
participants reporting TEAEs in each treatment group will be tabulated by system organ class, 
preferred term, and severity for the double-blind treatment period. The number and percentage of 
participants reporting treatment related TEAEs in each treatment group will be tabulated by 
system organ class and preferred term for the double-blind treatment period.
If more than 1 AE is coded to the same preferred term for the same participant, the participant 
will be counted only once for that preferred term using the most severe for the summarizations 
by severity.
Listings of SAEs and AEs leading to discontinuation by participant will be presented.


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11.2 Clinical Laboratory Assessments
Descriptive statistics for clinical laboratory values (in SI units) at baseline, postbaseline, and 
changes from baseline values at each postbaseline timepoint will be presented by treatment 
group for the following laboratory parameters:
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, 
magnesium, gamma glutamyl transferase, phosphate, 
glucose, blood urea nitrogen, creatinine, creatine 
phosphokinase, total protein, alkaline phosphatase, albumin, 
bilirubin (total; direct; indirect), ALT, AST, total 
cholesterol, low-density lipoprotein, high-density 
lipoprotein, triglycerides
Urinalysis:
Specific gravity, pH, protein, glucose, ketones, and blood
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 Table 11-1.
Table 11-1
List of Selected Parameters Reported in Conventional Unit
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


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Number
Laboratory Parameter
Conventional Unit
19
Uric Acid
mg/dL
20
Hemoglobin
G/dL
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 11-2. The number and 
percentage of participants who have PCS postbaseline clinical laboratory values will be tabulated 
by treatment group for the double-blind treatment period. The percentages will be calculated 
relative to the number of participants with available non-PCS baseline values and at least 
1 postbaseline assessment for the double-blind treatment period. The numerator will be the total 
number of participants with available non-PCS baseline values and at least 1 PCS postbaseline 
value for the double-blind treatment period. A supportive tabular display of participants with 
PCS postbaseline values will be provided, including the PID number, baseline and all 
postbaseline (including non-PCS) values. 
In addition, a tabular display showing all AEs that occurred in participants who had PCS 
postbaseline clinical laboratory values will be provided.
The number and percentage of participants meeting potential Hy’s Law criteria (elevation of 
alanine aminotransferase [ALT] or aspartate aminotransferase [AST] ≥ 3x ULN with total 
bilirubin ≥ 2x ULN and alkaline phosphatase < 2x ULN in a 24-hour period) will be tabulated by 
double-blind treatment group starting from the first dose of double-blind study treatment to 
within 30 days after the last dose of double-blind study treatment for the Safety Population. A 
supportive listing will also be provided.
Table 11-2
Criteria for Potentially Clinically Significant Laboratory Values
Laboratory Parameter
SI Unit
Conversion 
Factora
Conventional 
Unit
PCS Criterionb 
Low Value
PCS Criterionb 
High Value
Hematology
Hemoglobin
g/L
0.1
g/dL
< 0.9 × LLN
—
Hematocrit
Volume 
fraction
100
%
< 0.9 × LLN
—
Eosinophils
%
1
%
—
> 10
Neutrophils
%
1
%
< 30
> 90
Basophils
%
1
%
—
> 6
Monocytes
%
1
%
—
> 20
Lymphocytes
%
1
%
< 10
> 60
Absolute neutrophil count
× 109/L
1
1000/μL
< 1.0
—
Platelet count
× 109/L
1
1000/μL
≤75
≥ 700
White blood cell count
× 109/L
1
1000/μL
≤ 2.5
≥ 15
Chemistry
Albumin
g/L
0.1
g/dL
< 0.9 × LLN
> 1.1 × ULN
Alkaline phosphatase
U/L
1
U/L
—
≥ 3 × ULN
Alanine aminotransferase 
U/L
1
U/L
—
≥ 3 × ULN


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Table 11-2
Criteria for Potentially Clinically Significant Laboratory Values
Laboratory Parameter
SI Unit
Conversion 
Factora
Conventional 
Unit
PCS Criterionb 
Low Value
PCS Criterionb 
High Value
(ALT)
Aspartate 
aminotransferase (AST)
U/L
1
U/L
—
≥ 3 × ULN
Gamma-glutamyl 
transferase (GGT)
U/L
1
U/L
—
≥ 3 × ULN
Lactate dehydrogenase 
(LDH)
U/L
1
U/L
—
≥ 3 × ULN
Blood urea nitrogen or 
Urea
mmol/L
2.8011
mg/dL
—
> 1.2 × ULN
Calcium
mmol/L
4.008
mg/dL
< 0.9 × LLN
> 1.1 × ULN
Chloride
mmol/L
1
mg/dL
< 0.9 × LLN
> 1.1 × ULN
Total cholesterol
mmol/L
38.6698
mg/dL
—
> 1.3 × ULN
High-density lipoprotein
(HDL) cholesterol
mmol/L
39
mg/dL
< 0.8 × LLN
—
Low-density lipoprotein
(LDL) cholesterol
mmol/L
39
mg/dL
—
> 1.2 × ULN
Creatine phosphokinase 
(CPK)
U/L
1
U/L
—
> 1.5 × ULN
Creatinine
μmol/L
0.0113
mg/dL
—
> 1.3 × ULN
Glucose, fasting
mmol/L
18.018
mg/dL
< 0.8 × LLN
> 1.2 × ULN
Magnesium
mmol/L
2
mEq/L
< 0.9 × LLN
> 1.1 × ULN
Potassium
mmol/L
1
mEq/L
< 0.9 × LLN
> 1.1 × ULN
Sodium
mmol/L
1
mEq/L
< 0.9 × LLN
> 1.1 × ULN
Total bilirubin
μmol/L
0.0585
mg/dL
—
> 1.5 × ULN
Total protein
g/L
0.1
g/dL
< 0.9 × LLN
> 1.1 × ULN
Triglycerides, fasting
mmol/L
88.4956
mg/dL
—
> 1.2 × ULN
Uric acid or Urate
μmol/L
0.0168
mg/dL
—
> 1.1 × ULN
Urinalysis
Protein
—
—
—
—
At least 2 +
Glucose
—
—
—
—
At least 2 +
Blood
—
—
—
—
At least 2 +
a
Conversion factor from SI units to conventional (traditional) units.
b
Criteria refer to SI units.
Blood urea nitrogen or Urea are the same parameters, and Uric acid or Urate are the same parameters.
LLN = lower limit of normal; PCS = potentially clinically significant; SI = Le Système International d’Unités (International 
System of Units); ULN = upper limit of normal laboratory reference range.
11.3 Vital Signs
Descriptive statistics for vital signs (systolic and diastolic blood pressures, pulse rate, and 
weight) values at baseline, postbaseline, and changes from baseline values at each postbaseline 
timepoint will be presented by treatment group.
Vital sign values will be considered PCS if they meet both the observed value criterion and the 
change from baseline value criterion, if both criteria are available, or meet either the observed 


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value criterion or the change from baseline value criterion that will be detailed in
Table 11-3. The number and percentage of participants who have PCS postbaseline vital sign 
values will be tabulated by study treatment for each assessment. The percentages will be 
calculated relative to the number of participants who have available baseline or non-PCS 
baseline (for parameters with only the observed value criterion) values and at least 1 postbaseline 
assessment. The numerator will be the total number of participants with at least 1 PCS 
postbaseline value. A supportive listing of participants with PCS postbaseline values will be 
provided. In addition, a tabular display showing all AEs that occurred in participants who had 
PCS postbaseline vital sign values will be provided.
Table 11-3
Criteria for Potentially Clinically Significant Vital Signs
Parameter
Flag
Criteriaa
Observed Value
Change From Baseline
Supine systolic 
blood pressure, 
mm Hg
High
≥ 180
Increase of ≥ 20
Low
≤ 90
Decrease of ≥ 20
Supine diastolic 
blood pressure, 
mm Hg
High
≥ 105
Increase of ≥ 15
Low
≤ 50
Decrease of ≥ 15
Supine pulse rate, 
bpm
High
≥ 120
Increase of ≥ 15
Low
≤ 50
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 Electrocardiograms
Descriptive statistics for ECG parameters (ie, heart rate, PR interval, QRS interval, QT interval, 
and QTc interval) at baseline, postbaseline, and changes from baseline values at each 
postbaseline timepoint will be presented by treatment group.
ECG parameter values are considered PCS if ECG values meeting either the actual value or 
change from baseline PCS high criteria listed in Table 11-4. The number and percentage of 
participants with PCS postbaseline values will be tabulated by study treatment. The percentages 


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will be calculated relative to the number of participants with an available non-PCS baseline value 
and at least one postbaseline assessment. The numerator will be the total number of participants 
with an available non-PCS baseline value and at least one PCS postbaseline ECG value. A 
supportive listing of participants with PCS postbaseline values will be provided and will include 
the participant number and the baseline and postbaseline values. 
Table 11-4
Criteria for Potentially Clinically Significant Electrocardiograms
Parameter
Unit
Higher Limit
QRS interval
msec
≥ 150
PR interval
msec
≥ 250
QTcB 
msec
> 500
QTcF
msec
> 500
QTc = QT interval corrected for heart rate. 
QTcB = QT interval corrected for heart rate using the Bazett formula.
QTcF = QT interval corrected for heart rate using the Fridericia formula.
A listing of all AEs for participants with PCS ECG values 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. A 
tabular display of participants with postbaseline clinically significant ECG abnormalities 
according to the investigator’s overall interpretation will be provided.
11.5  Other Safety Parameters
11.5.1 Brief Psychiatric Rating Scale—Positive Symptoms Subscale 
Descriptive statistics for BPRS+ score and changes from the baseline values at each assessment 
time point will be presented by treatment group. BPRS+ total score is defined as the sum of 4 
positive individual scores including suspiciousness, unusual thought content, hallucinations, and 
conceptual disorganization.  If more than 1 item is missing, then the total score will be set to 
missing.


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11.5.2 Clinician Administered Dissociative States Scale
Descriptive statistics for CADSS score and changes from the baseline values at each assessment 
time point will be presented by treatment group. CADSS total score is the sum of scores for 23 
subjective items. If more than 4 items are missing, then the total score will be set to missing.
11.5.3 Symbol Digit Coding
Descriptive statistics will be presented at each assessment timepoint by treatment for the SDC
parameters including the number of symbols completed, the rate of completion (number of
symbols completed/time of trial), the number of corrected responses (symbols completed
correctly), and the number of errors (symbols completed incorrectly).
11.5.4 Columbia-Suicide Severity Rating Scale
For C-SSRS, the number and percentage of participants with suicidal ideation or suicidal 
behavior as recorded on the C-SSRS will be summarized by treatment group for the Safety 
Population. The distribution of responses for most severe suicidal ideation and most severe 
suicidal behavior during the participant’s lifetime, during the double-blind treatment period, and 
during the safety follow-up period will also be presented by treatment group. Supportive listings 
will be provided and will include the PID number, study center number, treatment group, lifetime 
history, and postbaseline values. Intensity of suicidal ideation and suicidal behavior type will 
also be included in these listings.  A listing of all AEs occurring in participants who have suicidal 
ideation or suicidal behavior will also be provided.
12 Health Outcome Analyses
Not Applicable.
13 Interim Analysis
No interim analysis is planned for this study.
14 Determination of Sample Size
The sample size of approximately 50 randomized participants in each of the 5 treatment groups
is not based on statistical power consideration due to the lack of information of AGN-241751 for
the variability of change from baseline to 1 day after first dose in MADRS total score.
15 Statistical Software
Statistical analyses will be performed using version 9.4 (or newer) of SAS.


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16 Data Handling Convention
16.1 Visit Time windows
Table 16-1
Efficacy and Safety Analysis Visit Definitions
Derived Visit
Scheduled Visit Daya
Window
Baseline
Day 1d (visit 2)
Last record on or before Index1a
4-hour Post Dose
4-hour Post Dose (visit 2a)
4-hour post dose
Day 2
Day 2 (visit 3)
Index1a+1
Day 5
Day 5 (visit 4)
Days [Index1a +2, IndexAb-1]
Day 8
Day 8d (visit 5)
IndexAb
Day 9
Day 9 (visit 6)
Day IndexAb+1
Day 12
Day 12 (visit 7)
Days [IndexAb +2, IndexBc-1]
Day 15
Day 15d (visit 8)
IndexBc
  Week 3
    Day 22 (visit 9)
Days [IndexBc+1, day of final double-
blind visit or ET Visit occurring after 
IndexBc+1]
End of double-blind 
treatment period (end of 
Week 3)
The last available post-baseline assessment during the double-blind 
treatment period
End of safety follow-up 
period
The last available post-baseline assessment during the safety follow-up 
period.
a
Index1: Day of first double-blind dose
b
IndexA: Day of second double-blind dose, if not received, use Index1 + 7 days
c
IndexB: Day of third double-blind dose, if not received, use IndexA + 7 days.
d      Study treatment administration in clinic.
16.2 Repeated or Unscheduled Assessments of Safety Parameters
Baseline is defined as the last assessment made before the first dose of double-blind study 
treatment. If end-of-study assessments are repeated or if unscheduled visits occur, the last 
nonmissing postbaseline assessment will be used as the end-of-study assessment for generating 
summary statistics. However, all postbaseline assessments will be used for PCS value 
determinations, and all assessments will be presented in the data listings.
16.3 Missing Date of the Last Dose of Study treatment 
Since participants will receive their double-blind study treatment doses under the direct 
supervision of study center personnel, the date of the last dose of study treatment will be 
available, i.e. missing data imputation rule is not applicable. 


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16.4 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 study 
treatment, 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 study treatment, 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.
16.5 Missing Causal Relationship to Study treatment for Adverse Events
If the causal relationship to the double-blind study treatment is missing for an AE that started on 
or after the date of the first dose of double-blind study treatment, a causality of yes will be 
assigned. The imputed values for causal relationship to double-blind treatment will be used for 
the incidence summary; the values will be shown as missing in the data listings.
16.6 Missing Date Information for Adverse Events
The following imputation rules only apply to cases in which the start date for AEs is incomplete 
(ie, partly missing).
Missing month and day

If the year of the incomplete start date is the same as the year of the first dose of double-blind 
study treatment, the month and day of the first dose of double-blind study treatment 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 
study treatment, 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 study 
treatment, 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 study treatment, the day of the first dose of double-blind study 
treatment 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 study treatment 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 study treatment, the 
last day of the month will be assigned to the missing day


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
If either the year of the incomplete start date is after the year of the date of the first dose of 
double-blind study treatment 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 study treatment, the 
first day of the month will be assigned to the missing day
If the stop date is complete and the imputed start date as above is after the stop date, the start 
date will be imputed by the stop date.
If the start date is completely missing and the stop date is complete, the following algorithm will 
be used to impute the start date:

If the stop date is after the date of the first dose of double-blind study treatment, the date of 
the first dose of double-blind study treatment will be assigned to the missing start date

If the stop date is before the date of the first dose of double-blind study treatment, the stop 
date will be assigned to the missing start date
16.7 Missing Date Information for Prior or Concomitant Medications
For prior or concomitant medications, including rescue medications, incomplete (ie, partly 
missing) start dates and/or stop dates will be imputed. When the start date and the stop date are 
both incomplete for a participant, the start date will be imputed first.
16.7.1 Incomplete Start Date
The following rules will be applied to impute the missing numeric fields for an incomplete prior 
or concomitant medication start date. If the stop date is complete (or imputed) and the imputed 
start date is after the stop date, the start date will be imputed using the stop date.
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 
study treatment, the month and day of the first dose of double-blind study treatment 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 
study treatment, 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 study 
treatment, 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 study treatment, the day of the first dose of double-blind study 
treatment 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 study treatment 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 study treatment, 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 study treatment 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 study treatment, the 
first day of the month will be assigned to the missing day
16.7.2 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 study treatment is missing, 
impute it as descripted in Section 15.3. If the imputed stop date is before the start date (imputed 
or nonimputed 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 study 
treatment, the month and day of the last dose of study treatment will be assigned to the 
missing fields

If the year of the incomplete stop date is before the year of the last dose of study treatment, 
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 study treatment, 
January 1 will be assigned to the missing fields
Missing month only

If only the month is missing, the day will be treated as missing and both the month and the 
day will be replaced according to the above procedure
Missing day only

If the month and year of the incomplete stop date are the same as the month and year of the 
last dose of study treatment, the day of the last dose of study treatment 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 
study treatment 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 study treatment, the last day of the month will 
be assigned to the missing day


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
If either the year of the incomplete stop date is after the year of the date of the last dose of 
study treatment 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 study treatment, the first day of the month will 
be assigned to the missing day
16.8 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.


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17 CHANGES TO ANALYSES SPECIFIED IN PROTOCOL
None.


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18 REFERENCES
Kenward MG, Roger JH. Small sample inference for fixed effects from restricted maximum 
likelihood. Biometrics 1997; 53:983-97.
Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960; 23:56–62.
Bretz, F., Maurer, W. and Hommel, G. (2011), Test and power considerations for multiple 
endpoint analyses using sequentially rejective graphical procedures. Statistics in Medicine, 30: 
1489-1501.