Clinical trial NCT03726658
Conditions: Major Depressive Disorder
Sponsor: Syndeio Biosciences, Inc
Start date: 2018-11-08; Completion date: 2019-10-23
Enrollment: 226 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of AGN-241751 in participants with Major Depressive Disorder

Detailed description:

Arms: arm 1: AGN-241751, oral administration, once per day in Part A. Twice per day (BID) in Part B arm 2: AGN-241751, oral administration, once per day arm 3: AGN-241751, oral administration, once per day in Part A. Twice per day (BID) in Part B arm 4: Placebo, oral administration, once per day in part A. Twice per day (BID) in Part B
Interventions: intervention 1: AGN-241751 intervention 2: Placebo
Intervention descriptions: intervention 1: AGN-241751 is supplied in tablet form intervention 2: Placebo is supplied in tablet form

Protocol documents:
Prot_000.pdf: 
 
 
Protocol 
A Two-Part, Double-Blind, Placebo-Controlled, Single- and Multiple-Dose (Part A) or 
Twice Daily Dose (Part B) Study of AGN-241751 in Adult Participants with Major 
Depressive Disorder 
 
NCT Number 03726658 
 
Document Date May 3, 2019 


CONFIDENTIAL
AGN-241751
Protocol 3125-104-002 Amendment 2
1
Title Page
Protocol Title: A Two-Part, Double-Blind, Placebo-Controlled, Single- and Multiple-Dose 
(Part A) or Twice Daily Dose (Part B) Study of AGN-241751 in Adult Participants with Major 
Depressive Disorder
Brief Protocol Title: AGN-241751 in the treatment of major depressive disorder 
Protocol Number: 3125-104-002
Amendment Number: 2
Study Phase: 1b/2a
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
Approval Date: 03 May 2019
Sponsor Signatory:
Armin Szegedi, MD, PhD
Vice President, Clinical Development
CNS Therapeutic Area Head
The signature of the sponsor signatory is collected on the protocol approval page.


CONFIDENTIAL
AGN-241751
Protocol 3125-104-002 Amendment 2
2
Protocol Amendment Summary of Changes Table
DOCUMENT HISTORY
Document
Date
Amendment 2
May 2019
Amendment 1
March 2019
Original Protocol
August 2018
Amendment 2 (May 2019)
Overall Rationale for the Amendment:
The primary reason for this amendment was to add a 2nd cohort (Part B) to this study, which will 
evaluate twice daily [BID] dosing for 14 days. This BID dosing cohort was added because the 
effective dose and regimen of AGN-241751 within MDD participants may require weekly, once 
daily, and BID administration. The once weekly and once daily dosing information is included as 
Part A and the BID dosing is now added as Part B. Revisions were made throughout the protocol 
to clarify sections that are included in Part A and to add new information that pertains to Part B 
of the study. In addition, minor administrative, editorial, and formatting changes have been made 
throughout the protocol.
Revisions to Part A included additions and clarifications to current efficacy and safety 
assessments, updates and clarifications to the objectives and endpoints for consistency with 
presentation for Part B, and other minor revisions (eg, in-clinic to inpatient) for consistency with 
Part B. The title of the protocol was revised to reflect the newly added cohort.
The new Part B includes, but is not limited to, the following modifications: 

New schedule of activities

Updated objectives and endpoints

Study design, study information, sample size, study treatment, and treatment compliance 

New efficacy, pharmacokinetic, and pharmacodynamic assessments
o
Likert Patient Depressive Symptom Scales
o
Hopkins Verbal Learning Test–Revised
o
Quantitative electroencephalography/event related potential assessments and outputs
o
Cerebrospinal fluid analysis (optional)

Updated statistical analyses

Additional appendices


CONFIDENTIAL
AGN-241751
Protocol 3125-104-002 Amendment 2
3
Table of Contents
Title Page ........................................................................................................................................1
Protocol Amendment Summary of Changes Table .........................................................................2
Table of Contents...........................................................................................................................3
List of Figures.................................................................................................................................7
1.
Synopsis............................................................................................................................8
2.
Schedule of Activities (SoA).........................................................................................19
2.1.
Part A..............................................................................................................................19
2.2.
Part B ..............................................................................................................................21
3.
Introduction...................................................................................................................24
3.1.
Study Rationale...............................................................................................................27
3.2.
Background.....................................................................................................................27
3.3.
Benefit/Risk Assessment ................................................................................................28
4.
Objectives and Endpoints ............................................................................................29
4.1.
Part A..............................................................................................................................29
4.2.
Part B ..............................................................................................................................30
5.
Study Design..................................................................................................................32
5.1.
Overall Design ................................................................................................................32
5.1.1.
Part A ..............................................................................................................................32
5.1.2.
Part B ..............................................................................................................................34
5.2.
Participant and Study Completion ..................................................................................37
5.2.1.
Part A ..............................................................................................................................37
5.2.2.
Part B ..............................................................................................................................37
5.3.
End of Study Definition..................................................................................................37
5.4.
Scientific Rationale for Study Design ............................................................................38
5.5.
Justification for Dose......................................................................................................38
6.
Study Population...........................................................................................................39
6.1.
Inclusion Criteria ............................................................................................................39
6.2.
Exclusion Criteria ...........................................................................................................40
6.3.
Lifestyle Restrictions ......................................................................................................44
6.3.1.
Meals and Dietary Restrictions.......................................................................................44
6.3.2.
Caffeine, Alcohol, and Tobacco .....................................................................................44
6.3.3.
Activity ...........................................................................................................................44
6.4.
Screen Failures................................................................................................................44
7.
Treatments.....................................................................................................................45
7.1.
Treatments Administered................................................................................................45
7.1.1.
Part A ..............................................................................................................................45
7.1.2.
Part B ..............................................................................................................................46
7.2.
Dose Modification ..........................................................................................................48


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AGN-241751
Protocol 3125-104-002 Amendment 2
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7.3.
Method of Treatment Assignment ..................................................................................48
7.4.
Blinding/Masking ...........................................................................................................48
7.5.
Preparation/Handling/Storage/Accountability................................................................49
7.6.
Treatment Compliance....................................................................................................49
7.6.1.
Part A ..............................................................................................................................49
7.6.2.
Part B ..............................................................................................................................50
7.7.
Concomitant Therapy .....................................................................................................50
7.7.1.
Prohibited Treatments.....................................................................................................51
7.7.2.
Permitted Treatments......................................................................................................51
7.8.
Treatment after the End of the Study..............................................................................52
8.
Discontinuation/Withdrawal Criteria.........................................................................53
8.1.
Discontinuation of Study Treatment...............................................................................53
8.2.
Withdrawal from the Study.............................................................................................54
8.3.
Lost to Follow Up...........................................................................................................54
9.
Study Assessments and Procedures.............................................................................56
9.1.
Efficacy Assessments .....................................................................................................56
9.1.1.
Diagnostic Assessments..................................................................................................57
9.1.2.
The Montgomery-Åsberg Depression Rating Scale .......................................................57
9.1.3.
The Clinical Global Impressions-Severity......................................................................57
9.1.4.
The Hamilton Anxiety Rating Scale (Part A Only) ........................................................57
9.1.5.
Likert Patient Depressive Symptom Scales (Part B Only) .............................................58
9.1.6.
Hopkins Verbal Learning Test-Revised (Part B Only)...................................................58
9.2.
Adverse Events ...............................................................................................................58
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information .....................................................................................................................59
9.2.2.
Method of Detecting AEs and SAEs ..............................................................................59
9.2.3.
Follow-up of AEs and SAEs...........................................................................................59
9.2.4.
Regulatory Reporting Requirements for SAEs...............................................................60
9.2.5.
Pregnancy........................................................................................................................60
9.2.6.
Potential Hy’s Law .........................................................................................................61
9.2.7.
Medication Errors ...........................................................................................................61
9.3.
Treatment of Overdose ...................................................................................................61
9.4.
Safety Assessments.........................................................................................................62
9.4.1.
Physical Examinations....................................................................................................62
9.4.2.
Vital Signs.......................................................................................................................62
9.4.3.
Electrocardiograms .........................................................................................................63
9.4.4.
Clinical Safety Laboratory Assessments ........................................................................63
9.4.5.
Columbia-Suicide Severity Rating Scale........................................................................64
9.4.6.
Brief Psychiatric Rating Scale—Positive Symptoms Subscale......................................64
9.4.7.
Clinician Administered Dissociative States Scale ..........................................................64
9.5.
Pharmacokinetics (Part B Only) .....................................................................................65
9.6.
Pharmacodynamics (Part B Only) ..................................................................................65


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AGN-241751
Protocol 3125-104-002 Amendment 2
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9.6.1.
Quantitative Electroencephalography and Event Related 
Potential Assessments and Outputs ................................................................................65
9.7.
Genetics ..........................................................................................................................68
9.8.
Biomarkers......................................................................................................................68
9.9.
Medical Resource Utilization and Health Economics ....................................................68
10.
Statistical Considerations ............................................................................................68
10.1.
Sample Size Determination ............................................................................................68
10.1.1.
Part A ..............................................................................................................................68
10.1.2.
Part B ..............................................................................................................................68
10.2.
Populations for Analyses ................................................................................................69
10.2.1.
Part A ..............................................................................................................................69
10.2.2.
Part B ..............................................................................................................................69
10.3.
Statistical Analyses .........................................................................................................69
10.3.1.
Efficacy Analyses (Part A and Part B) ...........................................................................70
10.3.2.
Exploratory Analyses......................................................................................................73
10.3.3.
Pharmacokinetic Analysis (Part B Only) ........................................................................74
10.3.4.
Pharmacodynamic Analysis (Part B Only) .....................................................................74
10.3.5.
Safety Analyses (Part A and Part B)...............................................................................74
10.3.6.
Interim Analyses .............................................................................................................77
11.
References......................................................................................................................78
12.
Appendices.....................................................................................................................81
12.1.
Appendix 1: Abbreviations and Trademarks ..................................................................81
12.2.
Appendix 2: Clinical Laboratory Tests ..........................................................................84
12.3.
Appendix 3: Study Governance Considerations.............................................................87
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting.........................................................90
12.5.
Appendix 5: Contraceptive Guidance and Collection of 
Pregnancy Information ...................................................................................................96
12.6.
Appendix 6: Concomitant Medications ..........................................................................99
12.7.
Appendix 7: Standard Discontinuation Criteria............................................................104
12.8.
Appendix 8: Montgomery-Åsberg Depression Rating Scale .......................................105
12.9.
Appendix 9: Clinical Global Impressions–Severity .....................................................109
12.10.
Appendix 10: Brief Psychiatric Rating Scale – Positive 
Symptoms Subscale ......................................................................................................110
12.11.
Appendix 11: Clinician Administered Dissociative States Scale .................................111
12.12.
Appendix 12: Columbia-Suicide Severity Rating Scale –
Baseline/Screening........................................................................................................116
12.13.
Appendix 13: Columbia–Suicide Severity Rating Scale - Since 
Last Visit.......................................................................................................................119
12.14.
Appendix 14: Hamilton Anxiety Rating Scale (Part A Only) ......................................123
12.15.
Appendix 15: Likert Patient Depressive Symptom Scales (Part B 
Only) .............................................................................................................................124


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AGN-241751
Protocol 3125-104-002 Amendment 2
6
12.16.
Appendix 16: Hopkins Verbal Learning Test-Revised (Part B 
Only) .............................................................................................................................136
12.17.
Appendix 17: Karolinska Sleepiness Scale (Part B Only)............................................137
12.18.
Appendix 18: CSF Sample Collection, Handling, and Storage 
Instructions (Part B Only).............................................................................................138
12.19.
Appendix 19: Sample Shipment Guide (Part B Only)..................................................139
12.20.
Appendix 20: qEEG and ERP Assessments and Outputs (Part B 
Only) .............................................................................................................................141
12.21.
Appendix 21: Protocol Amendment History ................................................................144


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AGN-241751
Protocol 3125-104-002 Amendment 2
7
List of Figures
Figure 5–1
Study Design Diagram – Part A........................................................................ 33
Figure 5–2
Study Design Diagram – Part B ........................................................................ 37


CONFIDENTIAL
AGN-241751
Protocol 3125-104-002 Amendment 2
8
1.
Synopsis
Protocol Title: A Two-Part, Double-Blind, Placebo-Controlled, Single- and Multiple-Dose 
(Part A) or Twice Daily Dose (Part B) Study of AGN-241751 in Adult Participants with Major 
Depressive Disorder
Protocol Number: 3125-104-002 Amendment 2
Brief Title: AGN-241751 in the treatment of major depressive disorder 
Study Phase: 1b/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 2-part 
(Part A and Part B) proof-of-concept study of AGN-241751 monotherapy for the treatment of 
patients with major depressive disorder (MDD). Part A includes weekly and once daily
administrations of AGN-241751, and Part B includes twice daily (BID) administration. Part B 
participants should not have participated in Part A at any time, and Part A participants should not 
have participated at any time in Part B (ie, Part A is not a contingent step to participate in 
Part B).
Objectives and Endpoints:
Part A:
The primary objective of Part A is to evaluate the efficacy, as measured by improvement in 
Montgomery-Asberg Depression Rating Scale (MADRS) total score, at 1 day after the initial 
single oral dose of AGN-241751 compared with placebo in participants with MDD (Day 1 
[predose, defined as baseline] vs Day 2). The key secondary objectives are to evaluate the 
efficacy at Day 8, at Day 9 after a single oral dose, at Day 15 after repeated doses of 
AGN-241751, and at Day 22 (7 days after completion of AGN-241751 dosing) compared with 
placebo in participants with MDD.
Objectives
Endpoints
Primary

To evaluate the efficacy at 1 day post 
the initial single oral dose of 
AGN-241751 compared with placebo 

Change from baseline (Day 1, predose) in 
MADRS total score at 1 day after the first 
dose of treatment (Day 2)


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AGN-241751
Protocol 3125-104-002 Amendment 2
9
Objectives
Endpoints
in participants with MDD
Key Secondary

To evaluate the efficacy at Day 8, at
Day 9 (single dose), at Day 15 (repeated 
dose) of AGN-241751 administered 
orally once daily, and at Day 22 (7 days 
after completion of AGN-241751 
dosing) compared with placebo in 
participants with MDD

Change from baseline (Day 1, predose) in 
MADRS total score at Day 8, Day 9, Day 15, 
and Day 22
Additional

Additional endpoint to be explored to 
determine differences between 
AGN-241751 and placebo in 
participants with MDD

Change from baseline in CGI-S total score at 
Day 2, Day 8, Day 9, and Day 15 

Rate of responders on MADRS or CGI S at 
Day 2, Day 8, Day 9, Day 15, and Day 22

Rate of remitters on MADRS at Day 2, 
Day 8, Day 9, Day 15, and Day 22

Time to first response on MADRS

Time to first remission on MADRS

Change from baseline (Day 1, predose) in 
HAM-A at Day 2, Day 8, and Day 15

Safety Measures

AE recording, clinical laboratory measures, 
vital sign parameters, ECGs, and physical 
examinations

Measure of psychotomimetic effects: BPRS+ 

Measure of dissociative effects: CADSS

Measure of suicidality: C-SSRS
Part B:
The primary objective of Part B is to evaluate the efficacy of the change from baseline in 
Montgomery-Asberg Depression Rating Scale (MADRS) total score at 7 days after the 1st dose 
of AGN-241751 (3 mg and 25 mg) compared with placebo in participants with MDD. The key 
secondary objectives are to evaluate the efficacy at Day 2, Day 11, Day 14, Day 18, and Day 21
after the 1st dose of AGN-241751 (3 mg and 25 mg) compared with placebo in participants with 
MDD. In addition, optional CSF samples will be collected in a subset of participants for 
pharmacokinetic analysis, and qEEG and ERP assessments will be collected in a subset of 
participants for pharmacodynamic analysis.


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AGN-241751
Protocol 3125-104-002 Amendment 2
10
Objectives
Endpoints
Primary

To evaluate the efficacy at Day 7 of 
AGN-241751 compared with placebo in 
participants with MDD dosed twice daily 
(BID)

Change from baseline in MADRS at 
7 days after the first dose of treatment
Key Secondary

To evaluate the efficacy on Day 2,
Day 11, Day 14, Day 18, and Day 21
(7 days after completion of dosing) after 
BID administration of AGN-241751 
compared with placebo in participants 
with MDD dosed BID

Change from baseline in MADRS total 
score at Day 2, Day 11, Day 14, Day 18, 
and Day 21 
Additional

Additional endpoints to be explored to 
determine differences between 
AGN-241751 and placebo in participants 
with MDD dosed BID

Change from baseline in CGI-S total score 
by visit

Rate of responders on MADRS at Day 2, 
Day 7, Day 11, Day 14, Day 18, and 
Day 21

Rate of remitters on MADRS at Day 2, 
Day 7, Day 11, Day 14, Day 18, and 
Day 21

Rate of responders on CGI-S by visit 

Time to first response on MADRS

Time to first remission on MADRS

Symptoms over time based on Likert 
Patient Depressive Symptom Scales

Total recall scores at specified timepoints 
in HVLT-R

Evaluation of pharmacodynamic 
endpoints (qEEG/ERP) and CSF between 
AGN-241751 and placebo in participants 
with MDD dosed BID

Change from baseline in qEEG 
parameters collected during Day 1, Day 7, 
Day 14, and Day 21

Change from baseline in ERP parameters 
collected during Day 1, Day 7, Day 14, 
and Day 21

Descriptive analysis of CSF 
concentrations of AGN-241751


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AGN-241751
Protocol 3125-104-002 Amendment 2
11
Objectives
Endpoints

Safety Measures

AE recording, clinical laboratory 
measures, vital sign parameters, ECGs, 
and physical examinations

Measure of psychotomimetic effects: 
BPRS+ 

Measure of dissociative effects: CADSS

Measure of suicidality: C-SSRS
Overall Study Design:
Part A of this study is a multicenter, randomized, double-blind, placebo-controlled, 
parallel-group (4 arms), weekly and once daily dose, 2-week double-blind treatment in 
participants with MDD. Part B of this study is a multicenter, randomized, double-blind, 
placebo-controlled, parallel-group (3 arms), BID dose, 2-week double-blind treatment in 
participants with MDD.  
Part A:
Part A of the study will include a total of 7 visits and will be approximately 5 weeks in duration:

Up to 2-week screening period 

2-week double-blind treatment period 

1-week safety follow-up period 
After providing written consent, participants will enter a screening period of up to 14 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. Participants meeting the eligibility 
criteria at the end of Visit 2 (Day 1 of the randomized inpatient treatment) will be assigned a 
treatment and enter the double-blind treatment period.
Approximately 100 participants are planned for enrollment in the double-blind treatment period 
(25 participants each in 3 different AGN-241751 dose groups and a placebo group). Participants 
will be randomized in a ratio of 1:1:1:1 to 1 of 4 treatment groups: 3 mg, 10 mg, and 25 mg dose 
AGN-241751 and placebo.  All participants will be randomized to receive active treatment or
placebo (Day 1 and Days 8 to 15) and placebo alone (Days 2 through 7). 
AGN-241751 is being developed for once-weekly dosing; however, the impact of repeated
administration of AGN-241751 requires testing. In order to minimize participant’s expectations 
and control for placebo response while changing dosing regimens, all treatments will be 
presented to participants as oral daily dosing throughout the study. On Day 1, all participants will 
be randomized to receive the first treatment (ie, 4 treatment groups: 3 mg, 10 mg, and 25 mg 
dose AGN-241751 or placebo), followed by blinded placebo on Days 2 through 7. Starting on 


CONFIDENTIAL
AGN-241751
Protocol 3125-104-002 Amendment 2
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Day 8, participants will then start 7 consecutive days of randomized treatment, administered 
once daily through Day 15.  
On Day 1, site staff will give the participant the single dose of double-blind study treatment from 
Bottle 1 (for applicable visit) to take by oral ingestion in the clinic (ie, the first dose of study 
treatment for that week). Site staff will then give Bottle 2 (for applicable visits), 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 (Days 2 through 7). On Day 8, site staff will give 
the participant the single dose of double-blind study treatment from Bottle 1 (for applicable visit) 
to take by oral ingestion in the clinic (ie, the first dose of study treatment for that week). Site 
staff will then give Bottle 2 (for applicable visits), which contains double-blind study treatment, 
to the participant with the instruction to take 1 tablet daily by oral ingestion for the remainder of 
that week (Days 9 through 15).
Participants will have 7 study visits during the study. The first 6 visits will occur in the following 
pattern: the Screening Visit (Visit 1; up to Day –14); at Visit 2 (Day 1 of the randomized 
inpatient treatment); at Visit 3 (1 day following the inpatient treatment day); at Visit 4 (7 days 
following the first inpatient treatment day, which is the 2nd inpatient treatment day); at Visit 5
(1 day following the 2nd inpatient treatment day); and at Visit 6 (7 days following the 
2nd inpatient 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 4 and 5 must be conducted 1 day apart). Participants will 
enter a 1-week safety follow-up period and return for Visit 7. Participants who prematurely 
discontinue from the study before completing the 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.


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AGN-241751
Protocol 3125-104-002 Amendment 2
13
Study Design Diagram – Part A
FU = follow-up; IP = investigational product.
All treatments will be presented to participants as oral once daily dosing throughout the study. 
Daily dosing of AGN-241751 should occur at a similar time throughout the entire study. 
At Visit 2 (Day 1 of the randomized inpatient treatment), all participants will be randomized to 
receive the first treatment, followed by blinded placebo on Days 2 through 7.
Starting at Visit 4 (Day 8), participants will then start 7 consecutive days of randomized 
treatment, administered once daily through Day 15.
Part B:
Part B of this study will include a total of 14 visits and will be approximately 5 weeks in duration 
as described below.

Up to a 2-week screening period 

2-week double-blind treatment period (Week 1 inpatient, Week 2 outpatient)

1-week outpatient safety follow-up period 
IP Administered
IP Administered


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AGN-241751
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Approximately 120 participants are planned for randomization in the double-blind treatment 
period (40 placebo participants, 40 AGN-241751 3 mg participants, 40 AGN-241751 25 mg
participants). Eligible participants will be randomized in a ratio of 1:1:1 to one of 3 double-blind 
oral administration treatment groups: 3 mg dose of AGN-241751, 25 mg dose of AGN-241751, 
or placebo, administered BID. Participants who enrolled (were randomized) in Part A will not be 
permitted to screen into Part B (and vice versa).
Screening Period
After providing written consent, participants will enter a screening period of up to 14 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. Participants will wash out of any ADT 
and prohibited medications under the supervision of the study investigator staff during the 
screening period. At Visit 2 (Day –1), study procedures required to determine eligibility will be 
completed prior to admission to the clinic. Participants meeting the eligibility criteria at Visit 2 
(Day –1, Baseline) will be admitted to the inpatient facility, and the remainder of the Visit 2 
study procedures will be completed. A urine pregnancy test should be done on Day –1 (at 
baseline), if more than a week has passed since the serum pregnancy test was done at Screening.
Participants are required to not use any nicotine substances 1 hour prior to administration of the 
HVLT-R.
Double-Blind Treatment Period
Participants will be randomized in a ratio of 1:1:1 to 1 of 3 treatment groups (AGN-241751 3 mg 
BID, AGN-241751 25 mg BID, or placebo BID) for the 2-week double-blind treatment. 
Participants will be administered 1 tablet in the morning and 1 tablet in the afternoon. At Visit 3 
(Day 1), the participant will be randomized and assigned a treatment by the interactive web 
response system (IWRS), and the 1st dose of study medication will be administered in the 
morning after all predose asessments have been completed.
Week 1 Inpatient Double-Blind Treatment Period 

It is expected that participants in the double-blind treatment period will remain inpatient
during the 1st week (Visit 2 to Visit 10/Discharge).

During the inpatient treatment period, participants will have 7 visits (Visits 3 to 9); each 
visit will occur daily with no visit windows.

At Visit 3 (Day 1) during the predose evaluation period, if there is a significant change 
(worsening or improvement in depressive symptoms) from the baseline Visit 2 (Day –1) 
MADRS based on the judgment of the PI, a MADRS assessment should be performed prior 
to the 1st dose of study medication.

Participants will be discharged at Visit 10 (Day 8) after all predose assessments, morning 
dosing, and 4-hour postdose assessments are completed.


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AGN-241751
Protocol 3125-104-002 Amendment 2
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
During the inpatient treatment period, predose assessments will be performed prior to 
morning dosing at all inpatient visits (Visit 3 through Visit 10). Postdose assessments will be 
performed, as follows:
o
Visit 3 to Visit 6: 1, 2, 4, 8, and 12 hours after the morning dose (± 20 minutes) 
o
Visit 7 to Visit 9: 4, 8, and 12 hours after the morning dose (± 20 minutes)
o
Visit 10: 4 hours after the morning dose (± 20 minutes) 

Within each timepoint, multiple assessments will be performed, as follows:
o
Assessments should be performed within  ± 20 minutes of each other
o
All psychiatric assessments (Likert Patient Depressive Symptom Scales, CSSR-S, 
MADRS, and CGI-S) are to be completed first prior to any other assessments (ie, qEEG, 
ERP) within the timepoint.
o
Participants are required to not use any nicotine substances 1 hour prior to administration 
of the HVLT-R.

The afternoon dose of study medication is to be administered 8 hours (± 1 hour) after the 
morning dose.
Week 2 Outpatient Double-Blind Treatment Period

During the outpatient treatment period, there will be 2 visits conducted every 3 days
(Visit 11 [Day 11] and Visit 12 [Day 14/ET]). If necessary, these study visits may be 
conducted up to 1 day before or after the scheduled visit day.

All participants who receive study medication should complete Visit 12 (Day 14/ET)

At Visit 10 (Day 8) prior to discharge, the participant will be dispensed Bottle 2 of study 
medication (refer to Section 7.1.2 for dosing instruction). Participants will be instructed to 
bring the study medication bottle to Visit 11 for the site staff to confirm dosing compliance

The study medication bottle will be returned at Visit 12; site staff will confirm dosing 
compliance.

A Patient Diary will be provided at Visit 10 and Visit 11 for completion by the participant at 
home. At Visits 11 and 12, the participant will return the diary which was provided at the 
prior visit. Site staff will review the diary to confirm compliance and proper completion of 
the diary. At Visit 11 and Visit 12, prior to leaving the clinic, the participant will be given a 
new diary. 

The Patient Diary will include a Study Medication Dosing Log and Likert scales.
o
Study Medication Dosing Log: Participants will be instructed by site staff to record the 
date and time of the Visit 10 (Day 8) afternoon dose and each subsequent dose the 
participant has taken (morning and afternoon) at home, inclusive of doses on days when 
the participant has a clinic visit (Visit 11 [Day 11] and Visit 12/ET [Day 14/ET]). 


CONFIDENTIAL
AGN-241751
Protocol 3125-104-002 Amendment 2
16
o
Likert Patient Depressive Symptom Scales: Participants will be instructed by site staff to 
complete the Likert assessments at home on Day 9 and Day 10 (between Visit 10 and 
Visit 11) and on Day 12 and Day 13 (between Visit 11 and Visit 12/ET). The date and 
time each Likert assessment was completed are also to be recorded. The Likert 
assessments on days when the participant has a clinic visit (Visit 11 [Day 11] and 
Visit 12 [Day 14/ET]) will be completed by the participant in the clinic (ie, the 
participant will not complete the Likert assesssment at home on these days). 
Safety Follow-Up Period (Visit 13 [Day 18] and Visit 14 [Day 21])

Participants completing the double-blind treatment period should enter the 1-week safety 
follow-up period. Participants who prematurely discontinue from the study before 
completing 2 weeks of double-blind treatment should complete the early termination (ET) 
visit and then enter the 1-week safety follow-up period.
o
A Patient Diary of Likert scales will be provided at Visit 12/ET (Day 14/ET) and at 
Visit 13 (Day 18). The Patient Diary will include Likert scales, and participants will be 
instructed by site staff to complete the Likert assessments at home on Days 15, 16, and 17 
(between Visits 12 and 13) and on Days 19 and 20 (between Visits 13 and 14). The date 
and time each Likert assessment was completed are to be recorded. The Likert 
assessment on the day of Visit 13 will be completed by the participant in the clinic 
(ie, the participant will not complete the Likert assesssment at home on this day).
o
Additional follow-up visits may be scheduled within 30 days of last dose of study 
medication or last study visit, if necessary, for safety reasons.
Study Design Diagram – Part B


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AGN-241751
Protocol 3125-104-002 Amendment 2
17
Number of Participants:
Part A:
In Part A, approximately 100 participants who meet eligibility criteria at Visit 2 (Day 1 of the 
randomized inpatient treatment) will be randomly assigned to study treatment such that 
approximately 25 participants per arm will be allocated in a 1:1:1:1 ratio.
Part B:
In Part B, approximately 120 participants who meet eligibility criteria will be randomly assigned 
at Visit 3 (Day 1) to receive study treatment starting on Day 1 such that approximately 
40 participants per arm will be allocated in a 1:1:1 ratio. Participants who enrolled (were 
randomized) in Part A will not be permitted to screen into Part B (and vice versa).
Treatment Groups and Study Duration:
Part A Treatment Groups: AGN-241751 3 mg, 10 mg, and 25 mg and placebo, dosed weekly 
and then once daily for 14 days.
Part B Treatment Groups: AGN-241751 3 mg and 25 mg and placebo, dosed BID for 14 days.
Study Duration: approximately 5 weeks
Dosage Regimen: 
Part A:
During the 2-week double-blind treatment period, a single tablet of double-blind study treatment 
(placebo, AGN-241751 3 mg, 10 mg, or 25 mg) will be administered orally on Day 1 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, Days 2 through 7. On Day 8, a single tablet of double-blind study treatment 
(placebo, AGN-241751 3 mg, 10 mg, or 25 mg) will be administered orally in the clinic. A bottle 
of double-blind study treatment will be dispensed for the participant to take 1 tablet once daily 
by oral ingestion through the remainder of that corresponding week, Days 9 through 15.
Part B:
During the 1st week of the double-blind BID treatment period (inpatient), randomized 
participants will be dosed BID from Bottle 1 starting at Visit 3 (Day 1) through Visit 9 (Day 7) 
in the clinic. Each day, participants will be administered a single tablet of double-blind study 
treatment (AGN-241751 3 mg, AGN-241751 25 mg, or placebo) orally in the morning after the 
daily predose assessments are completed, and another single tablet will be administered 8 hours 
(± 1 hour) after the morning dose. On Visit 10 (Day 8), Bottle 2 will be dispensed. The 1st tablet 
from Bottle 2 will be taken in the clinic after predose assessments are completed. Upon discharge 
at Visit 10 (Day 8), the participant will take Bottle 2 home. The 2nd tablet from Bottle 2 will be 
taken at home by the participant in the afternoon on Day 8. Participants will continue to take 
1 tablet in the morning and take the 2nd tablet in the afternoon daily at home by oral ingestion 
starting in the afternoon of Visit 10 (Day 8) through Visit 12/ET (Day 14/ET). During the 
outpatient period of the study, participants should try to adhere to the relative dosing times used 


CONFIDENTIAL
AGN-241751
Protocol 3125-104-002 Amendment 2
18
within the inpatient phase (ie, morning and afternoon doses, approximately 8 hours apart).
Should a dose not be administered accordingly, the participant should be instructed as follows:

If within 4 hours of the scheduled dosing time, the participant should take the dose as 
soon as possible and continue to proceed with the relative dosing times used within the 
inpatient phase.

If greater than 4 hours from the scheduled dosing time, the participant should abstain 
from taking this dose and proceed with the next dose at the subsequent scheduled dosing 
time used within the inpatient phase. 
Number of Sites:
Approximately 5 sites in the United States (Part A) and approximately 3 to 6 sites in the United 
States (Part B)


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AGN-241751
Protocol 3125-104-002 Amendment 2
19
2.
Schedule of Activities (SoA)
2.1.
Part A
Double-blind Treatment Period
Safety Follow-up 
Period
Visit
Screening (1)
2
3
4
5
6/ETa
7
Study Day
up to –14 days
1
2
8
9
15
22
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
x
Urine drug screen
x
x
Serum pregnancy test
x
x
Pharmacogenomics consent and samplec
x
Vital signsd
x
x
x
x
x
x
x
ECG
x
x
Physical examination
x
x
SCID
x
MADRS
x
x
x
x
x
x
x
CGI-S
x
x
x
x
x
x


CONFIDENTIAL
AGN-241751
Protocol 3125-104-002 Amendment 2
20
Double-blind Treatment Period
Safety Follow-up 
Period
Visit
Screening (1)
2
3
4
5
6/ETa
7
Study Day
up to –14 days
1
2
8
9
15
22
BPRS+
x
x
x
x
x
CADSS
x
x
x
x
x
C-SSRS
x
x
x
x
x
x
x
HAM-Ae
x
x
x
x
AEs
x
x
x
x
x
x
Concomitant medications
x
x
x
x
x
x
x
Study treatment administration in the clinic
x
x
Study treatment compliance
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. 
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 4 and 5 must be conducted 1 day apart). 
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 laboratory 
blood tests. Clinical laboratory tests can be done at any visit for safety reasons at the discretion of the investigator.
c
A separate ICF must be signed before the pharmacogenomic blood sample is taken. Participation is optional. This ICF may be signed at any visit during the study; 
however, the sample should be collected at any visit after the participant has been randomized.
d
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.
e
HAM-A will be assessed predose at Visits 2, 3, 4, and 6/ET.  The HAM-A will be collected only from participants entering the study after the amendment has been 
IRB approved.


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AGN-241751
Protocol 3125-104-002 Amendment 2
21
2.2.
Part B
OutPt
Inpatient
Outpatient
Double-Blind Treatment
Safety 
Follow-
Upa
Visitb
V1
Screeni
ng
V2
Base
-
line
V3
V4
V5
V6
V7
V8
V9
V10
Dis-
charge
V1
1
V12/
ET c,d
V13
V1
4
Study Day
Up to 
14
days
D
–1
Adm
it
D1 (First Day of 
Dosing)
D2
D3 
D4
D5
D6
D7
D8
D1
1
D14/
ET
D18
D2
1
Assessment Time 
Relative to Morning 
Dose (hours) e
N/A
P
r
e
1
&
2
4
8
12
P
r
e
1 
&
2
4
8
12
P
r
e
1
&
2
4
8
12
P
r
e
1
&
2
4
8
12
P
r
e
4
8
12
P
r
e
4
8
12
P
r
e
4
8
12
P
r
e
4
N/A
ICF
X
MedHx/PsyHx
X
Prior & ConMed
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Exam
X
X
Incl/Excl
X
X
Vital Signs f
X
X
X
X
X
X
Randomize
X
SCID
X
Likert Patient 
Depressive Symptom 
Scales 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
MADRS
X
X
X
g
X
X
X
X
X
X
CGI-S 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
C-SSRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CADSS
X
X
X
X
X
BPRS+
X
X
X
X
X
X
ECG 
X
X
X
Clinical Laboratory 
Determinations h,i
X
X
X
X
Hepatitis Serology
X
Urine Drug Screenj
X
X
X
X
Serum Pregnancy 
Test k
X
X
X
X
Pharmacogenetic 
Consent and 
X


CONFIDENTIAL
AGN-241751
Protocol 3125-104-002 Amendment 2
22
OutPt
Inpatient
Outpatient
Double-Blind Treatment
Safety 
Follow-
Upa
Visitb
V1
Screeni
ng
V2
Base
-
line
V3
V4
V5
V6
V7
V8
V9
V10
Dis-
charge
V1
1
V12/
ET c,d
V13
V1
4
Study Day
Up to 
14
days
D
–1
Adm
it
D1 (First Day of 
Dosing)
D2
D3 
D4
D5
D6
D7
D8
D1
1
D14/
ET
D18
D2
1
Assessment Time 
Relative to Morning 
Dose (hours) e
N/A
P
r
e
1
&
2
4
8
12
P
r
e
1 
&
2
4
8
12
P
r
e
1
&
2
4
8
12
P
r
e
1
&
2
4
8
12
P
r
e
4
8
12
P
r
e
4
8
12
P
r
e
4
8
12
P
r
e
4
N/A
Sampling (Opt.) l
HVLT-R m
X
X
X
X
X
X
X
KSS/qEEG/ERP 
(mid-day)
X
KSS/qEEG/ERP 
(afternoon)
X
KSS/qEEG/ERP n,o
X
X
X
X
X
X
X
X
X
X
X 
X
CSF Pre-Dose 
Consent and 
Sampling
(Opt. 1x per pt.) p
X
CSF Post-Dose 
Consent and 
Sampling
(Opt. 1x per pt.) p
X
Adverse Event
X
Rescue Med (Sleep/
Benzo) q
None
PRN (withhold 12 hours prior to scale assessments and qEEG/ERPs)
Provide Patient Diary
X
X
X
X
Return & Review 
Diary
X
X
X
X
Assign/Dispense
study treatment
X
X
Study Treatment
Compliance (Return)
X
X
X
Discharge Pt r
X


CONFIDENTIAL
AGN-241751
Protocol 3125-104-002 Amendment 2
23
Benzo=benzodiazepines; B/L=baseline; D=day; ET=early termination; Excl=exclusion; h=hour(s); ICF=informed consent form; Incl=inclusion; LFT=liver function test; MedHx=medical 
history; PD1=post first dose; PRN=as needed; PsyHx=psychiatric history; Pt=participant; OutPt=outpatient; V=visit.
a If necessary, these study visits may be conducted up to 1 day before or after the scheduled visit day.
b During the inpatient treatment period, participants will have 7 visits (Visits 3 to 9); each visit will occur daily with no visit windows.A Patient Diary containing a Study Medication Dosing 
Log and Likert scales will be provided at Visits 10 and 11 for completion by the participant at home. In addition, the Patient Diary will be provided during the safety follow-up period at 
Visit 12 and at Visit 13. Participants will return the diary for review by site staff at Visits 11 through 14.
c 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 may be scheduled.
d This visit is performed for all participants who received at least 1 dose of study treatment.
e Assessments at a given timepoint should be conducted ± 20 minutes of each other, and all psychiatric assessments (Likert Patient Depressive Symptom Scales, CSSR-S, MADRS, and 
CGI-S) are to be completed first prior to any other assessments.
f Height will be measured only at Visit 1 (Screening); pulse rate, blood pressure, temperature, and body weight will be assessed at the visits indicated in the table. Blood pressure and pulse 
rate will be assessed while the participant is supine and standing.
g If significant change (worsening or improvement in depressive symptoms) at Visit 3 (Day 1) prior to morning dosing based on the judgment of the PI, a MADRS assessment should be 
performed prior to the 1st dose of study medication.
h Abnormal LFT values will be repeated (refer to Section 9.4.4 and Appendix 2 for details).
i Participants will be requested to fast for at least 8 hours.
j Participants with a positive UDS at Visit 1 may be allowed in the study provided certain circumstances are met (seeSection 6.2). Participants testing positive for cocaine, barbiturates, 
methadone, or phencyclidine in the UDS at Visit 1 should be excluded from the study, with no exceptions.
k A urine pregnancy test should be done on Day –1 (at baseline), if more than a week has passed since the serum pregnancy test was done at Screening. Additional urine pregnancy tests may 
be done at the PI’s discretion throughout the study. If urine test is positive at Day –1 (baseline) or at any time during the study, a serum β-hCG pregnancy test should be done for 
confirmation. Serum pregnancy tests may be conducted at other visits not indicated per Investigator judgment.
l A separate consent will be collected at Screening (or prior to sample collection) for optional pharmacogenetic sampling. If participants are randomized and consent to this sampling, the 
sample will be collected predose at Visit 9 (Day 7). 
m Withhold nicotine 1 hour before assessment.
n KSS is to be completed prior to qEEG/ERP assessments. Error windows permitted for the qEEG measurements will be ± 30 minutes at any collection timepoint up to 12 hours postdose 
and ± 1 hour at any collection timepoint up to 24 hours postdose. The qEEG/ERP test times should not be confounded by food intake; eg, if baseline is done 30 minutes after lunch, the test 
should be 30 minutes after lunch. The ERPs will be measured approximately 10 minutes following each corresponding qEEG measurement.
o To be conducted at selected sites.
p CSF optional at all sites; preferred at V5 (if not done at V5, sample can be taken at V4 or V6). Within each site, 1 sample (either pre-dose or post-dose sample) per participant will be 
collected, and study staff will alternate between predose and postdose for participants (eg, 1st patient sample is collected predose, 2nd participant sample is collected postdose, 3rd 
participant sample is collected predose, etc.). 
q Withhold 12 hours prior to psychiatric and qEEG/ERP assessments.
r Discharge post qEEG/ERP.


CONFIDENTIAL
AGN-241751
Protocol 3125-104-002 Amendment 2
24
3.
Introduction
Disease Burden of 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
SSRIs and 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 et al 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).
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 


CONFIDENTIAL
AGN-241751
Protocol 3125-104-002 Amendment 2
25
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 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 to or failing current 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 
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 


CONFIDENTIAL
AGN-241751
Protocol 3125-104-002 Amendment 2
26
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 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 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 (0.25 mg up to 25 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 Tmax at 
1 hour post dose in rats. Brain to plasma and CSF to plasma 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 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, 


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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.
Data from completed and 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 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 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 2-part (Part A and Part B) proof-of-concept study of AGN-241751 monotherapy
for the treatment of patients with MDD. Part A includes weekly and once daily administrations 
of AGN-241751, and Part B includes BID administration. Part B participants should not have 
participated in Part A at any time, and Part A participants should not have participated at any 
time in Part B (ie, Part A is not a contingent step to participate in Part B).
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.


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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
Clinical Hypothesis
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.
4.1.
Part A
The primary objective of Part A is to evaluate the efficacy, as measured by improvement in 
MADRS total score, at 1 day after the initial single oral dose of AGN-241751 compared with 
placebo in participants with MDD (Day 1 [predose, defined as baseline] vs Day 2). The key 
secondary objectives are to evaluate the efficacy at Day 8, at Day 9 after single oral dose, at
Day 15 after repeated dose, and at Day 22, 7 days after the completion of AGN-241751 dosing, 
when administered orally once daily compared with placebo in participants with MDD.
Objectives
Endpoints
Primary

To evaluate the efficacy at 1 day post 
the initial single oral dose of 
AGN-241751 compared with placebo 
in participants with MDD

Change from baseline (Day 1, predose) in 
MADRS total score at 1 day after the first 
dose of treatment (Day 2)
Key Secondary

To evaluate the efficacy at Day 8, at 
Day 9 (single dose), at Day 15 (repeated 
dose) of AGN-241751 administered 
orally once daily, and at Day 22 (7 days 
after completion of AGN-241751 
dosing) compared with placebo in 
participants with MDD

Change from baseline (Day 1, predose) in 
MADRS total score at Day 8, Day 9, Day 15, 
and Day 22
Additional

Additional endpoint to be explored to 
determine differences between 
AGN-241751 and placebo in 
participants with MDD

Change from baseline in CGI-S total score at 
Day 2, Day 8, Day 9, and Day 15 

Rate of responders on MADRS or CGI S at 
Day 2, Day 8, Day 9, Day 15, and Day 22

Rate of remitters on MADRS at Day 2, Day 
8, Day 9, Day 15, and Day 22

Time to first response on MADRS

Time to first remission on MADRS

Change from baseline (Day 1, predose) in 
HAM-A at Day 2, Day 8, and Day 15


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Objectives
Endpoints

Safety Measures

AE recording, clinical laboratory measures, 
vital sign parameters, ECGs, and physical 
examinations

Measure of psychotomimetic effects: BPRS+ 

Measure of dissociative effects: CADSS

Measure of suicidality: C-SSRS
4.2.
Part B
The primary objective of Part B is to evaluate the efficacy of the change from baseline in 
MADRS total score at 7 days after the 1st dose of AGN-241751 (3 mg and 25 mg) compared 
with placebo in participants with MDD. The key secondary objectives are to evaluate the 
efficacy at Day 2, Day 11, Day 14, Day 18, and Day 21 after the 1st dose of AGN-241751 (3 mg 
and 25 mg) compared with placebo in participants with MDD. In addition, optional CSF samples 
will be collected in a subset of participants for PK analysis, and qEEG and ERP assessments will 
be collected in a subset of participants for pharmacodynamic analysis.
Objectives
Endpoints
Primary

To evaluate the efficacy at Day 7 of 
AGN-241751 compared with placebo in 
participants with MDD dosed BID

Change from baseline in MADRS at 
7 days after the first dose of treatment
Key Secondary

To evaluate the efficacy on Day 2,
Day 11, Day 14, Day 18, and Day 21
(7 days after completion of dosing) after 
BID administration of AGN-241751 
compared with placebo in participants 
with MDD dosed BID

Change from baseline in MADRS total 
score at Day 2, Day 11, Day 14, Day 18, 
and Day 21 


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Objectives
Endpoints
Additional

Additional endpoints to be explored to 
determine differences between 
AGN-241751 and placebo in participants 
with MDD dosed BID

Change from baseline in CGI-S total score 
by visit

Rate of responders on MADRS at Day 2, 
Day 7, Day 11, Day 14, Day 18, and 
Day 21

Rate of remitters on MADRS at Day 2, 
Day 7, Day 11, Day 14, Day 18, and 
Day 21

Rate of responders on CGI-S by visit 

Time to first response on MADRS

Time to first remission on MADRS

Symptoms over time based on Likert 
Patient Depressive Symptom Scales

Total recall scores at specified timepoints 
in HVLT-R

Evaluation of pharmacodynamic 
endpoints (qEEG/ERP) and CSF between 
AGN-241751 and placebo in participants 
with MDD dosed BID

Change from baseline in qEEG 
parameters collected during Day 1, Day 7, 
Day 14, and Day 21

Change from baseline in ERP parameters 
collected during Day 1, Day 7, Day 14, 
and Day 21

Descriptive analysis of CSF 
concentrations of AGN-241751

Safety Measures

AE recording, clinical laboratory 
measures, vital sign parameters, ECGs, 
and physical examinations

Measure of psychotomimetic effects: 
BPRS+ 

Measure of dissociative effects: CADSS

Measure of suicidality: C-SSRS


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5.
Study Design
5.1.
Overall Design
Part A of this study is a multicenter, randomized, double-blind, placebo-controlled, 
parallel-group (4 arms), weekly and once daily dose, 2-week double-blind treatment in 
participants with MDD. Part B of this study is a multicenter, randomized, double-blind, 
placebo-controlled, parallel-group (3 arms), BID dose, 2-week double-blind treatment in 
participants with MDD.  
5.1.1.
Part A
Part A of the study will include a total of 7 visits and will be approximately 5 weeks in duration:

Up to 2-week screening period 

2-week double-blind treatment period 

1-week safety follow-up period 
After providing written consent, participants will enter a screening period of up to 14 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. Participants meeting the eligibility 
criteria at the end of Visit 2 (Day 1 of the randomized inpatient treatment) will be assigned a 
treatment and enter the double-blind treatment period.
Approximately 100 participants are planned for enrollment in the double-blind treatment period 
(25 participants each in 3 different AGN-241751 dose groups and a placebo group). Participants 
will be randomized in a ratio of 1:1:1:1 to 1 of 4 treatment groups: 3 mg, 10 mg, and 25 mg dose 
AGN-241751 and placebo.  All participants will be randomized to receive active treatment or 
placebo (Day 1 and Days 8 to 15) and placebo alone (Days 2 through 7). 
AGN-241751 is being developed for once-weekly dosing; however, the impact of repeated
administration of AGN-241751 requires testing. In order to minimize participant’s expectations 
and control for placebo response while changing dosing regimens, all treatments will be 
presented to participants as oral daily dosing throughout the study. On Day 1, all participants will 
be randomized to receive the first treatment (ie, 4 treatment groups: 3 mg, 10 mg, and 25 mg 
dose AGN-241751 or placebo), followed by blinded placebo on Days 2 through 7.  Starting on 
Day 8, participants will then start 7 consecutive days of randomized treatment, administered 
once daily through Day 15.  
On Day 1, site staff will give the participant the single dose of double-blind study treatment from 
Bottle 1 (for applicable visit) to take by oral ingestion in the clinic (ie, the first dose of study 
treatment for that week). Site staff will then give Bottle 2 (for applicable visits), 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 (Days 2 through 7). On Day 8, site staff will give 


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the participant the single dose of double-blind study treatment from Bottle 1 (for applicable visit) 
to take by oral ingestion in the clinic (ie, the first dose of study treatment for that week). Site 
staff will then give Bottle 2 (for applicable visits), which contains double-blind study treatment, 
to the participant with the instruction to take 1 tablet daily by oral ingestion for the remainder of 
that week (Days 9 through 15).
Participants will have 7 study visits during the study. The first 6 visits will occur in the following 
pattern: the Screening Visit (Visit 1; up to Day –14); at Visit 2 (Day 1 of the randomized 
inpatient treatment); at Visit 3 (1 day following the inpatient treatment day); at Visit 4 (7 days 
following the first inpatient treatment day, which is the 2nd inpatient treatment day); at Visit 5 
(1 day following the 2nd inpatient treatment day); and at Visit 6 (7 days following the 
2nd inpatient 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 4 and 5 must be conducted 1 day apart). Participants will 
enter a 1-week safety follow-up period and return for Visit 7. Participants who prematurely 
discontinue from the study before completing the 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 – Part A
IP Administered
IP Administered


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All treatments will be presented to participants as oral once daily dosing throughout the study. 
Daily dosing of AGN-241751 should occur at a similar time throughout the entire study. 
At Visit 2 (Day 1 of the randomized inpatient treatment), all participants will be randomized to 
receive the first treatment, followed by blinded placebo on Days 2 through 7.
Starting at Visit 4 (Day 8), participants will then start 7 consecutive days of randomized 
treatment, administered once daily through Day 15.
5.1.2.
Part B
Part B of this study will include a total of 14 visits and will be approximately 5 weeks in duration 
as described below.

Up to a 2-week screening period 

2-week double-blind treatment period (Week 1 inpatient, Week 2 outpatient)

1-week outpatient safety follow-up period 
Approximately 120 participants are planned for randomization in the double-blind treatment 
period (40 placebo participants, 40 AGN-241751 3 mg participants, 40 AGN-241751 25 mg 
participants). Eligible participants will be randomized in a ratio of 1:1:1 to one of 3 double-blind 
oral administration treatment groups: 3 mg dose of AGN-241751, 25 mg dose of AGN-241751, 
or placebo, administered BID. Participants who enrolled (were randomized) in Part A will not be 
permitted to screen into Part B (and vice versa).
Screening Period
After providing written consent, participants will enter a screening period of up to 14 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. Participants will wash out of any ADT 
and prohibited medications under the supervision of the study investigator staff during the 
screening period. At Visit 2 (Day –1), study procedures required to determine eligibility will be 
completed prior to admission to the clinic. Participants meeting the eligibility criteria at Visit 2 
(Day –1, Baseline) will be admitted to the inpatient facility, and the remainder of the Visit 2 
study procedures will be completed. A urine pregnancy test should be done on Day –1 (at 
baseline), if more than a week has passed since the serum pregnancy test was done at Screening.
Participants are required to not use any nicotine substances 1 hour prior to administration of the 
HVLT-R.
Double-Blind Treatment Period
Participants will be randomized in a ratio of 1:1:1 to 1 of 3 treatment groups (AGN-241751 3 mg 
BID, AGN-241751 25 mg BID, or placebo BID) for the 2-week double-blind treatment. 
Participants will be administered 1 tablet in the morning and 1 tablet in the afternoon. At Visit 3 
(Day 1), the participant will be randomized and assigned a treatment by the interactive web 
response system (IWRS), and the 1st dose of study medication will be administered in the 
morning after all predose asessments have been completed.


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Week 1 Inpatient Double-Blind Treatment Period 

It is expected that participants in the double-blind treatment period will remain inpatient 
during the 1st week (Visit 2 to Visit 10/Discharge).

During the inpatient treatment period, participants will have 7 visits (Visits 3 to 9); each 
visit will occur daily with no visit windows.

At Visit 3 (Day 1) during the predose evaluation period, if there is a significant change 
(worsening or improvement in depressive symptoms) from the baseline Visit 2 (Day –1) 
MADRS based on the judgment of the PI, a MADRS assessment should be performed prior 
to the 1st dose of study medication.

Participants will be discharged at Visit 10 (Day 8) after all predose assessments, morning 
dosing, and 4-hour postdose assessments are completed.

During the inpatient treatment period, predose assessments will be performed prior to 
morning dosing at all inpatient visits (Visit 3 through Visit 10). Postdose assessments will be 
performed, as follows:
o
Visit 3 to Visit 6: 1, 2, 4, 8, and 12 hours after the morning dose (± 20 minutes) 
o
Visit 7 to Visit 9: 4, 8, and 12 hours after the morning dose (± 20 minutes)
o
Visit 10: 4 hours after the morning dose (± 20 minutes) 

Within each timepoint, multiple assessments will be performed, as follows:
o
Assessments should be performed within  ± 20 minutes of each other
o
All psychiatric assessments (Likert Patient Depressive Symptom Scales, CSSR-S, 
MADRS, and CGI-S) are to be completed first prior to any other assessments (ie, qEEG, 
ERP) within the timepoint.
o
Participants are required to not use any nicotine substances 1 hour prior to administration 
of the HVLT-R.

The afternoon dose of study medication is to be administered 8 hours (± 1 hour) after the 
morning dose.
Week 2 Outpatient Double-Blind Treatment Period

During the outpatient treatment period, there will be 2 visits conducted every 3 days 
(Visit 11 [Day 11] and Visit 12 [Day 14/ET]). If necessary, these study visits may be 
conducted up to 1 day before or after the scheduled visit day.

All participants who receive study medication should complete Visit 12 (Day 14/ET)

At Visit 10 (Day 8) prior to discharge, the participant will be dispensed Bottle 2 of study 
medication (refer to Section 7.1.2 for dosing instruction). Participants will be instructed to 
bring the study medication bottle to Visit 11 for the site staff to confirm dosing compliance

The study medication bottle will be returned at Visit 12; site staff will confirm dosing 
compliance.


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
A Patient Diary will be provided at Visit 10 and Visit 11 for completion by the participant at 
home. At Visits 11 and 12, the participant will return the diary, which was provided at the 
prior visit. Site staff will review the diary to confirm compliance and proper completion of 
the diary. At Visit 11 and Visit 12, prior to leaving the clinic, the participant will be given a 
new diary. 

The Patient Diary will include a Study Medication Dosing Log and Likert scales.
o
Study Medication Dosing Log: Participants will be instructed by site staff to record the 
date and time of the Visit 10 (Day 8) afternoon dose and each subsequent dose the 
participant has taken (morning and afternoon) at home, inclusive of doses on days when 
the participant has a clinic visit (Visit 11 [Day 11] and Visit 12/ET [Day 14/ET]). 
o
Likert Patient Depressive Symptom Scales: Participants will be instructed by site staff to 
complete the Likert assessments at home on Day 9 and Day 10 (between Visit 10 and 
Visit 11) and on Day 12 and Day 13 (between Visit 11 and Visit 12/ET). The date and 
time each Likert assessment was completed are also to be recorded. The Likert 
assessments on days when the participant has a clinic visit (Visit 11 [Day 11] and 
Visit 12 [Day 14/ET]) will be completed by the participant in the clinic (ie, the 
participant will not complete the Likert assesssment at home on these days). 
Safety Follow-Up Period (Visit 13 [Day 18] and Visit 14 [Day 21])

Participants completing the double-blind treatment period should enter the 1-week safety 
follow-up period. Participants who prematurely discontinue from the study before 
completing 2 weeks of double-blind treatment should complete the early termination (ET) 
visit and then enter the 1-week safety follow-up period.
o
A Patient Diary of Likert scales will be provided at Visit 12/ET (Day 14/ET) and at 
Visit 13 (Day 18). The Patient Diary will include Likert scales, and participants will be 
instructed by site staff to complete the Likert assessments at home on Days 15, 16, and 17 
(between Visits 12 and 13) and on Days 19 and 20 (between Visits 13 and 14). The date 
and time each Likert assessment was completed are to be recorded. The Likert 
assessment on the day of Visit 13 will be completed by the participant in the clinic 
(ie, the participant will not complete the Likert assesssment at home on this day).
o
Additional follow-up visits may be scheduled within 30 days of last dose of study 
medication or last study visit, if necessary, for safety reasons.


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Figure 5–2
Study Design Diagram – Part B
5.2.
Participant and Study Completion
5.2.1.
Part A
Approximately 100 participants who meet eligibility criteria at Visit 2 (Day 1 of the randomized 
inpatient treatment) will be randomly assigned to study treatment such that approximately 
25 participants per arm will be allocated in a 1:1:1:1 ratio.
5.2.2.
Part B
Approximately 120 participants who meet eligibility criteria will be randomly assigned at 
Visit 3 (Day 1) to double-blind study treatment starting on Day 1 such that approximately 
40 participants per arm will be allocated in a 1:1:1 ratio. Participants who enrolled (were 
randomized) in Part A will not be permitted to screen into Part B (and vice versa).
5.3.
End of Study Definition
The end of the study is defined as the completion of enrollment (Part A)/randomization (Part B)
and completion of all periods of the study. Part A and Part B will each end when the last enrolled
(Part A)/randomized (Part B) patient terminates the study.
A participant is considered to have completed the study if he/she has completed the double-blind 
treatment period of the study.


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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. 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 (3 mg, 10 mg, and 25 mg weekly and daily in Part A 
and 3 mg and 25 mg BID in Part B) 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, the doses for each part are expected to
provide similar clinical exposures that demonstrated potentiation of NMDAR activity; 
strengthening NMDAR-dependent LTP; and producing lasting anti-depressant-like effects in 
rat models. 

Given the similar mechanism of activity with rapastinel and ketamine (ie, NMDA 
modulation), single-dose administration of AGN-241751 may result in lasting improvements 
in MADRS scores and, therefore, justifying the weekly interval between dosing within 
Part A. Conversely, more frequent dosing of AGN-241751 may be required for 
improvement in MADRS scores. As such, once daily and BID administration of 
AGN-241751 may be required to result in lasting improvements in MADRS scores and,
therefore, justifying the once daily and BID administration in Part A and Part B, 
respectively.

Within healthy volunteers, there was evidence from multiple pharmacodynamic tests 
(qEEG) that AGN-241751 had beneficial effects on electroencephalographic parameters, 
such as activation and increasing dominant frequency at doses up to 25 mg. As such, similar 
doses are being utilized within this study.

Compared to the available preclinical toxicology studies, the proposed top doses of 25 mg 
(Part A) or 25 mg BID (Part B) are expected to result in substantial margins below the 
28-day study NOAELs designated in the rat (225-fold) and dog (4-fold).

AGN-241751 has demonstrated acceptable safety and tolerability when administered in 
doses of 50 mg administered once or 50 mg administered daily for 10 consecutive days in 
healthy male and female volunteers. Hence, it is expected that the proposed top dose in 
Part B of 25 mg BID, for 14 consecutive days, will likely 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. 
Inclusion criteria apply to Parts A and B unless otherwise noted.
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 DSM-5 criteria (American Psychiatric Association 2013) for MDD (based on 
confirmation from the modified 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 at both Screening 
(Visit 1) and Visit 2 (Day 1 in Part A and Day –1 [Baseline] in Part B).
5. Have a CGI-S score ≥ 4 at both Screening (Visit 1) and Visit 2 (Day 1 in Part A and 
Day –1 [Baseline] in Part B).
6. Part A: Have a negative serum β-human chorionic gonadotropin (β-hCG) pregnancy test at 
Screening (Visit 1) if a WOCBP. Part B: If a WOCBP, have a negative serum β-hCG 
pregnancy test at Screening (Visit 1) AND a negative urine pregnancy test on Day –1 
(baseline), if more than a week has passed since the serum pregnancy test at Screening. If 
urine pregnancy test is positive on Day –1, then a serum β-hCG pregnancy test should be 
done for confirmation.
7. 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 4 to 5 weeks after the last dose of study treatment.


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8. 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 
10 weeks after the last dose of study treatment and refrain from donating sperm during 
this period. 
9. Able, as assessed by the investigator, and willing to follow study instructions and likely to 
complete all required study visits.
10. Normal physical-examination findings, clinical-laboratory test results, and 12-lead ECG 
results from Screening or abnormal results that are determined to be not clinically 
significant by the investigator.
11. BMI within the range 18 and 40 kg/m2 (inclusive).
6.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply. Exclusion criteria 
apply to Parts A and B unless otherwise noted.
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
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 Screening (Visit 1).


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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 
the following:
a.
Adjunctive treatment with an antipsychotic or inadequate response to ECT, a 
monoamine oxidase inhibitor, or ketamine
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 
Screening (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 Screening (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.
Having received in the current episode more than 2 ADTs, either in combination or 
sequentially, for an adequate dose and duration
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 Screening (Visit 1) from the UDS test for any prohibited medication.
Exception: Participants with a positive UDS at Screening for opiates, cannabinoids, or 
episodic use of benzodiazepines (ie, up to approximately 2 mg/day lorazepam equivalent 
dose and for up to 3 consecutive days at a time) given for anxiety-related conditions and 
agitation may be allowed in the study provided:
a.
The drug was used for a legitimate medical purpose.
b.
The drug can be safely discontinued prior to participation in the study (except for 
episodic use of benzodiazepines which may be continued). 
Part B participants who have regularly been using benzodiazepines (even for 
legitimate medical purposes) for more than 2 months should not be included in the 
study if there is doubt that the medication can be safely discontinued during 
screening.
AND


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c.
A repeat UDS is negative for these substances prior to enrollment (except for episodic 
use of benzodiazepines which may be continued). 
Part B participants who have regularly been using benzodiazepines (even for 
legitimate medical purposes) for more than 2 months should not be included in the 
study if there is doubt that the medication can be safely discontinued during 
screening.
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 Screening (Visit 1) or Visit 2
c.
MADRS Item 10 score ≥ 5 at Screening (Visit 1) or Visit 2 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. Initiation or termination of psychotherapy for depression within the 3 months preceding 
Screening (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.)
13. Ongoing treatment with phototherapy, or termination of phototherapy within 1 month of 
Visit 1.
14. Known allergy or sensitivity to the study medication or its components.
Other Medical Criteria
15. BMI < 18 kg/m2 or > 40 kg/m2 at Screening. 
16. Females who are pregnant, breastfeeding, or planning to become pregnant or breastfeed 
during the study.
17. WOCBP and male partners of WOCBP, not using a reliable means of contraception 
(Appendix 5).


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18. 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.
19. Any cardiovascular disease that is clinically significant, unstable, or decompensated.
20. Heart rate (supine) of ≤ 45 bpm or ≥ 120 bpm, or any heart rate that is clinically 
symptomatic at Screening (Visit 1) or Visit 2 based upon vital signs.
21. Any systolic and/or diastolic BP that is symptomatic or clinically significant in the 
opinion of the investigator.
22. History of congenital QTc prolongation or QTc prolongation (screening ECG with QTcF 
≥450 msec for men and QTcF ≥ 470 msec for women).
23. Hypothyroidism or hyperthyroidism, unless stabilized on appropriate pharmacotherapy 
with no change in dosage for at least 1 month before Screening (Visit 1).
24. History of seizure disorder, stroke, significant head injury, tumor of the central nervous 
system, or any other condition that predisposes to seizure.
25. Known HIV infection.
26. Positive hepatitis C antibody on screening, with the exception of participants for whom 
the reflex HCV RNA test is negative.
27. Positive test for hepatitis B surface antigen and/or hepatitis B core antibody 
immunoglobulin M.
28. Part A: Screening liver enzyme test (AST and/or ALT) results > 2 times the ULN. 
Part B: History of, or symptoms/signs suggestive of, liver cirrhosis, OR Screening liver 
enzyme test (AST and/or ALT) results > 1.5 times the ULN.
29. Part B: Previously diagnosed hearing loss; current hearing aid users (within the last 
6 months), or history of gross hearing loss, such as conductive hearing loss, congenital 
hearing loss, sudden hearing loss, hearing loss due to recent noise or occupational 
exposure.


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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 (Part A) or within 3 months of entry into 
this study (Part B). 
31. Part A: Prior participation in any investigational study of AGN-241751. Part B: Prior 
participation in any investigational study of AGN-241751, rapastinel, ketamine, or 
esketamine. Part B participants should not have participated in Part A at any time, and 
Part A participants should not have participated in Part B at any time (ie, Part A is not a 
contingent step to participate in Part B).
32. Employee, or immediate relative of an employee, of the sponsor, any of its affiliates or 
partners, or the study center. 
33. 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.
6.3.
Lifestyle Restrictions
6.3.1.
Meals and Dietary Restrictions
None
6.3.2.
Caffeine, Alcohol, and Tobacco
Participants should refrain from consuming alcohol during the entire 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 
CONSORT publishing requirements and to respond to queries from regulatory authorities. 
Minimal information includes demography, screen failure details, eligibility criteria, and any 
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
7.1.1.
Part A
On Day 1, site staff will give the participant the single dose of double-blind study treatment from 
Bottle 1 (for applicable visit) to take by oral ingestion in the clinic (ie, the first dose of study 
treatment for that week). Site staff will then give Bottle 2 (for applicable visits), 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 (Days 2 through 7). On Day 8, site staff will give 
the participant the single dose of double-blind study treatment from Bottle 1 (for applicable visit) 
to take by oral ingestion in the clinic (ie, the first dose of study treatment for that week). Site 
staff will then give Bottle 2 (for applicable visits), which contains double-blind study treatment, 
to the participant with the instruction to take 1 tablet daily by oral ingestion for the remainder of 
that week (Days 9 through 15).
Study Treatment Name
AGN-241751
Placebo
Dosage Formulation
Tablet
Tablet
Unit Dose Strengths
3 mg
10 mg
25 mg
-
Route of Administration
Oral
Oral
Dosing Instructions
(Part A)
At Day 1, the first dose from 
Bottle 1 (for applicable visit) given 
by site staff to the participant for
oral ingestion in the clinic; Bottle 2 
(for applicable visits) will be given 
to participant to take home with 
instructions to take 1 tablet orally 
every day for the rest of the week.
At Day 8, the first dose from 
Bottle 1 (for applicable visit) given 
by site staff to the participant for 
oral ingestion in the clinic; Bottle 2 
(for applicable visits) will be given 
to participant to take home with 
instructions to take 1 tablet orally
every day for the rest of the week.
Same as for active treatment


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Study Treatment Name
AGN-241751
Placebo
Packaging and Labeling
Allergan will provide study 
treatment in the form of identically 
appearing tablets containing 
AGN-241751 doses of 3 mg, 
10 mg, 25 mg, or placebo. 
All participants will receive 
single-blind placebo tablets for 
Days 2 to 7.
Allergan will provide study 
treatment in the form of identically 
appearing tablets containing 
AGN-241751 doses of 3 mg, 
10 mg, 25 mg, or placebo. 
Manufacturer
Allergan, Inc.
Allergan, Inc.
7.1.2.
Part B
During the 1st week of the double-blind BID treatment period, the randomized participant will be 
dosed BID from Bottle 1 starting at Visit 3 (Day 1) through Visit 9 (Day 7) in the clinic. Each 
day, participants will be administered a single tablet of double-blind study treatment 
(AGN-241751 3 mg, AGN-241751 25 mg, or placebo) orally in the morning after the daily 
predose assessments are completed, and another single tablet will be administered 8 hours 
(± 1 hour) after the morning dose. At Visit 10 (Day 8), Bottle 2 will be dispensed. The 1st tablet 
from Bottle 2 will be taken in the clinic after predose assessments are completed. Upon discharge 
at Visit 10 (Day 8), the participant will take Bottle 2 home. The 2nd tablet from Bottle 2 will be 
taken at home by the participant in the afternoon on Day 8. Participants will continue to take 
1 tablet in the morning and take the 2nd tablet in the afternoon daily at home by oral ingestion 
starting in the afternoon of Visit 10 (Day 8) through Visit 12/ET (Day 14/ET). During the 
outpatient period of the study, participants should try to adhere to the relative dosing times used 
within the inpatient phase (ie, morning and afternoon doses, approximately 8 hours apart). 
Should a dose not be administered accordingly, the participant should be instructed as follows:

If within 4 hours of the scheduled dosing time, the participant should take the dose as soon 
as possible and continue to proceed with the relative dosing times used within the inpatient
phase.

If greater than 4 hours from the scheduled dosing time, the participant should abstain from 
taking this dose and proceed with the next dose at the subsequent scheduled dosing time 
used within the inpatient phase. 


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Study Treatment Name
AGN-241751
Placebo
Dosage Formulation
Tablet
Tablet
Unit Dose Strengths
3 mg
25 mg
NA
Route of Administration
Oral
Oral
Dosing Instructions
(Part B)
Starting with inpatient Visit 3 
(Day 1; after the participant has 
been in the inpatient unit since the 
previous day), participants will be 
administered 1 tablet in the morning 
and 1 tablet in the afternoon from 
Bottle 1 after all predose asessments 
have been completed. From Days 2 
to 7 inpatient, each day the site staff 
will give the participant 1 tablet in 
the morning and 1 tablet in the 
afternoon at 8 hours (± 1 hour) after 
the morning dose, administered 
from Bottle 1.
At Visit 10 (Day 8) prior to 
discharge, the participant will be 
dispensed Bottle 2 of study 
treatment and will be instructed to 
each day take 1 tablet in the 
morning and 1 tablet in the 
afternoon at 8 hours (± 1 hour) after 
the morning dose. Participants will 
also be instructed to bring the 
unused study treatment to 
Visits 11 and 12 for the site staff to 
confirm dosing compliance. 
A Patient Diary containing a Study 
Medication Dosing Log will be 
provided at Visits 10 and 11 for 
completion by the participant at 
home. Participants will be 
instructed by site staff to record the 
date and time of the Visit 10 
(Day 8) afternoon dose and each 
subsequent dose taken (morning 
and afternoon) at home, inclusive of 
doses on days when the participant 
has a clinic visit (Visit 11 and 
Visit 12/ET).
Same as for active treatment


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Study Treatment Name
AGN-241751
Placebo
At Visits 11 and 12, the participant 
will return the diary provided at the 
prior visit. Site staff will review the 
diary to confirm compliance and 
proper completion of the diary. At 
Visits 11 and 12, prior to leaving 
the clinic, the participant will be 
given a new diary.
Packaging and Labeling
Allergan will provide double-blind
study treatment in the form of 
identically appearing tablets 
containing AGN-241751 doses of
3 mg, 25 mg, or placebo. 
Allergan will provide double-blind 
study treatment in the form of 
identically appearing tablets 
containing AGN-241751 doses of
3 mg, 25 mg, or placebo. 
Manufacturer
Allergan, Inc.
Allergan, Inc.
7.2.
Dose Modification
Dose modification is not allowed in either Part A or Part B.  For Part B, should a dose not be 
administered accordingly, the participant should be instructed as follows:

If within 4 hours of the scheduled dosing time, the participant should take the dose as soon 
as possible and continue to proceed with the relative dosing times used within the inpatient
phase. 

If greater than 4 hours from the scheduled dosing time, the participant should abstain from 
taking this dose and proceed with the next dose at the subsequent scheduled dosing time 
used within the inpatient phase. The participant should record this as a missed dose within 
the diary.
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 2.1 [Part A] and Section 2.2 [Part B]). 
Returned study treatment should not be re-dispensed to the participants.
7.4.
Blinding/Masking
For both Part A and Part B, 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 


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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 after breaking the blind. The date and reason that the blind was broken must be 
recorded in the source documentation and 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 to 8°C) and must be protected from 
heat and moisture. Once the bottles are dispensed to participants, they can be stored at room 
temperature.
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 randomized 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
7.6.1.
Part A
Compliance with administration of double-blind study treatment in the clinic at Visits 4 and 6
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. 


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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. 
7.6.2.
Part B
Site staff personnel will administer morning and afternoon doses of double-blind study treatment 
to the participant during the inpatient double-blind treatment period (Visit 3 [Day 1] through 
Visit 10 [Day 8]) each day and will capture the date and time the participant ingested each dose. 
If a scheduled ingestion does not occur, the reason must be captured in the eCRF.
During the outpatient double-blind treatment period, participants will be instructed by site staff 
to try to adhere to the relative dosing times used within the inpatient phase (ie, morning and 
afternoon doses, approximately 8 hours apart). Should a dose not be administered accordingly, 
the participant should be instructed as per Section 7.2.
During the 2nd week of the outpatient double-blind treatment period from Visit 10 (Day 8) 
afternoon dose through Visit 12/ET (Day 14/ET), participants will be instructed to record the 
date and time of the morning and afternoon dose and any missed doses on the Study Medication 
Dosing Log in the Patient Diary on each day. The participant will be instructed to bring the study 
medication bottle to the clinic at Visit 11 and at Visit 12/ET. The outpatient dosing compliance 
will be monitored by site staff personnel at Visit 11 (Day 11) and Visit 12/ET (Day 14/ET) by 
reconciling the number of tablets in the bottle at each visit and by reviewing the dosing log in the 
Patient Diary (see Section 5.1.2).
Study center personnel will make every effort to collect all unused study treatment and empty 
bottles on Visit 12/ET (Day 14/ET). 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.
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.


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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, as follows:
Part A—not permitted within 8 hours of psychiatric or neurological measures
Part B—not permitted within 12 hours of psychiatric or neurological measures or a scheduled 
qEEG/ERP measurement
The medications are permitted at the following doses:

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 (Part A) or within 12 hours (Part B) of 
psychiatric or neurological assessments or a scheduled qEEG/ERP measurement.
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 psychiatric or neurological assessments [Part A] or not 
permitted within 12 hours of psychiatric or neurological assessments or a scheduled qEEG/ERP 
measurement [Part B]).
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 the Follow-Up Visit. Participants 
who prematurely discontinue from the study before completing 2 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. 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 may be scheduled.
See the schedule of activities (Section 2.1 [Part A] and Section 2.2 [Part B]) for data to be 
collected at the ET 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 2.1 [Part A] and Section 2.2 [Part B]).

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 by the investigator or qualified 
designee 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. 
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. Efficacy assessments will 
be performed as specified in the schedule of activities in Section 2.1 (Part A) and Section 2.2
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9.1.1.
Diagnostic Assessments
For Part A and Part B, 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 qualifications standards set by the sponsor and rater training vendor.
9.1.2.
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) at each investigational center will conduct the MADRS assessment.  
For Part A, at Screening (Visit 1) and Visit 2 (predose), 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.”
For Part B, at Visit 1 (Screening) and Visit 2 (Day –1, 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.” 
MADRS assessments will be performed as specified in the schedule of activities in Section 2.1
(Part A) and Section 2.2 (Part B).
9.1.3.
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
participant will be rated on a scale from 1 to 7 with 1 indicating a “normal, not at all ill” and 
7 indicating “among the most extremely ill patients.” 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.
For Part A and Part B, at Screening (Visit 1) and Visit 2, 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.”
CGI-S assessments will be performed as specified in the schedule of activities in Section 2.1
(Part A) and Section 2.2 (Part B).
9.1.4.
The Hamilton Anxiety Rating Scale (Part A Only)
The HAM-A (Hamilton 1959) is a clinician-rated scale to rate the severity of anxiety symptoms 
(Appendix 14). The participant will be tested using 14 questions, and responses will be rated on a 


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scale from 0 to 4, with 0 indicating “none” (ie, no anxiety) and 4 indicating a response of “severe, 
gross disabling” anxiety. The HAM-A will be administered at Visit 2, Visit 3, Visit 4, and Visit 6 
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.
The HAM-A will be collected only from participants entering the study after the amendment has 
been IRB approved.
9.1.5.
Likert Patient Depressive Symptom Scales (Part B Only)
The Likert Patient Depressive Symptom Scales are a set of questions framed in a Likert format, 
which is the most widely used approach to scaling responses in survey research aimed to capture 
the full domain/indication under study. In the BID cohort part of the study, a set of Likert Patient 
Depressive Symptom Scales will be used to collect the participant self-reported outcomes on 
domains related to MDD, including depression, anxiety, and sleep quality (Appendix 15). The 
Likert Patient Depressive Symptom Scales will be completed by the research participant as 
specified in the schedule of activities in Section 2.2.
During the outpatient double-blind treatment week and the safety follow-up, the Likert Patient 
Depressive Symptom Scale questions will be provided to the participants in a diary to be 
completed at home.
9.1.6.
Hopkins Verbal Learning Test-Revised (Part B Only)
The HVLT-R is the most recent (Shapiro et al 1999) version of the verbal learning and episodic 
memory test. It includes 6 different forms aimed to reduce practice effects, which this trial will 
employ in respective study visits. The HVLT-R is comprised of immediate recall trials of 
12 nouns with 3 different categories and a delayed recall followed by a recognition task
(Appendix 16). For the immediate recall, on each trial, the participant is asked to say as many
words enunciated by the rater administering the test as possible. For the delayed recall, after 
approximately 20 to 25 minutes of the immediate recall trials, the participant is requested to 
evoke all words he/she can remember without any cues. The recognition trial is composed of 
24 words, including 12 target words and 12 false-positives, and the participant is asked which of 
the 24 words were the ones read during the immediate recall trial. The HVLT-R will be 
administered by the trained site professional as specified in the schedule of activities in 
Section 2.2.
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 


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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 2.1 [Part A] and Section 2.2 [Part B]), 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 2.1 [Part A] and Section 2.2 [Part B]), 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.
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 
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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.

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.


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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. For 
Part B, participants should be instructed as described in Section 7.2 (Dose Modification) for
missed doses.
9.3.
Treatment of Overdose
AGN-241751 has a short half-life; hence, even in the event of an overdosage, the likelihood of 
lasting high exposures would be minimal. Although not observed within healthy volunteers 
receiving 50 mg of AGN-241751 for 10 consecutive days, minimal liver findings have been 


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observed in toxicology studies within the dog. Part B safety laboratory tests, including AST and 
ALT, will be performed at Visit 9 (Day 7), Visit 12/ET (Day 14/ET), and Visit 14 (Day 21) 
(Safety Follow-Up) to monitor participants should dosing errors occur. Unscheduled safety 
assessments may be performed as clinically indicated at any time during the study at the 
discretion of the investigator.
9.4.
Safety Assessments
Planned timepoints for all safety assessments are provided in the schedule of activities
(Section 2.1 and Section 2.2). In addition, unscheduled assessments of vital signs, clinical 
laboratory tests, and ECGs may be performed as clinically indicated at any time during the study
at the discretion of the investigator.
9.4.1.
Physical Examinations
A complete physical examination will be performed at Screening and at Visit 6/ET (Part A) or at 
Screening and Visit 12/ET (Part B) 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 (Part A) and at Screening, Baseline (Day –1), 
4 hours postdone at Visit 3 and Visit 10/Discharge (Day 8), Visit 12/ET (Day 14/ET), and 
Visit 14 (Day 21) (Part B). Height will be assessed at Screening only in both parts of the study.
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 to 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 
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9.4.3.
Electrocardiograms
A 12-lead ECG will be performed at Screening and Visit 6/ET (Part A) and at Visit 1 
(Screening), Visit 12/ET (Day 14/ET), and Visit 14 (Day 21) (Part B). 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 
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. In case of any abnormal ECG finding, unscheduled ECGs may be conducted at the 
discretion of the PI.
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 2.1 [Part A] and Section 2.2 [Part B]) 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
For liver function tests, if a participant has the following, an unscheduled retest should be 
performed: ALT or AST ≥ 3 × ULN, total bilirubin ≥ 2 × ULN, and/or alkaline 
phosphatase < 2 × ULN (see also Section 9.2.6).
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.


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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), 
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. 
For Part A and Part B, the C-SSRS will be completed at all study visits (once per visit; predose 
at applicable visits) (see Section 2.1 [Part A] and Section 2.2 [Part B]). At 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. For Part A and Part B, at Screening (Visit 1), the BPRS+ will be administered with a 
look-back timeframe of 1 week. At all other evaluations, the BPRS+ will be administered with a 
look-back timeframe of “since last evaluation.” The BPRS+ will be completed as specified in the 
schedule of activities in Section 2.1 (Part A) and Section 2.2 (Part B) (including the designated 
look-back periods for each BPRS+ administration).
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. For Part A and Part B, at Screening (Visit 1), the CADSS will be administered with a 


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look-back timeframe of 1 week. At all other evaluations, the CADSS will be administered with a 
look-back timeframe of “since last evaluation.”
The CADSS will be completed as specified in the schedule of activities in Section 2.1 (Part A) 
and Section 2.2 (Part B) (including the designated look-back periods for each CADSS 
administration).
9.5.
Pharmacokinetics (Part B Only)
In Part B of this study, collection of a single CSF sample is an optional procedure, as participants 
may/may not choose to allow this sample collection without impacting their participation in the 
study. For those participants who agree and have given consent to provide a CSF sample for PK 
analysis, lumbar puncture will be used to collect CSF, and a maximum of 4 mL of CSF will be 
collected. Collection of CSF is preferred at Visit 5 (Day 3), but can be done at Visit 4 or Visit 6,
either immediately prior to the morning dose or at 8 hours after the morning dose. Within each 
site, 1 sample per participant will be collected, and study staff will alternate between predose and 
postdose for participants (eg, 1st participant sample is collected predose, 2nd participant sample 
is collected postdose, 3rd participant sample is collected predose, etc.). Additional details of the 
CSF sample collection, handling, and storage are presented in Appendix 18. 
Additional exploratory analysis may be performed on collected CSF samples.  
9.6.
Pharmacodynamics (Part B Only)
9.6.1.
Quantitative Electroencephalography and Event Related Potential Assessments 
and Outputs
In Part B of the study, evaluation of pharmacodynamic endpoints (qEEG/ERP) between 
AGN-241751 and placebo (double-blinded) will be performed at selected sites using the 
measures described below.
9.6.1.1.
Karolinska Sleepiness Scale
The KSS is a 9-point self-reported scale of subjective assessment of a participant’s level of 
drowsiness at the time (Appendix 17). The KSS will be conducted prior to each qEEG 
measurement to assess for sleep-deficit related differences between qEEG measurements. The 
scale will control for any sleepiness variations in the qEEG and ERP outputs.The scale will be 
measured as follows:

Baseline: Mid-day (approximately 1200 hours), and afternoon (approximately 1700 hours)
(window of ± 2 hours between mid-day and afternoon assessments)

Day 1: Predose and 4, 8, and 12 hours postdose

Day 2: 24 hours post Day 1 morning dose (prior to the Day 2 morning dose)

Day 7: Predose and and 4, 8, and 12 hours postdose

Day 8: 24 hours post Day 7 morning dose (prior to the Day 8 morning dose)


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
Day 14

Day 21
Error windows permitted for the KSS measurements will be ± 30 minutes at any collection 
timepoint up to 12 hours postdose and ± 1 hour at any collection timepoint up to 24 hours 
postdose. 
9.6.1.2.
Event-Related Potential and Electroencephalography Measurements
The qEEG and ERP are noninvasive tests that analyze the electrical activity of the brain using 
data from surface electrodes in contact with 19 or more areas of the scalp. Engagement of the 
NMDA receptor by AGN-241751 is expected to result in measurable changes in qEEG and ERP 
data.
Prior to the qEEG assessments on Day –1, each participant will undergo a hearing test to ensure 
detection of the stimuli used for the ERP assessments. Should a participant not be able to detect 
the planned stimuli, the intensity of the stimuli may be adjusted accordingly.  
The qEEG will be measured as follows:

Baseline: Mid-day (approximately 1200 hours), and afternoon (approximately 1700 hours)
(window of ± 2 hours between mid-day and afternoon assessments)

Day 1: Predose and 4, 8, and 12 hours postdose

Day 2: 24 hours post Day 1 morning dose (prior to the Day 2 morning dose)

Day 7: Predose and and 4, 8, and 12 hours postdose

Day 8: 24 hours post Day 7 morning dose (prior to the Day 8 morning dose)

Day 14

Day 21
Error windows permitted for the qEEG measurements will be ± 30 minutes at any collection 
timepoint up to 12 hours postdose and ± 1 hour at any collection timepoint up to 24 hours 
postdose. Test times should not be confounded by food intake; eg, if baseline is done 30 minutes 
after lunch, the test should be 30 minutes after lunch. 
The ERPs will be measured approximately 10 minutes following each corresponding qEEG 
measurement. 
qEEG and ERP Assessments and Outputs
At the times specified above, a 5-minute resting qEEG with eyes closed, a 5-minute resting 
qEEG with eyes open, a 10.5-minute MMN task (Appendix 20) and a 10.5-minute ASSR task 
(Appendix 20) will be performed with participants seated comfortably in a sound-attenuated 
room. In addition to 19 qEEG leads according to the international 10/20 system, vertical and 
horizontal EOGs will be recorded. The reference electrode will be left mastoid (A1) with ear 
lobe (A2) recorded as an active lead. Digital referencing to linked ears will be done off-line. An 


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additional electrode on the nose (Nz) is required for accurate identification of the MMN. The 
resting qEEGs will be evaluated by means of spectral analysis, coherence analysis, and 
frequency analysis. After artifact rejection or correction, the mean absolute amplitude spectra 
(square root of power spectral density function) will be computed. The primary qEEG endpoints
will be changes from predose baseline in the absolute spectral amplitudes in 1 Hz bands from 1.0 
to 50.0 Hz. Secondary measures will include changes from predose baseline in the absolute
spectral amplitudes and magnitude squared coherences in various clinical bands (Delta [1.0 - 4.0 
Hz], Theta [4.0 - 8.0 Hz], Alpha [8.0 - 12.0 Hz], Beta [12.0 - 25.0 Hz], Hi-Beta [25.0 - 30.0 Hz], 
Gamma [30.0 - 50.0 Hz], Alpha 1 [8.0 - 10.0 Hz], Alpha 2 [10.0 - 12.0 Hz], Beta 1 
[12.0 - 15.0 Hz], Beta 2 [15.0 - 18.0 Hz], Beta 3 [18.0 - 25.0 Hz], Gamma 1 [30.0 - 35.0 Hz], 
Gamma 2 [35.0 - 40.0 Hz], Gamma 3 [40.0 - 50.0 Hz]; coherence in these bands) and derived 
frequency measures. Additional secondary endpoints will include coherences and derived 
frequency measures, for each of which the endpoints will be changes from predose baseline 
values. Magnitude squared coherence will be measured for specific pairwise combinations of the 
19 qEEG electrodes in the same clinical bands. These pairs will capture the relevant inter- and 
intra-hemispheric coherences and will include F3-F4, C3-C4, P3-P4, O1-O2, F3-P3, and F4-P4. 
Derived frequency analysis will consist of computing the dominant frequency in the range of 
6.0 to 12.5 Hz, the ASI, and the TBR.
Each ERP task will be assessed in sequential multiple blocks. For the MMN task, the assessment 
will be done using deviant stimuli differing in pitch from standard stimuli. For the ASSR task,
the assessment will be done using stimulus rates of 30/s and 40/s. 
Each ERP task will yield several measurements, which will serve to compute primary ERP 
endpoints. For the MMN task, the components include P50, N100, and P200 for the standard and 
deviant stimuli, and the MMN, which derives from a difference of deviant-standard ERPs. For 
all ERP components, measures of peak latency, peak amplitude, and average amplitude (AUC) 
will be computed and analyzed for change with respect to predose baseline. Baseline-adjusted 
ERP component measures will serve as endpoints for statistical analysis. The primary ASSR 
measure is the peak-to-peak amplitude of the sustained portion (latency > 150 ms) of the ASSR 
in the time domain. Secondary measures include the averaged wavelet magnitude and inter-trial 
phase coherence (Appendix 20). Baseline-adjusted ASSR measures will serve as endpoints for 
statistical analysis.
For all qEEG and ERP endpoints, the baselines for computing changes at each postdose 
timepoint will be the mean of the 3 baseline values on Day –1 (mid-day), Day –1 (afternoon),
and Day 1 (predose). Change scores will be computed as normalized differences ((V(t) – V(b) / 
V(t) + V(b)), where V(b) is the value at mean baseline and V(t) is the value at a specific 
timepoint. Other change metrics may also be examined, such as simple differences from baseline 
and simple ratios of postdose to baseline values, as these provide different levels of control for 
baseline variation. The change metric that shows the greatest sensitivity to changes without 
introducing excessive bias will be selected for formal analyses of variance.


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9.7.
Genetics
For Part A, randomized participants may consent to participate in the genetic analysis component 
of the study. For those randomized participants who agree, the consent may be collected at any 
time prior to collection of the sample. For Part B, if participants consent to this sampling and are 
randomized, the sample will be collected predose at Visit 9 (Day 7).
For both Part A and Part B, for those who consent and are randomized, a 4 mL sample for DNA 
isolation will be collected at any time during the study after the consent has been signed (Part A) 
or at Visit 9 (Day 7) (Part B). With the samples, polymorphisms within the NMDA receptors 
may be assessed to understand treatment response to AGN-241751. Additional exploratory 
assessments may also be conducted from DNA collected within these samples. Participation is 
optional. Participants who do not wish to participate in the genetic research may still participate 
in the study. Participant confidentiality will be maintained at all times.
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.
10.
Statistical Considerations 
10.1.
Sample Size Determination
10.1.1.
Part A
The sample size of approximately 25 randomized participants in each of the 4 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. 
10.1.2.
Part B
In Part B of the study, the sample size of approximately 40 randomized participants in each of 
the 3 treatment groups is not based on statistical power consideration since this is an exploratory 
study. 


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10.2.
Populations for Analyses
10.2.1.
Part A
The analysis populations will consist of participants as defined below:

The 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.
10.2.2.
Part B
The analysis populations in Part B will consist of participants as defined below:

The 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.

The PD population includes all randomized participants who received ≥ 1 administration 
of study treatment and have Day –1 qEEG and ERP assessments and at least 
1 postbaseline assessment for the qEEG and ERP assessments during the double-blind 
treatment period. Participants will be summarized according to the randomized study 
treatment.

The PK population includes all randomized participants who received ≥ 1 administration 
of study treatment and have at least 1 CSF collection in Part B. Participants will be 
summarized according to the randomized study treatment.
10.3.
Statistical Analyses
There will be 2 separate SAPs, 1 each for Part A and Part B. Each SAP will be developed and 
finalized before database lock for that part of the protocol and will describe in detail the 
participant populations to be included in the analyses, the safety and efficacy analysis, and the 


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procedures for accounting for missing or unscheduled data. This section is a summary of the
planned statistical analyses of the primary and secondary endpoints. 
10.3.1.
Efficacy Analyses (Part A and Part B)
The efficacy analyses will be based on the mITT population of each Part, A or B, respectively. 
Baseline for efficacy for Part A and Part B, respectively, is defined as the last nonmissing 
efficacy assessment before the 1st dose of study treatment in each corresponding part of the 
study. 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 for at least 1 treatment group 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.
10.3.1.1.
Primary and Secondary Endpoints (Part A and Part B)
10.3.1.1.1. Part A
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 
more detail in the SAP for Part A.
Primary efficacy endpoint for Part A of the study:

Change from baseline (Day 1, predose) in MADRS total score at 1 day after the first dose 
of treatment (Day 2)
Secondary efficacy endpoint for Part A of the study:

Change from baseline (Day 1, predose) in MADRS total score at Day 8 and Day 9 after 
single oral dose, on Day 15 after repeated dose, and on Day 22, 7 days after the 
completion of AGN-241751 dosing
10.3.1.1.2. Part B
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 
more detail in the SAP for Part B.
Primary efficacy endpoint for Part B of the study:

Change from baseline in MADRS at 7 days after first dose of treatment


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Secondary efficacy endpoint for Part B of the study:

Change from baseline in MADRS total score at Day 2, Day 11, Day 14, Day 18, and 
Day 21, 7 days after the completion of AGN-241751 BID dosing
10.3.1.2.
Primary Analyses (Part A and Part B)
The primary analysis for the primary and secondary endpoints in Part A and Part B 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 MI approach under 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 SAPs prior to the study database locks.
10.3.1.3.
Additional Efficacy Parameters (Part A and Part B)
10.3.1.3.1. Part A
Additional efficacy parameters are as follows, with the Day 1 (predose) value serving as the 
baseline:

Change from baseline in CGI-S total score at Day 2, Day 8, Day 9, and Day 15 

Rate of responders on MADRS or CGI-S at Day 2, Day 8, Day 9, Day 15, and Day 22

Rate of remitters on MADRS at Day 2, Day 8, Day 9, Day 15, and Day 22

Time to first response on MADRS

Time to first remission on MADRS
Analysis of change from baseline in MADRS total score and CGI-S score will be performed 
using a similar MMRM to that used for the key secondary parameter.
CGI-S responder is defined as participants achieving a score of ≤ 2 on the CGIS of Illness ̀
scale.
CGI-S sustained responder: Meet responder criteria at ≥ 2 consecutive visits and continued 
through to final assessment.


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During the randomized treatment period, 4 types of events for MADRS total score will be 
defined based on the following criteria:

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
Rates of responders and remitters will be reported by treatment group for each timepoint of 
assessment (Day 1 [predose] defined as baseline and Days 2, 8, 9, 15, and 22 after first dose of 
randomized treatment). A logistic regression model will be used to model the probability of a 
response or the probability of a remission as a function of a treatment group, and baseline 
MADRS or CGI-S total score.
The time to onset of first event is defined as the number of days from the first randomized dosing 
to the first event. The time to onset in days will be calculated for each type of event (response or 
remission) in person level. Participants who do not meet the criteria for respective type of event 
will be censored at the time of their last MADRS assessment during the treatment period. 
For each type of event, the proportion of participants with onset of first events, Kaplan-Meier 
estimate in terms of the median time to onset of first event, and its 95% CI will be presented for 
each treatment group. Plots of the Kaplan-Meier estimate of the distribution of the time to onset 
of events will also be provided for each treatment arm. Log-rank tests comparing the time to
onset of event distribution between each AGN-241751 dose and placebo will be conducted.
10.3.1.3.2. Part B
Additional efficacy parameters are as follows, with the Day –1 (predose) value serving as the 
baseline:

Change from baseline in CGI-S total score by visit

Rate of responders on MADRS at Day 2, Day 7, Day 11, Day 14, Day 18, and Day 21

Rate of responders on CGI-S by visit 

Rate of remitters on MADRS at Day 2, Day 7, Day 11, Day 14, Day 18, and Day 21

Time to first response on MADRS

Time to first remission on MADRS
Analysis of change from baseline in MADRS total score and CGI-S score will be performed 
using a similar MMRM to that used for the key secondary parameter.


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During the randomized treatment period, 2 types of events will be defined based on the following 
criteria:

Responder: ≥ 50% reduction from baseline MADRS total score

Remitter:  MADRS total score ≤ 10
Rates of responders and remitters will be reported by treatment group for each timepoint of 
assessment (Day –1 [predose] defined as baseline and Days 2, 7, 11, 14, 18, and 21 after the 
1st dose of randomized treatment). A logistic regression model will be used to model the 
probability of a response or the probability of a remission as a function of a treatment group, and 
baseline MADRS or CGI-S total score. 
The time to onset of first event is defined as the number of days from the first randomized dosing 
to the first event. The time to onset in days will be calculated for each type of event (response or 
remission) in person level. Participants who do not meet the criteria for respective type of event 
will be censored at the time of their last MADRS assessment during the treatment period. 
For each type of event, the proportion of participants with onset of first events, Kaplan-Meier 
estimate in terms of the median time to onset of first event, and its 95% CI will be presented for 
each treatment group. Plots of the Kaplan-Meier estimate of the distribution of the time to onset 
of events will also be provided for each treatment arm. Log-rank tests comparing the time to 
onset of event distribution between each AGN-241751 dose and placebo will be conducted.
10.3.2.
Exploratory Analyses
10.3.2.1.
Part A
The exploratory analyses of HAM-A scores 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 exploratory parameters will include change from baseline in HAM-A 
scores Day 2, Day 8, and Day 15. At Visit 2, the HAM-A will be administered with a look-back 
timeframe of 1 week. At all other evaluations, the HAM-A will be administered with a look-back 
timeframe of “since last evaluation.” The HAM-A will be collected only from participants 
entering the study after the amendment has been IRB approved.


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10.3.2.2.
Part B
The exploratory analyses include the following:

Analysis of Likert Patient Depressive Symptom Scales of each assessed domains 
(including depression, anxiety, and sleep quality, etc.) will be performed based on the 
safety population for the double-blind treatment period and for the safety follow-up 
period, if applicable, and will be described descriptively and in more detail in the SAP 
for Part B.

Analysis of HVLT-R assessment 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 described in more detail in the SAP for Part B. 
10.3.3.
Pharmacokinetic Analysis (Part B Only)
Analysis of the CSF concentrations of AGN-241751 will be performed using the PK population 
for the double-blind treatment period. Descriptive analysis of the CSF concentrations will be 
performed.
10.3.4.
Pharmacodynamic Analysis (Part B Only)
Analysis of the qEEG and ERP assessments will be performed using the PD population for the 
double-blind treatment period. Initial details of the analysis of the qEEG and ERP data are 
described in Appendix 20, but will be fully defined in a PD SAP. 
10.3.5.
Safety Analyses (Part A and Part B)
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 for 
each Part A and Part B of the study. The safety parameters will include AEs, clinical laboratory 
including potential Hy’s law cases, vital signs, ECG, C-SSRS, BPRS+, and CADSS 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.
10.3.5.1.
Adverse Event (Part A and Part B)
For each part of the study, A and B, an AE will be considered a TEAE if the AE began or
worsened (increased in severity or became serious) on or after the date of the first dose of study 
medication. However, an AE that occurs more than 30 days after the last dose of study 
medication of each part A and B, respectively, will not be counted as a TEAE. An AE will be 
considered a TESAE if it is a TEAE that additionally meets any SAE criteria.
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.


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An AE will be considered a 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 TESAE if it is a TEAE that additionally meets any SAE criteria
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.
10.3.5.2.
Clinical Laboratory Assessments (Part A and Part B)
For Part A and Part B of the study, 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 PCS laboratory values will be detailed in the SAP for Part A and the SAP for 
Part B, respectively. 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.


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10.3.5.3.
Vital Signs (Part A and Part B)
For Part A and Part B of the study, 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 for Part A and the SAP 
for Part B, respectively. 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 an available baseline value 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.
10.3.5.4.
Electrocardiograms (Part A and Part B)
For Part A and Part B of the study, 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 for Part A and the 
SAP for Part B, respectively. 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.
10.3.5.5.
Other Safety Parameters (Part A and Part B)
Other safety parameters for Part A and Part B include the BPRS+, CADSS, and C-SSRS.


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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.
10.3.6.
Interim Analyses
An interim analysis is not planned at this time but may be conducted if deemed appropriate.


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11.
References
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Disorders, 5th edition: DSM-5. Washington, DC: American Psychiatric Association.
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Psychopharmacology Research Branch, Division of Extramural Research Programs. pp 218-222.
Hamilton, M. The assessment of anxiety states by rating. Br J Med Psychol 1959;32:50-55.


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Kenward MG, Roger JH. Small sample inference for fixed effects from restricted maximum 
likelihood. Biometrics 1997; 53:983-997.
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Videbech P and Ravnkilde B. Hippocampal volume and depression: a meta-analysis of MRI 
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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 
ASI
alpha slow wave index
ASSR
Auditory Steady-State Response
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
BID
twice daily
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
CIOMS
Council for International Organizations of Medical Sciences
Cmax
maximum concentration
CNS
central nervous system
CONSORT
Consolidated Standards of Reporting Trials
CSF
cerebrospinal fluid
C–SSRS
Columbia–Suicide Severity Rating Scale
CWT
continuous wavelet transform
DALY
disability adjusted life years
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition
ECT
electroconvulsive therapy
ECG
electrocardiogram, electrocardiographic
eCRF
electronic case report form
EEG
electroencephalography
EOG
electro-oculograms
ERP
event related potential
ERSP
event-related spectral perturbation
ET
early termination
FDA
Food and Drug Administration
FSH
follicle stimulating hormone
GCP
good clinical practice
HAM-A
Hamilton Anxiety Rating Scale


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HbA1c
Hemoglobin A1c
β-hCG 
β-human chorionic gonadotropin
HCV
hepatitis-C virus
HIPAA
Health Insurance Portability and Accountability Act of 1996
HIV
human immunodeficiency virus 
HRT
hormonal replacement therapy
HVLT-R
Hopkins Verbal Learning Test–Revised
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use
IEC
independent ethics committee
IP
investigational product
IRB
Institutional Review Board
ITPC
inter-trial phase coherence
ITT
Intent-to-Treat
IWRS
Interactive Web Response System
KSS
Karolinska Sleepiness Scale
LOCF
last observation carried forward
LTP
long-term potentiation
MADRS
Montgomery- Åsberg Depression Rating Scale
MDD
major depressive disorder
MI
multiple imputation
mITT
modified intent-to-treat
MMN
mismatch negativity
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
OC
observed case
PCS
potentially clinically significant
PD
pharmacodynamic(s)
PI
principal investigator
PK
pharmacokinetic(s)
qEEG
quantitative electroencephalography
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)
RMS
root means square


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SAE
serious adverse event
3-SAOT
3–stimulus auditory oddball task
SAP
Statistical Analysis Plan
SCID
Structured Clinical Interview for DSM Disorders
SDMT
Symbol Digit Modalities Test
SNRI
selective serotonin and norepinephrine reuptake inhibitor
SOA
stimulus onset asynchrony
SPL
sound pressure level
SSRI
selective serotonin reuptake inhibitor
T3
triiodothyronine
T4
thyroxine
TBR
theta-beta ratio
TEAE
treatment-emergent adverse event
TESAE
treatment-emergent serious adverse event
Tmax
time to reach maximum concentration 
TSH
thyroid-stimulating hormone (
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 2.1 [Part A] and Section 2.2 [Part B]). 
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. 
For Part A and Part B, the following clinical laboratory levels will be measured at Screening
only:
Clinical laboratory 
screening tests:
HbA1c, fasting insulin, TSH, T3, and free T4
Hepatitis screening:
HCV 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 Screening, Visit 2, and Visit 6/ET
(Part A) and at Screening, predose at Visit 9 (Day 7), Visit 12/ET (Day 14/ET), and Visit 
14 (Day 21) (Safety Follow-Up) (Part B) unless otherwise noted:
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, triglyceridesa
Urinalysis:
Specific gravity, pH, protein, glucose, ketones, and blood
UDS:
Benzoylecgonine (cocaine), barbiturates, amphetamines, 
benzodiazepines, cannabinoids, opiates, methadone, 
phencyclidine
Pregnancy (Part A):
Serum β-hCG at Screening and Visit 6/ET
Pregnancy (Serum) 
(Part B) (for WOCBP: 
Serum β-hCG at Screening, predose at Vist 9 (Day 7), 
Visit 12/ET (Day 14/ET), and Visit 14 (Day 21)
Pregnancy (Urine) 
(Part B) (for WOCBP):
Serum β-hCG pregnancy test at Screening (Visit 1) AND a 
negative urine pregnancy test on Day –1 (baseline), if more 
than a week has passed since the serum pregnancy test at 
Screening. If urine pregnancy test is positive on Day –1, 
then a serum β-hCG pregnancy test should be done for 
confirmation. Additional urine pregnancy tests may be done 
at the investigator’s discretion throughout the study. If any 
urine pregnancy test during the study is positive, a serum 
β-hCG pregnancy test should be done for confirmation.
a Abnormal liver function test values will be repeated.
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 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 


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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.
For Part A of the study, serum pregnancy tests will be conducted at Screening and Visit 6/ET as 
specified in the schedule of activities (Section 2.1) and at investigator’s discretion at any time 
during this part of the study. Positive results on the pregnancy test at 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:

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.
For Part B of the study, serum pregnancy tests will be conducted at Screening, predose at Visit 9 
(Day 7), at Visit 12/ET (Day 14/ET), and at Visit 14 (Day 21) (Safety Follow-Up) as specified in 
the schedule of activities (Section 2.2). At entry, the female participant, if a WOCBP, must have 
a negative serum β-hCG pregnancy test at Screening (Visit 1) AND a negative urine pregnancy 
test on Day –1 (baseline), if more than a week has passed since the serum pregnancy test at 
Screening. If the urine pregnancy test is positive on Day –1, then a serum β-hCG pregnancy test 
should be done for confirmation. Additional urine pregnancy tests may be done at the 
investigator’s discretion throughout this part of the study. If any urine pregnancy test during the 
study is positive, a serum β-hCG pregnancy test should be done for confirmation.
For both Part A and Part B, 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 CIOMS international ethical guidelines

Applicable ICH 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, 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 AESI (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 


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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.
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.


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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.

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 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.


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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 FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or 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
o
Female partners of male study participants reliably use one of the following:
o
Hormonal contraceptives (ie, oral, patch, injection, implant)
o
Vaginal contraceptive ring 


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o
Intrauterine device
o
Bilateral tubal ligation
o
Ensure 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 vaginal intercourse 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.

Hormonal contraceptives (ie, oral, patch, injection, implant) 

Vaginal contraceptive ring 

Intrauterine device

Bilateral tubal ligation

Essure placement with correct placement verified by hysterosalpingogram

Surgical sterilization

Male or female condom with spermicide 

Cap, diaphragm, or sponge with spermicide

Abstinence (as described above)

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.


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
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.
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.
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, 
cyclosprorin, and immunomodulator drugs are not
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
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 psychiatric or neurological measures
for Part A or within 12 hours of psychiatric or 
neurological measures or a scheduled qEEG/ERP 
measurement for Part B).
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 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 3 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 psychiatric or neurological measures for 
Part A or within 12 hours of psychiatric or 
neurological measures or a scheduled qEEG/ERP 
measurement for Part B).
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
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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
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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: Hamilton Anxiety Rating Scale (Part A Only)


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12.15.
Appendix 15: Likert Patient Depressive Symptom Scales (Part B 
Only)


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12.16.
Appendix 16: Hopkins Verbal Learning Test-Revised (Part B Only)
Due to copyright restriction, the HVLT-R scale is not included.


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12.17.
Appendix 17: Karolinska Sleepiness Scale (Part B Only)


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12.18.
Appendix 18: CSF Sample Collection, Handling, and Storage 
Instructions (Part B Only)
A local anesthetic may be applied to minimize discomfort to the subject. Once the spinal needle 
is inserted to the lumber region (eg, L3-4 or L4-L5), collect approximately 4 mL of CSF fluid at 
a rate of 0.5 mL/minute. This collection is carried out under ambient conditions. Upon 
completion, transfer harvested CSF immediately into 4 prechilled, labeled polypropylene 
cryovials (Nalgene® 1.5 mL polypropylene External Thread Cryogenic Vials, Catalog 
#5000-1020), placing approximately 1 mL in each of the 4 polypropylene vials. Tubes should be 
labeled with the study number, participant identification number, date, and timepoint. 
Immediately place and store upright the frozen tubes in freezer maintained at nominal –20°C 
±10°C. Samples will be batched and shipped according to the sponsor or at the end of the study.


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12.19.
Appendix 19: Sample Shipment Guide (Part B Only)
BIOLOGICAL SAMPLES INCOMING TO KEYSTONE BIOANALYTICAL
Samples will be batched and shipped according to the sponsor or at the end of the study.
Ship CSF samples on sufficient dry ice to keep them frozen for a minimum of 96 hours.
Sample Packing

Place the samples by subject number in compartmentalized boxes, label the box(es) with 
study number and subject number(s). Place the box in a freezer bag(s)

Place the samples in a thick-wall foam shipping box (eg, 19″ × 19″ × 12″) that has a slab 
of dry ice on the bottom and on 2 of the 4 sides. Pack the remaining spaces with dry ice or 
ice pellets

Make a note in the source documents, air bill, and shipping box of the estimated weight of 
the dry ice used per box

Put lid on box and seal lid with tape

To the lid of the box, attach a sample transfer record and an inventory of the samples 
contained inside (eg, 3125-104-002 CSF samples, Subject 301-001-001, 
Subject 301-001-002). Include a note explicitly stating any scheduled samples that may 
have been missed or not included in the shipment

Put the box in a cardboard shipping carton, if available, and seal
Shipping Label

Mark the outside of the cartons with the tally number (1 of 5, 2 of 5, etc.)

Affix to each box an address label with the following information:
Kaiwen Su
Keystone Bioanalytical, Inc.
501 Dickerson Road
North Wales, PA 19454, USA

Put 1 “PERISHABLE GOODS” label on each carton

Mark each carton “KEEP FROZEN”


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
Put on each carton 2 carbon dioxide labels, inscribed with the following:
Carbon Dioxide Solid UN-1845
Class 9 PKG GR III
Quantity (weight to nearest pound)

Put the return address and name of the contact person on each carton

Notification

Notify Allergan and Keystone Bioanalytical by e mail immediately after the samples leave 
your premises. The notification should include the following:
1. Name of courier or transport company
2. Time and date the shipment left your premises
3. Airway bill number
4. Allergan study number and period number
5. Name, telephone number, and fax number of the appropriate contact person at your 
study center
Your contact person at Keystone Bioanalytical for all shipments is:
Kaiwen Su
Keystone Bioanalytical, Inc.
Phone: +1-212-699-8885
E-mail: ksu@keystonebioanalytical.com
Your contact person at Allergan Department of Clinical Pharmacology (Irvine, CA) is:
Lisa Borbridge
Phone: +1-714-246-5845
E-mail: Lisa.Borbridge@allergan.com


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12.20.
Appendix 20: qEEG and ERP Assessments and Outputs (Part B 
Only)
Single-Deviant Mismatch Negativity Task 
In the MMN task, 1 standard tone (standard tone, probability 0.9, 1000 Hz, 50 msec duration, 
5 msec rise/fall time, 80 dB SPL) will be presented binaurally through headphones with a 
constant SOA of 0.5 sec, randomly interrupted by higher-pitch deviant tone bursts (deviant tone, 
probability 0.1, 1500 Hz, 50 msec duration, 5 msec rise/fall time, 70 dB SPL). The total number 
of tones presented will be 600 per block, of which 60 will be deviant tones. Two blocks will be 
performed with a total task duration of approximately 10.5 minutes. Participants will be seated 
comfortably in a chair facing a monitor and viewing a slowly changing slide show of nature 
scenes (landscapes, animals). Participants will be instructed to ignore the tones and silently count 
the number of different nature scenes shown. No responses are required during the MMN task; 
however, participants will be asked to report the number of slide show scenes they counted, and 
this number will be recorded by the task software. Including an additional electrode on the nose 
(Nz) is required for accurate identification of the MMN. The primary ERP measurements are the 
peak amplitude, latency, and area under the curve or AUC of the MMN, which is a negative-
going peak in the difference wave computed by subtracting the ERP average for standard stimuli 
from the ERP average for deviant stimuli. Secondary outcome measures will include peak 
amplitude, latency, and AUC measures of the P50, N100, and P200 components for the standard 
and deviant ERPs. The latency windows for peak and AUC measures will be defined using the 
grand averages of ERPs across all participants and then applied to each participant. The window 
will extend from the point on the rising edge of the component where it reaches half the peak 
amplitude to the point on the falling edge of the component where it reaches half the peak 
amplitude. Each measurement will be made at a single key electrode for each component. The 
key electrode will be defined as the electrode showing the maximum absolute peak amplitude of 
the component in the grand average ERP across participants.
Auditory Steady-State Response Task
The ASSR is continuous scalp-recorded potential composed of superimposed overlapping 
transient event-related potentials produced by brief stimuli presented at high rates. Bursts of 
clicks at rates of 30/s or 40/s are presented repeatedly with short periods of silence in between 
the bursts. The task includes four blocks of 150 stimuli consisting of 500-ms long trains of 1-ms 
white noise bursts (clicks) at 80 dB SPL with a 1.0-s SOA: Block 1: 30/s (500 ms train of 1-ms 
noise bursts at 30 per second); Block 2: 40/ s (500 ms train of 1-ms noise bursts at 40 per 
second); Block 3: repeat Block 1; Block 4: repeat Block 2. Participants will be seated 
comfortably in a chair facing a monitor and viewing a slowly changing slide show of nature 
scenes (landscapes, animals). Participants will be instructed to ignore the tone bursts and silently 
count the number of different nature scenes shown. No responses are required during the ASSR 
task; however, participants will be asked to report the number of slide show scenes they counted, 
and this number will be recorded by the task software. The primary ASSR measure is the peak-
to-peak amplitude of the sustained portion (latency > 150 ms) of the ASSR in the time domain. 
Secondary measures include the averaged wavelet magnitude and inter-trial phase coherence. All 


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endpoints of the ASSR task will be measured at the electrode with the maximal ASSR response. 
This electrode will be determined during the analysis for each subject separately.
Peak-to-peak endpoint
In MATLAB the time-domain peak-to-peak endpoint will be computed. Because of the expected 
zero-mean noise in the signal, the RMS of the zero-mean post-stimulus time period will be 
computed. This effectively represents the standard deviation of the signal. Then, 99.9% of the 
signal distribution is equal to 6.6*RMS and this will be taken as the estimate of the peak-to-peak 
endpoint. For each subject, the interval within the 500 ms stimulation period that represents the 
maximum continuous response will serve for the RMS estimate. Time-frequency endpoints, that 
is, event-related spectral perturbation and inter-trial phase coherence, will be computed for each 
data segment by decomposition into its time-frequency representation using the continuous 
complex Morlet wavelet.  The result of this decomposition is a set of complex wavelet 
coefficients for each time sample in the original EEG time series and each of several frequency 
scales. Scales corresponding to the frequency range of 5 to 60 Hz with a step of 1 Hz will be 
used. To equalize scales (frequency bands) of the CWT coefficients an energy-based 
normalization approach will be applied. Dividing every CWT coefficient cwt(s,t) at a given scale 
s and time sample t by the square root of the corresponding scale value carries out this 
normalization:
This square root division is applied separately for the real and imaginary part of the CWT 
coefficient. In the permutation testing step, the normalization allows for a balanced statistical 
correction for multiple comparisons ERSP: ERSP is a measure of mean power difference from 
baseline. The ERSP measure is defined as:


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where cwt(f,t,n) represents the CWT coefficient computed for the epoch n, frequency f and time 
sample t. N is the total number of epochs and T_B represents all time samples from the baseline, 
pre-stimulus period. The norm symbol | . | represents a complex norm. Inter-trial phase 
coherence (ITPC): ITPC (sometimes named the phase locking index/value) is sensitive to 
phase-locked activity regardless of its magnitude, so represents a more pure estimate of 
phase-locking in contrast to the ERSP measure. This could be important when the change in the 
brain activity is mostly arising from phase or response-onset variability as opposed to the power 
of a response. The ITPC measure is defined as:
where the cwt(f,t,n) coefficient and other equation indexes are defined in the same way as  in the 
case of ERSP. The ITPC value can range from 0 (absence of synchronization) to 1 (perfect 
synchronization or phase reproducibility across trials at a given time sample and frequency).


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12.21.
Appendix 21: Protocol Amendment History
Amendment 1 (March 2019)
Overall Rationale for the Amendment:
As part of this proof-of-concept study in participants with major depressive disorder (MDD), an 
additional exploratory assessment, the Hamilton Anxiety Rating Scale (HAM-A), has been 
added to the study design to further characterize the potential pharmacology of AGN-241751. 
The HAM-A is designed to assess potential improvements in feelings of anxiety within MDD 
study participants.
In addition, minor administrative, editorial, and formatting changes have been made throughout 
the protocol; these revisions are not included in the table below.
Section No. and Name
Description of Change
Brief Rationale
Synopsis
For the primary objective, baseline 
was defined as Day 1 (predose) 
and it was clarified that 1 day after 
the first dose is Day 2. 
This information was updated in the text and 
table of objectives and endpoints as a 
clarification.
For the key secondary objective, 
baseline was defined as Day 1 
(predose), it was clarified that 
1 day after the first dose is Day 2, 
and Day 9 was added as an 
endpoint.
This information was updated as a 
clarification.
An additional exploratory 
objective was included regarding
evaluation of change from Day 1 
(predose) in Hamilton Anxiety 
Rating Scale (HAM-A) scores 
compared with placebo.
This objective was added because it will be 
considered an exploratory endpoint for 
AGN-241751 treatment compared with 
placebo in participants with MDD.   
In the overall study design section, 
a statement was added to indicate 
that daily dosing of AGN-241751 
should occur at a similar time 
throughout the entire study.  
This statement was added as a clarification on 
daily dosing.


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Section No. and Name
Description of Change
Brief Rationale
2 Schedule of Activities
The HAM-A assessment (and 
corresponding footnote with more 
information) was added to the 
schedule of activities at Visits 2, 3, 
4, and 6/ET. It was also noted that 
the HAM A will be collected only 
from participants entering the 
study after the amendment has 
been IRB approved.
The HAM-A assessment was added because 
evaluation of this instrument is now an 
exploratory objective in the study.
The timing for the consent and 
sample for pharmacogenomics was 
revised to have one “x” for all 
timepoints for this assessment 
instead of under only Screening. In 
addition, the corresponding 
footnote was updated to indicate 
that the ICF may be signed at any 
visit during the study and that the 
same should be collected at any 
visit after the participant has been 
randomized.
This information was updated as a 
clarification.
4 Objectives and 
Endpoints
For the primary objective, baseline 
was defined as Day 1 (predose) 
and it was clarified that 1 day after 
the first dose is Day 2
This information was updated as a 
clarification.
For the key secondary objective, 
baseline was defined as Day 1 
(predose), it was clarified that 
1 day after the first dose is Day 2, 
and Day 9 was added as an 
endpoint.
This information was updated as a 
clarification.
For the additional endpoint of 
CGI-S, it was noted that this 
assessment gives a total score, 
baseline was defined as Day 1 
(predose), and Day 2 and Day 9 
were added.
This information was updated as a 
clarification.
An additional exploratory 
objective/endpoint to determine 
differences between AGN-241751 
and placebo was added, as follows:
Change from baseline in HAM-A 
at Day 1 (predose, defined as 
baseline) and at Day 2, Day 8, and 
Day 15
This objective was updated to describe the 
evaluation of change from baseline in HAM-A 
scores compared with placebo was added 
because evaluation of this instrument is now 
an exploratory objective in the study.


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Section No. and Name
Description of Change
Brief Rationale
4 Objectives and 
Endpoints
For the rate of responders, 
MADRS and CGI-S were added as 
the parameter being measured and 
predose was added after Day 1. In 
addition, for rate of remitters, time 
to first response, and time to first 
remission endpoints, MADRS was 
added as the parameter being 
measured and predose was added 
after Day 1.
This information was updated as a 
clarification.
5.1 Study Design
A statement was added to indicate 
that daily dosing of AGN-241751 
should occur at a similar time 
throughout the entire study.  
This statement was added as a clarification on 
daily dosing.
5.5 Justification for 
Dose
The following changes (shown in 
bold italics and strikethroughs) 
were made:

Compared to the available 
preclinical toxicology studies, 
the proposed top dose of 
25 10 mg is expected to result 
in substantial margins below 
the 28-day study NOAELs 
designated in the rat 
(225575-fold) and dog 
(410-fold).
This information was updated as a correction.
6.1 Inclusion Criteria
Inclusion criterion #6 was updated 
to indicate the assessment is done 
at Screening (Visit 1).
This criterion was updated as a clarification.
Inclusion criterion #12 regarding 
eligibility being confirmed through 
a formal adjudication process was 
removed.
This criterion was removed as a correction.
9.1.3 The Hamilton 
Anxiety Rating Scale
A section was added to describe 
the HAM-A scale and the 
timepoints at which it will be 
administered. It was also noted that 
the HAM A will be collected only 
from participants entering the 
study after the amendment has 
been IRB approved.
This section was added to provide information 
regarding the HAM-A, which is now an 
assessment in the study.
9.7 Genetics
This section was revised to 
indicate that that the sample for 
DNA isolation will be collected at 
any visit after the participant has 
been randomized.
This information was updated as a clarification


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Section No. and Name
Description of Change
Brief Rationale
10.3.1 Efficacy 
Analyses
The statement that the LOCF 
approach will be used to impute 
missing postbaseline values was 
removed.
This statement was removed to simplify the 
statistical analysis of study outputs.
The statement regarding by-visit 
analyses being carried out for all 
efficacy parameters using the 
MMRM and LOCF approaches 
was removed.
This statement was removed to simplify the 
statistical analysis of study outputs.
10.3.1.1 Primary and 
Secondary Endpoints
For the primary efficacy endpoint, 
baseline was defined as Day 1 
(predose) and it was clarified that 
1 day after the first dose is Day 2.
This information was updated as a 
clarification.
For the secondary efficacy 
endpoint, baseline was defined as 
Day 1 (predose), it was clarified 
that 1 day after the first dose is 
Day 2, and Day 9 was added.
This information was updated as a 
clarification.
10.3.1.2 Primary 
Analyses
The statement that the LOCF 
approach will be used to impute 
missing postbaseline values 
provided that at least 
1 postbaseline assessment is 
available was removed.
In addition, the other information 
regarding a sensitivity analysis 
using the LOCF approach for the 
primary efficacy parameter was 
revised to using a multiple 
imputation approach under missing 
not at random assumptions for the 
primary and secondary efficacy 
parameters. In addition, a 
statement was added that the 
detailed methods and procedures 
for the sensitivity analyses will be 
documented in the statistical 
analysis plan prior to database 
lock.
The LOCF statement has been removed as part 
of the study outputs. As such, the sensitivity 
analysis using the multiple imputation (MI) 
approach under missing not at random 
(MNAR) assumptions will be performed on 
the primary efficacy and key secondary 
parameters.
10.3.1.3 Multiple 
Comparisons Procedure
The section on the multiple 
comparisons procedure was 
removed
This section was removed as a correction.


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Section No. and Name
Description of Change
Brief Rationale
10.3.1.3 Additional 
Efficacy Parameters
In this section (formerly 
Section 10.3.1.4 and now 
Section 10.3.1.3), baseline was 
defined as Day 1 (predose) for the 
assessments. For the rate of 
responders, MADRS and CGI-S 
were added as the parameter being 
measured and predose was added 
to Day 1. In addition, for rate of 
remitters, time to first response, 
and time to first remission 
endpoints, MADRS was added as 
the parameter being measured and 
predose was added to Day 1. For 
CGI-S, it was also noted that this 
assessment gives a total score, 
baseline was defined as Day 1 
(predose), and Day 2 and Day 9 
were added.
This information was updated as a 
clarification.
10.3.2 Exploratory 
Analyses
A section regarding statistical 
information for the exploratory 
analysis of HAM-A was added. It 
was also noted that the HAM-A 
will be collected only from 
participants entering the study after 
the amendment has been IRB 
approved.
This section was added to explain the 
statistical analysis methods for the newly 
added efficacy parameter of HAM-A.
10.3.3.2 Clinical 
Laboratory 
Assessments
The following revisions were made 
(shown in bold italics):
The numerator will be the total 
number of participants with 
available non-PCS baseline 
values and at least 1 PCS 
postbaseline value.
This section was revised as a correction.


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Section No. and Name
Description of Change
Brief Rationale
10.3.3.3 Vital Signs
The following revisions were made 
(shown in bold italics and 
strikethroughs):
Vital sign values will be 
considered to be 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 value criterion or 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 
an available baseline or non-PCS 
baseline (for parameters with only 
the observed value criterion) 
values and at least 1 postbaseline 
assessment. 
This section was revised as a correction.
11 References
The following reference was
added: 
Hamilton, M. The assessment of 
anxiety states by rating. British J 
Medical Psychol 1959;32:50-55.
This reference was added because it is cited in 
the protocol for the newly added efficacy 
parameter of HAM-A.
12.2. Appendix 2: 
Clinical Laboratory 
Tests
The timing of the final clinical 
laboratory tests was changed from 
Follow-up Visit to Visit 6/ET. 
The timing of the final clinical laboratory test 
was clarified.
12.14 Appendix 14 
Hamilton Anxiety 
Rating Scale
This scale was added as an 
appendix.
This scale was added to an appendix because 
the HAM-A is now an efficacy assessment in 
the study.

SAP_001.pdf: 
 
 
Statistical Analysis Plan 
A Two-Part, Double-Blind, Placebo-Controlled, Single- and Multiple-Dose (Part A) or 
Twice Daily Dose (Part B) Study of AGN-241751 in Adult Participants with Major 
Depressive Disorder 
STATISTICAL ANALYSIS PLAN for Part A 
 
NCT Number 03726658 
 
Document Date June 7, 2019 


Allergan PLC
Page 1
AGN-241751
3125-104-002 Statistical Analysis Plan
1.0
TITLE PAGE
3125-104-002
A Two-Part, Double-Blind, Placebo-Controlled, Single- and Multiple-Dose 
(Part A) or Twice Daily Dose (Part B) Study of AGN-241751 in Adult Participants 
with Major Depressive Disorder
STATISTICAL ANALYSIS PLAN for Part A
Final: 7 June 2019
Confidentiality Statement
This document is the property of Allergan, Inc. and may notin full or partbe passed 
on, reproduced, published, distributed to any person, or submitted to any regulatory 
authority without the express written permission of Allergan, Inc.


Allergan PLC
Page 2
AGN-241751
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2.0
TABLE OF CONTENTS
1.0
TITLE PAGE....................................................................................................................................1
2.0
TABLE OF CONTENTS..................................................................................................................2
2.1
List of Tables......................................................................................................................4
2.2
List of Figures.....................................................................................................................4
3.0
LIST OF ABBREVIATIONS...........................................................................................................5
4.0
INTRODUCTION ............................................................................................................................6
5.0
OBJECTIVES.................................................................................................................................11
6.0
PARTICPANT POPULATIONS....................................................................................................12
6.1
MODIFIED Intent-to-Treat Population ............................................................................12
6.2
Safety Population..............................................................................................................12
7.0
PARTICIPANT DISPOSITION .....................................................................................................13
8.0
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS........................................14
9.0
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE................................................16
9.1
Extent of Exposure ...........................................................................................................16
9.2
Measurement of Treatment Compliance...........................................................................16
10.0
EFFICACY ANALYSES ...............................................................................................................17
10.1
Primary Efficacy Parameter..............................................................................................18
10.2
Secondary Efficacy Parameter..........................................................................................18
10.3
Additional Efficacy parameters ........................................................................................19
11.0
SAFETY ANALYSES....................................................................................................................22
11.1
Adverse Events .................................................................................................................22
11.2
Clinical Laboratory Parameters ........................................................................................23
11.3
Vital Signs ........................................................................................................................26
11.4
Electrocardiogram.............................................................................................................27
11.5
Other Safety Parameters ...................................................................................................28
11.5.1
Columbia-Suicide Severity Rating Scale............................................................28
11.5.2
Potential Hy’s Law.............................................................................................28
11.5.3
Brief Psychiatric Rating Scale—Positive Symptoms Subscale..........................28
11.5.4
Clinician Administered Dissociative States Scale..............................................29
11.5.5
The Hamilton Anxiety Rating Scale...................................................................29
12.0
HEALTH OUTCOMES ANALYSES............................................................................................31
13.0
INTERIM ANALYSIS ...................................................................................................................32
14.0
DETERMINATION OF SAMPLE SIZE .......................................................................................33
15.0
STATISTICAL SOFTWARE.........................................................................................................34


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16.0
DATA HANDLING CONVENTIONS ..........................................................................................35
16.1
Visit Time Windows.........................................................................................................35
16.2
Derived Variables .............................................................................................................35
16.3
Repeated or Unscheduled Assessments of Safety Parameters..........................................36
16.4
Missing Date of the Last Dose of STudy Treatment.........................................................36
16.5
Missing Severity Assessment for Adverse Events............................................................36
16.6
Missing Causal Relationship to stuyd drug for Adverse Events.......................................37
16.7
Missing Date Information for Adverse Events .................................................................37
16.8
Missing Date Information for Prior or Concomitant Medications....................................38
16.8.1
Incomplete Start Date.........................................................................................38
16.8.2
Incomplete Stop Date .........................................................................................39
16.9
Character Values of Clinical Laboratory Parameters........................................................40
17.0
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL..........................................................42
18.0
REFERENCES ...............................................................................................................................43
DOCUMENT HISTORY PAGE...................................................................................................................44


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2.1
LIST OF TABLES
Table 4-1
Schedule of Activities (SoA).......................................................................................9
Table 8-1
Criteria for ADT medication .....................................................................................15
Table 11-1
Criteria for Potentially Clinically Significant Clinical Laboratory Tests ..................24
Table 11-2
Selected Parameters Reported in Conventional Units ...............................................25
Table 11-3
Criteria for Potentially Clinically Significant Vital Signs .........................................26
Table 11-4
Criteria for Potentially Clinically Significant Electrocardiograms............................27
Table 16-1
Visit Time Windows..................................................................................................35
Table 16-2
Imputation Scenarios .................................................................................................38
Table 16-3
Examples of Coding Speci al Character Values for Clinical Laboratory 
Parameters .................................................................................................................41
2.2
LIST OF FIGURES
Figure 4-1
Study Design Diagram.................................................................................................8


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3.0
LIST OF ABBREVIATIONS
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
ECG
electrocardiogram, electrocardiographic
ET
early termination
ICF
informed consent form
LOCF
last observation carried forward
mITT
modified intent to treat
MMRM
mixed-effects model for repeated measures
MADRS
Montgomery- Åsberg Depression Rating Scale
MedDRA
Medical Dictionary for Regulatory Activities
MDD
major depressive disorder
OC
observed cases
PCS
potentially clinically significant
PID
patient identification
QTc
QT interval corrected for heart rate
QTcB
QT interval corrected for heart rate using the Bazett formula
(QTcB = QT/(RR)½)
QTcF
QT interval corrected for heart rate using the Fridericia formula 
(QTcF = QT/(RR)⅓)
SAE
serious adverse event
SI
Le Système International d’Unités (International System of Units)
TEAE
treatment-emergent adverse event
TESAE
treatment-emergent serious adverse event
ULN
upper limit of normal
LLN
lower limit of normal


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4.0
INTRODUCTION
This statistical analysis plan (SAP) provides a more technical and detailed elaboration of 
the statistical analyses of the efficacy and safety data for part A as outlined and/or 
specified in the final protocol of Study 3125-104-002 and the most recent protocol 
amendment (Amendment 1 dated 05 March 2019; Amendment 2 dated 03 May 2019).
Specifications of tables, figures, and data listings are contained in a separate document.
Part A of study 3125-104-002 is a Phase 1b, multicenter, randomized, double-blind, 
placebo-controlled, parallel-group (4 arms), weekly and once daily dose, 2-week study of 
AGN241751 in participants with major depressive disorder (MDD). The study will 
include a total of 7 visits and will be approximately 5 weeks in duration: 

Up to 2-week screening period 

2-week double-blind treatment period 

1-week safety follow-up period 
After providing written consent, participants will enter a screening period of up to 
14 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, including the 
rater-administered montgomery- asberg depression rating scale (MADRS). Participants 
meeting the eligibility criteria at the end of Visit 2 (Day 1 of the randomized inpatient
treatment) will be assigned a treatment and enter the double-blind treatment period.
Approximately 100 participants are planned for enrollment in the double-blind treatment 
period (25 participants each in the AGN-241751 and placebo groups). Participants will be 
randomized in a ratio of 1:1:1:1 to 1 of 4 treatment groups: 3 mg, 10 mg, and 25 mg dose 
AGN-241751 and placebo. All participants will be randomized to receive active 
treatment or placebo (Day 1, and Days 8 to 15) and placebo alone (Days 2 through 7).
AGN-241751 is being developed for once-weekly dosing; however, the impact of 
repeated administration of AGN-241751 requires testing. In order to minimize 
participant’s expectations and control for placebo response while changing dosing 
regimens, all treatments will be presented to participants as oral daily dosing throughout 
the study. On Day 1, all participants will be randomized to receive the first treatment 
(ie, 4 treatment groups: 3 mg, 10 mg, and 25 mg dose AGN-241751 or placebo), 
followed by blinded placebo on Days 2 through 7. Starting on Day 8, participants will 
then start 7 consecutive days of randomized treatment, administered once daily through 
Day 15.


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On Day 1, site staff will give the participant the single dose of double-blind study 
treatment from Bottle 1 (for applicable visit) to take by oral ingestion in the clinic (ie, the 
first dose of study treatment for that week). Site staff will then give Bottle 2 (for 
applicable visits), 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 
(Days 2 through 7). On Day 8, site staff will give the participant the single dose of 
double-blind study treatment from Bottle 1 (for applicable visit) to take by oral ingestion 
in the clinic (ie, the first dose of study treatment for that week). Site staff will then give 
Bottle 2 (for applicable visits), which contains double-blind study treatment, to the 
participant with the instruction to take 1 tablet daily by oral ingestion for the remainder of 
that week (Days 9 through 15). 
Participants will have 7 study visits during the study. The first 6 visits will occur in the 
following pattern: the Screening Visit (Visit 1; up to Day -14); at Visit 2 (Day 1 of the 
randomized inpatient treatment); at Visit 3 (1 day following the inpatient treatment day); 
at Visit 4 (7 days following the first inpatient treatment day, which is the second inpatient
treatment day); at Visit 5 (1 day following the second inpatient treatment day); and at 
Visit 6 (7 days following the second inpatient 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 4 
and 5 must be conducted 1 day apart). Participants will enter a 1week safety follow-up 
period and return for Visit 7. Participants who prematurely discontinue from the study 
before completing the 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.


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Figure 4-1
Study Design Diagram
FU = follow-up; IP = investigational product.
All treatments will be presented to participants as oral once daily dosing throughout the 
study. 
At Visit 2 (Day 1 of the randomized inpatient treatment), all participants will be 
randomized to receive the first treatment, followed by blinded placebo on Days 2 through 
7. 
Starting at Visit 4 (Day 8), participants will then start 7 consecutive days of double 
blinded randomized treatment, administered once daily through Day 15. 
The schedule of activities for Study 3125-104-002 is presented in Table 4-1. The 
double-blind treatment period starts with the first dose of study (Day 1) treatment and 
ends with the last dosing day (Day 15).
IP Administered
IP Administered


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Table 4-1
Schedule of Activities (SoA)
Double-blind Treatment Period
Safety Follow-up 
Period
Visit
Screening (1)
2
3
4
5
6/ETa
7
Study Day
up to -14 days
1
2
8
9
15
22
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
x
Urine drug screen
x
x
Serum pregnancy test
x
x
Pharmacogenomics consent and samplec
x
Vital signsd
x
x
x
x
x
x
x
ECG
x
x
Physical examination
x
x
SCID
x
MADRS
x
x
x
x
x
x
x
CGI-S
x
x
x
x
x
x
BPRS+
x
x
x
x
x
CADSS
x
x
x
x
x


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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. 
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 4 and 5 must be conducted 1 day apart). 
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 laboratory blood tests. Clinical laboratory tests can be done at any visit for safety reasons at the discretion of the investigator.
c A separate ICF must be signed before the pharmacogenomic blood sample is taken. Participation is optional. This ICF may be signed at any visit 
during the study; however, the sample should be collected at any visit after the participant has been randomized.
d 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.
e. HAM-A will be assessed predose at Visits 2, 3, 4, and 6/ET. The HAM-A will be collected only from participants entering the study after the 
amendment has been IRB approved.
C-SSRS
x
x
x
x
x
x
x
Double-blind Treatment Period
Safety Follow-up 
Period
Visit
Screening (1)
2
3
4
5
6/ETa
7
Study Day
up to -14 days
1
2
8
9
15
22
HAM-Ae
x
x
x
x
AEs
x
x
x
x
x
x
Concomitant medications
x
x
x
x
x
x
x
Study treatment administration in the 
clinic
x
x
Study treatment compliance
x
x
x
x


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5.0
OBJECTIVES
The primary objective is to evaluate the efficacy, as measured by improvement in 
MADRS total score, at 1 day after the initial single oral dose of AGN-241751 compared 
with placebo in participants with MDD. The key secondary objectives are to evaluate the 
efficacy at Day 8, Day 9 after single oral dose, at Day 15 after repeated dose, and at
Day 22, 7 days after the completion of AGN-241751 dosing, when administered orally 
once daily compared with placebo in participants with MDD.


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6.0
PARTICPANT POPULATIONS
6.1
MODIFIED INTENT-TO-TREAT POPULATION
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.
6.2
SAFETY POPULATION
The safety population includes all participants who received at least 1 administration of 
study treatment. Participants will be summarized according to the study treatment they 
actually received.


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7.0
PARTICIPANT DISPOSITION
The number and percentage of participants in 2 of the study populations (Safety and
mITT) 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 (i.e., 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. 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. Similar disposition information to the double-blind treatment period will be 
presented for the safety follow-up period. The end of the study is defined as the 
completion of enrollment and completion of all periods of the study. All participants who 
prematurely discontinue during the double-blind treatment period or the safety follow-up 
period will be listed by discontinuation reason.


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8.0
DEMOGRAPHICS 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 mITT populations. Continuous variables will be summarized by 
number of participants and mean, SD, median, Q1 (25 percentile), Q3 (75 percentile), 
minimum, and maximum values. Categorical variables will be summarized by number 
and percentage of participants.
Abnormalities in participants’ medical and surgical histories will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA), version 22.0. The number and 
percentage of participants with abnormalities in medical and surgical histories in each 
system organ class and preferred term will be summarized by treatment group for the 
Safety Population.
Prior medication is defined as any medication taken before the date of the first dose of 
study treatment. Concomitant medication is defined as any medication taken on or after 
the date of the first dose of study treatment. 
Both prior and concomitant medications will be coded by drug name and therapeutic 
class. The use of prior and concomitant medications will be summarized by the number 
and percentage of participants in each treatment group for the Safety Population. If a 
participant took a specific medication multiple times or took multiple medications within 
a specific therapeutic class, that participants would be counted only once for the coded 
drug name or therapeutic class. 
Formulations (including salts, esters, etc) containing the same active ingredient will be 
pooled under the coded drug name of the base compound. Medications containing 
multiple active ingredients of different coded drug names will be reviewed during the 
course of the study and may be pooled under a single coded drug name for analyses.
The number and percentage of participants taking each antidepressant therapy (ADT) and 
the number of ADTs (0, 1, 2, and >2) received in current episodes of major depressive 
disorder prior to randomization will be summarized by treatment group for the Safety 
Population. ADT medication selection criteria is included in Table 8-1.


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Table 8-1
Criteria for ADT medication
ADT Class
Medication List
Atypical
BUPROPION
MIRTAZAPINE
VILAZODONE and/or VILAZODONE HYDROCHLORIDE
VORTIOXETINE and/or VORTIOXETINE HYDROBROMIDE
SNRI
DESVENLAFAXINE and/or DESVENLAFAXINE SUCCINATE
DULOXETINE and/or DULOXETINE HYDROCHLORIDE
LEVOMILNACIPRAN and/or LEVOMILNACIPRAN HYDROCHLORIDE
VENLAFAXINE and/or VENLAFAXINE HYDROCHLORIDE
SSRI
CITALOPRAM and/or CITALOPRAM HYDROBROMIDE
ESCITALOPRAM and/or ESCITALOPRAM OXALATE
FLUVOXAMINE
FLUOXETINE and/or FLUOXETINE HYDROCHLORIDE
PAROXETINE and/or PAROXETINE HYDROCHLORIDE
SERTRALINE
World Health Organization (WHO) Drug Dictionary, March 2017, will be used to 
classify prior and concomitant medications by therapeutic class and drug name.
Data for medical history with onset dates prior to the Screening visit will be tabulated and 
presented using the Safety population. An overall total will be provided for the study as 
well as by treatment group. Medical history data will be coded using the MedDRA
version 22.0 dictionary. No statistical comparisons will be performed.
A significant protocol deviations listing will be provided for protocol deviations for the 
Randomized Participants. Protocol deviations will be defined in a separate document, 
including importance classification.


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9.0
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE
9.1
EXTENT OF EXPOSURE
Exposure to the study treatment for the Safety Population during the double-blind 
treatment period will be summarized by treatment group (placebo, 3mg, 10mg and 
25mg). Descriptive statistics (number of participants, mean, SD, median, Q1
(25 percentile), Q3 (75 percentile), minimum, and maximum) will be presented for each 
study day from Day 1 to Day 15.
The following parameters for the study treatment will also be summarized using 
descriptive statistics by treatment group:

Treatment duration overall and by treatment regimen intervals (Day 1, Day 2-Day 7, 
Day 8-Day 15). Treatment duration will be calculated as the number of days from the 
date of the first dose of study treatment to the date of the last dose of study treatment, 
inclusive.
9.2
MEASUREMENT OF TREATMENT COMPLIANCE
Dosing compliance for the double-blind treatment period is defined as the number of 
tablets actually taken by a participant during that period divided by the number of days 
the participants are expected to be taken during the same period multiplied by 100.
If a participant achieved 80 to 120 percent compliance, then participant is considered as a 
compliant. Descriptive statistics (number and percentage) will be used to summarize 
compliant rates.


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10.0
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. 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 for at least 1 treatment group in the mITT Population. 
number. Small centers will be pooled to form pseudo-centers so that each treatment group 
includes at least 2 mITT participants within the center.  Pooling will be done within each 
country using the following algorithm:
1. Based on the number of mITT participants, small centers will be ordered from the 
largest to the smallest, and centers of the same size will be ordered from the 
largest center number to the smallest center number. 
2. The pooling process starts with the largest small center from the top, which will 
be pooled with the smallest from the bottom until a non-small center is formed. 
3. The process will be repeated using the small centers left out after the first pass.
If any centers are left out at the end of the process, they will be pooled with the smallest 
pseudo-center. If there is more than 1 smallest pseudo-center, the pseudo-center with the 
smallest center number will be selected. In case that the pseudo center formed by pooling 
all small centers is still a small center, it will be pooled with the smallest non-small 
center. If there is more than 1 smallest non-small center, the one with the smallest center 
number will be selected.
The pseudo-centers will be used for all efficacy analyses when the model is adjusted for 
study center.
The rater-administered MADRS will be used for the efficacy analyses.


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10.1
PRIMARY EFFICACY PARAMETER
The primary efficacy parameter will be the change from baseline in MADRS total score 
at 1 day after first dose and will be analyzed using a mixed-effects model for repeated 
measures (MMRM) model 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 observed cases (OC) without imputation of missing 
values. MADRS assessments at all study visits will be included in the MMRM model. 
Primary endpoint descriptive statistics and associated statistical testing results from the 
MMRM model will be presented.
10.2
SECONDARY EFFICACY PARAMETER
The secondary efficacy parameter will be the change from baseline in MADRS total 
score at Day 8 and Day 9 after single oral dose, on Day 15 after repeated dose, and on 
Day 22, 7 days after the completion of AGN-241751 dosing. The primary analysis for the 
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. 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. The Day 1 predose 
MADRS will be used as baseline for all analysis. MADRS assessments at all study visits 
will be included in the MMRM model. Key secondary endpoint descriptive statistics and 
associated statistical testing results from the MMRM model will be presented by visit.
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 key 
secondary efficacy parameters. 
For the sensitivity analysis of the primary endpoint, change from baseline in MADRS 
totals score at 1-day post Day 1 and secondary endpoint, change from baseline in 
MADRS totals score at Day 8, Day 9, Day 15, and Day 22, the following steps will be 
followed to generate datasets and analyze the data:


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1. Generate the imputed datasets: 
The implementation of the pattern-mixture model (PMM) with control-based pattern 
imputation of Ratitch and O’Kelly (2011) will be used to impute missing data under the 
MNAR assumption.
-
Intermittent (non-monotone) missing data in both treatment groups are imputed 
using the Monte-Carlo Markov chain (MCMC) method under the MAR 
assumption.
-
Remaining monotone missing data are imputed using a PMM approach using a 
sequential regression imputation model estimated based on data from the placebo 
arm only. 50 imputed datasets will be generated.
2. Model based key estimates LSMean difference between treatment group and standard
error) will be obtained for the change from baseline in MADRS total score at day 2 
(1 day after first dose), Day 8, Day 9, Day 15, and Day 22 for each imputed dataset 
using the same MMRM.
3. Calculation of the combined mean difference, 95% CI, and p-value for the change 
from baseline in MADRS total score at day 2 (1 day after first dose), Day 8, Day 9, 
Day 15, and Day 22 will be done using the method proposed by Rubin (1987) via 
PROC MIANALYZE.
10.3
ADDITIONAL EFFICACY PARAMETERS
Additional efficacy parameters are as follows:

Change from baseline in Clinical Global Impressions-Severity (CGI-S) at Day 2
(1 day after first dose), Day 8, Day 9 and Day 15 

MADRS responder status at Day 2 (1 day after first dose), Day 8, Day 9, Day 15
and Day 22

CGI-S responder status at Day 2 (1 day after first dose), Day 8, Day 9 and 
Day 15

MADRS remitter status at Day 2 (1 day after first dose), Day 8, Day 9, Day 15 and 
Day 22

Time to first response

Time to first remission


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Analysis of change from baseline in CGI-S score will be performed using a similar 
MMRM to that used for the key secondary parameter. Multiple comparison procedure 
will not be applied to the above additional efficacy parameters.
Plots of fitted (least squares) mean values and their standard errors based on the MMRM 
model for the change from baseline in MADRS total score and in CGI-S score, 
respectively, will be presented by treatment group and by visit. 
CGI-S responder is defined as participants achieving a score of ≤ 2 on the CGI-S of 
Illness scale.
During the randomized treatment period, 2 types of events for MADRS total score will be 
defined based on the following criteria:

Responder: ≥ 50% reduction from baseline MADRS total score

Remitter: MADRS total score ≤ 10
Rates of responders and remitters will be reported by treatment group for each timepoint 
(Days 2, 8, 9, 15, and 22 after first dose of randomized treatment). A 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 baseline MADRS or 
CGI-S total score. 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. Bar charts for the rates of
responders and remitters in MADRS total score will be presented by treatment group and 
by study day.
Descriptive statistics for the first three additional endpoints and their associated statistical 
testing results from the MMRM models and logistic regression will be respectively 
presented by visit.
The time to onset of first event (i.e. first response or first remission) is defined as the 
number of days from the first randomized dosing to the first event. The time to onset in 
days will be calculated for each type of event (first response or first remission) in person 
level. Participants who do not meet the criteria for respective type of event will be 
censored at the time of their last MADRS assessment during the treatment period. 


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For each type of event, the proportion of participants with onset of first events, 
Kaplan-Meier estimate in terms of the median time to onset of first event, and its 95% CI 
will be presented for each treatment group. Plots of the Kaplan-Meier estimate of the 
distribution of the time to onset of events will also be provided for each treatment arm. 
Log-rank tests comparing the time to onset of event distribution between each 
AGN-241751 dose and placebo will be conducted.


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11.0
SAFETY ANALYSES
The safety analysis will be performed using the safety population. The safety parameters 
will include adverse events (AEs), clinical laboratory including, vital signs, 
electrocardiographic (ECG), C-SSRS, BPRS+, and CADSS parameters. The last 
nonmissing safety assessment before the first dose of 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, Q1 (25 percentile), Q3 
(75 percentile), minimum, and maximum values. Categorical variables will be 
summarized by number and percentage of participants.
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 22.0.
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 
study medication. However, an AE that occurs more than 30 days after the last dose of 
study medication will not be counted as a TEAE. Per case report form instructions, a new 
AE record will be created with a new AE onset date for any AE that worsens. Therefore 
TEAEs can simply be identified as those AEs with recorded onset date on or after the 
date of the first dose of study intervention and within 30 days after the last dose of study 
intervention. 
The number and percentage of participants reporting TEAEs in each treatment group will 
be summarized overall and weekly. The number and percentage of participants reporting 
TEAEs in each treatment group will be tabulated by descending percentage in any group, 
by system organ class and preferred term, and further categorized by severity and causal 
relationship to the study treatment. If more than 1 AE is coded to the same preferred term 
for the same patient, the patient will be counted only once for that preferred term using 
the greatest severity and strictest causality for the summarization by severity and causal 
relationship.
The total number of TEAEs by system organ class and preferred term; system organ 
class, preferred term, and severity; system organ class, preferred term, and causal 
relationship to the study treatment will be summarized by treatment group.
The incidence of common (≥ 2% of participants in any treatment group) TEAEs will be 
summarized by preferred term and treatment group and sorted by decreasing frequency 
for the test treatment highest dose. It will be reported for Safety population overall.
The number and percentage of participants in the Safety Population who have AEs 
leading to premature discontinuation of the study treatment will be summarized by 
preferred term and treatment.


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The number and percentage of participants who have TESAEs (treatment-emergent 
serious adverse event) will be summarized by preferred term and treatment group. An AE 
will be considered a TESAE if it is a TEAE that additionally meets any SAE criteria. 
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.
11.2
CLINICAL LABORATORY PARAMETERS
Descriptive statistics for clinical laboratory values (in SI units) and changes from the 
baseline values at each assessment time point will be presented by treatment group for the 
following laboratory parameters, measured at Screening and Visit 6/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
Urine drug screen (UDS):
Benzoylecgonine (cocaine), barbiturates, amphetamines, 
benzodiazepines, cannabinoids, opiates, methadone, 
phencyclidine
Pregnancy at Screening 
and Visit 6/ET:
Serum β-hCG
The following clinical laboratory levels will be measured at Screening only:
Clinical laboratory 
screening tests:
HbA1c, fasting insulin, TSH, T3, and free T4
Hepatitis screening:
HCV 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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Clinical laboratory test values will be considered potentially clinically significant (PCS) 
if they meet either the lower-limit or higher-limit PCS criteria listed in Table 11-1. The 
number and percentage of participants who have PCS postbaseline clinical laboratory 
values will be tabulated by treatment group. The percentages will be calculated relative to 
the number of participants with 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 value and at least one postbaseline assessment. 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.
Table 11-1
Criteria for Potentially Clinically Significant Clinical Laboratory Tests
Laboratory Parameter
SI Unit
Conversion 
Factora
Traditional 
Unit
PCS Criteriab 
Low Values
PCS Criteriab 
High Values
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
Abs Neutrophils (ANC)
109/L
1
1000/μL
< 1.0
—
Platelet count
109/L
1
1000/μL
≤ 75
≥ 700
White 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
ALT (SGPT)
U/L
1
U/L
—
≥ 3 × ULN
AST (SGOT)
U/L
1
U/L
—
≥ 3 × ULN
Gamma-glutamyl 
transferase (GGT)
U/L
1
U/L
—
≥ 3 × ULN
Blood urea nitrogen 
(BUN)
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
Cholesterol
mmol/L
38.6698
mg/dL
—
> 1.3 × ULN
High-density lipoprotein
(HDL) cholesterol
mmol/L
39
mg/dL
< 0.8 × LLN
—


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Laboratory Parameter
SI Unit
Conversion 
Factora
Traditional 
Unit
PCS Criteriab 
Low Values
PCS Criteriab 
High Values
Low-density lipoprotein
(LDL) cholesterol
mmol/L
39
mg/dL
—
> 1.2 × ULN
CPK
u/L
1
mg/dL
—
> 1.5 × ULN
Creatinine
μmol/L
0.0113
mg/dL
—
> 1.3 × ULN
Glucose, fasting
mmol/L
18
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
—
—
< 0.9 × LLN
> 1.1 × ULN
Triglycerides, fasting
mmol/L
88.6
mg/dL
—
> 1.2 × ULN
Urinalysis
Protein
—
—
—
—
At least 2 +
Glucose
—
—
—
—
At least 2 +
Blood
—
—
—
—
At least 2 +
a Conversion factor from SI units to 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 of laboratory reference range.
In addition, descriptive statistics for clinical laboratory 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 11-2.
Table 11-2
Selected Parameters Reported in Conventional Units
Number
Laboratory Parameter
Conventional Unit
1
Alanine Aminotransferase (SGPT)
U/L
2
Albumin
G/dL
3
Alkaline Phosphatase
U/L
4
Aspartate Aminotransferase (SGOT)
U/L
5
Bilirubin, Direct (Conjugated)
mg/dL
6
Bilirubin, Indirect (Unconjugated)
mg/dL
7
Bilirubin, Total
mg/dL
8
Blood Urea Nitrogen
mg/dL
9
Calcium
mg/dL
10
Cholesterol, HDL
mg/dL
11
Cholesterol, LDL
mg/dL
12
Cholesterol, LDL direct and calculated (combined)
(may be reported with #11)
mg/dL
13
Cholesterol, Total
mg/dL
14
Creatine Kinase
U/L


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Number
Laboratory Parameter
Conventional Unit
15
Creatinine
mg/dL
16
Glucose
mg/dL
17
Insulin
uIU/mL
18
Triglycerides
mg/dL
19
Uric Acid
mg/dL
20
Hemoglobin
G/dL
11.3
VITAL SIGNS
Descriptive statistics of actual values and change from baseline for vital signs (systolic 
and diastolic blood pressures, pulse rate, weight, and temperature) will be presented at 
each assessment timepoint by treatment.
Vital sign values will be considered PCS if they meet both the observed-value criterion
and the change-from-baseline criteria listed in Table 11-3. The number and percentage of 
participants who have PCS postbaseline vital sign values will be tabulated by treatment 
group. The percentages will be calculated relative to the number of participants who have 
available baseline value and at least 1 postbaseline assessment. The numerator will be the 
total number of participants with available non-PCS baseline value and at least one 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%
Temperature, oC
High
> 38
—
Low
< 35
—
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.


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11.4
ELECTROCARDIOGRAM
Descriptive statistics of actual values and change from baseline for ECG parameters 
(ie, heart rate, PR interval, QRS interval, QT interval, and QTc interval according to 
QTcB and QTcF) will be presented at each assessment timepoint by treatment group.
Electrocardiographic parameter values are considered PCS if they meet the higher-limit
PCS criteria listed in Table 11-4 The number and percentage of participants with PCS 
postbaseline values will be tabulated by study treatment group. The percentages will be 
calculated relative to the number of participants with available non-PCS baseline value 
and at least one postbaseline assessment. The numerator will be the total number of 
participants with 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 Screening to Day 15 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.
Table 11-4
Criteria for Potentially Clinically Significant Electrocardiograms
Parameter
Unit
Higher Limit
QRS interval
msec
≥ 150
PR interval
msec
≥ 250
QTcB, QTcF
msec
>500 or Change from baseline 
(increase of > 60)
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.


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11.5
OTHER SAFETY PARAMETERS
11.5.1
Columbia-Suicide Severity Rating Scale
For the Columbia-Suicide Severity Rating Scale (C-SSRS), the number and percentage of 
participants with suicidal ideation and suicidal behavior before the double-blind treatment 
period and during double-blind treatment and safety follow-up periods will be 
summarized by treatment group for the Safety population. Supportive tabular display of 
participants with all values will be provided, including study center, PID number, 
treatment group, visit number, intensity of suicidal ideation, suicidal behavior type, and 
lethality of suicidal behavior.
11.5.2
Potential Hy’s Law
Potential Hy’s Law criteria within a 24 hours window is defined by a post baseline 
elevation of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 3x 
ULN, along with total bilirubin (TBL) ≥ 2x ULN and a non-elevated alkaline 
phosphatase (ALP) < 2x ULN, all based on blood draws collected within a 24 hour 
period.
Potential Hy’s Law criteria without time window (e-DISH) is defined by maximum of 
post baseline elevation of ALT or AST ≥ 3x ULN, along with maximum of post baseline 
elevation of TBL ≥ 2x ULN.
Participants who meet the potential Hy’s Law criteria from the first dose of study drug to 
within 30 days after the last dose of study treatment will be summarized. Supportive 
tabular displays will also be provided.
11.5.3
Brief Psychiatric Rating Scale—Positive Symptoms 
Subscale 
The BPRS+ total score is defined as the sum of 4 positive individual scores including 
conceptual disorganization, suspiciousness, hallucinatory behavior, and unusual thought 
content. Each question is presented on a 7-point Likert scale with a choice for NA as not 
assessed. If any item were not observed, not assessed, or missing, then the total score was 
missing.
Descriptive statistics of actual values at baseline, post baseline, and change from baseline 
for BPRS+ total score as well as for 4 positive individual scores will be presented by 


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treatment group. Plots of mean values and their standard errors for the BPRS+ total score 
will be presented by treatment group and by visit for Safety population.
A participant will be considered to have a treatment-emergent symptom in the BPRS 
scale if any of the following BPRS items scores are ≤ 2 at baseline and > 2 after baseline: 
conceptual disorganization, suspiciousness, hallucinatory behavior, or unusual thought 
content. The number and percentage of participants reporting treatment-emergent 
symptoms in the BPRS scale will be tabulated for each individual item and for all 4 items 
specified above.
Listings of participants with treatment-emergent symptoms will be provided and will 
include the participant identification number and baseline and postbaseline values. 
Listings of all adverse events occurring in participants who have treatment-emergent 
symptoms will also be provided.
11.5.4
Clinician Administered Dissociative States Scale 
CADSS total score is defined as of 23 non-negative individual scores. Each question is 
presented on a 5-point Likert scale with 0 meaning “not at all” and 4 meaning “extreme”. 
If more than 4 items were missing, then the total score was set to missing; if there were 
4 or fewer items missing, then the total score is set to the sum of non-missing items 
multiplied by the total number of items divided by the number of non-missing items.
Descriptive statistics of actual values at baseline, post baseline, and change from baseline 
for CADSS total score will be presented by treatment group at each assessment 
timepoint. Plots of mean values and their standard errors for the CADSS total score will 
be presented by treatment group and by visit for Safety population.
11.5.5
The Hamilton Anxiety Rating Scale
The HAM-A is a clinician-rated scale to rate the severity of anxiety symptoms. The
participant tested over 14-questions, and rated on a scale from 0 to 4, with 1 indicating a 
“not present” response and 4 indicating a “severe” response. The HAM-A 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.
The exploratory analysis of HAM-A scores will be performed using the safety population 
for the double-blind treatment period and for the safety follow-up period, if applicable, P. 


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The exploratory parameters will include change from baseline in HAM-A total scores at 
Day 2, 8, and 15. Descriptive statistics of actual values at baseline, post baseline, and 
change from baseline for HAM-A total score will be presented by treatment group at each 
assessment timepoint.


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12.0
HEALTH OUTCOMES ANALYSES
Not Applicable.


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


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14.0
DETERMINATION OF SAMPLE SIZE
The sample size of approximately 25 randomized participants in each of the 4 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.


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15.0
STATISTICAL SOFTWARE
Statistical analyses will be performed using version 9.4 or newer of SAS.


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16.0
DATA HANDLING CONVENTIONS
16.1
VISIT TIME WINDOWS
Table 16-1 presents the visits assigned for efficacy and safety analyses and the 
corresponding range of treatment days (window) during which an actual visit may occur.
Table 16-1
Visit Time Windows
Derived Visit
Scheduled Visit Daya
Window
Baseline
Screening/Day 1 (Visit 2)
last nonmissing assessment before Index1a
Day 2
Day 2 (Visit 3)
Days (Index1a+1, IndexAb-1)
Day 8
Day 8 (Visit 4)
IndexAb
Day 9
Day 9 (Visit 5)
Days (IndexAb +1, IndexAb+4)
Day 15
Day 15 (Visit 6)
Days (IndexAb+5, day of final double blind
visit or ET Visit occurring after
IndexAb+5)
End of Double-Blind 
Treatment
The last available post-baseline assessment (unscheduled assessments) during 
the double-blind treatment period
Safety Follow-up (Day 
22)
Days [Day after final double-blind visit or ET visit occurring after Day 15 
(Visit 6)/Early Termination visit]
a Index1: Day of first double-blind dose
b IndexA: Day of second double-blind dose, if not received, use Index1 + 7 days
If the assessment date (if the assessment date is unavailable, use visit date instead) is on 
or after the date of the first dose of study treatment, the study day is calculated by 
assessment date – date of the first dose of study treatment + 1. If the assessment date is 
before the date of the first dose of study treatment, the study day is calculated by 
assessment date – date of the first dose of study treatment. Therefore, a negative day 
indicates a day before the start of the study treatment.
If a participant has 2 or more visits within the same window, the last visit with a 
nonmissing value will be used for analysis.
16.2
DERIVED VARIABLES
The efficacy variables are derived as follows:

MADRS total score is the sum of the 10 items from the MADRS. If more than 
2 items of the MADRS are missing, the total score will be set to missing

Responder on MADRS is defined as a participant with ≥ 50% reduction from baseline 
MADRS total score


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
Responder on CGI-S is defined as participant achieving a score of ≤ 2 on the CGI-S 
of Illness scale.

Remitter on MADRS is defined as a participant with MADRS total score ≤ 10 

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

CADSS total score is defined as the sum of scores for 23 subjective items. If more 
than 4 items are missing, then the total score will be set to missing.
The total score at a particular visit will be calculated using (sum of nonmissing 
items) × (total number of items) / (number of nonmissing items) only if the number of 
missing items is less than the specified number for each variable. Otherwise, the total 
score will be set to missing. 
16.3
REPEATED OR UNSCHEDULED ASSESSMENTS OF SAFETY 
PARAMETERS
If a participant has repeated assessments before the start of the first treatment, the results 
from the final nonmissing assessment made prior to the start of the study treatment will 
be used as baseline. If end of double-blind treatment period assessments are repeated or if 
unscheduled visits occur during the double-blind treatment period, the last nonmissing
postbaseline assessment will be used as the end of double-blind treatment period
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.
16.4
MISSING DATE OF THE LAST DOSE OF STUDY TREATMENT
When the date of the last dose of study treatment is missing for a participant in the Safety 
Population, all efforts should be made to obtain the date from the Investigator. If after all 
efforts are made it is still missing, the last available dosing record date will be used as the 
last dose date.
16.5
MISSING SEVERITY ASSESSMENT FOR ADVERSE EVENTS
If severity is missing for an AE that started before the date of the first dose of 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 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.


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16.6
MISSING CAUSAL RELATIONSHIP TO STUYD DRUG FOR 
ADVERSE EVENTS
If the causal relationship to the study treatment is missing for an AE that started on or 
after the date of the first dose of study treatment, a causality of yes will be assigned. The 
imputed values for causal relationship to study treatment will be used for the incidence 
summary; the values will be shown as missing in the data listings.
16.7
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 study 
treatment, the month and day of the first dose of 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 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 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 study treatment, the day of the first dose of 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 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 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 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 study treatment, the first 
day of the month will be assigned to the missing day


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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 study treatment, the date of the first 
dose of study treatment will be assigned to the missing start date

If the stop date is before the date of the first dose of study treatment, the stop date will 
be assigned to the missing start date
Table 16-2
Imputation Scenarios
Scenario
Complete
Imputable
Year
Month
Day
1
Yes
Yes
Yes
Complete
2
Yes
Yes
—
Yes
3
Yes
—
Yes
  No1
4
Yes
—
—
Yes
5
—
Yes
Yes
  No1
6
—
Yes
—
  No1
7
—
—
Yes
  No1
8
—
—
—
Yes
1 Not allowed per database design
16.8
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.
16.8.1
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 study 
treatment, the month and day of the first dose of study treatment will be assigned to 
the missing fields


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
If the year of the incomplete start date is before the year of the first dose of 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 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 study treatment, the day of the first dose of 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 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 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 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 study treatment, the first 
day of the month will be assigned to the missing day
16.8.2
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 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


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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

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
16.9
CHARACTER VALUES OF CLINICAL LABORATORY 
PARAMETERS
If the reported value of a clinical laboratory parameter cannot be used in a statistical 
summary table because, for example, a character string is reported for a parameter of the 
numeric type, a coded value must be appropriately determined for use in the statistical 
analyses. The actual values, however, as reported in the database will be presented in the 
data listings.
Table 16-3 shows examples of how some possible laboratory results should be coded for 
the analysis.


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Table 16-3
Examples of Coding Speci
al Character Values for Clinical Laboratory 
Parameters
Laboratory Test
Possible Laboratory Results
(in SI Units)
Coded Value for Analysis
Chemistry: ALT
< 5
5
Chemistry: AST
< 5
5
Chemistry: bilirubin, total
< 2
2
Urinalysis: ketones
> 0
Positive
≤ 0, Negative
Negative
Urinalysis: pH
> 8.0, ≥ 8.0
8.0
≥ 8.5
8.5
Urinalysis: glucose
≤ 50
0
(50, 100]
1+
(100, 250]
2+
(250, 500]
3+
(500, 1000]
4+
≥ 1000
5+
Urinalysis: protein
≤ 15
0
(15, 30]
1+
(30, 100]
2+
(100, 500]
3+
≥ 500
4+
ALT = alanine aminotransferase; AST = aspartate aminotransferase; SI = Le Système International d’Unités
(International System of Units).


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17.0
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL
None


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18.0
REFERENCES
Kenward MG, Roger JH. Small sample inference for fixed effects from restricted 
maximum likelihood. Biometrics 1997; 53:983-997.


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