A Multicenter, Randomized, Double-blind, Placebo-controlled Study of the Safety and Efficacy of TS-121 as an Adjunctive Treatment for Patients With Major Depressive Disorder With an Inadequate Response to Current Antidepressant Treatment
Phase: PHASE2
Conditions: Major Depressive Disorder
Sponsor: Taisho Pharmaceutical R&D Inc.

A Multicenter, Randomized, Double-blind, Placebo-controlled Study of the Safety 
and Efficacy of TS-121 as an Adjunctive Treatment for Patients with Major 
Depressive Disorder with an Inadequate Response to Current Antidepressant 
Treatment 
TS121-US201 
Apr 23, 2018 
Amendment 4 
Taisho Pharmaceutical R&D Inc. 
Confidential 
Page 1 of 72 
Protocol Number: TS121-US201 
A Multicenter, Randomized, Double-blind, Placebo-controlled Study of the Safety 
and Efficacy of TS-121 as an Adjunctive Treatment for Patients with Major 
Depressive Disorder with an Inadequate Response to Current Antidepressant 
Treatment 
Investigational Product: TS-121 
Sponsor 
Taisho Pharmaceutical R&D Inc. 
350 Mt. Kemble Avenue 
Morristown, NJ 07960 
Tel: 1-973-285-0870 
Fax: 1-973-285-1665 
Version:  
Amendment 4 
Document Dates: 
Apr 23 2018  
Original Protocol: 
Version 1.0, Nov 23 2016 
Confidentiality Statement 
The information in this document is confidential and is not to be disclosed without the written 
consent of Taisho Pharmaceutical R&D Inc. except to the extent that disclosure would be required 
by law and for the purpose of evaluating and/or conducting a clinical study for Taisho 
Pharmaceutical R&D Inc.  You are allowed to disclose the contents of this document only to your 
Institutional Review Board (IRB) and study personnel directly involved with conducting this 
protocol.  Persons to whom the information is disclosed must be informed that the information is 
confidential and proprietary to Taisho Pharmaceutical R&D Inc. and that it may not be further 
disclosed to third parties. 
NCT03093025

A Multicenter, Randomized, Double-blind, Placebo-controlled Study of the Safety 
and Efficacy of TS-121 as an Adjunctive Treatment for Patients with Major 
Depressive Disorder with an Inadequate Response to Current Antidepressant 
Treatment 
TS121-US201 
Apr 23, 2018 
Amendment 4 
 
Taisho Pharmaceutical R&D Inc. 
 
Confidential 
Page 3 of 72 
INVESTIGATOR SIGNATURE SHEET 
A Multicenter, Randomized, Double-blind, Placebo-controlled Study of the Safety, 
and Efficacy of TS-121 as an Adjunctive Treatment for Patients with Major 
Depressive Disorder with an Inadequate Response to Current Antidepressant 
Treatment  
Protocol Number: TS121-US201 
Protocol Amendment 4 
By signing below, I attest that I have read, understood, and agree to abide by all conditions, 
instructions, and restrictions contained in this protocol (including appendices).  I will not initiate 
this study without approval from the appropriate Institutional Review Board (IRB) and I 
understand that any changes in the protocol must be approved in writing by the Sponsor and the 
IRB before they can be implemented, except where necessary to eliminate immediate hazards 
to the subject. 
Approval Signature: 
 
Principal Investigator:  
 
 
 
 
               
 
      
 
 
 
 
Name  
 
                                      Date 
 
 
 
 
 
 
 
 
 
          
 
 
 
Name of Facility 
 
 
 
 
 
 
 
 
          
 
 
 
Address 
 
 
 
 
 
 
 
 
          
 
 
 
City, State, Zip Code 
 
 
 
 
 
 
 
 
          
 
 
 
Phone Number  
 
 
 
 
 
 
 
 
             
 
 
 
Fax Number 

A Multicenter, Randomized, Double-blind, Placebo-controlled Study of the Safety 
and Efficacy of TS-121 as an Adjunctive Treatment for Patients with Major 
Depressive Disorder with an Inadequate Response to Current Antidepressant 
Treatment 
TS121-US201 
Apr 23, 2018 
Amendment 4 
 
Taisho Pharmaceutical R&D Inc. 
 
Confidential 
Page 5 of 72 
 
1 
Table of Contents 
1 
Table of Contents ............................................................................................................ 5 
2 
LIST OF ABBREVIATIONS .................................................................................................. 9 
3 
SYNOPSIS...................................................................................................................... 11 
4 
BACKGROUND INFORMATION ....................................................................................... 16 
4.1 
Introduction ...................................................................................................................... 16 
4.2 
Mechanism of Action of Vasopressin Receptor 1b (V1b Receptor) ........................................ 16 
4.3 
Name and Description of Investigational Product ............................................................... 17 
4.4 
Summary of Nonclinical and Clinical Findings ..................................................................... 18 
 
Summary of Nonclinical Findings ........................................................................................ 18 
4.4.1
 
Summary of Clinical Findings .............................................................................................. 19 
4.4.2
 
Known and Potential Risks to Human Subjects ................................................................... 19 
4.4.3
4.5 
Study Rationale ................................................................................................................. 20 
5 
STUDY OBJECTIVES ....................................................................................................... 22 
5.1 
Primary Objectives ............................................................................................................ 22 
5.2 
Exploratory Objective ........................................................................................................ 22 
6 
STUDY DESIGN .............................................................................................................. 23 
6.1 
Study Design ..................................................................................................................... 23 
6.2 
Randomization Procedure ................................................................................................. 23 
6.3 
Blinding ............................................................................................................................ 23 
6.4 
Unblinding ........................................................................................................................ 24 
6.5 
Early Discontinuation ........................................................................................................ 24 
7 
STUDY POPULATION ..................................................................................................... 25 
7.1 
Study Population ............................................................................................................... 25 
 
Inclusion Criteria ................................................................................................................. 25 
7.1.1
 
Exclusion Criteria ................................................................................................................. 26 
7.1.2
 
Replacement Patients ......................................................................................................... 29 
7.1.3
8 
TREATMENT OF PATIENTS .............................................................................................. 30 
8.1 
Investigational Product ...................................................................................................... 30 
 
Packaging and Labeling ....................................................................................................... 30 
8.1.1
 
Handling, Dispensing, and Administration of Investigational Product ................................ 30 
8.1.2
 
Treatment Compliance ........................................................................................................ 31 
8.1.3

A Multicenter, Randomized, Double-blind, Placebo-controlled Study of the Safety 
and Efficacy of TS-121 as an Adjunctive Treatment for Patients with Major 
Depressive Disorder with an Inadequate Response to Current Antidepressant 
Treatment 
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Investigational Product Accountability................................................................................ 31 
8.1.4
 
Return or Destruction of Investigational Product ............................................................... 32 
8.1.5
8.2 
Concomitant Drug Therapy ................................................................................................ 32 
8.3 
Prohibited / Restricted Concomitant Therapy ..................................................................... 32 
8.4 
Duration of Patient Participation ........................................................................................ 33 
8.5 
Discontinuation Criteria and Procedures ............................................................................ 33 
9 
STUDY PROCEDURES AND OBSERVATIONS ..................................................................... 35 
9.1 
Study Procedures and Observations ................................................................................... 35 
9.2 
Study Assessments ............................................................................................................ 38 
 
Explain Study and Obtain Written Informed Consent ......................................................... 38 
9.2.1
 
Review Inclusion/Exclusion Criteria Including Concomitant Medications .......................... 38 
9.2.2
 
Demographics ..................................................................................................................... 38 
9.2.3
 
Medical History ................................................................................................................... 38 
9.2.4
 
Psychiatric History ............................................................................................................... 38 
9.2.5
 
Diagnostic and Screening Assessments ............................................................................... 39 
9.2.6
 
Safety Assessments ............................................................................................................. 40 
9.2.7
 
Efficacy Assessments ........................................................................................................... 45 
9.2.8
 
AiCure: Medication Adherence and Reminder System ....................................................... 46 
9.2.9
 
Pharmacodynamics Assessments........................................................................................ 46 
9.2.10
 
Pharmacokinetics Assessment ............................................................................................ 48 
9.2.11
 
Pharmacogenomic Blood Sampling .................................................................................... 49 
9.2.12
9.3 
Visit and Time Windows ................................................................................................... 49 
10 
STATISTICAL METHODS .............................................................................................. 51 
10.1 
Sample Size Determination ................................................................................................ 51 
10.2 
Analysis Populations.......................................................................................................... 51 
10.3 
General Analysis Conventions ............................................................................................ 51 
10.4 
Demographic and Baseline Characteristics ......................................................................... 51 
10.5 
Endpoint Analysis .............................................................................................................. 52 
 
Safety Analysis ..................................................................................................................... 52 
10.5.1
 
Efficacy Analysis .................................................................................................................. 53 
10.5.2
 
Pharmacodynamic (PD) Analysis ......................................................................................... 54 
10.5.3
 
Pharmacokinetic (PK) Analysis ............................................................................................ 54 
10.5.4
 
Pharmacogenomic (PGx) Analysis ....................................................................................... 54 
10.5.5
11 
ADVERSE EVENT REPORTING ..................................................................................... 55 
11.1 
Definitions, Grading & Relationship, Outcome and Follow-up ............................................. 55 
 
Definitions ........................................................................................................................... 55 
11.1.1

A Multicenter, Randomized, Double-blind, Placebo-controlled Study of the Safety 
and Efficacy of TS-121 as an Adjunctive Treatment for Patients with Major 
Depressive Disorder with an Inadequate Response to Current Antidepressant 
Treatment 
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Grading and Relationship .................................................................................................... 56 
11.1.2
 
Outcome .............................................................................................................................. 59 
11.1.3
 
AE Follow-Up ....................................................................................................................... 59 
11.1.4
11.2 
Serious Adverse Event Reporting ....................................................................................... 59 
 
Definition of Serious Adverse Event .................................................................................... 59 
11.2.1
 
Serious Adverse Event Reporting Procedure ....................................................................... 60 
11.2.2
 
SAE Follow-Up ..................................................................................................................... 61 
11.2.3
11.3 
Events of Clinical Significance ............................................................................................. 61 
 
Suicidal Ideation and Behavior ............................................................................................ 61 
11.3.1
 
Lens Opacity ........................................................................................................................ 62 
11.3.2
 
EOCS Reporting Procedure .................................................................................................. 62 
11.3.3
11.4 
Worsening of Depression ................................................................................................... 62 
11.5 
Pregnancy Reporting ......................................................................................................... 63 
11.6 
Overdose .......................................................................................................................... 63 
 
Definition of Overdose ........................................................................................................ 63 
11.6.1
 
Overdose Reporting ............................................................................................................ 63 
11.6.2
12 
INVESTIGATOR OBLIGATIONS ..................................................................................... 64 
12.1 
Ethical Considerations ....................................................................................................... 64 
12.2 
Institutional Review Board (IRB) Approval .......................................................................... 64 
12.3 
Informed Consent .............................................................................................................. 64 
 
Study Informed Consent ..................................................................................................... 64 
12.3.1
 
Pharmacogenomic Informed Consent ................................................................................ 65 
12.3.2
 
Health Insurance Portability and Accountability (HIPAA) Authorization............................. 65 
12.3.3
12.4 
Patient Confidentiality ....................................................................................................... 66 
12.5 
Patient’s Financial Responsibilities During the Study .......................................................... 66 
13 
DOCUMENTATION, RECORD KEEPING, AND DATA MANAGEMENT .............................. 67 
13.1 
Source Data/Documents .................................................................................................... 67 
13.2 
Records Retention ............................................................................................................. 67 
13.3 
Data Management............................................................................................................. 67 
14 
CHANGES TO THE PROTOCOL AND STUDY TERMINATION ........................................... 68 
14.1 
Protocol Amendment ........................................................................................................ 68 
14.2 
Study Termination ............................................................................................................. 68 
15 
STUDY MONITORING ................................................................................................. 69 
15.1 
Clinical Monitoring ............................................................................................................ 69 
15.2 
Auditing Procedures .......................................................................................................... 69 

A Multicenter, Randomized, Double-blind, Placebo-controlled Study of the Safety 
and Efficacy of TS-121 as an Adjunctive Treatment for Patients with Major 
Depressive Disorder with an Inadequate Response to Current Antidepressant 
Treatment 
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16 
REFERENCES .............................................................................................................. 70 
17 
APPENDIX 1: Excluded CYP3A4 Concomitant Medications .......................................... 72 
 

A Multicenter, Randomized, Double-blind, Placebo-controlled Study of the Safety 
and Efficacy of TS-121 as an Adjunctive Treatment for Patients with Major 
Depressive Disorder with an Inadequate Response to Current Antidepressant 
Treatment 
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3 
SYNOPSIS 
Protocol Title 
A Multicenter, Randomized, Double-blind, Placebo-controlled Study of the 
Safety and  Efficacy of TS-121 as an Adjunctive Treatment for Patients with 
Major Depressive Disorder with an Inadequate Response to Current 
Antidepressant Treatment  
Protocol Number 
TS121-US201 
Phase of 
Development 
2a 
Number of Study 
Sites 
Approximately 25 US sites 
Study Drug 
TS-121: An oral, investigational new drug with antagonistic activity of the 
vasopressin 1b receptor  (V1b receptor) 
Indication 
Major Depressive Disorder (MDD) 
Number of 
Patients 
Approximately 180 randomized male and female MDD patients between 18 
and 65 years of age inclusive 
• 
Placebo Group: 60 patients 
• 
TS-121 10 mg Group: 60 patients 
• 
TS-121 50 mg Group: 60 patients 
Objectives 
Primary Objectives 
• 
To evaluate the safety and tolerability of TS-121 compared to placebo 
in MDD patients  
• 
To evaluate the efficacy of two dose levels of TS-121 compared to 
placebo on MDD symptoms in MDD patients 
Exploratory Objective 
• 
To evaluate the effectiveness of biomarkers in predicting TS-121 
response with retrospective stratification of patients via baseline 
values of HPA axis and inflammatory biomarkers 
Safety 
assessments 
Safety and tolerability will be assessed from the time the patient is 
administered the investigational product through the final study procedure. 
Safety variables for assessment will include: 
• 
Adverse events 
• 
Physical examination 
• 
Columbia Suicide Severity Rating Scale (C-SSRS) 
• 
Body weight 
• 
Vital signs 

A Multicenter, Randomized, Double-blind, Placebo-controlled Study of the Safety 
and Efficacy of TS-121 as an Adjunctive Treatment for Patients with Major 
Depressive Disorder with an Inadequate Response to Current Antidepressant 
Treatment 
TS121-US201 
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• 
Clinical laboratory tests (hematology, biochemistry and urinalysis) 
• 
12-lead electrocardiogram (ECG) 
• 
Ophthalmological examinations 
Efficacy 
assessments 
Primary Endpoint 
• 
Change in MADRS total score from Visit 3 (Baseline) to Visit 6 (EOT) 
Secondary Endpoints 
• 
Changes from Visit 3 (Baseline) to Visit 6 (EOT) for CGI-S, SDQ, and 
HAM-A total scores 
• 
Percentage of CGI-I improvers (“Very much improved” or “Much 
improved”) 
• 
Percentage of MADRS responders (≥ 50% reduction in total score)  
Pharmacodynamic 
and 
Pharmacokinetic 
assessments 
Exploratory Endpoints 
• 
Pharmacokinetic data from Visit 6 may be explored relative to study 
results (mental health assessments and/or laboratory values) 
• 
Change from Visit 3 (Baseline) to Visit 6 (EOT) for plasma copeptin and 
inflammatory markers (TNF-α, IL-1, IL-6, HS-CRP) 
• 
To evaluate the effectiveness of biomarkers in predicting TS-121 
response with retrospective stratification of patients via baseline values 
of HPA axis and inflammatory biomarkers consisting of: 
o Hair cortisol 
o Salivary cortisol 
o Urine cortisol 
o Plasma copeptin, and  
o Inflammatory markers (TNF-α, IL-1, IL-6, HS-CRP) 

A Multicenter, Randomized, Double-blind, Placebo-controlled Study of the Safety 
and Efficacy of TS-121 as an Adjunctive Treatment for Patients with Major 
Depressive Disorder with an Inadequate Response to Current Antidepressant 
Treatment 
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Study Design: 
 
 
 
Schedule of PD Marker Collection: 
 

A Multicenter, Randomized, Double-blind, Placebo-controlled Study of the Safety 
and Efficacy of TS-121 as an Adjunctive Treatment for Patients with Major 
Depressive Disorder with an Inadequate Response to Current Antidepressant 
Treatment 
TS121-US201 
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Taisho Pharmaceutical R&D Inc. 
 
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Study Design 
and Procedures 
 
This multicenter study is comprised of a screening period of up to 4 weeks, 
with a 2-week single-blind placebo lead-in period followed by a 6-week 
randomized, double-blind, placebo-controlled treatment period with a 2-week 
follow-up period, comparing the safety, efficacy, pharmacokinetics, and 
exploratory pharmacodynamics of TS-121 to placebo as an adjunctive 
treatment for patients with MDD. Patients must remain on the same single 
antidepressant (SSRI, SNRI or bupropion) for 6 weeks, and fixed dose for 4 
weeks prior to Visit 1.1.  Patients will remain on their current antidepressant 
therapy (ADT) with a fixed dose throughout the course of the study.  
Visit 1 (Screening):  Patients will visit the site for screening assessments 
and an initial review of study requirements. In addition to confirming the 
diagnosis of MDD by MINI, a trained site rater will employ the 17-items 
Hamilton depression scale (HAM-D), which will be subsequently confirmed 
through an additional HAM-D assessment conducted by a central rater (Visit 
1.1) prior to a 2-week placebo lead-in period. Patients will schedule a phone 
call for central rater assessments.  
Visit 1.1 (Screening): The central rater will contact the patient as scheduled, 
and will administer the Massachusetts General Hospital Antidepressant 
Treatment Response Questionnaire (MGH ATRQ) for assessment of current 
ADT, adequacy of duration and dose of prior and current ADT, as well as 
degree of improvement. The central rater will also complete the HAM-D 
assessment and SAFER inventory for confirmation of placebo lead-in 
eligibility. Results will be communicated to the site prior to Visit 2.  
Visit 2 (Start of Placebo Lead-In):  Following initial eligibility confirmation, 
qualified patients will return to the site initiating a 2-week, single-blind 
placebo lead-in period. Patients will be instructed to take 3 capsules of 
investigational product (placebo) once-daily in the morning and to maintain 
their current ADT regimen for two consecutive weeks. Patients will download 
AiCure software to their smart phone or receive an AiCure device that will 
monitor medication adherence during the 2-week placebo lead-in period (and 
for the duration of the 6-week treatment period) using AiCure’s interactive 
mobile device technology. An ophthalmologist will conduct a thorough eye 
examination (including slit lamp under mydriasis). Patients will be provided 
with supplies and instructions for at-home collection of saliva and urine for 
exploratory HPA axis assessment. Patients will schedule another phone call 
for central rater assessments (Visit 2.1), and Visit 3 will be scheduled.  
Visit 2.1 (End of Placebo Lead-In): Response to placebo will be assessed 
using HAM-D by a central rater via phone. Results will be communicated to 
the site prior to Visit 3. The current HAM-D score and change in HAM-D 
score from Visit 1.1 to Visit 2.1 will be used to determine eligibility.       
Visit 3 (Baseline):  After completing the placebo lead-in period, patients will 
return to the site for baseline evaluations.  Outpatient biological samples will 
be collected. Laboratory, safety and efficacy assessments will be performed. 
Placebo lead-in dosing compliance will be assessed.  Following confirmation 
of eligibility, patients will be randomly assigned to receive TS-121 10 mg, 50 
mg, or placebo in a 1:1:1 ratio.  Patients will be instructed to continue taking 
investigational product once-daily in the morning and to maintain their current 

A Multicenter, Randomized, Double-blind, Placebo-controlled Study of the Safety 
and Efficacy of TS-121 as an Adjunctive Treatment for Patients with Major 
Depressive Disorder with an Inadequate Response to Current Antidepressant 
Treatment 
TS121-US201 
Apr 23, 2018 
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Taisho Pharmaceutical R&D Inc. 
 
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Page 15 of 72 
ADT regimen.  Visit 4 will be scheduled.  
Visits 4 (Week 2):  Patients will return to the site for safety and efficacy 
assessments. Drug accountability and dispensing of a new supply of 
investigational product will be performed.  Compliance with the dosing 
schedule will be assessed.  Visit 5 will be scheduled.   
Visit 5 (Week 4): Patients will return to the site for safety and efficacy 
assessments. Drug accountability and dispensing of a new supply of 
investigational product will be performed. Compliance with the dosing 
schedule will be assessed. Visit 6 will be scheduled, which includes an 
ophthalmological examination.   
Visit 6 (Week 6):  Patients will return to the site for end-of-treatment safety, 
efficacy, pharmacokinetic, and exploratory pharmacodynamic assessments. 
Final drug accountability will be performed.  Visit 7 will be scheduled, which 
includes an ophthalmological examination.   
Visit 7 (Follow-up):  Patients will return to the site for a follow-up evaluation 
of safety and efficacy assessments approximately two weeks after Visit 6.   

A Multicenter, Randomized, Double-blind, Placebo-controlled Study of the Safety 
and Efficacy of TS-121 as an Adjunctive Treatment for Patients with Major 
Depressive Disorder with an Inadequate Response to Current Antidepressant 
Treatment 
TS121-US201 
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Taisho Pharmaceutical R&D Inc. 
 
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4 
BACKGROUND INFORMATION 
4.1 Introduction 
Depression is ranked as the leading cause of disability worldwide by the World Health 
Organization (WHO Fact Sheet No. 369; Oct. 2012). In particular, major depressive disorder 
(MDD) is a psychiatric illness that is characterized by the occurrence of one or more major 
depressive episodes, along with an absence of any history of manic, mixed, or hypomanic 
episodes. It is a serious, often recurrent medical condition, which is associated with a 15.9% 
lifetime risk of suicide attempt (Chen, 1996). Results of the World Mental Health Survey Initiative 
(2011) found that the average lifetime incidence of DSM-IV major depressive episodes was 
14.6%, with a 12-month prevalence of 5.5% in higher income counties (Bromet, 2011).  
Stress has also been hypothesized to be a pivotal factor in the pathophysiology of depression, 
specifically by way of the hypothalamus-pituitary-adrenal (HPA) axis, which appears to be a 
prominent mechanism by which the brain reacts to both acute and chronic stress through 
feedback loops involving several neuroendocrine hormones, including adrenocorticotropic 
hormone (ACTH) and cortisol. In addition, both corticotropin-releasing factor (CRF) and arginine 
vasopressin (AVP) both of which are produced in the paraventricular nucleus of the 
hypothalamus (Vale, 1981; Aguilera, 2000), are considered primary factors in the regulation of 
HPA axis activity. Receptor subtypes for these neuropeptides, which may be involved in the 
regulation of HPA axis activity, have attracted much attention as potential targets for the 
treatment of depression and anxiety.  
Despite the availability of numerous pharmacological and psychological treatment options, 
fewer than 50% of all patients with depression show full remission with optimized treatment, 
including trials on numerous medications with and without concurrent psychotherapy (Rush, 
2006). Thus, there is a clear need for efficacious and well-tolerated agents to treat and prevent 
recurrent episodes of depression, and current research continues to investigate novel molecular 
and cellular mechanisms of depression.  
TS-121 (drug substance code 
) is an investigational new drug with antagonistic activity 
of the vasopressin receptor 1b (V1b receptor), which plays a role in the modulation of stress and 
mood. Based on nonclinical studies conducted by Taisho Pharmaceutical Co., Ltd. Research 
Center (Japan), TS-121 appears to be a promising candidate for clinical development with a 
novel mode of action that may benefit MDD patients. 
4.2 Mechanism of Action of Vasopressin Receptor 1b (V1b Receptor) 
AVP, a cyclic nonapeptide, together with CRF, are principal factors in the regulation of ACTH 
release from the anterior pituitary (Aguilera, 2000), and have been reported to play an important 

A Multicenter, Randomized, Double-blind, Placebo-controlled Study of the Safety 
and Efficacy of TS-121 as an Adjunctive Treatment for Patients with Major 
Depressive Disorder with an Inadequate Response to Current Antidepressant 
Treatment 
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Page 17 of 72 
role in mood regulation. AVP is synthesized in the parvocellular division of the paraventricular 
nucleus of the hypothalamus, which is linked to activation of the HPA axis, and upon stress 
exposure. AVP is released from the median eminence into the pituitary portal circulation, where 
it strongly potentiates the effects of CRF on the release of ACTH. Clinically, the plasma AVP 
levels are elevated in patients with MDD, compared with healthy controls (de Winter, 2003), (van 
Londen, 1997). In previous studies, subjects with melancholic-type or anxious-retarded 
depression exhibited elevated plasma AVP levels. Plasma AVP levels are also reportedly 
positively correlated with cortisol levels during depression, particularly in suicide victims (Inder, 
1997).  
AVP exerts its effects via three receptor subtypes: V1a, V1b and V2. These subtypes are G-
protein coupled receptors (GPCRs) (Serradeil-Le Gal, 2002b). Among them, the V1b receptor is 
mainly expressed in the anterior pituitary and is thought to be involved in the regulation of HPA 
axis activity and emotional processes (Lolait, 1995). Indeed, SSR149415, a non-peptide V1b 
receptor antagonist with high affinity and potent antagonistic activity for the V1b receptor (Griebel, 
2005), has been reported to attenuate increases in plasma ACTH induced by CRH+AVP 
(Serradeil-Le Gal, 2002a), and to exhibit antidepressant- and anxiolytic-like activities in a variety 
of rodent models of depression and anxiety, with more pronounced effects in models involving 
stressful situations (Serradeil-Le Gal, 2002a; Griebel, 2005; Iijima, 2007). Therefore, blockade 
of V1b receptor may provide a novel approach to treating stress-related disorders such as 
depression and anxiety disorders. 
 is a potent and selective antagonist of V1b receptor, both in in vitro and in ex vivo 
studies, and has been shown to possess antidepressant activity in several animal models of 
depression, including one which mimics severely impaired HPA axis function. 
Additional details can be found in Section 3 of the Investigator’s Brochure. 
4.3 Name and Description of Investigational Product 
 is the name of the active ingredient of TS-121. 
 
 
 
 

A Multicenter, Randomized, Double-blind, Placebo-controlled Study of the Safety 
and Efficacy of TS-121 as an Adjunctive Treatment for Patients with Major 
Depressive Disorder with an Inadequate Response to Current Antidepressant 
Treatment 
TS121-US201 
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Taisho Pharmaceutical R&D Inc. 
 
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4.4  Summary of Nonclinical and Clinical Findings 
 Summary of Nonclinical Findings 
4.4.1
To date, a series of single and repeat dose oral toxicity studies in rats and dogs have been 
conducted to assess the systemic toxic potential of 
 and to support Phase 1 and 
Phase 2 clinical studies. Though the relevance to human subjects is not yet fully understood, the 
findings presented below were noted in nonclinical studies. 
Additional details are described in the Sections 7.3.1 and 7.3.2 of the Investigator’s Brochure. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A Multicenter, Randomized, Double-blind, Placebo-controlled Study of the Safety 
and Efficacy of TS-121 as an Adjunctive Treatment for Patients with Major 
Depressive Disorder with an Inadequate Response to Current Antidepressant 
Treatment 
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 Summary of Clinical Findings 
4.4.2
Three Phase 1 studies, a single ascending dose (SAD) study (TS121-US101), a multiple 
ascending dose (MAD) study (TS121-US102), and a positron emission tomography (PET) 
receptor occupancy study (TS121-US103) have been conducted.  Overall, 78 healthy male and 
female adult subjects were administered TS-121 to date. A top dose of 50 mg for 10 days was 
deemed safe and well tolerated. There were no deaths or serious adverse events reported in 
any of the studies.  
Treatment emergent ventricular arrhythmias have been reported following single and multiple 
dose administrations of TS-121.  
No safety trends were observed in clinical laboratory, vital signs, or physical examinations. In 
consideration of the nonclinical findings at the time of the MAD study, comprehensive eye 
examinations were performed; no abnormalities in the eyes relating to lens opacity were 
reported, including at the highest dose level of 50 mg for 10 days. 
Additional details are described in Sections 8 and 9 of the Investigator’s Brochure. 
 Known and Potential Risks to Human Subjects 
4.4.3
Though the relevance to human subjects is not yet fully understood, nonclinical findings 
suggested that potential risks include cataract, hepatotoxicity, effects on the gastrointestinal 
system and effects on the renal system. To date, no apparent trends related to these potential 
risks were noted in the clinical studies. 
Treatment emergent ventricular arrhythmias have been reported following single and multiple 
dose administrations of TS-121.  During the SAD study (TS121-US101), two subjects exposed 
to 2.5 mg of TS-121 had defined intervals of ventricular arrhythmias while on telemetry.  Plasma 
levels were approximately 50% of Cmax values (40 to 70 ng/mL).  The events were without 
symptoms, resolved without intervention, and produced no residual effects. The events were 
considered mild in intensity and possibly related to the study drug.  One subject was 
discontinued from the trial, and one subject completed the trial.   
In the MAD study (TS121-US102), one subject showed a single episode of 4 consecutive 
premature ventricular contractions without symptoms while on telemetry approximately 15 hours 

A Multicenter, Randomized, Double-blind, Placebo-controlled Study of the Safety 
and Efficacy of TS-121 as an Adjunctive Treatment for Patients with Major 
Depressive Disorder with an Inadequate Response to Current Antidepressant 
Treatment 
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after receiving 50 mg dose of TS-121 on Day 9.  The investigator assessed the episode as a 
clinically significant event and described the event as mild and possibly related to TS-121.  The 
subject completed the trial with no additional events.   
In a PET receptor occupancy study (TS121-US103), no abnormal ECG results were reported 
following single TS-121 doses of up to 50 mg. See Sections 8 and 9 of the Investigator’s 
Brochure for additional information.   
4.5 Study Rationale 
This multicenter study is comprised of a screening period of up to 4 weeks, with a 2-week 
single-blind placebo lead-in period followed by a 6-week randomized, double-blind, placebo-
controlled treatment period with a 2-week follow-up period, comparing the safety, efficacy, 
pharmacokinetics, and exploratory pharmacodynamic effects of TS-121 to placebo as an 
adjunctive treatment for patients with MDD. To assess for primary effect of TS-121 vs. placebo, 
patients must remain on the same ADT for 6 weeks, and fixed dose for 4 weeks prior to 
screening.  Patients will remain on their current antidepressant treatment and dose throughout 
the course of the study. 
The study employs multiple quality attributes to reduce placebo response and to monitor patient 
compliance.  Placebo response in MDD trials is well documented.  The study employs a 2-week 
placebo lead-in to enrich the population with placebo non-responders.  Additionally, to reduce 
investigator bias, a central rater assessment will be employed during the screening and the 
placebo lead-in periods to evaluate initial eligibility and to assess placebo response by use of 
the HAM-D.  Furthermore, central raters will remain involved in the trial with oversight of the 
MADRS instrument during the treatment period.  Patient compliance with dosing will be 
assessed during the placebo lead-in through completion of the trial by use of AiCure platform of 
real-time dose monitoring.  
TS-121 is postulated to work primarily through the HPA axis.  Biomarkers for HPA axis will be 
assessed at Visit 3, prior to randomized treatment administration, to assess potential screening 
and/or stratification factors in future trials.  There is insufficient predictive knowledge of MDD 
patients’ HPA axis biomarkers and MDD patient response to V1b receptor antagonist.  Therefore, 
a post-hoc exploratory analysis may be conducted comparing patient response to baseline 
patient profiles.  
 is a high affinity antagonist for the human vasopressin receptor 1b (V1b receptor) that 
has been shown to work in a number of animal models for depression, suggesting that TS-121 
may be a useful treatment option for individuals experiencing MDD.  TS-121 dose selection was 
based on accumulated experience from preclinical studies and three previous clinical trials.  The 
SAD study (TS121-US101) and MAD study (TS121-US102) provide safety and tolerability 

A Multicenter, Randomized, Double-blind, Placebo-controlled Study of the Safety 
and Efficacy of TS-121 as an Adjunctive Treatment for Patients with Major 
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support for the current doses. 
 
 
 
   

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5 
STUDY OBJECTIVES 
5.1 Primary Objectives 
• 
To evaluate the safety and tolerability of TS-121 compared to placebo in MDD patients  
• 
To evaluate the efficacy of two dose levels of TS-121 compared to placebo on MDD 
symptoms in MDD patients 
5.2 Exploratory Objective 
• 
To evaluate the effectiveness of biomarkers in predicting TS-121 response with 
retrospective stratification of patients via baseline values of HPA axis and inflammatory 
biomarkers 

A Multicenter, Randomized, Double-blind, Placebo-controlled Study of the Safety 
and Efficacy of TS-121 as an Adjunctive Treatment for Patients with Major 
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6 
STUDY DESIGN 
6.1 Study Design 
 
Figure 1. Study Design 
 
6.2 Randomization Procedure 
A subject number will be assigned to each patient at the time of informed consent at each site. 
At Visit 3 (Baseline), following completion of the 2-week placebo lead-in, patients who continue 
to meet all entry criteria will be assigned a randomization number by IWRS. A patient cannot be 
assigned more than one randomization number. Patients will retain their subject and 
randomization numbers for the duration of the study. 
Each eligible patient at Visit 3 will be randomly assigned to receive either TS-121 10mg, 50mg 
or placebo in a ratio of 1:1:1. The kit number dispensed by IWRS will correspond to the 
assigned treatment. 
Treatment assignments of patients will be held by IWRS throughout the study. 
6.3 Blinding 
To maintain the blind, matching placebo capsules will be provided for the TS-121 capsules.  The 
placebo lead-in period will be single-blind for patients.  Following completion of the placebo 
lead-in period, the treatment period will be double-blinded (neither the investigator nor the 
patient will have knowledge of the treatment assignment). The sponsor and CRO study 
personnel, including those involved in monitoring, data management and data analysis will also 

A Multicenter, Randomized, Double-blind, Placebo-controlled Study of the Safety 
and Efficacy of TS-121 as an Adjunctive Treatment for Patients with Major 
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be blinded to the treatment assignment during the trial.   
6.4 Unblinding 
The randomized investigational product administered to each patient will not be known to the 
patient or to study site personnel, except for: 
• 
Designated IWRS personnel including study-independent personnel from the CRO (if 
applicable)  
• 
Designated personnel for drug packaging 
• 
The bioanalytical laboratory performing the PK analysis 
Under normal circumstances, the blind should not be broken until all patients have completed 
the study and the database has been locked and finalized. The blind may be broken if specific 
emergency treatment would be indicated by knowing the treatment status of the patient. The 
blind may also be broken for events of clinical significance (see Section 11.3). In the event that 
the sponsor decides to break the blind for events of clinical significance, the sponsor must 
inform the investigator of the unblinding. The date, time and reason for the unblinding must be 
documented in the study source records and recorded on the CRF.  If data are unblinded, 
access to the unblinded data should be limited to maintain data integrity of the study. Additional 
details will be described in the safety plan. 
6.5 Early Discontinuation 
Patients may discontinue study participation at any time in this trial.  All randomized patients 
who prematurely discontinue participation after receiving at least one dose of investigational 
product will return to the site for an Early Termination Visit as early as possible after 
discontinuation, and separately, for a follow-up visit approximately 14 days after their last dose.   
Patients who discontinue prior to randomization at Visit 3 will be considered screening failures. 
If discontinued once entering the placebo lead-in period at Visit 2 but prior to randomization, 
discontinued patients will be required to undergo a physical examination and completion of the 
C-SSRS before being discharged from the study. 

A Multicenter, Randomized, Double-blind, Placebo-controlled Study of the Safety 
and Efficacy of TS-121 as an Adjunctive Treatment for Patients with Major 
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7 
STUDY POPULATION 
7.1 Study Population 
This study will screen approximately 300 patients and randomize approximately 180 MDD 
patients. These patients are defined by the inclusion and exclusion criteria described in the 
following sections. 
 Inclusion Criteria 
7.1.1
Patients must meet all of the following criteria to be eligible for enrollment: 
1. Adult males and females between 18 and 65 years of age inclusive (at time of initial 
informed consent)  
2. Patients with a current diagnosis of MDD by DSM-5, confirmed through a structured 
interview using  MINI 
3. Patients who receive the same antidepressant (SSRI, SNRI or bupropion monotherapy) for 
the current episode for at least 6 weeks of continuous treatment prior to Visit 1.1 and at least 
4-weeks on a fixed dose prior to Visit 1.1 (the dosing duration and appropriateness of the 
dosage will be confirmed at Visit 1.1 by the central rater using MGH ATRQ) 
[Note: Patients who currently receive 2 or more antidepressants are excluded with exception 
of Trazodone (≤ 50 mg/day) for sleep as outlined in Section 8.3. Fluvoxamine is prohibited 
as it is a moderate CYP 3A4 inhibitor (see exclusion criterion #14 and Appendix 1)] 
4. Patients willing to remain on the same primary ADT and fixed dose throughout the course of 
the study 
5. Patients who meet the total score on the HAM-D as listed below (as determined by Site or 
Central Raters): 
• 
HAM-D ≥ 18 at Visit 1 (Site) 
• 
HAM-D ≥ 18 at Visit 1.1 (Central) 
• 
HAM-D ≤ 25% improvement from Visit 1.1  to Visit 2.1 (Central) 
• 
HAM-D ≥ 18 at Visit 2.1 (Central) 
6. Patients who are rated as eligible based on the SAFER Inventory conducted at Visit 1.1 
7. Female patients of childbearing potential must agree to use one of the accepted barrier 
methods of contraception (listed below) during the study (including the screening period 
prior to receiving trial medication), for at least 90 days following the last dose. 
• 
condom (male or female) with spermicide 
• 
diaphragm or cervical cap with spermicide and condom (male) 

A Multicenter, Randomized, Double-blind, Placebo-controlled Study of the Safety 
and Efficacy of TS-121 as an Adjunctive Treatment for Patients with Major 
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[Note: Oral contraception, vasectomy of the partner and IUD alone are not considered 
sufficient contraception.  One of the aforementioned barrier methods listed above must be 
used.  Females who are not currently sexually active must also consent to use one of these 
accepted methods of contraception should they become sexually active while participating in 
the study.] 
Female patients of non-childbearing potential must be either surgically sterile or post-
menopausal (absence of spontaneous menses for 12 consecutive months) 
Male patients with partners of childbearing potential must agree to use appropriate and 
effective measures of contraception (e.g., condom plus diaphragm with spermicide; condom 
plus spermicide) and/or refrain from donating sperm from Visit 2 and for at least 90 days 
following the last dose. 
8. Body Mass Index (BMI) ≥ 18 and ≤ 38 kg/m2 at Visit 1 using the following formula: 
weight (kg) / [height (m)]2 
9. Patients who are able and willing to provide written informed consent and authorization for 
protected health information disclosure in accordance with Good Clinical Practice  
10. Patients who are able to read, speak and understand English 
 Exclusion Criteria 
7.1.2
Patients are to be excluded from study participation if they meet any of the following exclusion 
criteria:   
1. Patients with first episode of depression >60 years of age  
2. Patients with inadequate response to ≥2 prior antidepressant treatments (not including 
current antidepressant) of at least 4 weeks duration each for the current episode at Visit 1 
(to be confirmed at Visit 1.1 by the central rater using MGH ATRQ) 
3. Patients whose current depressive episode is diagnosed with psychotic features, catatonic 
features, post-partum (primary onset), or is secondary to a general medical disorder 
4. Patients with a diagnosis of any of the following DSM-5 class disorders 
• 
Schizophrenia spectrum and other psychotic disorders 
• 
Bipolar and related disorders 
• 
Anxiety disorders 
[Note: Co-morbid generalized anxiety disorder and social anxiety disorder will be 
allowed in the study if the primary diagnosis is MDD, and if in the opinion of the 

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and Efficacy of TS-121 as an Adjunctive Treatment for Patients with Major 
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investigator, the comorbid anxiety is not likely to interfere with the subject’s ability to 
participate in the trial or affect study outcome] 
• 
Obsessive-compulsive and related disorders 
• 
Trauma- and Stressor-related disorders 
5. Patients who received electroconvulsive therapy (ECT) within 12 months of Visit 1, received 
more than one course of ECT in their lifetime or plan to receive ECT during the study 
6. Patients who received repetitive transcranial magnetic stimulation (rTMS) within 12 months 
of Visit 1 (Screening) or plan to receive rTMS during the study 
7. Patients who plan to initiate or terminate cognitive or behavioral psychotherapy or alter the 
frequency of ongoing therapy during this study 
8. Patients who have attempted suicide within the past 6 months 
9. Patients who have a C-SSRS suicidal ideation score of 5 or “yes” response for any of the C-
SSRS suicidal behavior questions at Visit 1 or Visit 3 
10. Patients with history or presence of intellectual disability, pervasive developmental disorder, 
cognitive disorder, neurodegenerative disorder (e.g., Alzheimer disease, Parkinson disease, 
multiple sclerosis, Huntington disease), or brain injury  
11. Patients with any history or complication of convulsive disorder (e.g., epilepsy) 
12. Patients with history or presence of medical conditions associated with HPA dysfunction 
(e.g., Cushing syndrome) 
13. Patients who are undergoing treatment with drugs that might influence HPA axis function, 
including psychotropic medications, benzodiazepines, metyrapone, lithium and/or 
corticosteroids 
[Please refer to Section 8.3 for a more detailed list of prohibited concomitant medications] 
14. Patients who need/plan to take moderate to strong CYP3A4 inhibitors/inducers (food, 
beverages, medications and supplements) during this study (see Appendix 1) 
15. Patients who work night shifts or need to work night shifts during the trial 
16. Females who are pregnant, intend to become pregnant (within 90 days of the last dose), or 
who are breastfeeding 
17. Patients with significant hepatic, renal, cardiovascular, hemodynamic, pulmonary, 
gastrointestinal, 
hematological, 
locomotor, 
immunologic, 
ophthalmologic, 
metabolic, 
neurological, or endocrine disease that in the opinion of the investigator would confound 
participation or study results 

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and Efficacy of TS-121 as an Adjunctive Treatment for Patients with Major 
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18. Patients with clinically significant ECG* findings at Visit 1 or Visit 3, or hematology, 
biochemistry, or urinalysis abnormalities at Visit 1 (abnormal laboratory values considered to 
be not clinically significant as per the investigator are acceptable) 
[* Note: QTcF interval of > 450 msec in males or > 470 msec in females, will be the basis for 
exclusion from the study; ECG may be repeated once for confirmatory purposes, if an initial 
value is obtained that exceeds the values specified] 
19. Patients with history or presence of cataract (lens opacities with vision disturbances), 
glaucoma, chronic inflammatory eye disease, significant eye trauma, any ophthalmic 
surgical procedure (e.g. cataract or glaucoma) or any ocular laser surgery in either eye 
20. Patients with lens opacity based on ophthalmological examination performed at Visit 2 as 
listed below: 
• 
Nuclear opalescence (NO) with a LOCSIII classification > 3.0 in either eye 
• 
Nuclear color (NC) with a LOCSIII classification > 3.5 in either eye 
• 
Cortical lens opacities (C) with a LOCSIII classification > 2.0 in either eye 
• 
Posterior subcapsular lens opacities (P) with a LOCSIII classification > 0.3 in either 
eye 
21. Patients with a history (within 5 years) or presence of malignancy at Visit 1 
[Note: History (within 5 years) of non-metastatic, non-progressive basal and/or squamous 
cell carcinoma of the skin, in situ cervical and prostate cancer are exceptions (currently in 
remission)] 
22. Patients with history of alcohol or illicit substance abuse / dependence  within 12 months of 
Visit 1 or positive urine drug results at Visit 1 
[Note: Patients with positive urine drug results may be eligible at investigator’s discretion if 
the results are reasonably explained as false positive] 
23. Patients with history and/or current evidence of serologic positive results for hepatitis B 
surface antigen, hepatitis C antibodies, or HIV antibodies 1 and 2 at Visit 1 
24. Patients who have received treatment with an investigational product or device that has not 
received regulatory approval for any indication, or who have participated in a clinical 
research study within 90 days prior to Visit 1 
25. Patients who have been previously administered TS-121 
26. Investigative site personnel or their immediate families (spouse, parent, child or sibling 
whether biological or legally adopted)  
27. Taisho employee or their immediate families (spouse, parent, child or sibling whether 

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and Efficacy of TS-121 as an Adjunctive Treatment for Patients with Major 
Depressive Disorder with an Inadequate Response to Current Antidepressant 
Treatment 
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biological or legally adopted) 
28. Patients with poor treatment compliance (<75%) in taking the investigational product 
between Visit 2 and Visit 3 
[Note: Treatment compliance should be calculated as the percentage of days a patient is 
compliant in taking the full daily dose of investigational product (3 capsules/day)] 
29. Any patient not able to meet study requirements 
 Replacement Patients 
7.1.3
Patients withdrawn for safety or tolerability will not be replaced.  Patients discontinued due to 
other reasons, e.g., dosing compliance, may be replaced at the discretion of the sponsor in 
order to achieve the study objectives.  

A Multicenter, Randomized, Double-blind, Placebo-controlled Study of the Safety 
and Efficacy of TS-121 as an Adjunctive Treatment for Patients with Major 
Depressive Disorder with an Inadequate Response to Current Antidepressant 
Treatment 
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8 
TREATMENT OF PATIENTS 
8.1 Investigational Product 
Physical characteristics of the investigational product are listed in Table 1.  A detailed description 
of the investigational product as well as a listing of excipients is included in Section 4.2.1 of the 
Investigator’s Brochure. 
Table 1. 
Investigational product description 
INVESTIGATIONAL PRODUCT 
DESCRIPTION 
TS-121 capsules (drug units of 10 mg and 20 mg) 
White, opaque, hard gelatin capsule 
Matching placebo capsule for TS-121 
White, opaque, hard gelatin capsule 
 Packaging and Labeling 
8.1.1
Investigational product (TS-121 and matching placebo) will be provided as Size 2, white, hard 
gelatin capsules. TS-121 capsules will contain 10 and 20 mg active pharmaceutical ingredient. 
The investigational product will be packaged in child resistant blister packs and assembled as 
patient kits. Each kit will be labeled as required in 21 CFR Section 312.6.   
Each blister pack will contain a 1-week supply of investigational product, and will include an 
additional 2-day supply to account for visit windows. In total, a 2-week supply of investigational 
product (2 blister packs) will be dispensed to the patient at each visit.  
 Handling, Dispensing, and Administration of Investigational Product 
8.1.2
The investigational product should be stored in a secure area at room temperature and 
protected from moisture, freezing and excessive heat. It is the responsibility of the investigator 
to ensure that the investigational product is only dispensed to eligible study patients. The 
investigational product must only be dispensed from the study site by authorized personnel as 
indicated in the site delegation log. 
Patients will be instructed to take their daily dose by mouth once in the morning, preferably after 
breakfast. In case a patient misses dosing in the morning, the patient should skip the dose for 
that day and resume taking the investigational product on the morning of the next day. Patients 
will maintain current ADT dosing schedules.  Compliance will be monitored using the AiCure 
platform (see Section 8.1.3). The patient will be instructed to take 3 capsules as described in 
Table 2 in addition to their ongoing ADT. 
 
 

A Multicenter, Randomized, Double-blind, Placebo-controlled Study of the Safety 
and Efficacy of TS-121 as an Adjunctive Treatment for Patients with Major 
Depressive Disorder with an Inadequate Response to Current Antidepressant 
Treatment 
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Table 2. 
Investigational product administration 
Group 
Dose strength and number of capsules to be administered 
TS-121 10 mg 
TS-121 (drug unit of 10 mg) capsule; 1 capsule 
TS-121 Placebo capsule; 2 capsules 
TS-121 50 mg 
TS-121 (drug unit of 10 mg) capsule; 1 capsule 
TS-121 (drug unit of 20 mg) capsule; 2 capsules 
Placebo 
(including investigational product 
for Placebo Lead-in period) 
TS-121 Placebo capsule; 3 capsules 
 Treatment Compliance 
8.1.3
Designated study personnel will dispense the investigational product. Accountability and 
compliance verification should be documented in the site drug accountability log. 
Patients must maintain adherence to scheduled dosing according to inclusion and exclusion 
criteria during the placebo lead-in period.  Patient compliance with the placebo lead-in and 
randomized treatment will be monitored by the AiCure platform. Daily dosing by patients will be 
monitored using mobile device technology. Using smartphones, the site will be able to confirm 
each investigational product ingestion along with the patient’s current ADT. Built-in reminders 
and a communication system will allow real-time intervention in the event of dosing interruptions. 
See Section 9.2.9 for additional information on the AiCure platform.  
 Investigational Product Accountability 
8.1.4
The Investigator is responsible for ensuring that all investigational product received at the site is 
inventoried and accounted for throughout the study.  The dispensing of investigational product 
(TS-121 and placebo) must be documented on a Drug Accountability Form which should 
include: 
• 
Number of patient kits received 
• 
Amount currently being stored 
• 
Kit numbers  
• 
Dates and initials of person/s responsible for each investigational product inventory 
entry/movement 
• 
Patient identifiers for dispensing and return 
• 
Number of kits returned to sponsor or sponsor’s authorized designee 

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 Return or Destruction of Investigational Product 
8.1.5
All unused, partially used, or unopened supplies of investigational product will be returned from 
each site to the sponsor’s designee and will be destroyed upon sponsor request. 
Documentation and certificates of drug destruction will be forwarded to the sponsor, as 
applicable.  Confirmation of receipt of returns will be sent to study sites.  
8.2 Concomitant Drug Therapy 
All concomitant medications taken during the study will be recorded on the CRF for each patient, 
along with the indication (reason taken), dosage information and start and stop dates. Allowed 
concomitant medications include any prescription or over-the-counter medication not specifically 
excluded by the protocol.  Patients requiring excluded drugs will be discontinued from the study. 
For a list of prohibited concomitant drugs, see Section 8.3.  
If the patient requires concomitant medication for an AE, it must be reported in the patient’s 
study source records and captured electronically.  Any changes to concomitant medications 
during the study must be clearly recorded and the reason for the change should be documented.   
8.3 Prohibited / Restricted Concomitant Therapy 
Any antidepressants other than the current single SSRI, SNRI or bupropion will be prohibited 
throughout the study. Dosage of the current SSRI, SNRI or bupropion must remain unchanged 
throughout the study. 
Trazodone (≤ 50 mg/day), in addition to the current ADT will be permitted if it is prescribed to be 
taken regularly as a sleep aid, has been initiated at least 3 months before the screening visit 
(Visit 1), and the medication and dosage is to remain unchanged throughout the study (a PRN 
dosing regimen of trazodone will not be allowed). 
Beyond the patient’s current ADT, drugs that might influence HPA axis function, including 
benzodiazepines, metyrapone, lithium and/or corticosteroids, as well as psychotropic 
medications or drugs that treat excluded mental disorders are prohibited from Visit 1 to 7. 
Strong/moderate inhibitors/inducers of CYP3A4 are prohibited from Visit 2 to 6.  See Section 17 
(Appendix 1) for a list of CYP3A4 excluded medications.  The use of non-benzodiazepine 
hypnotics (i.e., zolpidem, zaleplon, zopiclone and eszopiclone) is permitted if treatment has 
been initiated before the study and the medication and dosage remains unchanged throughout 
the study. 
The study is designed to assess HPA axis V1b receptor treatment, and will limit potential 
confounding comorbidities and treatments beyond SSRI, SNRI or bupropion.  Benzodiazepines 
are excluded due to clear evidence of the effect on HPA axis with short-term use, and unknown 
effects of long-term use on HPA axis. Likewise, metyrapone is excluded, due to primary 

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and Efficacy of TS-121 as an Adjunctive Treatment for Patients with Major 
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pharmacology effecting HPA axis; its primary indication of Cushing’s syndrome is also excluded. 
Lithium is excluded for effects on HPA axis and primary use in excluded mental disorders.  
Corticosteroids are excluded due to primary effects on HPA axis.  Moderate to strong CYP3A4 
inhibitors or inducers are excluded, based on preclinical in vitro testing.  See Section 6.5 of the 
Investigator’s Brochure for additional information on testing.   
8.4 Duration of Patient Participation 
This study is comprised of a screening period of up to 28 days, a 2-week placebo lead-in, a 6-
week treatment period and up to 2-weeks for a follow-up visit.  Eligible patients will be entered 
into a 2-week placebo lead-in at Visit 2, and if all entry criteria are met, randomized at Visit 3.  
Patients will remain in the treatment period of the study until Visit 6, and will return for a follow-
up visit at Visit 7. Patients will participate in the study for approximately 3 months. 
8.5 Discontinuation Criteria and Procedures 
In accordance with the Declaration of Helsinki, ICH Good Clinical Practice Guidelines, and the 
United States Food and Drug Administration (FDA) Regulations, a patient has the right to 
withdraw from the study at any time for any reason without prejudice to his/her future medical 
care by the physician or at the institution.  
The investigator and sponsor also have the right to withdraw patients from the study for reasons 
including the following: 
• 
Significant protocol violation on the part of the investigator or patient; 
• 
Unblinding by the patient, investigator or unauthorized site personnel;  
• 
Self-withdrawal, or refusal by the patient to continue treatment or observations; 
• 
Unacceptable toxicity; 
• 
Decision by the investigator that termination is in the patient’s best medical interest 
and/or for safety reasons; 
• 
Unrelated medical illness or complication(s); 
• 
Sponsor decision to discontinue the study. 
If it is determined that a patient is at imminent risk of suicide, the investigator should evaluate for 
discontinuation as outlined in Section 11.3.1. Patients with a CGI-I score of 6 or 7 at any time 
during the study should be evaluated for possible discontinuation from the study as outlined in 
Section 11.4. 
The sponsor may choose to terminate the study at any time for any reason.  Should a patient 
decide to withdraw, all efforts will be made to complete and report the required observations as 

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and Efficacy of TS-121 as an Adjunctive Treatment for Patients with Major 
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thoroughly as possible.   
Should a patient discontinue prior to completion of the study, the reason for the withdrawal 
should be recorded.  An early discontinuation evaluation should be made at the time of the 
patient’s withdrawal according to the procedures outlined in Section 6.5. In the event that the 
patient cannot return for the follow-up visit, the site should make all necessary attempts to 
contact the patient to follow any adverse events. 

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9 
STUDY PROCEDURES AND OBSERVATIONS 
9.1 Study Procedures and Observations 
Procedures 
Visit 1**** 
(Screening) 
Day -28 to 
Day -7 
Visit 1.1**** 
(Screening) 
Day -13 to 
Day -2 
Visit 2 
(Start of 
Placebo 
Lead-in) 
Day 1 
Visit 2.1 
(End of 
Placebo 
Lead-in) 
Day 13 (±2) 
Screen* 
failure 
ONLY 
End of 
Study 
Visit 3** 
(Baseline) 
Day 15 (+3) 
Visit 4 
(Week 2) 
Day 29 (±3) 
Visit 5 
(Week 4) 
Day 43 
(±3) 
Visit 6 
(Week 6) 
Day 57 
(±3) 
Visit 7 
(Follow-up) 
Day 71 
(±3) 
ET*** 
ET 
Follow 
Up 
Site Visit 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Informed Consent (Study, PGx, HIPAA)a 
X 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
Inclusion and Exclusion Criteria 
X 
 
X 
 
 
X 
 
 
Evaluation of Medical and Psychiatric History 
X 
 
X 
 
 
 
 
Evaluation of Prior Medication History 
X 
 
 
 
 
 
Serology Screen 
X 
 
 
 
 
 
Urine Drug Screen 
X 
 
 
 
X 
 
 
Urine Pregnancy (all females) 
X 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
Body Weight 
X 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Body Mass Index (BMI) 
X 
 
 
 
 
 
Physical and Neurological Examination 
X 
 
 
X 
X 
X 
X 
X 
X 
Ophthalmological Examinations b 
 
 
X 
 
 
 
 
 
X 
X 
X 
X 
Columbia Suicide Severity Rating Scale (C-SSRS) 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
MINI 
X 
 
 
 
 
 
 
 
 
 
 
 
HAM-D (SITE Rater) 
X 
 
 
 
 
 
 
 
 
 
 
 
MGH ATRQ (Central Rater) 
 
X 
 
 
 
 
 
 
 
 
 
 
HAM-D (Central Rater) 
 
X 
 
X 
 
 
 
 
 
 
 
 
SAFER Inventory (Central Rater) 
X 
 
 
 
 
MADRS c 
 
 
 
X 
X 
X 
X 
X 
 

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Procedures 
Visit 1**** 
(Screening) 
Day -28 to 
Day -7 
Visit 1.1**** 
(Screening) 
Day -13 to 
Day -2 
Visit 2 
(Start of 
Placebo 
Lead-in) 
Day 1 
Visit 2.1 
(End of 
Placebo 
Lead-in) 
Day 13 (±2) 
Screen* 
failure 
ONLY 
End of 
Study 
Visit 3** 
(Baseline) 
Day 15 (+3) 
Visit 4 
(Week 2) 
Day 29 (±3) 
Visit 5 
(Week 4) 
Day 43 
(±3) 
Visit 6 
(Week 6) 
Day 57 
(±3) 
Visit 7 
(Follow-up) 
Day 71 
(±3) 
ET*** 
ET 
Follow 
Up 
MADRS Central Rater Oversight 
 
 
 
 
 
X 
 
 
 
X 
 
 
CGI-S 
 
 
 
X 
X 
X 
X 
X 
 
CGI-I 
 
 
 
X 
X 
X 
X 
 
HAM-A 
 
 
 
X 
X 
X 
X 
X 
 
SDQ 
 
 
 
 
 
X 
X 
X 
X 
X 
 
 
Vital Signs (seated)  
X 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
12-Lead Electrocardiogram (ECG) 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Clinical Laboratory Tests 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Exploratory Safety Assessments 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Hair Cortisol Level 
 
 
 
 
 
X 
 
 
 
 
 
 
Plasma Copeptin Level 
 
 
 
 
X 
 
 
X 
 
 
 
Salivary Cortisol Level (at home) d 
 
Dispense Kit 
 
 
X 
 
 
 
 
 
 
Urine Cortisol Level (pooled for 8 hr at home) d 
 
Dispense Kit 
 
 
X 
 
 
 
 
 
 
Inflammatory Markers (TNF-α, IL-1, IL-6, HS-CRP) 
 
 
 
 
X 
 
 
X 
 
 
 
Pharmacokinetic Blood Sampling 
) 
 
 
 
 
 
 
 
 
X 
 
 
 
Pharmacogenomic Blood Sampling 
 
 
 
X 
 
 
Placebo administration under single-blind  
 
 
X 
 
 
X 
 
 
 
 
 
 
Randomization 
 
 
 
X 
 
 
Investigational product dispensing, accountability 
and compliance checke 
 
 
X 
 
 
X 
X 
X 
X 
 
 
 
Dose administration under double-blind 
 
 
 
X 
X 
 
 
Drug adherence (AiCure) f 
 
X 
 
 
X 
 
 
Adverse Event Inquiry & Reporting 
 
 
X 
 
 
 
 
 
 
X 
X 
X 

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Procedures 
Visit 1**** 
(Screening) 
Day -28 to 
Day -7 
Visit 1.1**** 
(Screening) 
Day -13 to 
Day -2 
Visit 2 
(Start of 
Placebo 
Lead-in) 
Day 1 
Visit 2.1 
(End of 
Placebo 
Lead-in) 
Day 13 (±2) 
Screen* 
failure 
ONLY 
End of 
Study 
Visit 3** 
(Baseline) 
Day 15 (+3) 
Visit 4 
(Week 2) 
Day 29 (±3) 
Visit 5 
(Week 4) 
Day 43 
(±3) 
Visit 6 
(Week 6) 
Day 57 
(±3) 
Visit 7 
(Follow-up) 
Day 71 
(±3) 
ET*** 
ET 
Follow 
Up 
Concomitant Medication Inquiry & Reporting 
X 
 
 
 
X 
X 
X 
* End of Study (Screen failure only): Patients who discontinue between Visits 2 and 3 only will undergo the procedures specified above. 
** Visit 3 must be performed after obtaining results for Visit 2.1.  
*** The Early Termination (ET) visit should be performed as early as possible after discontinuation. ET follow-up visit will also be necessary approximately 14 days after the patient’s last dose. 
**** Visit 1 must be performed prior to Visit 1.1. 
a Informed consent for PGx must be obtained prior to blood collection at Visit 3.  
b Ophthalmological Examination: LOCS III assessment must be conducted by an ophthalmologist. Best corrected visual acuity (BCVA) must be performed by the ophthalmologist, optometrist or trained
ophthalmic technician.  Examination can be performed within -5 days of study Day 1 (Day -5 to Day 1) as Visit 2 assessment.  
c MADRS should be conducted prior to any other mental health assessments and safety/PK/PD assessments.  
d Urinary and Salivary Cortisol: Dispense kits at Visit 2.  
e Investigational product dispensing, accountability and compliance checks: Accountability and compliance checks will be performed at Visits 3 to 6. Administration of the investigational product for the 
placebo lead-in period will start on the morning following Visit 2 (study Day 2).  Administration of the investigational product for the treatment period will start on the morning following Visit 3 (study Day 16). 
f Drug Adherence: Daily dosing by patients of current ADT and investigational product (TS-121 or placebo) will be monitored using AiCure technology on the patient’s smart phone or a device provisioned by 
the site (See Section 8.1.3, Treatment Compliance). 
 
 

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9.2 Study Assessments 
 Explain Study and Obtain Written Informed Consent 
9.2.1
The investigator or qualified designee will explain the study and all study requirements to the 
patient, answer all of his/her questions, and obtain written informed consent before performing 
any study-related procedure.  A copy of the informed consent will be given to the patient.  Date 
of consent will be recorded in the patient’s study source records and captured electronically. 
 Review Inclusion/Exclusion Criteria Including Concomitant Medications 
9.2.2
The inclusion and exclusion criteria will be reviewed by the investigator or qualified designee to 
ensure that the patient qualifies for the study at all specified visits.  All appropriate treatment 
will be discussed with the patient.  All medications used during the study will be recorded in the 
patient’s study source records and captured electronically.   
 Demographics  
9.2.3
The patient's age (at the time of informed consent), ethnicity, gender and race will be recorded 
in the patient’s study source records and captured electronically. 
 Medical History 
9.2.4
A detailed medical and/or surgical history will be obtained by the investigator or qualified 
designee and will be recorded in the patient’s study source records and captured electronically.  
Medical history should include information on hepatic, renal, gastrointestinal, and 
cardiovascular disorders, eye disease, and/or any other clinically significant medical condition.  
New or existing medical conditions reported prior to first administration of the investigational 
product will be captured as medical history, whereas any new, untoward, or worsening medical 
condition reported after first administration of the investigational product will be captured as 
adverse events. 
 Psychiatric History 
9.2.5
History and/or presence of mental illness will include assessment of onset of symptoms and 
behaviors, prior mental health history, treatments, history of physical or sexual abuse or 
perpetration issues, history of alcohol or illicit drug use, and history of family psychiatric illness, 
will be recorded in the patient’s study source records and captured electronically.  New or 
existing psychiatric condition reported prior to first administration of the investigational product 
will be captured as psychiatric history, whereas any new, untoward, or worsening psychiatric 
conditions reported after first administration of the investigational product will be captured as 
adverse events. 

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 Diagnostic and Screening Assessments 
9.2.6
9.2.6.1 Serology Screen 
A blood sample will be collected at screening for Hepatitis B surface antigen, HIV screening 
and serum antibodies to hepatitis C. Tests will be performed according to standard local 
procedures.  A plan must be in place at the site(s) for the management of a positive test result 
according to local requirements.  Test results will be recorded in the patient’s study source 
records and captured electronically. 
9.2.6.2 Height 
Height will be measured at Visit 1 only. The height measurement will be recorded in 
centimeters (cm) in the patient’s study source records and captured electronically. 
9.2.6.3 Body Mass Index (BMI) 
BMI should be calculated using the following formula and recorded in the patient’s study 
source records only:   
BMI = Weight (kg)/Height (m)2 
Height (cm) and weight (kg) used to calculate BMI should be up to one decimal place. 
9.2.6.4 Urine Drug Screen 
A urine sample will be collected at Visit 1 to screen for controlled substances, and will also be 
collected at Visit 3 for confirmatory purposes.  The following controlled substances will be 
tested: amphetamine, barbiturates, benzodiazepines, cocaine, methadone, morphine/opiates, 
methamphetamine, marijuana (THC), phencyclidine (PCP), and ecstasy (MDMA). Negative 
drug screens are required for study eligibility. Test results will be recorded in the patient’s study 
source records and captured electronically. 
[Note: Patients with positive urine drug results may be eligible at investigator’s discretion if the 
results are reasonably explained as false positive] 
9.2.6.5 Urine Pregnancy 
For all female participants, urine pregnancy samples will be tested at specified visits.  Patients 
with a positive pregnancy test at screening or prior to the first dose will not be allowed to enter 
into the study (screen failure).  Patients with a positive pregnancy test any time after first dose 
will be discontinued from the study.  The pregnancy will be monitored and recorded according 
to Sections 9.1 and 11.4.   

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9.2.6.6 Screening and Baseline Mental Health Assessments 
9.2.6.6.1 MINI-International Neuropsychiatric Interview (MINI) 
The MINI (Version 7.0.2) will be administered by the investigator at Visit 1.  The results of the 
MINI interview are to be recorded in the patient’s study source records only.   
9.2.6.6.2 17-Item Hamilton Rating Scale (HAM-D) 
The HAM-D (October 2010 for the DUAG-8 project) is completed with a structured interview 
guide by the clinician based on his/her assessment of the patient's symptoms. The 17-item 
version of the HAM-D will be used to determine illness severity in order to fulfill the inclusion 
criteria. 
An initial HAM-D will be conducted by the investigator or designee (trained site rater) at Visit 1 
to support the diagnosis of MDD as per the MINI by providing information on severity. A remote 
HAM-D interview will then be conducted by central raters at Visit 1.1 as a part of phone 
interview and at Visit 2.1. Central Rater interviews will be performed remotely, and the patient 
will be contacted at an off-site location. Sites will be notified of the results prior to next visits. 
Results are to be captured electronically and included in the patient’s study records. 
9.2.6.6.3 MGH Antidepressant Treatment Response Questionnaire (MGH ATRQ) 
The MGH ATRQ (TAISHO_ATRQ 2.7.2017) is a clinician-rated questionnaire examining 
antidepressant treatment history using specific anchor points to define the adequacy of both 
dose and duration of each antidepressant trial, as well as the degree of symptomatic 
improvement obtained with each trial.  It will also be used to assess the adequacy of current 
ADT for the trial.  Results are to be captured electronically and included in the patient’s study 
records. 
9.2.6.6.4 SAFER Interview  
To ensure that appropriate patients are entered into the trial, a central rater interview will be 
conducted by phone. The assessments administered will be the SAFER Inventory (Taisho 
TS121-US201), and includes the HAM-D and the MGH ATRQ (detailed above).  The interview 
will be performed remotely by the central rater, and the patient will be contacted at Visit 1.1. 
Sites will be notified of the results prior to Visit 2.  Results are to be captured electronically and 
included in the patient’s study records.  
 Safety Assessments 
9.2.7
9.2.7.1  Adverse Events 
See Section 11.1 on capture and reporting of Adverse Events.  

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9.2.7.2 Physical Examination 
A routine physical examination will be performed at the visits indicated in Section 9.1. 
The results of the physical examination are to be recorded in the patient’s study source records. 
Any abnormalities noted prior to first administration of the investigational product will be listed 
as medical history.  Findings after first administration of the investigational product that meet 
the criteria of an AE (Section 11.1) will be captured as AEs. 
The physical examination will include, but not be limited to, assessments of the following: 
• 
General Appearance 
• 
Abdomen 
• 
Head/ Face 
• 
Skin, Hair, and Nails 
• 
Eyes 
• 
Musculoskeletal: Extremities, Spine 
• 
Ears/Hearing 
• 
Lymphatic 
• 
Nose 
• 
Chest/Lungs  
• 
Mouth, Teeth and Throat 
 
• 
Neck & Thyroid 
 
• 
Vascular/Circulatory 
 
9.2.7.3 Neurological Examination 
The comprehensive neurological examination will include assessments of the following: 
• 
Cranial Nerves Function: Reactivity to Light, Accommodation of pupils, and Extraocular 
Eye Movements 
• 
Coordination: Finger to Nose, Finger Tapping, Rapid alternating Hand Movements, Gait, 
and Romberg Test 
• 
Deep Tendon Reflexes: Brachioradialis, Patellar, and Achilles 
• 
Presence of Tremors: Resting, Postural, and Intension 
• 
Sensory Exam: Pin Prick and Tactile Soft Touch 
• 
Motor System: Spastic gait, Cerebellar ataxia, Sensory ataxia, Akinetic-rigid gait, Step 
age gait, Upper/Lower body strength 
The results of the neurological examination will be recorded in the patient’s study record. Any 
abnormalities noted prior to first administration of the investigational product will be listed as 
medical history.  Findings after first administration of the investigational product that meet the 
criteria of an AE (Section 11.1) will be captured as AEs. 

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9.2.7.4 Ophthalmological Examination 
Ophthalmological examinations will be performed on all patients at the visits indicated in 
Section 9.1.  The Lens Opacities Classification System III (LOCS III) grading must be 
conducted by an ophthalmologist, with active certification for LOCS III grading. The Best 
Corrected Visual Acuity (BCVA) measurement must be conducted by the ophthalmologist, 
optometrist or a trained ophthalmic technician. LogMAR score should be confirmed by the 
ophthalmologist. Rating by the same ophthalmologist, optometrist or a trained ophthalmic 
technician and same equipment is preferred for the duration of the trial for each patient for the 
LOCS III grading and the BCVA measurement. Ophthalmological examination will include the 
following:  
• 
BCVA as measured with the ETDRS chart, and scored in LogMAR 
• 
Evaluation of the crystalline lens through a maximally dilated pupil using LOCS III, 
including the following features; 
o Posterior subcapsular cataract (P) 
o Cortical cataract (C) 
o Nuclear opalescence (NO) 
o Nuclear color (NC)  
Examination of the anterior chamber depth, optic nerve head, and the intraocular pressure by 
applanation tonometry should be performed by the ophthalmologist prior to dilation of pupils. 
Mydriatics will be used to achieve maximal mydriasis before any retro illumination or slit lamp 
photographs are obtained.  Photographs of both eyes will be captured on all patients at each 
examination.  The ophthalmologist should not review the previous LOCS III assessments until 
completion of the LOCS III assessment of a current visit.   
 (See the Ophthalmological Examination Manual for detailed instructions).  
Results of the ophthalmological examination will be recorded in the patient’s study source 
records and captured electronically.  Any of clinically significant ophthalmological findings 
defined in Section 11.3.2 will be recorded as AEs.  The sponsor will engage a third-party 
blinded ophthalmologist to review clinically significant ophthalmological findings or consult with 
the investigators or sponsor Medical Monitor.   
9.2.7.5 Body Weight 
Body weight will be measured at specified visits indicated in Section 9.1. Results of the body 
weight are to be recorded in kilograms (kg) in the patient’s study source records and captured 

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electronically. 
9.2.7.6 Vital Signs 
Vital signs with the patient in a seated position (sitting for ≥ 5 minutes) will be collected at 
specified visits indicated in Section 9.1.  
Vital signs will include systolic and diastolic blood pressure (mmHg), pulse rate (bpm) and oral 
temperature (°C). Oral temperature should be measured after a minimum of 20 minutes 
without oral fluids.  Vital signs are to be recorded in the patient’s study source records and 
captured electronically.  
9.2.7.7 Electrocardiogram 
A standard 12-lead ECG (ventricular rate, RR, PR, QRS, QT, QTcB and QTcF) will be 
performed by the investigator or designee after the patient has been in the supine position for 
at least 5 minutes at specified visits indicated in Section 9.1.  The patient must remain in a 
supine position while the ECG is obtained.  Electrocardiogram tracings and results with 
investigator’s interpretation are to be included and summarized in the patient’s study source 
records. Results will be recorded in the patient’s study source records and captured 
electronically. 
On the electrocardiogram should be recorded the date, time, patient demographics (e.g., age, 
and sex) and subject number.   
9.2.7.8 Safety Laboratory Tests 
Table 3 summarizes the laboratory tests to be evaluated in the study.  All laboratory reports 
must be reviewed by the investigator, and any abnormalities must be assessed for clinical 
significance. Abnormal hematology, biochemistry or urinalysis results may be repeated at the 
investigator’s discretion to rule out laboratory error, or to confirm patient eligibility or safety. The 
results are to be included in the patient’s study source records. 
Table 3. 
Summary of Laboratory Tests 
Hematology 
Biochemistry 
Urinalysis 
Red Blood Cell count (RBC) 
 
Total Protein 
Hydrogen ion concentration 
(pH) 
White Blood Cell count 
(WBC) 
Albumin 
Specific gravity 
WBC differential 
Calcium 
Protein 
Hemoglobin 
Inorganic phosphorus 
Glucose 
Hematocrit 
Cholesterol (total, LDL, HDL) 
Ketones 
Mean Corpuscular 
Hemoglobin (MCH) 
Triglycerides 
Leukocyte esterase 

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 Efficacy Assessments 
9.2.8
9.2.8.1 Montgomery-Asberg Depression Rating Scale (MADRS) 
The MADRS will be administered specifically with a structured interview guide developed by 
MGH. The time frame for this scale is the past 7 days. 
MADRS will be administered by the investigator or designee (trained site rater) at specified 
visits indicated in Section 9.1. Site staff administering the MADRS will be certified by CTNI 
prior to administering the assessment. 
The same certified staff is preferred for the duration of the trial for each patient.  Results are to 
be captured electronically and included in the patient’s study source records. 
9.2.8.1.1 Site Rater Surveillance 
In order to insure consistency of ratings administered by the site raters, CTNI will review 
MADRS assessments conducted by the site raters. These reviews will be conducted by CTNI 
clinicians.  Through a tablet based system provided by the eC/PRO vendor, site raters will be 
able to record each MADRS as it is administered at the site.   
9.2.8.1.2 eC/PRO Services    
CTNI will engage NESS (New England Survey Systems) to provide e-C/PRO (electronic 
Clinician and Patient Rated Outcome) services for the study. NESS will provide tablets 
programmed with the study assessments for the sites to use for administering the scales.  The 
tablets have a recording function that enables the reviewer to listen to the interview while 
reviewing the site rater’s scoring. The tablet system is FDA 21 CFR Part 11 compliant. 
Results of HAM-D, MADRS, MGH ATRQ and SAFER inventory for each question will be 
captured through the tablet system. 
9.2.8.2 Clinical Global Impressions - Severity (CGI-S) and Improvement (CGI-I) Scales  
These clinician-rated scales rate the severity of the disorder and the global improvement since 
beginning of the study. The time frame for these two scales is the past 7 days. 
CGI-S and CGI-I will be administered by the investigator or designee (trained site rater) at 
specified visits indicated in Section 9.1. Results will be recorded in the patient’s study source 
records and captured electronically. 
9.2.8.3 Hamilton Anxiety Scale (HAM-A) 
HAM-A (SIGH-A, Version 5/92) will be administered by the investigator or designee (trained 
site rater) at specified visits indicated in Section 9.1. The time frame for this scale is the past 7 
days. Results will be recorded in the patient’s study source records and captured electronically 

A Multicenter, Randomized, Double-blind, Placebo-controlled Study of the Safety 
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for each question. 
9.2.8.4 Symptoms of Depression Questionnaire (SDQ) 
The SDQ will be completed by the patient at specified visits indicated in Section 9.1. The time 
frame for this scale is the past 7 days. Results will be recorded in the patient’s study source 
records and captured electronically for each question.  
 AiCure: Medication Adherence and Reminder System 
9.2.9
This trial will employ a medication adherence monitoring platform using AiCure proprietary 
technology. The platform uses artificial intelligence on smartphones to confirm medication 
ingestion, with built-in reminders and a communication system that allows real-time 
intervention in case of drug interruptions. Use of this platform will in no way supersede or 
replace the physician and/or trial prescribed medication protocol of the patients. 
The monitoring platform requires that patients take each dose of the medication using a 
smartphone.  The platform will be provided to a patient preloaded on a smartphone, or 
downloaded to their device. Study patients will receive a medication reminder at a time within a 
predefined window to take their medication using the platform.  Study patients will follow a 
series of prescribed steps in front of the front-facing webcam to visually confirm ingestion of 
the medication.  
After local determination by the device of proper medication administration, all video 
recordings are encrypted and then transmitted to a secure centralized location for further 
analysis, including testing for duplicate enrollment.  The captured data and video is reviewable 
through roles and rules restricted HIPAA-compliant system ensuring privacy of the information.  
Patients who are found to regularly not take their medication will be contacted by healthcare 
providers, or other study monitoring personnel for retraining. 
 Pharmacodynamics Assessments 
9.2.10
Samples for PD markers are collected at specified visits indicated in Section 9.1. This study 
will explore single time points of collection for exploratory analysis to guide future trials and 
multiple time points of collection for PD effects assessments. All assays will be performed at a 
central laboratory.   

A Multicenter, Randomized, Double-blind, Placebo-controlled Study of the Safety 
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Figure 2.  Pharmacodynamic Schedule 
 
9.2.10.1 Plasma Copeptin 
Venous blood samples will be collected at specified visits indicated in Section 9.1.  
9.2.10.2 Salivary Cortisol 
Saliva samples will be self-collected at home for specified visits indicated in Section 9.1. Saliva 
samples will be collected the day before specified visit at on the following schedule:  
• 
Sample 1: Between 30 and 60 minutes prior to bedtime 
• 
Sample 2: Between 30 and 60 minutes after awakening 
No food or drink is permitted for 30 minutes prior to sample collection.  Date and time of 
sample collection, bedtime, time of awakening and time of breakfast will be recorded in the 
patient’s study source records and captured electronically for each sample collected.  Detailed 
processing and handling instructions are available in the Laboratory Manual.   
9.2.10.3 Urine Cortisol 
Urine samples for urinary cortisol will be collected by the patient at home overnight, starting at 
10:00 p.m. on the night prior to Visit 3 and continuing until 06:00 a.m. the next morning (visit 
day) in order to provide a continuous pooled 8-hour sample. Patients will be given collection 
materials and instructions at the prior visit.   Detailed processing and handling instructions are 

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available in the Laboratory Manual.  Total urine volume will be recorded in the patient’s study 
source records and captured electronically. 
9.2.10.4 Hair Cortisol 
A single tuft of hair will be collected at the study site with the assistance of study site personnel, 
according to the schedule in section 9.1 if the patient has a sufficient amount of hair to provide 
for measurement.  Detailed procedures for hair collection, processing and analysis will be 
documented in the Laboratory Manual.   
9.2.10.5 Inflammatory Markers (TNF-α, IL-1, IL-6, HS-CRP) 
Venous blood samples will be collected at specified visits indicated in Section 9.1.  TNF-α, IL-1, 
and IL-6, will be analyzed by a central laboratory with standard methodology.  C-reactive 
protein will be analyzed by a high-sensitivity method (HS-CRP) by a central laboratory.   
 Pharmacokinetics Assessment  
9.2.11
9.2.11.1 
 (TS-121) 
Plasma samples will be analyzed to determine concentrations of 
 using a validated, 
specific and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method.  
The determination of 
 will be performed by 
.  
9.2.11.1.1 Pharmacokinetics: Blood Sampling for 
 
A single venous blood sample (approximately 4 mL of whole blood) will be collected for 
determination of 
 pharmacokinetics at Visit 6.  The exact dates and times of the blood 
sampling and the last investigational product administration before blood sampling must be 
recorded in the patient’s study source records and captured electronically.   
Blood collection tubes: 4 mL plastic vacuum tubes containing K2 EDTA. 
Plasma sample storage vessels: 2 mL polypropylene tubes 
After collection, the blood sample will be kept in an ice bath (or other cooling systems, except 
for refrigerator) until centrifuged.  Samples must be centrifuged (4ºC, 3000 rpm, 10 minutes) 
within 30 minutes after blood collection to obtain plasma. After centrifugation, plasma samples 
shall be distributed into two polypropylene tubes as follows: 
• 
0.5 mL (Primary) for 
 pharmacokinetic analysis 
• 
0.5 mL (Backup) for 
 pharmacokinetic analysis 
All tubes will preferably be stored at or below -70ºC. If -70ºC freezer is not available, all tubes 
will be stored at or below -20ºC. 

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9.2.11.1.2 Pharmacokinetics: Shipping for 
 
 
 
 
 
  
 
 
 
 
 
   
 
  
 
 
 
 
 
 
 
 
 
 Pharmacogenomic Blood Sampling 
9.2.12
A single blood sample (approximately 8.5 mL of whole blood) for pharmacogenomics (PGx) will 
be obtained from eligible patients consenting to PGx during Visit 3. The dates of the blood 
sampling will be recorded in the patient’s study source records and captured electronically. 
Instructions for preparation, storage and shipping of the pharmacogenomic samples are found 
in the Laboratory Manual. 
9.3 Visit and Time Windows 
Visit and time windows for each visit are summarized in Section 9.1.  Visit 1 can be performed 
from Day -28 to Day -7, and must be performed prior to Visit 1.1.  Visit 1.1 can be performed 
from Day -13 to Day -2. Visit 2.1 has a ±2 day window. Visit 3 has a +3 day window and must 
be performed after obtaining results for Visit 2.1. All visits after Visit 3 will have a visit window 
of ±3 days. The ophthalmological examination at Visit 2 can be performed within -5 days of 

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study Day 1 (Day -5 to Day 1). 

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10 STATISTICAL METHODS 
In addition to this section of the study protocol, a more detailed Statistical Analysis Plan (SAP) 
will be provided in a separate document.  Any revisions (both alternative and additional 
methods) to the SAP that are used in the final report, and reasons for such revisions, will be 
described in the final report. This is a pilot project and the results obtained will be used to 
estimate the effect size and to support future studies. 
10.1 Sample Size Determination 
The total number of patients enrolled in the study is based on practical consideration and not 
on statistical power calculations. These sample sizes are considered adequate to meet the 
study objectives based on clinical considerations and allow for assessments of the safety, 
efficacy and PD effects of TS-121 in this patient population. 
10.2 Analysis Populations 
The safety analysis population will include all patients who received at least one dose of 
investigational product (including placebo during the placebo lead-in period). 
The intent to treat population will include all patients who were randomized and received at 
least one dose of investigational product. 
The exploratory PD analysis population will include all randomized patients who completed the 
assessment and have sufficient mental health assessments completed.  This could be 
independent of receiving the investigational product.  Missing data will not be imputed and are 
to be excluded from the analysis.  
The PK analysis population will include all patients who were randomized and received 
investigational product with evaluable PK data and may exclude those that are considered 
invalid due to relevant missing values, or if any other problems occurring during sampling, 
laboratory analysis, dosing, or AEs that invalidate the concentration measurements  
10.3 General Analysis Conventions 
For continuous measures, data will be summarized by descriptive statistics.  Where 
appropriate, change from baseline and visit-to-visit will be summarized.  For categorical 
measures, data will be summarized with frequency counts and percentages. All data analyzed 
will be displayed in detailed listings.  No interim analysis is planned.  
10.4 Demographic and Baseline Characteristics 
Demographics and baseline characteristics including but not limited to age, gender, body 
weight, height, body mass index, medical history, and psychiatric history will be tabulated by 
group using descriptive statistics.  

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10.5 Endpoint Analysis 
 Safety Analysis 
10.5.1
Safety will be assessed based on reported adverse events, abnormal findings from physical 
and ophthalmological examination, body weight, vital signs measurements, 12-lead ECGs, C-
SSRS score and clinical laboratory assessment results.  Additional details will be described in 
the SAP. 
10.5.1.1 Adverse Events 
Adverse events will be listed by preferred terms and summarized by system organ class with 
preferred term based on the MedDRA coding system.  The number and percentage of patients 
who experience one or more AEs will be tabulated.  The tabulation will be further classified by 
severity and relationship to investigational product.    
10.5.1.2 Clinical Laboratory Values 
Laboratory data from each sampling and changes from baseline will be summarized by 
descriptive statistics. Laboratory analyses will utilize Visit 3 assessments as baseline values. 
Parameters will be categorized as low, normal, or high according to the laboratory normal 
range specifications.   
Clinical laboratory outlier criteria will be used to identify values and trends of potential medical 
importance.  A summary for the number and percentage of patients with clinical laboratory 
outliers for each specified laboratory test will be presented.  Similar analyses will be performed 
for clinically noteworthy changes which would show magnitude of change from baseline. 
Criteria for clinical laboratory outliers and clinically noteworthy changes will be described in the 
SAP. 
10.5.1.3 Vital Signs 
Vital signs at each measured time point and changes from baseline will be summarized by 
descriptive statistics.  
10.5.1.4 Electrocardiogram 
Characteristics of cardiac events at each reading and changes from baseline will be 
summarized descriptively for interval data (ventricular rate, RR, PR, QRS and QTc) will be 
calculated for each group.  The incidence of abnormalities, based on the clinical interpretations 
from the investigator, will be enumerated.  
QTc as corrected by the Fridericia and Bazett methods will be used as the primary measure of 
change in QT interval.  Changes from baseline for each of the ECG parameters will be 
summarized using descriptive statistics.  Borderline and prolonged QTc will be listed and 

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frequency table provided.  Additionally, the numbers of patients with change from baseline in 
QTc at appropriate visits categorized as <30 msec, 30 to 60 msec, and >60 msec, will be 
tabulated and summarized by treatment group as will the number of patients with a QTc 
interval >500 msec.   
10.5.1.5 Ophthalmological Examinations 
Any of clinically significant ophthalmological findings as defined in Section 11.3 will be 
analyzed as adverse events. 
The LOCS III grading scores and best corrected visual acuity scores observed during the study 
will be listed. 
Additional details will be described in the SAP. 
10.5.1.6 C-SSRS 
Any suicidal ideation or behavior on the C-SSRS that develops during the study will be listed. 
Additional details will be described in the SAP. 
 Efficacy Analysis 
10.5.2
10.5.2.1 Primary Endpoint 
To evaluate the efficacy of TS-121 compared to placebo on MDD symptoms in MDD patients, 
Mixed Model Repeated Measures analysis (MMRM)/non-parametric methods will be used to 
compare the difference between the three treatment groups on the primary endpoint (change 
in MADRS score) depending on the distribution of the data. On the primary endpoint (change 
in MADRS score), as assessed at Week 6, a statistically significant GROUP*TIME interaction 
effect, with greater reductions in MADRS scores in the TS-121 groups, will be interpreted as 
indicating efficacy (GROUP: Placebo, TS-121 10 mg and TS-121 50 mg, TIME: Week 2, Week 
4 and Week 6). 
10.5.2.2 Secondary Endpoint 
With respect to the secondary outcome variables, the same MMRM/non-parametric methods 
as described above will also be used to compare the difference between the three treatment 
groups on the each secondary endpoint depending on the distribution of the data.  
Changes from Baseline (Visit 3) to EOT (Visit 6) for the following: 
• 
CGI-S score 
• 
HAM-A total score 
• 
SDQ score 

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Chi-square test or Fisher’s exact test will be used to compare the difference of active treatment 
groups to placebo group on the following secondary endpoint. 
• 
Percentage of MADRS responders (≥ 50% reduction in total score) 
• 
Percentage of CGI-I improvers (“Very much improved” or “Much improved”) 
 Pharmacodynamic (PD) Analysis 
10.5.3
With respect to the PD outcome variables, the same MMRM/non-parametric methods as 
described in Section 10.5.2.1 will be used to compare the difference between the three 
treatment groups on the each of PD endpoint depending on the distribution of the data.  
Changes from Baseline (Visit 3) to EOT (Visit 6) for the following: 
• 
Plasma copeptin 
• 
Inflammatory markers (IL-1, IL-6, HS-CRP, and TNF-α) 
Pharmacodynamic biomarkers (salivary cortisol, hair cortisol, plasma copeptin, 8h urinary 
cortisol and inflammatory markers (IL-1, IL-6, HS-CRP, and TNF-α)) will be evaluated post-hoc 
to explore relationship of responders and non-responders to baseline characteristics.  The 
analysis will be used to inform, potentially, on future trial design.  A separate plan will document 
analyses of PD samples. All results, including baseline PD biomarkers (salivary cortisol, hair 
cortisol, plasma copeptin, 8h urinary cortisol and inflammatory markers (IL-1, IL-6, HS-CRP, 
and TNF-α)), will be listed with relevant metadata.  
 Pharmacokinetic (PK) Analysis 
10.5.4
Visit 6 samples will be limited to evaluation of TS-121 PK.  The individual plasma concentration 
of 
, the last dosing date and time, and actual sampling date and time will be listed.  
Additional details will be described in the SAP.  
 Pharmacogenomic (PGx) Analysis 
10.5.5
If study results warrants further investigation of genomic variation postulated to be involved in 
the metabolism, toxicity, pharmacological response, or emerging MDD data to TS-121 or MDD, 
the sponsor may conduct genetic and other biomedical research on specimens, including 
genetic analyses (DNA).  PGx samples for patients who received TS-121 (including placebo) 
will be stored for up to 15 years and may be evaluated as information is gained on TS-121 
and/or MDD.   

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11 ADVERSE EVENT REPORTING 
11.1 Definitions, Grading & Relationship, Outcome and Follow-up 
 Definitions 
11.1.1
Adverse Event (AE): Any untoward medical occurrence in a patient administered an 
investigational product, and which does not necessarily have a causal relationship to 
investigational product.  An AE can be any unfavorable or unintended sign (including an 
abnormal finding), symptom, or disease. AEs include any occurrence that is new in onset or 
aggravated in severity or frequency from the baseline condition, or abnormal results of 
diagnostic procedures (including clinically-significant laboratory test abnormalities).  Overdose 
defined in Section 11.6.1 will also be considered as an AE whether or not it is associated with 
symptoms or abnormal laboratory results. 
Events should be considered AEs if they: 
• 
result in discontinuation from the study, 
• 
require treatment or any other therapeutic intervention, 
• 
require further diagnostic evaluation (excluding a repetition of the same procedure 
to confirm the abnormality), 
• 
are associated with clinical signs or symptoms judged by the investigator to have 
a significant clinical impact. 
Appropriate therapeutic action and follow-up measures will be performed by the investigator in 
accordance with GCP.  These actions and measures will continue until the condition is 
resolved and/or the etiology is identified.  Any non-serious AEs (including laboratory results or 
other clinical findings) that result in the patient’s withdrawal from the study will require the 
patient to undergo early discontinuation procedures.  
Laboratory Abnormalities: It is the responsibility of the investigator to review all laboratory 
findings for all patients.  Abnormal values should be commented upon as to clinical relevance 
or importance in the study source records or the laboratory report as appropriate. An abnormal 
laboratory value may be considered an adverse event if the identified laboratory abnormality 
leads to any type of intervention whether prescribed in the protocol or not.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory abnormality 
should be classified as an adverse event. 
All laboratory abnormalities considered to constitute an adverse event should be reported on 
the appropriate section of the patient’s study source records. Laboratory abnormalities do not 
need to be listed as separate adverse events if they are considered to be part of a clinical 

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syndrome that is being reported as an adverse event. 
 Grading and Relationship 
11.1.2
The investigator will evaluate all AEs as to their severity, and record the outcome and action 
taken.  The investigator will also judge the likelihood that the AE was related to the 
investigational product and document this in the patient’s study source records.  See Table 4 
below: 

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Table 4. Classification of Adverse Events 
Severity 
Mild 
awareness of sign or symptom, but easily tolerated  
 
Moderate 
discomfort enough to cause interference with usual activity  
 
Severe 
incapacitating with inability to work or do usual activity  
Duration 
Record the start and stop dates of the adverse experience. If less than 1 day, indicate the appropriate length of time and units 
Action taken  
Did the adverse experience cause the test drug to be discontinued? Interrupted? Dosage increased or decreased? Other action? 
Relationship 
to test drug  
Did the test drug cause the adverse experience? The determination of the likelihood that the test drug caused the adverse experience will be 
provided by an investigator. The investigator’s signed/dated initials on the source document supporting the causality noted on the AE form 
ensures that a medically qualified assessment was done. This initialed document must be retained for the required regulatory time frame. The 
criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug 
and the adverse experience based upon the available information.  The greater the correlation with the components and their respective 
elements (in number and/or intensity), the more likely the test drug caused the adverse experience: 
 
Exposure 
Is there evidence that the patient was actually exposed to the test drug such as: reliable history, 
acceptable compliance assessment (pill count, diary, etc.), expected pharmacologic effect, or 
measurement of drug/metabolite in bodily specimen? 
 
Time Course 
Did the AE follow in a reasonable temporal sequence from administration of the test drug?  
Is the time of onset of the AE compatible with a drug-induced effect? 
 
Likely Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other 
drug(s)/vaccine(s), or other host or environmental factors? 
Dechallenge 
Was the dose of test drug discontinued or reduced? 
If yes, did the AE resolve or improve? 
If yes, this is a positive dechallenge. If no, this is a negative dechallenge. 
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; 
(2) the AE resolved/improved despite continuation of the test drug; or (3) the study is a 
single-dose drug study.) 
 
Rechallenge 
Was the patient re-exposed to the test drug in this study? 
If yes, did the AE recur or worsen? 
If yes, this is a positive rechallenge. If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if:  
(1) the initial AE resulted in death or permanent disability, or (2) the study is a single-dose 
drug study.) 
 
 
Consistency with Investigational 
Product Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the 
test drug or drug class pharmacology or toxicology? 
 
The assessment of relationship will be reported on the case report forms/worksheets by an investigator according to his/her best clinical 
judgment, including consideration of the above elements. 
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a drug relationship). 
 
Definitely related  
A clinical event, including laboratory test abnormality, occurring in a plausible time relationship to 
drug administration, and which cannot be explained by concurrent disease or other drugs or 
chemicals. The response to withdrawal of the drug (dechallenge) should be clinically plausible. 
The event must be definitive pharmacologically or phenomenologically, using a satisfactory 

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rechallenge procedure if necessary. 
 
Probably related  
A clinical event, including laboratory test abnormality, with a reasonable time sequence to 
administration of the drug, unlikely to be attributed to concurrent disease or other drugs or 
chemicals, and which follows a clinically reasonable response on withdrawal (dechallenge). 
Rechallenge information is not required to fulfil this definition. 
 
Possibly related  
A clinical event, including laboratory test abnormality, with a reasonable time sequence to 
administration of the drug, but which could also be explained by concurrent disease or other drugs 
or chemicals. Information on drug withdrawal may be lacking or unclear. 
 
Not related  
A clinical event, including laboratory test abnormality, with a temporal relationship to drug 
administration which makes a causal relationship improbable, and in which other drugs, chemicals 
or underlying disease provide plausible explanations. 
 

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 Outcome 
11.1.3
The seriousness of an event is determined by its outcome (e.g., hospitalization, death, etc.).  
The action taken to treat an AE and the outcome of the action must be recorded.  Outcomes 
may be categorized as shown below: 
• 
FATAL: The termination of life as a result of an adverse event. Death Related to 
Adverse Event  
• 
NOT RESOLVED: One of the possible results of an adverse event outcome that 
indicates that the event has not improved or recuperated.  
• 
RESOLVED: One of the possible results of an adverse event outcome that 
indicates that the event has improved or recuperated.  
• 
RESOLVED WITH SEQUELAE: One of the possible results of an adverse event 
outcome where the patient recuperated but retained pathological conditions 
resulting from the prior disease or injury.  
• 
RESOLVING: One of the possible results of an adverse event outcome that 
indicates that the event is improving.  
• 
UNKNOWN: Not known, not observed, not recorded, or refused. 
 AE Follow-Up 
11.1.4
Any AEs that are ongoing after the Follow-up Visit should be followed for 30 days, with the 
exception of serious adverse events that are followed until resolution or stabilization. 
Information collected after the Follow-up Visit, however, will not be captured in the database, 
but will be maintained in the patient’s study source records and made available upon request. 
11.2 Serious Adverse Event Reporting 
 Definition of Serious Adverse Event 
11.2.1
A serious adverse event (SAE) is an untoward medical occurrence that at any dose:  
• results in death (Note: Death is an outcome and not an event and the cause of death 
should be listed as the SAE); 
• is life-threatening (i.e., the patient was at immediate risk of death from the AE); 
• requires inpatient hospitalization or prolongation of existing hospitalization; 
• results in persistent or significant disability/ incapacity; or 
• is a congenital anomaly or birth defect (in the child of a patient who was exposed to the 
investigational product) 

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Any other important medical event that may result in death, be life-threatening, or require 
hospitalization, may be considered a SAE when, based upon appropriate medical judgment, 
the event may jeopardize the patient and may require medical or surgical intervention to 
prevent one of the outcomes listed above.  
 Serious Adverse Event Reporting Procedure 
11.2.2
If in the opinion of the investigator, the event meets the criteria of an SAE, the following 
procedures will be followed: 
On discovery, all SAEs should immediately (within 24 hours of awareness of the event) be 
reported to 
 by:  
 Completing the SAE report form and faxing the documents to 
, using 
the 
 SAE fax number below:  
• 
24/7 Fax:  
 
 Or, by completing the SAE report form and submitting it to 
 via email 
utilizing the address below: 
• 
SAE Reporting e-mail: 
 
 In the event that the site is unable to complete the SAE form to report the event 
within 24 hours of awareness of the event, the investigator may report the SAE over 
the telephone and then provide the completed SAE form via (fax/email). If questions 
arise regarding the reporting procedures or the specifics of the reporting of an event, 
the site may call utilizing the following number:  
 
 
• 
The following documents will be forwarded to 
 within 24 hours of reporting 
the event: 
1. SAE Report 
2. Con Med CRF page 
3. Medical History page 
4. Any other applicable information 
• 
The sponsor must be notified within 24 hours of awareness of the event as specified in the 
Safety Plan.   
• 
The initial report of an SAE may be submitted by email.  The investigator must provide the 
minimal information: i.e. the protocol number, subject number, date of SAE, SAE term, 

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short description of the event, causality (if determined) and the reason why the event is 
categorized as serious. 
• 
The investigator will also notify the Institutional Review Board (IRB) of the event within the 
time frame specified in the IRB’s Standard Operating Procedures after becoming aware of 
the SAE.  An initial report followed promptly by a complete report will be forwarded to the 
IRB, or in accordance with the IRB policy. 
• 
The patient will be observed and monitored carefully until (1) the condition stabilizes and/or 
resolves; (2) its cause is identified; or (3) it is otherwise determined by the Medical Monitor 
and investigator.  Follow-up information relating to the SAE must be submitted to 
 
 by email as soon as additional information related to the event is available. 
• 
If a patient is hospitalized due to the SAE, the hospital discharge summary should be 
obtained if possible when it becomes available. 
• 
If a death occurs and an autopsy is performed, a copy of the autopsy report should be 
obtained if possible when it becomes available.  All efforts must be undertaken to obtain 
follow-up information promptly. 
Any SAEs occurring from first administration of investigational product through 30 days after 
last administration must be reported.  All SAEs will be reported, whether or not they are 
deemed to be related to study product. Timely reporting of SAEs will be followed in accordance 
with regulatory requirements as outlined in the Safety Plan.  
 SAE Follow-Up 
11.2.3
If an SAE is reported while the event is still ongoing, the investigator must submit follow-up 
reports to 
 regarding the patient’s subsequent course.  All SAEs, including those 
that are ongoing at the end of the study or upon discontinuation must be followed until 
resolution or stabilization. 
11.3  Events of Clinical Significance 
Suicidal ideation and behavior, and lens opacity, as defined in the following sections, are 
considered as Event of Clinical Significance (EOCS). An EOCS should be recorded as an AE.  
All EOCS, regardless of whether the event meets criteria for SAE, should be reported to 
 within 24 hours of becoming aware of the event. 
 Suicidal Ideation and Behavior 
11.3.1
Any patient who, based on the investigator’s judgment, poses an imminent risk of suicide, as 
suggested by the C-SSRS suicidal ideation score of 5 or any “yes” response for any of the C-

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SSRS suicidal behavior questions should be discontinued from the study (see Section 8.5).  
Suicidal ideation or behavior should be recorded as AE and reported to 
 within 
24 hours of becoming aware of the event whether or not the event is considered an SAE or 
deemed to be related to investigational product. All efforts should be taken to minimize the risk 
of suicide and the investigator should carefully monitor the patient. Any patients who show 
evidence of suicidal behavior during the course of the study should be evaluated immediately 
and/or referred to their attending psychiatrist or to a local emergency room etc. so the patient 
can receive an appropriate care. The site should have the ability to direct any patient who 
requires emergency hospitalization to an emergency room or inpatient psychiatric unit. In 
addition, 24 hour contact information to site personnel should be provided to all patients should 
they have serious worsening of their condition. 
 Lens Opacity  
11.3.2
Class I lens event [increase from baseline in the LOCS III grade of ≥0.5 (Nuclear Opalescence), 
≥0.8 (Cortical) or ≥0.5 (Posterior Subcapsular)] and any changes considered to be clinically 
significant (e.g., incidence of cataract) as per the ophthalmologist will be immediately reported 
to the investigator. The investigator will report the event to the 
 within 24 hours of 
becoming aware of the event whether or not the event is deemed to be related to 
investigational product. A Class I lens event should be recorded as an AE and reported as an 
EOCS.  
 EOCS Reporting Procedure 
11.3.3
EOCS reporting procedure is as follows: 
• 
Immediately upon becoming aware of EOCS as defined above, the investigator will 
report the event by fax/email directly to 
 as described in Section 11.2.2. 
• 
The following documents will be forwarded to 
 within 24 hours of 
reporting the event: 
 
Results of ophthalmic examination (for lens opacity event only) 
 
Slit Lamp and retro illumination Photographs (for lens opacity event only) 
 
Any other applicable information  
11.4 Worsening of Depression 
Significant worsening in depression should be reported as an AE. A CGI-I score of 6 or 7 at 
any time during the study should be considered as an AE of worsening of depression, and the 
patient must be evaluated to see if the patient should discontinue the study. In addition, the 
investigator should document the decision to continue or discontinue the patient, along with a 
rationale for the decision. 

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11.5 Pregnancy Reporting 
If a patient does become pregnant during the course of the study, the patient should be 
discontinued immediately. The site must report all pregnancies to 
 via email or 
telephone within 24 hours of receiving the report of pregnancy. The site should record and 
maintain all relevant information on the appropriate study form, including the follow-up and 
outcome of the pregnancy. 
Pregnancy itself is not regarded as an AE/ SAE. Congenital abnormalities/birth defects and 
spontaneous miscarriages should be reported and handled as SAEs. Elective abortions 
without complications should not be handled as AEs. The outcome of all pregnancies 
(spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth or congenital 
abnormality) should be followed up and documented even if the patient was discontinued from 
the study (with the patient’s consent). 
Male patients should refrain from fathering a child or donating sperm during the study and for 
at least 90 days following the last dose. Pregnancy of the patient’s partner is not considered to 
be an AE; however, the outcome of all pregnancies should be followed up and documented if 
possible. 
11.6 Overdose 
 Definition of Overdose 
11.6.1
An overdose is defined in this protocol as ingestion of the investigational product (accidental or 
intentional) of more than 3 capsules in the same calendar day. 
Note: In case of a potential overdose, where the patient took investigational product from a 
combination of more than one row on the medication card but did not exceed 3 capsules in the 
same calendar day, an AE of “medication error” should be recorded. 
 Overdose Reporting 
11.6.2
If an overdose occurs, the overdose should be reported as an AE whether or not it is 
associated with symptoms or abnormal laboratory results. The event reported should include 
information on whether the event is accidental or intentional, and if the event is associated with 
symptoms or adverse reaction.  
The investigator will report all reports of overdose to the 
 within 24 hours of 
becoming aware of the overdose whether or not the overdose is intentional. 
 

A Multicenter, Randomized, Double-blind, Placebo-controlled Study of the Safety 
and Efficacy of TS-121 as an Adjunctive Treatment for Patients with Major 
Depressive Disorder with an Inadequate Response to Current Antidepressant 
Treatment 
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12 INVESTIGATOR OBLIGATIONS 
This study will be conducted in accordance with GCP, Title 21 of the CFR, Part 50, Subparts A 
and B; Part 56; and Part 312, Subpart D; and the Consolidated Guidance for Industry GCP E6, 
April 1999; and 1996 ICH GCP E6. 
12.1 Ethical Considerations 
The investigator will ensure that the study is conducted in full conformance with the FDA 
standards for human research as specified in 21 CFR 312, Part D (Responsibilities of 
Sponsors and Investigators) and in accordance with the Declaration of Helsinki. 
12.2 Institutional Review Board (IRB) Approval 
Prior to initiating the study and receiving investigational product, the investigator must obtain 
written approval to conduct the study from the appropriate IRB.  The investigator must have 
signed the protocol signature page.  When changes to the study protocol become necessary, 
protocol amendments will be submitted in writing by the investigator to the IRB for approval 
prior to implementation. Protocol administrative changes will also be submitted in writing by the 
investigator to the IRB for review and notification.  The IRB must be informed of all serious and 
unexpected AEs occurring during the study that are likely to affect the safety of the patients or 
the conduct of the study. 
In addition to the IRB approval, other documentation including FDA Form 1572, financial 
disclosure forms, investigator curriculum vitae (CV), applicable licensure for investigators and 
sub-investigators, a copy of the IRB approval, letter, and an IRB approved consent form must 
be collected and filed in the trial master file. 
12.3 Informed Consent 
 Study Informed Consent 
12.3.1
All potentially eligible patients for the study will be given a copy of the study informed consent 
form (ICF) to read.  All study patients must sign this ICF if he/she decides to participate in the 
study.  The study products will not be released to the patient who has not signed the ICF.  The 
investigator or designee will inform all patients as to the nature, aims, duration, potential 
hazards, and procedures to be performed during the study and that his or her medical records 
may be reviewed.  The investigator will explain all aspects of the study in lay language and 
answer all the patient’s questions regarding the study.  The investigator must also explain that 
the patients are completely free to refuse to enter the study or to withdraw from it at any time.  
All revisions of the protocol must be reflected in the ICF and reviewed by the IRB.  Patients 
who refuse to participate or who withdraw from the study will be treated without prejudice.  

A Multicenter, Randomized, Double-blind, Placebo-controlled Study of the Safety 
and Efficacy of TS-121 as an Adjunctive Treatment for Patients with Major 
Depressive Disorder with an Inadequate Response to Current Antidepressant 
Treatment 
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 Pharmacogenomic Informed Consent 
12.3.2
A separate signed informed consent will be administered to cover the conduct of PGx sample 
collection and analysis.  Only patients who have consented to allow PGx research may have 
sample collected.  The patient may choose to participate in the trial, but not participate in the 
PGx research.  Elements of the PGx consent will be included from the sponsor provided 
template and local policies, regulations and laws.   
 Health Insurance Portability and Accountability (HIPAA) Authorization 
12.3.3
The Health Insurance Portability and Accountability Act of 1996 (HIPAA) contains provisions to 
protect the confidentiality and security of personally-identifiable information that arises in the 
course of providing health care. In order to understand how HIPAA affects research, there are 
a few important terms that are defined by the law. A covered entity is the organization that has 
to comply with HIPAA. Such organizations may be a Hybrid Covered Entity because, in 
addition to providing health care at medical facilities, it also has other organizational activities 
such as education and research.  
The HIPAA Privacy Rule governs Protected Health Information (PHI) which is defined as 
information that can be linked to a particular person (ie., is person-identifiable) that arises in 
the course of providing a health care service.  
When PHI is communicated inside of a covered entity, this is called a use of the information. 
When PHI is communicated to another person or organization that is not part of the covered 
entity, this is called a disclosure. HIPAA allows both use and disclosure of PHI for research 
purposes, but such uses and disclosures have to follow HIPAA guidance and have to be part of 
a research plan that is reviewed and approved by an IRB. An institutionally approved HIPAA 
authorization must be completed for each patient.  The Authorization can be included as part of 
the main study informed consent, but must have a second signature section in addition to 
signature section of the study informed consent.  The HIPAA authorization will include the 
following attributes consistent with local privacy requirements:  
12.3.3.1 Authorization Core Elements  
• 
A description of the PHI to be used or disclosed, identifying the information in a specific 
and meaningful manner 
• 
The names or other specific identification of the person or persons (or class of persons) 
authorized to make the requested use or disclosure 
• 
The names or other specific identification of the person or persons (or class of persons) to 
whom the covered entity may make the requested use or disclosure 
• 
A description of each purpose of the requested use or disclosure 

A Multicenter, Randomized, Double-blind, Placebo-controlled Study of the Safety 
and Efficacy of TS-121 as an Adjunctive Treatment for Patients with Major 
Depressive Disorder with an Inadequate Response to Current Antidepressant 
Treatment 
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• 
Authorization expiration date or expiration event that relates to the individual or to the 
purpose of the use or disclosure ("end of the research study" or "none" are permissible for 
research, including for the creation and maintenance of a research database or repository) 
• 
Signature of the individual and date. If the individual's legally authorized representative 
signs the Authorization, a description of the representative's authority to act for the 
individual must also be provided 
12.3.3.2 Authorization Required Statements 
• 
A statement of the individual's right to revoke Authorization and how to do so, and, if 
applicable, the exceptions to the right to revoke Authorization or reference to the 
corresponding section of the covered entity's notice of privacy practices.  
• 
Whether treatment, payment, enrollment, or eligibility of benefits can be conditioned on 
Authorization, including research-related treatment and consequences of refusing to sign 
the Authorization, if applicable.  
• 
A statement of the potential risk that PHI will be re-disclosed by the recipient and no longer 
protected by the Privacy Rule. This may be a general statement that the Privacy Rule may 
no longer protect health information disclosed to the recipient. 
12.4 Patient Confidentiality 
All reports and patient samples will be identified only by a coded number to maintain patient 
confidentiality.  All records will be kept confidential to the extent permitted by law.  The 
investigator should keep a separate log of patients, codes, names and addresses.  Documents 
which identify the patient by name (informed consent) should be kept in strict confidence. 
Taisho Pharmaceutical R&D Inc. and its vendors agree to keep all patient information 
confidential.  Only coded, blinded data will be released.  Data resulting from analysis will be 
entered into a database that is not accessible to the public.  Patient data will be identified only 
by the subject number or randomization number, and not by other annotation or identifying 
information. Taisho Pharmaceutical R&D Inc. and its vendors will take every possible step to 
reduce the risk of releasing information to its customers that would enable the customer to 
personally identify patients. 
12.5 Patient’s Financial Responsibilities During the Study 
Patients will not be financially responsible for any procedures or tests of any investigational 
nature. Institutions shall not seek reimbursement for any medical services or for investigational 
product from any third-party payers if such costs are already covered by payments made under 
the study agreement. 

A Multicenter, Randomized, Double-blind, Placebo-controlled Study of the Safety 
and Efficacy of TS-121 as an Adjunctive Treatment for Patients with Major 
Depressive Disorder with an Inadequate Response to Current Antidepressant 
Treatment 
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Apr 23, 2018 
Amendment 4 
 
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13 DOCUMENTATION, RECORD KEEPING, AND DATA MANAGEMENT 
13.1 Source Data/Documents 
Source data is defined as all information in original records and certified copies of original 
records of clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial.  Source documents is defined as the first place that 
data is captured/recorded.  Any and all source data/documents must be maintained and be 
stored and/or retrievable at the site.  Patients’ data transferred to the CRF will be identified by 
a unique subject number.  As an exception, if it is necessary to identify the patient for safety or 
regulatory reasons, Taisho Pharmaceutical R&D Inc. and the investigator are bound to keep 
this information confidential.  
The investigator must maintain source data/documents for each patient in the study.  All 
information appearing on the CRFs must be traceable to its source (paper or electronic), which 
are generally maintained in the patient’s file/record. 
Corrections or changes to data that are transcribed or transferred to the CRF must be 
traceable to source and must be initialed and dated by the (authorized) person making the 
changes.  A reason for the change(s) or any discrepancies must be explained (i.e. audit trial). 
13.2 Records Retention 
Essential documents must be retained by the investigator for a period of at least two years 
after the last FDA marketing approval, or at least two years following the withdrawal of the NDA 
or cessation of investigational product development, or until written approval to destroy the 
documentation is provided by the sponsor.  Taisho Pharmaceutical R&D Inc. will notify the 
investigator/institution in writing when the study-related records are no longer required.  The 
investigator agrees to adhere to the document retention procedures by signing the protocol. 
Essential documents include, but are not limited to the documents described in ICH E6 
guideline section 8.2 to 8.4. 
The documentation must be retained longer, if so required by local law.  Investigators must 
notify the sponsor, in writing, of changes in address, sales or practices or site closures in order 
to make arrangements for the maintenance of study files. 
13.3 Data Management 
All data management procedures will be detailed in a separate Data Management Plan (DMP). 
 

A Multicenter, Randomized, Double-blind, Placebo-controlled Study of the Safety 
and Efficacy of TS-121 as an Adjunctive Treatment for Patients with Major 
Depressive Disorder with an Inadequate Response to Current Antidepressant 
Treatment 
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Apr 23, 2018 
Amendment 4 
 
Taisho Pharmaceutical R&D Inc.                                                    Confidential 
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14 CHANGES TO THE PROTOCOL AND STUDY TERMINATION  
14.1 Protocol Amendment 
All changes to the protocol must be documented by amendments, or administrative changes 
where applicable, and the amended protocol must be signed by the sponsor and the 
investigator(s) and submitted for approval to the IRB.  A copy of the approval will be provided 
to the site.  Where the local IRB regulations regarding protocol amendments differ from this 
policy, the local regulations will apply. 
14.2 Study Termination 
The sponsor and the investigator reserve the right to terminate the study at any time.  In 
terminating the study, the sponsor and the investigator will ensure that adequate consideration 
is given to the protection of each patient’s interest. 

A Multicenter, Randomized, Double-blind, Placebo-controlled Study of the Safety 
and Efficacy of TS-121 as an Adjunctive Treatment for Patients with Major 
Depressive Disorder with an Inadequate Response to Current Antidepressant 
Treatment 
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Apr 23, 2018 
Amendment 4 
 
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15 STUDY MONITORING 
15.1 Clinical Monitoring 
An initiation meeting will be conducted by the sponsor or an authorized representative (e.g., 
clinical monitor).  During this meeting, the protocol, CRFs, ICF and pertinent aspects of the US 
Code of Federal Regulations (CFR) will be reviewed with the investigator and all study staff. 
Interim monitoring visits will be conducted by a clinical research associate (CRA) during the 
study at predefined intervals.  Upon reasonable notice, the investigator and/or an authorized 
designee will set aside sufficient time to be available to the CRA to assist with the data query 
and resolution process, as well as to provide access to any additional records required for 
source data verification. During the course of the study, the responsible study staff will be 
available to discuss any matters relating to the conduct of the study. 
At each site visit, the CRA will review CRFs and source documents to verify that all items have 
been completed and that the data provided are accurate and obtained in the manner specified 
in the protocol.  Incorrect, inappropriate, or illegible entries onto the CRFs will be returned to 
the investigator and/or an authorized designee for correction. Monitoring visit agendas should 
also leave sufficient time to review the investigator site files for completeness and accuracy, 
and for investigational product inventories as appropriate. 
Further details will be outlined in a clinical monitoring plan. 
15.2 Auditing Procedures 
A quality assurance audit may be performed by authorized representatives of Taisho 
Pharmaceutical R&D Inc., a regulatory agency or an IRB.  If a regulatory authority requests an 
audit of the study site, the investigator is required to inform the sponsor and CRO immediately. 

A Multicenter, Randomized, Double-blind, Placebo-controlled Study of the Safety 
and Efficacy of TS-121 as an Adjunctive Treatment for Patients with Major 
Depressive Disorder with an Inadequate Response to Current Antidepressant 
Treatment 
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Apr 23, 2018 
Amendment 4 
 
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16 REFERENCES 
Aguilera G, Rabadan-Diehl C. Vasopressinergic regulation of the hypothalamic-pituitary-
adrenal axis: implications for stress adaptation. Regul Pept. 2000;96(1-2):23-29. 
Amorim P, Lecrubier Y, Weiller E et al. DSM-III-R Psychotic Disorders: procedural validity of the 
M.I.N.I. International Neuropsychiatric Interview (M.I.N.I.). Concordance and causes for 
discordance with the CIDI. European Psychiatry. 1998; 13:26-34. 
Bromet E, Andrade L H, Hwang I, et al. Cross-national epidemiology of DSM-IV major 
depressive episode. BMC Med. 2011;9:90. 
Chandler G M, Iosifescu D V, Pollack M H, et al. RESEARCH: Validation of the Massachusetts 
General Hospital Antidepressant Treatment History Questionnaire (ATRQ). CNS Neurosci Ther. 
2010;16(5):322-5. 
Chen Y W, Dilsaver S C. Lifetime rates of suicide attempts among subjects with bipolar and 
unipolar disorders relative to subjects with other Axis I disorders. Biol Psychiatry. 
1996;39(10):896-899. 
Chylack LT, Wolfe JK, Singer DM et al. The Lens Opacities Classification System III. Arch 
Ophthalmol. 1993; 111: 831-6. 
de Winter R F, van Hemert A M, DeRijk R H, et al. Anxious-retarded depression: relation with 
plasma vasopressin and cortisol. Neuropsychopharmacology. 2003;28(1):140-147. 
WHO, Fact sheet N°369, October 2012; http://www.who.int/mediacentre/factsheets/fs369/en/ 
Griebel G, Stemmelin J, Gal C S, Soubrie P. Non-peptide vasopressin V1b receptor 
antagonists as potential drugs for the treatment of stress-related disorders. Curr Pharm Des. 
2005;11(12):1549-1559. 
Iijima M, Chaki S. An arginine vasopressin V1b antagonist, SSR149415 elicits antidepressant-
like effects in an olfactory bulbectomy model. Prog Neuropsychopharmacol Biol Psychiatry. 
2007;31(3):622-627. 
Inder W J, Donald R A, Prickett T C, et al. Arginine vasopressin is associated with 
hypercortisolemia and suicide attempts in depression. Biol Psychiatry. 1997;42(8):744-747. 
Lecrubier Y, Sheehan D, Weiller E et al. The M.I.N.I. International Neuropsychiatric Interview 
(M.I.N.I.) A Short Diagnostic Structured Interview: Reliability and Validity According to the CIDI. 

A Multicenter, Randomized, Double-blind, Placebo-controlled Study of the Safety 
and Efficacy of TS-121 as an Adjunctive Treatment for Patients with Major 
Depressive Disorder with an Inadequate Response to Current Antidepressant 
Treatment 
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European Psychiatry. 1997; 12: 224-231. 
Lolait S J, O'Carroll A M, Mahan L C, et al. Extrapituitary expression of the rat V1b vasopressin 
receptor gene. Proc Natl Acad Sci U S A. 1995;92(15):6783-6787. 
Pedrelli P, Blais M A, Alpert J E, et al. Reliability and validity of the Symptoms of Depression 
Questionnaire (SDQ). CNS Spectr. 2014;19(6):535-46. 
Rush A J, Trivedi M H, Wisniewski S R, et al. Acute and longer-term outcomes in depressed 
outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 
2006;163(11):1905-1917. 
Serradeil-Le Gal C, Wagnon J, Simiand J, et al. Characterization of (2S,4R)-1-[5-chloro-1- 
[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxy-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-
hydroxy-N,N-dimethyl-2-pyrrolidine carboxamide (SSR149415), a selective and orally active 
vasopressin V1b receptor antagonist. J Pharmacol Exp Ther. 2002a;300(3):1122-1130. 
Serradeil-Le Gal C, Wagnon J, Valette G, et al. Nonpeptide vasopressin receptor antagonists: 
development of selective and orally active V1a, V2 and V1b receptor ligands. Prog Brain Res. 
2002b;139:197-210. 
Sheehan DV, Lecrubier Y, Harnett-Sheehan K et al. Reliability and Validity of the M.I.N.I. 
International Neuropsychiatric Interview (M.I.N.I.): According to the SCID-P. European 
Psychiatry. 1997; 12:232-241. 
Sheehan DV, Lecrubier Y, Harnett-Sheehan K et al. The M.I.N.I. International Neuropsychiatric 
Interview (M.I.N.I.): The Development and Validation of a Structured Diagnostic Psychiatric 
Interview. J. Clin Psychiatry, 1998;59(suppl 20):22-33. 
Vale W, Spiess J, Rivier C, Rivier J. Characterization of a 41-residue ovine hypothalamic 
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van Londen L, Goekoop J G, van Kempen G M, et al. Plasma levels of arginine vasopressin 
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A Multicenter, Randomized, Double-blind, Placebo-controlled Study of the Safety 
and Efficacy of TS-121 as an Adjunctive Treatment for Patients with Major 
Depressive Disorder with an Inadequate Response to Current Antidepressant 
Treatment 
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17 APPENDIX 1: Excluded CYP3A4 Concomitant Medications 
Strong
Moderate
boceprevir
aprepitant
cobicistat
cimetidine
conivaptan
ciprofloxacin
danoprevir and ritonavir
clotrimazole
elvitegravir and ritonavir
crizotinib
grapefruit juice
cyclosporine
indinavir and ritonavir
dronedarone
itraconazole
erythromycin
ketoconazole
fluconazole
lopinavir and ritonavir
fluvoxamine
paritaprevir and ritonavir and (ombitasvir and/or dasabuvir)
imatinib
posaconazole
tofisopam
ritonavir
verapamil
saquinavir and ritonavir
telaprevir
tipranavir and ritonavir
troleandomycin
voriconazole
carbamazepine
bosentan
enzalutamide
efavirenz
mitotane
etravirine
phenytoin
modafinil
rifampin
St. John’s wort
(List updated by FDA on 9/26/2016)
INHIBITORS
INDUCERS
 
Strong Inhibitors: drugs that increase the AUC of sensitive index substrates of a given 
metabolic pathway ≥5-fold 
Moderate inhibitors: drugs that increase the AUC of sensitive index substrates of a given 
metabolic pathway ≥2 to <5-fold 
Strong Inducers: drugs that decreases the AUC of sensitive index substrates of a given 
metabolic pathway by ≥80% 
Moderate Inducers: drugs that decreases the AUC of sensitive index substrates of a given 
metabolic pathway by ≥50% to <80% 
 
Refer to the following website for details/updates: 
[FDA Website] Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeli
ng/ucm093664.htm#inVivo