Clinical trial NCT03093025
Conditions: Major Depressive Disorder
Keywords: Major Depressive Disorder Adjunctive Treatment
Sponsor: Taisho Pharmaceutical R&D Inc.
Start date: 2017-07-03; Completion date: 2018-12-04
Enrollment: 51 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the safety, tolerability, and efficacy of TS-121 as an adjunctive treatment for patients with major depressive disorder with an inadequate response to current antidepressant Treatment (SSRI, SNRI or bupropion).

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None
Interventions: intervention 1: TS-121 10 mg intervention 2: TS-121 50 mg intervention 3: Placebo
Intervention descriptions: intervention 1: Orally taken once daily intervention 2: Orally taken once daily intervention 3: Orally taken once daily

Protocol documents:
Prot_000.pdf: 
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 
TS121-US201 
Apr 23, 2018 
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Taisho Pharmaceutical R&D Inc. 
 
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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 
TS121-US201 
Apr 23, 2018 
Amendment 4 
 
Taisho Pharmaceutical R&D Inc. 
 
Confidential 
Page 8 of 72 
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 
TS121-US201 
Apr 23, 2018 
Amendment 4 
 
Taisho Pharmaceutical R&D Inc. 
 
Confidential 
Page 11 of 72 
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 
Apr 23, 2018 
Amendment 4 
 
Taisho Pharmaceutical R&D Inc. 
 
Confidential 
Page 12 of 72 
• 
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 
TS121-US201 
Apr 23, 2018 
Amendment 4 
 
Taisho Pharmaceutical R&D Inc. 
 
Confidential 
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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 
Apr 23, 2018 
Amendment 4 
 
Taisho Pharmaceutical R&D Inc. 
 
Confidential 
Page 14 of 72 
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 
Amendment 4 
 
Taisho Pharmaceutical R&D Inc. 
 
Confidential 
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 
Apr 23, 2018 
Amendment 4 
 
Taisho Pharmaceutical R&D Inc. 
 
Confidential 
Page 16 of 72 
 
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 
TS121-US201 
Apr 23, 2018 
Amendment 4 
 
Taisho Pharmaceutical R&D Inc. 
 
Confidential 
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 
Apr 23, 2018 
Amendment 4 
 
Taisho Pharmaceutical R&D Inc. 
 
Confidential 
Page 18 of 72 
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 
TS121-US201 
Apr 23, 2018 
Amendment 4 
 
Taisho Pharmaceutical R&D Inc. 
 
Confidential 
Page 19 of 72 
 
 
 
 
 
 
 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 


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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 


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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 


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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 


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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. 


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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) 


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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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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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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.  


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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. 
 
 


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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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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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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 


A Multicenter, Randomized, Double-blind, Placebo-controlled Study of the Safety and Efficacy of TS-121 as an Adjunctive Treatment for 
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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 


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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.   


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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. 


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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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 
TS121-US201 
Apr 23, 2018 
Amendment 4 
 
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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 
TS121-US201 
Apr 23, 2018 
Amendment 4 
 
Taisho Pharmaceutical R&D Inc.                                                    Confidential 
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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 
TS121-US201 
Apr 23, 2018 
Amendment 4 
 
Taisho Pharmaceutical R&D Inc.                                                    Confidential 
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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 
TS121-US201 
Apr 23, 2018 
Amendment 4 
 
Taisho Pharmaceutical R&D Inc.                                                    Confidential 
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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 
TS121-US201 
Apr 23, 2018 
Amendment 4 
 
Taisho Pharmaceutical R&D Inc.                                                    Confidential 
Page 68 of 72 
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 
TS121-US201 
Apr 23, 2018 
Amendment 4 
 
Taisho Pharmaceutical R&D Inc.                                                    Confidential 
Page 69 of 72 
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 
TS121-US201 
Apr 23, 2018 
Amendment 4 
 
Taisho Pharmaceutical R&D Inc.                                                    Confidential 
Page 70 of 72 
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 
TS121-US201 
Apr 23, 2018 
Amendment 4 
 
Taisho Pharmaceutical R&D Inc.                                                    Confidential 
Page 71 of 72 
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 
peptide 
that 
stimulates 
secretion 
of 
corticotropin 
and 
beta-endorphin. 
Science. 
1981;213(4514):1394-1397. 
van Londen L, Goekoop J G, van Kempen G M, et al. Plasma levels of arginine vasopressin 
elevated in patients with major depression. Neuropsychopharmacology. 1997;17(4):284-292. 


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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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   

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
Taisho Pharmaceutical R&D Inc. 
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 
Version: Final 2.0 
Date: 18 Dec 2018 
NCT03093025


 
Statistical Analysis Plan 
Taisho Pharmaceutical R&D Inc. 
Protocol TS121-US201 
 Statistical Analysis Plan (SAP) 
Final 2.0 
 
 
18 Dec 2018 
CONFIDENTIAL 
 
 
 
Page 2 of 63 
Revision history 
Draft 1: 
30 Jun 2017 
Draft 2: 
 08 Aug 2017  
Draft 3: 
 16 Oct 2017  
Draft 4: 
 04 Jan 2018 
Final 1:  
21 Feb 2018 
Final 2: 
18 Dec 2018 
update per amended protocol, address missing values and local 
hematology results 
 
 
 
 


 
Statistical Analysis Plan 
Taisho Pharmaceutical R&D Inc. 
Protocol TS121-US201 
 Statistical Analysis Plan (SAP) 
Final 2.0 
 
 
18 Dec 2018 
CONFIDENTIAL 
 
 
 
Page 3 of 63 
SIGNATURE PAGE - TAISHO PHARMACEUTICAL R&D INC. 
Declaration 
Upon review, the undersigned approves the statistical analyses plan. The analysis methods and data 
presentation are acceptable. 
 
 
 
 
 
Date (dd mmm yyyy) 
 
 
 


 
Statistical Analysis Plan 
Taisho Pharmaceutical R&D Inc. 
Protocol TS121-US201 
 Statistical Analysis Plan (SAP) 
Final 2.0 
 
 
18 Dec 2018 
CONFIDENTIAL 
 
 
 
Page 4 of 63 
SIGNATURE PAGE - 
 
Declaration 
This Statistical Analysis Plan is authored and issued by: 
 
 
 
 
 
Date (dd mmm yyyy) 
 
 
 


 
Statistical Analysis Plan 
Taisho Pharmaceutical R&D Inc. 
Protocol TS121-US201 
 Statistical Analysis Plan (SAP) 
Final 2.0 
 
 
18 Dec 2018 
CONFIDENTIAL 
 
 
 
Page 5 of 63 
TABLE OF CONTENTS 
SIGNATURE PAGE - TAISHO PHARMACEUTICAL R&D INC. ............................................ 3 
SIGNATURE PAGE - 
 .................................................................................................. 4 
TABLE OF CONTENTS ................................................................................................................ 5 
List of Tables ...................................................................................................................... 8 
List of Figures .................................................................................................................... 8 
ABBREVIATIONS AND DEFINITIONS ..................................................................................... 9 
Statistical Analysis Plan ................................................................................................... 12 
Amended Statistical Analysis Plan .................................................................................. 12 
1. 
OVERVIEW OF THE STUDY ....................................................................................... 13 
2. 
STUDY OBJECTIVES AND ENDPOINTS ................................................................... 15 
2.1 
Primary Objectives .............................................................................................. 15 
2.2 
Exploratory Objective ......................................................................................... 15 
2.3 
Primary Efficacy Endpoint ................................................................................. 15 
2.4 
Secondary Efficacy Endpoint ............................................................................. 15 
2.5 
Exploratory Endpoint .......................................................................................... 16 
3. 
STUDY DESIGN ............................................................................................................. 16 
3.1 
Study Procedures and Observations .................................................................... 16 
4. 
STUDY POPULATION .................................................................................................. 20 
5. 
STATISTICAL BASIS FOR SAMPLE SIZE ................................................................. 20 
6. 
STATISTICAL ANALYSIS CONVENTIONS .............................................................. 20 
6.1 
Analysis Variables, Criteria for Evaluation ........................................................ 20 
6.1.1 
Demographic and Background Variables ........................................................ 20 
6.1.2 
Screening Mental Health Assessments ............................................................ 21 
6.1.2.1 
MINI-International Neuropsychiatric Interview (MINI) ................. 21 
6.1.2.2 
17 items Hamilton Rating Scale (HAM-D) ..................................... 22 
6.1.2.3 
SAFER Interview ............................................................................. 22 
6.1.3 
Safety Variables .............................................................................................. 22 
6.1.3.1 
Adverse Events ................................................................................ 23 
6.1.3.2 
Clinical Laboratory Tests ................................................................. 24 
6.1.3.3 
Vital Signs ........................................................................................ 24 
6.1.3.4 
Electrocardiograms .......................................................................... 24 
6.1.3.5 
Weight .............................................................................................. 25 
6.1.3.6 
Physical and Neurological Examination .......................................... 25 
6.1.3.7 
Ophthalmological Examination ....................................................... 25 
6.1.3.8 
Columbia Suicidal Severity Rating Scale (C-SSRS) ....................... 25 
6.1.3.9 
Exploratory Safety ........................................................................... 26 
6.1.4 
Treatment Compliance .................................................................................... 26 
6.1.5 
Pharmacokinetic Variables and Pharmacogenomic Blood Sampling ............. 27 


 
Statistical Analysis Plan 
Taisho Pharmaceutical R&D Inc. 
Protocol TS121-US201 
 Statistical Analysis Plan (SAP) 
Final 2.0 
 
 
18 Dec 2018 
CONFIDENTIAL 
 
 
 
Page 6 of 63 
6.1.6 
Pharmacodynamic Variables ........................................................................... 27 
6.1.7 
Efficacy Variables ........................................................................................... 28 
6.1.7.1 
Montgomery-Asberg Depression Rating Scale (MADRS) .............. 28 
6.1.7.2 
Clinical Global Impressions - Severity (CGI-S) and Improvement 
(CGI-I) Scales .................................................................................. 29 
6.1.7.3 
Hamilton Anxiety Scale (HAM-A) .................................................. 29 
6.1.7.4 
Symptoms of Depression Questionnaire (SDQ) .............................. 29 
6.1.7.5 
Handling of Individual Missing Items ............................................. 29 
6.2 
Data Sets Analyzed ............................................................................................. 29 
6.2.1 
Safety Analysis Population ............................................................................. 29 
6.2.2 
Intent to Treat Population ................................................................................ 29 
6.2.3 
Exploratory PD Analysis Population .............................................................. 30 
6.2.4 
Pharmacokinetic (PK) Analysis Population .................................................... 30 
6.3 
Statistical Analysis Methods ............................................................................... 30 
6.3.1 
Listings and Descriptive Statistics .................................................................. 30 
6.3.2 
Statistical Significance Level .......................................................................... 31 
6.3.3 
Software .......................................................................................................... 31 
6.3.4 
Missing Data ................................................................................................... 31 
6.3.5 
Interim Analysis .............................................................................................. 32 
6.3.6 
Blinded Efficacy Review ................................................................................ 32 
6.3.7 
Randomization Schema and Codes ................................................................. 32 
6.3.8 
Documentation of Statistical Methods ............................................................ 32 
6.3.9 
Patient Disposition .......................................................................................... 32 
6.3.10 
Protocol Deviations and Analysis Populations ............................................... 33 
6.3.11 
Demographic Data and Baseline Data ............................................................. 33 
6.3.11.1 Demographics .................................................................................. 33 
6.3.11.2 Hamilton Depression Scale (HAM-D) ............................................. 33 
6.3.11.3 Baseline Major Depressive Disorder Characteristics ....................... 34 
6.3.11.4 Medical and Psychiatric History ...................................................... 34 
6.3.11.5 Concomitant Medication .................................................................. 34 
6.3.11.6 Screening Laboratory Tests ............................................................. 34 
6.3.12 
Study Drug Exposure and Pharmacokinetic Concentration Data .................... 35 
6.3.12.1 Exposure to the Investigational Medicinal Product ......................... 35 
6.3.12.2 Pharmacokinetic Concentrations ..................................................... 35 
6.3.13 
Efficacy Analysis ............................................................................................ 35 
6.3.13.1 Primary Endpoint ............................................................................. 35 
6.3.13.2 Secondary Endpoints ....................................................................... 37 
6.3.13.3 Multiple Imputation for Missing Visits ........................................... 38 
6.3.14 
Pharmacodynamic (PD) Analysis ................................................................... 40 
6.3.14.1 Plasma Copeptin .............................................................................. 40 
6.3.14.2 Inflammatory Markers ..................................................................... 41 
6.3.14.3 Cortisol ............................................................................................. 41 
6.3.15 
Subgroup Analysis for Primary Endpoint ....................................................... 42 
6.3.16 
Safety Analysis ................................................................................................ 42 
6.3.16.1 Adverse Events ................................................................................ 43 
6.3.16.2 Clinical Safety Laboratory Tests (Biochemistry, Hematology and 
Urinalysis) ........................................................................................ 44 


 
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6.3.16.3 Vital Signs ........................................................................................ 46 
6.3.16.4 12-Lead Electrocardiogram ............................................................. 46 
6.3.16.5 Body Weight .................................................................................... 47 
6.3.16.6 Ophthalmological Examinations ...................................................... 47 
6.3.16.7 Columbia Suicidal Severity Rating Scale (C-SSRS) ....................... 47 
7. 
REFERENCES ................................................................................................................. 48 
APPENDIX A: CLINICALLY SIGNIFICANT LABORATORY OUTLIER CRITERIA ......... 60 
APPENDIX B: CRITERIA FOR CLINICALLY NOTEWORTHY LABORATORY CHANGES
 .......................................................................................................................................... 61 
APPENDIX C: CLASSIFICATION OF ADVERSE EVENTS ....................................................... 62 
 
 
 


 
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List of Tables 
Table 1 
Study Procedures and Observations ......................................................................... 17 
Table 2 
Tables to be Included in Section 14 of the Clinical Study Report ........................... 49 
Table 3 
Figures to be Included in Section 14 of the Clinical Study Report .......................... 53 
Table 4  
Listings to be Included in Section 16 of the Clinical Study Report ......................... 56 
  
List of Figures 
Figure 1. Study Design .................................................................................................................. 15 
Figure 2. Pharmacodynamic Schedule .......................................................................................... 28 
 


 
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ABBREVIATIONS AND DEFINITIONS 
Term 
Definition 
ADT 
Antidepressant therapy 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATRQ 
Antidepressant Treatment Response Questionnaire 
BLQ 
Below the lower limit of quantification 
BMI 
Body mass index 
bpm 
Beats per minute 
BUN 
Blood urea nitrogen 
C 
Cortical cataract 
CDISC 
Clinical Data Interchange Standards Consortium 
CFR 
Code of federal regulations 
CGI-I, S 
Clinical global impression- Improvement, -Severity 
CI 
Confidence interval 
Cl 
Chloride 
CPK 
Creatine phosphokinase 
CRF 
Case report form 
CS 
Clinically significant 
CSP 
Clinical study protocol 
CSR 
Clinical study report 
C-SSRS 
Columbia suicidality severity rating scale 
CV 
Coefficient of variation 
ECG 
Electrocardiogram 
eDISH 
Evaluation of drug-induced serious hepatoxicity 
EOCS 
Event of clinical significance 
EOT 
End of treatment 
ET 
Early termination 
ETDRS 
Early treatment diabetic retinopathy study 
FDA 
Food and drug administration 
GGT 
Gamma glutamyltransferase 
HAM-A 
Hamilton anxiety scale 
HAM-D 
17 items Hamilton depression scale 
HDL 
High-density lipoprotein 
HIV 
Human immunodeficiency virus 
HPA 
Hypothalamus-pituitary-adrenal 


 
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HS-CRP 
High sensitivity C-reactive protein 
IL 
Interleukin 
IRT 
Interactive response technology 
IWRS 
Interactive web response system 
K 
Potassium 
kg 
Kilograms 
LDH 
Lactate dehydrogenase 
LDL 
Low-density lipoprotein 
LLOQ 
Lower limit of quantification 
LOCS 
Lens opacities classification system 
LogMAR 
Logarithm of the minimum angle of resolution 
MADRS 
Montgomery-Asberg depression rating scale 
MAR 
Missing at random 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MDD 
Major depressive disorder 
MDMA 
3,4-methylenedioxy-N-methylamphetamine 
MedDRA 
Medical dictionary for regulatory activities 
MGH 
Massachusetts general hospital 
MI 
Multiple imputation 
MINI 
MINI-International neuropsychiatric Interview 
mg 
Milligrams 
Mg 
Magnesium 
mL 
Milliliter 
mmHg 
Millimeter of mercury 
MMRM 
Mixed model repeated measures analysis 
msec 
Milliseconds 
Na 
Sodium 
NC 
Nuclear color 
NCS 
Not clinically significant 
NK 
Not known 
NO 
Nuclear opalescence 
P 
Posterior subcapsular cataract 
PCP 
Phencyclidine 
PD 
Pharmacodynamics 
PGx 
Pharmacogenomics 
PK 
Pharmacokinetics 


 
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PT 
Preferred term 
QTcB 
Bazett’s corrected QT interval 
QTcF 
Fridericia’s corrected QT interval 
RBC 
Red blood cell 
RDW 
Red cell distribution width 
SAE 
Serious adverse event 
SAFER 
State versus trait; Assessable; Face validity; Ecological validity; and Rule 
of three Ps (pervasive, persistent, and pathological) 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SDQ 
Symptoms of depression questionnaire 
SDTM 
Study Data Tabulation Model 
SE 
Standard error 
sec 
Seconds 
SGOT 
Serum glutamic-oxaloacetic transaminase 
SGPT 
Serum glutamic-pyruvic transaminase 
SI 
Standard international 
SNRI 
Serotonin norepinephrine reuptake inhibitor 
SOC 
System organ class 
SSRI 
Selective serotonin reuptake inhibitor 
TBL 
Total bilirubin 
TEAE 
Treatment emergent AE 
THC 
Tetrahydrocannabinol 
 
 
TNF-α 
Tumor necrosis factor alpha 
WBC 
White blood cell 
WHO-DD 
World Health Organization - Drug Dictionary 
WHODDE 
World Health Organization - Drug Dictionary Enhanced 
 
 
 
 


 
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Statistical Analysis Plan 
The Statistical Analysis Plan (SAP) details the statistical methodology to be used in analyzing study 
data and outlines the statistical programming specifications, tables, figures, and listings. It describes 
the variables and populations, anticipated data transformations and manipulations, and other details 
of the analyses not provided in the clinical study protocol (CSP).  
The analyses described are based on the CSP Amendment 2 dated Mar 7 2017, Amendment 3 dated 
Oct 18 2017 and Amendment 4 dated Apr 23 2018. Table and listing shells, in an appended 
document, are based on the blank case report form (CRF) with date 11-Jul-2017 [Study Version 4.1 
Date 28 Aug 2018]. Statistical programming will be performed using Clinical Data Interchange 
Standards Consortium (CDISC) Study Data Tabulation Model (SDTM) data mapped as defined in 
the Data Management Plan (Version 1.0, 7 April 2017 date of final signature) and mapping 
specification document. 
The SAP describes the statistical analysis as it is foreseen when the study is being planned and will 
be finalized prior to database lock. 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 study and the results obtained will be used to estimate the effect size and to 
support future studies. 
Amended Statistical Analysis Plan 
The CSP Amendment 4 included changes to patient inclusion and exclusion criteria and to 
prohibited/ restricted concomitant therapy. Data collection and reporting specifications were 
updated for worsening of depression, medication error or potential overdose and events of clinical 
significance. Changes between CSP Amendment 3 to 4 with specific impact in data presentation 
were 
• Section 9.2.7.8 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. 
• Section 10.5.2.1 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) 


 
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• Section 11.3 Event of Clinical Significance (EOCS): Suicidal ideation and behavior, and lens 
opacity are considered as EOCS 
• Sections 8.5 and 11.4 Patients with a CGI-I score of 6 or 7 at any time during the study will 
also be evaluated for possible discontinuation from the study. In the case of CGI-I scores of 6 
or 7, the investigator will write a note justifying either discontinuation or continuation of the 
participant in the study. A CGI-I score of 6 or 7 at any time during the study should be 
considered as an AE of worsening of depression. 
The amended SAP addresses missing data of two types: missing item responses for a given rating 
scale for calculation of the scale’s total scores and missing visits data in the mixed model repeated 
measures analysis (MMRM). The amended SAP also describes presentation of local laboratory 
hematology data. 
1. 
OVERVIEW OF THE STUDY 
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. The objectives are to compare the safety, 
efficacy, pharmacokinetics, and exploratory pharmacodynamics of TS-121 (drug substance code 
) to placebo as an adjunctive treatment for patients with major depressive disorder 
(MDD) (Figure 1). Patients must remain on the same single antidepressant, selective serotonin 
reuptake inhibitor (SSRI), serotonin norepinephrine reuptake inhibitor (SNRI), or bupropion for 
6 weeks, with a fixed dose for 4 weeks prior to screening. Patients will remain on this fixed dose 
of their current antidepressant therapy (ADT) 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. 
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 


 
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assessment and inventory of symptoms: State versus Trait; Assessability; Face validity; Ecological 
validity; and Rule of three Ps (pervasive, persistent, and pathological) (SAFER) 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. An ophthalmologist will 
conduct a thorough eye examination (including slit lamp under mydriasis). 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. 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. 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 ADT. 
Visits 4 (Week 2) and 5 (Week 4): Patients will return to the site for safety and efficacy assessments, 
dosing compliance, drug accountability and dispensing of a new supply of investigational product. 
Compliance with the dosing schedule will be assessed. Visit 5 and Visit 6 will be scheduled. 
Visit 6 (Week 6): Patients will return to the site for end-of-treatment safety (including 
ophthalmological examination), efficacy, pharmacokinetic, and exploratory pharmacodynamic 
assessments and final drug accountability. 
End of Treatment (EOT): The EOT visit is Visit 6 for patients who complete treatment and is the 
last assessment closest to the last treatment day for patients who discontinued from treatment early 
or failed to complete Visit 6. 
Visit 7 (Follow-up): Patients will return to the site for a follow-up evaluation of safety (including 
ophthalmological examination) and efficacy assessments approximately two weeks after Visit 6. 
ET Follow-up:  The visit completed approximately 14 days after the patient’s last dose for patients 
who discontinued from treatment early. 


 
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Figure 1. Study Design 
2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
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 
2.2 
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 
2.3 
Primary Efficacy Endpoint 
• Change in MADRS total score from Visit 3 (Baseline assessment) to Week 6/EOT 
2.4 
Secondary Efficacy Endpoint 
• Change from Visit 3 to Week 6/EOT for CGI-S, SDQ, and HAM-A total scores 


 
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• Percentage of CGI-I improvers (“Very much improved” or “Much improved”) 
• Percentage of MADRS responders (≥ 50% reduction in total score) 
2.5 
Exploratory Endpoint 
• Pharmacokinetic data from Visit 6 may be explored relative to study results (mental health 
assessments and/or laboratory values) 
• Change from Visit 3 to Visit 6 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) 
3. 
STUDY DESIGN 
3.1 
Study Procedures and Observations 
Refer to Table 1. 


 
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Table 1 
Study Procedures and Observations 




 
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Table 1 
Study Procedures and Observations 
 
* 
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: Must be conducted by an ophthalmologist. 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 CSP Section 8.1.3, Treatment Compliance). 
 
 
 


 
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4. 
STUDY POPULATION 
It is estimated that the study will screen approximately 300 patients in order to randomize 
approximately 180 MDD patients. 
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. 
5. 
STATISTICAL BASIS FOR SAMPLE SIZE 
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 other MDD trials, and will allow trends to be 
detected with regards to efficacy and PD effects of TS-121 in this patient population. 
6. 
STATISTICAL ANALYSIS CONVENTIONS 
6.1 
Analysis Variables, Criteria for Evaluation 
6.1.1 
Demographic and Background Variables 
The following patient history, demographic and anthropometric information will be recorded: 
• Date of informed consent 
• Age calculated as (date of informed consent – date of birth)/365.25. Date of birth will be 
collected using interactive response technology (IRT) of the IWRS. 
• Gender 
• Ethnicity 
• Race 
• Height and weight 
• BMI 


 
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• Medical and/or psychiatric history (within the past 3 years)  
New or existing medical or psychiatric conditions reported prior to first administration of 
the investigational product [from the placebo lead-in period ] will be captured as medical 
history, whereas any new, untoward, or worsening medical or psychiatric conditions 
reported after first administration of the investigational product during the placebo lead-in 
period will be captured as adverse events. 
• Concomitant medications 
All medications used during the study will be recorded. Prior ADTs other than a current 
SSRI/SNRI/bupropion and prohibited medications that might influence HPA axis function 
used within 3 months of Visit 1 will also be recorded. 
• Screening laboratory test results will be recorded  
 Serology: Hepatitis B surface antigen (HBsAg), HIV screening and serum antibodies 
against Hepatitis C virus (anti-HCV antibody) 
 Urine drug screen: The following controlled substances will be tested at Visit 1 and at 
Visit 
3: 
amphetamine, 
barbiturates, 
benzodiazepines, 
cocaine, 
methadone, 
morphine/opiates, methamphetamine, marijuana (THC), phencyclidine (PCP), and 
ecstasy (MDMA).  
 Pregnancy: For all female participants, urine pregnancy samples will be tested at 
specified visits indicated in the Schedule of Procedures, Table 1.  
All medical history will be coded using Version 19.1 of the Medical Dictionary for Regulatory 
Activities (MedDRA). 
Concomitant medications will be coded using the World Health Organization Drug Dictionary 
Enhanced (WHODDE September 2016). 
6.1.2 
Screening Mental Health Assessments 
6.1.2.1 MINI-International 
Neuropsychiatric 
Interview 
(MINI) 
Results of the MINI (Version 7.0.2) administered at Visit 1 will be recorded in the patient’s 
source records only. 


 
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6.1.2.2 17 items Hamilton Rating Scale (HAM-D) 
Results of the HAM-D (October 2010 for the DUAG-8 project) conducted by the trained site 
rater at Visit 1 and of the remote HAM-D conducted by central raters at Visit 1.1 and Visit 2.1 
will be captured. 
6.1.2.3 SAFER Interview 
The interview conducted at Visit 1.1 includes the SAFER inventory of symptoms, the HAM-D 
and the MGH-ATRQ. Previous and current ADT information collected using the MGH-ATRQ 
will be recorded with prior and concomitant medications. Start date of MDD current episode 
will be recorded. 
6.1.3 
Safety Variables 
Safety and tolerability will be assessed from the time the patient is administered the 
investigational product during the placebo lead-in period through the final study procedure as 
specified in the Schedule of Procedures, Table 1. 
Safety measures include: 
• Adverse events  
• Clinical laboratory tests (hematology, biochemistry and urinalysis) 
• Vital signs 
• 12-Lead ECG 
• Body weight 
• Routine physical examination  
• Comprehensive neurological examination 
• Ophthalmological examination 
• Columbia Suicide Severity Rating Scales (C-SSRS) 
• Exploratory Safety Assessments 


 
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6.1.3.1 Adverse Events 
An adverse event (AE) is defined as 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). AEs also 
include an intentional or accidental overdose, whether or not it is associated with symptoms. 
An overdose is defined as ingestion of the investigational product (accidental or intentional) 
more than 3 capsules in the same calendar day. 
AEs will be recorded after the first administration of the investigational product in the placebo 
lead-in period through follow-up. AEs with onset date and time (if available) after the first 
administration of randomized treatment will be considered treatment emergent AE (TEAE). 
Any AEs with incomplete start and end dates/times will be treated as follows: 
• Adverse events with unknown start and/or end times (but where the date is known) will be 
imputed as post-dose for events on first treatment day of placebo lead-in or randomized 
treatment or with a time of 00:00 for other days. The missing time will be shown blank in 
the listings. 
• Adverse events with incomplete start day and known month will be imputed as the later of: 
day of first placebo lead-in dose or first randomized dose started in that month or first of the 
month. Missing day will be printed -- in the listings. 
• Adverse events with incomplete start dates missing month and day will be considered as the 
later of: day of first placebo lead-in dose or first randomized dose started in that year or 
January 1. Missing month and day will be printed ----- in the listings. 
• Adverse events with completely unknown start dates will be considered as treatment 
emergent for the tabulations and the missing dates will be shown as --------- in the listings. 
Details of AE classification for severity (mild, moderate or severe), action taken and 
relationship to test drug (not related, possibly related, probably related and definitely related) 
are provided in Appendix C. All AEs will be coded using MedDRA Version 19.1. 


 
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Serious Adverse Event 
AEs that result in death, life-threatening, requiring inpatient hospitalization or prolongation of 
existing hospitalization, persistent or significant disability/incapacity, a congenital anomaly or 
birth defect, or any other important medical event, as defined in the CSP Section 11.2.1, will be 
recorded as serious adverse events (SAE). 
Event of Clinical Significance 
AEs that are suicidal ideation and behavior or lens opacity, as defined in the CSP Section 11.3, 
will be recorded as events of clinical significant (EOCS). 
6.1.3.2 Clinical Laboratory Tests 
Laboratory tests listed in the CSP Section 9.2.7.8 will be performed at times indicated in 
Schedule of Procedures, Table 1. 
6.1.3.3 Vital Signs 
Vital signs will include systolic and diastolic blood pressure (mmHg), pulse rate (bpm) and oral 
temperature (°C) and will be collected at specified time points indicated in the Schedule of 
Procedures, Table 1. 
6.1.3.4 Electrocardiograms 
Electrocardiograms will be assessed for  
• Ventricular rate (beats per minute [bpm]) 
• RR interval (msec) 
• PR interval (msec) 
• QRS duration (msec) 
• QT interval (msec) 
• QT interval corrected using the Bazett correction formula (QTcB) (msec) 
• QT interval corrected using the Fridericia correction formula (QTcF) (msec) 
The ECG will be evaluated by the Investigator as ‘Normal’, ‘Abnormal, NCS’ or ‘Abnormal, 
CS’. Any abnormal CS ECG will be reported as an AE. 


 
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6.1.3.5 Weight 
Body weight will be recorded in kilograms (kg) at specified time points indicated in the 
Schedule of Procedures, Table 1. 
6.1.3.6 Physical and Neurological Examination 
Physical and neurological examinations will be performed and recorded as described in the 
Schedule of Procedures, Table 1.  
The results will 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 (CSP 
Section 11.1) will be captured as AEs. 
6.1.3.7 Ophthalmological Examination 
Ophthalmological examinations will include the following: 
• Best corrected visual acuity as measured with the ETDRS chart, and scored in LogMAR 
• Evaluation of the crystalline lens through a maximally dilated pupil using lens opacities 
classification system (LOCS III), including the following features; 
o Posterior subcapsular cataract (P) 
o Cortical cataract (C) 
o Nuclear opalescence (NO) 
o Nuclear color (NC) 
Events of clinical significance (EOCS) for ophthalmological findings, as defined in CSP Section 
11.3.2, will be recorded as AEs. 
6.1.3.8 Columbia Suicidal Severity Rating Scale (C-SSRS) 
C-SSRS (Screening, Version 1/14/09) which pertains to the previous 6 months will be 
administered at Visit 1, and then C-SSRS (Since Last Visit, Version 1/14/09) which pertains to 
changes since the last visit will be administered at Visits 3 through 7. 
At a minimum, responses to questions 1 (Wish to be Dead), 2 (Non-Specific Active Suicidal 
Thoughts) and suicidal behaviors will be recorded.  


 
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The suicidal ideation score is calculated as the maximum score of responses to the first 5 
questions.  
• Wish to be dead (positive response is scored 1) 
• Non-specific active suicidal thoughts (positive response is scored 2) 
• Active suicidal ideation with any methods (not plan) without intent to act (positive 
response is scored 3)  
• Active suicidal ideation with some intent to act, without specific plan (positive response is 
scored 4) 
• Active suicidal ideation with specific plan and intent (positive response is scored 5) 
The suicidal ideation score will be set Not Applicable (numeric score = 0) when Item 1 and Item 
2 responses are negative. An EOCS for suicidal ideation and behavior, as defined in CSP Section 
11.3.1, may be recorded for any patient who has a C-SSRS suicidal ideation score of 5 or a 
“yes” response for any of the C-SSRS suicidal behavior questions.  
The suicidal ideation intensity rating will be calculated as the sum of numbers endorsed on 5 
intensity items (Frequency, Duration, Controllability, Deterrents and Reasons for Ideation). 
6.1.3.9 Exploratory Safety 
Blood samples collected at visits indicated in the Schedule of Procedures will be stored at the 
central lab for possible exploratory safety assessments to be determined at a later stage based 
on the current understanding of toxicology. 
6.1.4 
Treatment Compliance 
Compliance will be monitored using the AiCure daily record of expected and actual medication 
taken. Any record reflecting that the daily dose was greater than expected will be noted as an 
overdose event but will be treated as only the expected daily dose (3 capsules) for calculation 
of compliance in each visit interval.  
Compliance over the treatment interval will be calculated as: 
Compliance (%) = 100 * Total number of days kept compliance (took 3 capsules per day)/ 
number of expected dosing days (The day after V3 to V6/ET visit day). 


 
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Treatment compliance will also be calculated for placebo lead-in, baseline to Week 2, Week 2 
to Week 4, and Week 4 to Week 6. Compliance will be calculated for any patient with at least 
one recorded dose in the interval.  
6.1.5 
Pharmacokinetic Variables and Pharmacogenomic Blood Sampling 
A single venous blood sample will be collected for determination of 
 
pharmacokinetics at Visit 6. Analysis of PGx data, if applicable, will be documented in a 
separate analysis plan. 
6.1.6 
Pharmacodynamic Variables 
This study will evaluate blood, urine, saliva and hair samples at specified time points indicated 
in the Schedule of Procedures, Table 1 for exploratory PD analysis, the results of which may 
guide in predicting TS-121 response in future trials. 
 


 
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Figure 2. Pharmacodynamic Schedule 
 
Samples for the following PD markers will be collected at visits indicated in Table 1 and Figure 
2:  
• Plasma Copeptin  
• Salivary Cortisol 
• Urine Cortisol 
• Hair Cortisol 
• Inflammatory Markers (TNF-α, IL-1, IL-6, HS-CRP) 
6.1.7 
Efficacy Variables 
Efficacy assessments will be performed at visits indicated in Table 1. The time frame for 
Montgomery-Asberg Depression Rating Scale (MADRS), Clinical Global Impressions - 
Severity (CGI-S) and Improvement (CGI-I) Scales, Hamilton Anxiety Scale (HAM-A) and 
Symptoms of Depression Questionnaire (SDQ) pertains to the previous 7 days. Assessments 
will be administered by a trained site rater. 
Questionnaire interviews will be captured by FDA 21 CFR Part 11 compliant electronic tablets. 
Results for each question of the HAM-D, MADRS, MGH-ATRQ and SAFER inventory will 
be captured through this tablet system. 
6.1.7.1 Montgomery-Asberg 
Depression 
Rating 
Scale 
(MADRS) 
Scoring information for MADRS is defined in Taisho TS121-US201 MADRS Version 1. 
Primary and secondary efficacy endpoints are based on MADRS total score change from 
baseline. The MADRS total score is calculated by summing the 10 item scores. The primary 
endpoint is change in MADRS total score from Visit 3 (Baseline) to Week 6/EOT and the 
secondary is percentage of MADRS responders, where a responder is defined as ≥ 50% 
reduction in total score from Baseline to Week 6/EOT. 


 
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6.1.7.2 Clinical Global Impressions - Severity (CGI-S) and 
Improvement (CGI-I) Scales 
Scoring information for CGI-S and CGI-I is defined in Taisho TS121-US201 CGI-S Version 1 
and Taisho TS121-US201 CGI-I Version 1, respectively. The secondary endpoint, percentage 
of CGI-I improvers, whereby a CGI-I improver is defined as patients with CGI-I score of 1 or 
2 (“Very much improved” or “Much improved”). 
6.1.7.3 Hamilton Anxiety Scale (HAM-A) 
Instructions for HAM-A administration and scoring are provided in HAM-A (SIGH-A, Version 
5/92). The HAM-A total score change from Baseline to Week 6/EOT is a secondary endpoint. 
6.1.7.4 Symptoms of Depression Questionnaire (SDQ) 
Scoring information for SDQ is defined in Taisho TS121-US201 SDQ Version 1. The SDQ 
total score is calculated by summing the scores of all 44 items. The SDQ total score change 
from Baseline to Week 6/EOT is a secondary endpoint. 
6.1.7.5 Handling of Individual Missing Items 
In case ≥ 25% of items used to calculate a total score for a given scale are missing for one patient 
and time point then the total scale score for that patient and time point will be considered 
missing. If < 25% of items are missing then the total score will be calculated as the mean of 
non-missing items multiplied by the total expected number of items and rounded to the nearest 
integer. 
6.2 
Data Sets Analyzed 
6.2.1 
Safety Analysis Population 
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). 
6.2.2 
Intent to Treat Population 
The Intent to Treat Population will include all patients who were randomized and received at 
least one dose of randomized treatment.  


 
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6.2.3 
Exploratory PD Analysis Population 
The exploratory PD analysis population will include all randomized patients who completed the 
baseline assessment of HPA axis and inflammatory biomarkers and have sufficient mental 
health assessments completed. Missing data will not be imputed and are to be excluded from 
the analysis. 
6.2.4 
Pharmacokinetic (PK) Analysis Population 
The PK analysis population will include all patients who were randomized and received 
randomized treatment 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 the occurrence of AEs that would invalidate the concentration 
measurements. 
Any data excluded will be described in the clinical study report (CSR).  
6.3 
Statistical Analysis Methods 
6.3.1 
Listings and Descriptive Statistics 
All original and derived parameters as well as population characteristics will be listed by subject 
number and described using summary statistics. Listings will be ordered by treatment group, 
subject number, date and time. Observations that are spurious (extreme relative to the majority 
of the data or difference from group median >1.5×[75th – 25th percentiles]) will be noted. These 
will not be altered or removed from any presentation of the data.  
Treatment order in summary tables will, in general, be TS-121 10 mg Group, TS-121 50 mg 
Group and Placebo Group. As appropriate, Total TS-121, Total Placebo Lead-in and Total 
Screened will also be summarized. Summaries of scheduled events will also be ordered by study 
period: As grouped in Table 1, screening will include Visit 1 and Visit 1.1 and extend from Day 
-28 through Day -2, placebo lead-in will include Visit 2 and Visit 2.1 and extend from Day 1 to 
Day 13 (±2), treatment period will include Visit 3 (Baseline), Visit 4, Visit 5 and Visit 6 or EOT 
and follow-up will include any visit or study day after Week 6/EOT. Frequency counts (number 
of patients [n]) and percentages will be reported for each qualitative variable. Descriptive 
statistics (n, arithmetic mean [mean], standard deviation [SD], standard error [SE], minimum, 


 
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median and maximum) will be calculated for each quantitative variable (unless otherwise 
stated).  
All statistical programming will use SDTM data and will be based on SDTM mapping rules for 
scheduled, unscheduled and repeat visits. No assessment or exclusions other than the mapping 
specifications will be performed for visits out of the planned visit window.  
Listings will include repeat and unscheduled measurements. 
The following rules will apply to repeat and unscheduled measurements in summary tables: 
• No more than one assessment per patient per time point will be used in the summary of each 
scheduled safety or efficacy endpoint. 
• If the repeated measurement occurs prior to the first dose of study drug for the treatment 
period, then the last obtained value of any repeated measurement will be used as baseline in 
the summary tables. 
• If the repeated measurement occurs after the first dose of study drug for the treatment period, 
then the first obtained value of any repeated measurements will be used in the summary 
tables. 
Unless specified otherwise, the baseline used for any change from baseline measurements will 
be the last measurement prior to the first dose of study drug for the treatment period. 
6.3.2 
Statistical Significance Level 
Any statistical test or confidence interval (CI) will be two-sided and will be performed at the 
5% level of significance, unless otherwise stated. No adjustment for multiple comparisons will 
be performed for calculation of CI or statistical significance. 
6.3.3 
Software 
All statistical analyses will be performed using SAS® Version 9.3 and Enterprise Guide Version 
7.15 or using SAS Version 9.4  
6.3.4 
Missing Data 
Rules for incomplete AE start and end dates/times are described in Section 6.1.3.1. Rules for 
handling missing efficacy items in calculating total scores are described in Section 6.1.7.5. No 
imputation of missing data will be performed for safety data or for the exploratory PD analysis. 


 
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In case an unscheduled clinical laboratory assessment was performed within the visit window 
for a missing assessment then the unscheduled assessment will be included in the visit summary. 
In these cases the unscheduled assessment closest to the scheduled time will be used. 
 Missing data are assumed to be missing at random (MAR). 
The primary endpoint for efficacy is Week 6/EOT. Efficacy assessments are not planned to be 
collected at early termination. The primary analysis will include all available efficacy 
assessments of the Intent to Treat Population.  The primary analysis will use MMRM, in which 
patients with no post baseline assessment are dropped from the model. A sensitivity analysis 
will assess the Week 6/EOT of each efficacy endpoint (MADRS total score, CGI, HAM-A total 
score and SDQ total score) based on a multiple imputation method using all patients with a 
baseline score, including patients with no post baseline assessment. 
6.3.5 
Interim Analysis 
No interim analysis is planned. 
6.3.6 
Blinded Efficacy Review 
Preliminary blind review of efficacy will be conducted prior to database lock. 
6.3.7 
Randomization Schema and Codes 
Subject number, randomization date and treatment will be listed [Listing 16.1.7].  
6.3.8 
Documentation of Statistical Methods 
In addition to this SAP, the record of statistical model calculations will be included in Section 
16.1.9 of the CSR.  
6.3.9 
Patient Disposition 
A record of IRT data, including subject number, placebo lead-in date, randomization date, 
treatment, first and last dose dates, screen/placebo lead-in fail date and primary reason, the 
completion status, the date of discontinuation and the reason for discontinuation of all screened 
patients will be listed. Unblinding date and reason will be listed if any unblinding event occurs 
[Listing 16.2.1.1]. The number of patients randomized, received the randomized treatment and 
the frequency and percentage of patients completing the study, patients withdrawing early, and 
primary reason for withdrawal will be summarized by treatment and overall for all randomized 


 
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patients [Table 14.1.1.1]. The number of patients entered placebo lead-in period and randomized 
or failed will be summarized by treatment and overall [Table 14.1.1.2]. An overall summary 
table of patients who signed informed consent with numbers of patients who screen failed prior 
to or after entering placebo lead-in, and reasons for failures will also be presented [Table 
14.1.1.3]. 
Disposition information will be presented in a flow diagram of number of patients screened, 
screen failures before start of placebo lead-in (Visit 2), placebo lead-in screen failures, patients 
randomized, patients dosed, reasons for any patient randomized but not dosed, total number of 
patients receiving double-blind treatment, number per treatment group starting double-blind 
treatment, number per treatment group of patients completing the study and summary counts, 
by treatment group, of the reasons that patients discontinued from the study [Figure 14.1.1]. 
6.3.10 
Protocol Deviations and Analysis Populations 
All protocol deviations will be recorded by the Investigator, incorporated to the mapped 
(SDTM) database and will be listed by subject number [Listing 16.2.2.1].  
Assignment to analysis populations and data exclusions for individual assessments and time 
points will be listed by subject number for the safety analysis population [Listing 16.2.3.1]. 
6.3.11 
Demographic Data and Baseline Data 
6.3.11.1 Demographics 
Demographics and baseline characteristics including date of informed consent, date of birth, 
age at informed consent date, sex, race, ethnicity, screening height, weight and BMI will be 
listed for the safety analysis population [Listing 16.2.4.1]. Age, sex, race, ethnicity, and 
screening height, weight and BMI will be summarized by treatment and overall for the safety 
analysis population [Table 14.1.2.1].  
6.3.11.2 Hamilton Depression Scale (HAM-D) 
The HAM-D total score and item scores from site and central raters will be listed for all screened 
patients [Listing 16.2.4.2.1]. HAM-D total score at Visits 1, 1.1 and 2.1 for screening will be 
summarized by treatment and overall for the Intent to Treat Population [Table 14.1.2.2]. It will 
be noted that the qualifying HAM-D total scale was changed in CSP amendment 4 from HAM-
D ≥ 21 to HAM-D ≥ 18 and Visit 1 and 1.1. 


 
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6.3.11.3 Baseline Major Depressive Disorder Characteristics 
Major depressive episode records from medical history will be listed with the calculated  
duration (months) of current depressive episode and duration from first MDD Diagnosis (years)  
[Listing 16.2.4.2.2] and presented in a summary table for the intent to treat population 
[Table 14.1.3].  The summary table will also present baseline MADRS total score and baseline 
HAM-A total score. 
6.3.11.4 Medical and Psychiatric History 
Any findings for medical and psychiatric history will be coded using MedDRA Version 19.1 
and will be listed by subject number for the safety analysis population. MedDRA system organ 
class (SOC) and preferred term (PT) where a condition or abnormality has been reported, will 
be listed for the safety analysis population [Listing 16.2.4.3].  
Medical history and psychiatric history will be presented in summary tables by treatment group 
and overall by SOC and PT for the safety analysis population [Table 14.1.4]. 
6.3.11.5 Concomitant Medication 
All concomitant medications for patients in the Safety Analysis Population will be listed with 
the identification number of any associated medical history or adverse event for the safety 
analysis population [Listing 16.2.4.4]. Prior and concomitant ADTs will be included in this 
listing and also listed separately [Listing 16.2.4.5]. The record of medications includes reported 
medication and WHO-DD preferred term. Concomitant medications and indications will be 
summarized by preferred term by treatment group and overall for the safety analysis population 
[Table 14.1.5]. Duration of current ADT will be summarized with baseline MDD characteristics 
[Table 14.1.3]. 
6.3.11.6 Screening Laboratory Tests 
Drug screening [Listing 16.2.4.6.1], screening serology [Listing 16.2.4.6.2] and pregnancy test 
results [Listing 16.2.4.6.3] will be listed for the safety analysis population. 


 
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6.3.12 
Study Drug Exposure and Pharmacokinetic Concentration Data 
6.3.12.1 Exposure to the Investigational Medicinal Product 
The record of dose compliance through the placebo lead-in period and treatment period will be 
listed [Listing 16.2.5.1] and summarized [Table 14.2.1] for the safety analysis population. 
6.3.12.2 Pharmacokinetic Concentrations  
The individual plasma concentration of 
, the date and time of last preceding dose, 
actual sampling date and elapsed time will be listed for the PK analysis population 
[Listing 16.2.5.2].  
Plasma 
 concentrations will be presented in a scatter plot figure representing 
concentration versus actual elapsed time post dose and different symbols for TS-121 10 mg or 
TS-121 50 mg treatment groups [Figure 14.2.1] for the PK analysis population.  
Handling of Values Below the Lower Limit of Quantification (BLQ)  
All concentrations BLQ or missing data will be labeled as such in the concentration data 
listings. The lower limit of quantification (LLOQ) will be reported in a listing footnote.  
• All BLQ values will be substituted by zeros in the figures. 
Significant Digits 
Individual drug concentrations values are reported with 3 significant digits. 
6.3.13 
Efficacy Analysis 
6.3.13.1 Primary Endpoint 
The Montgomery-Asberg Depression Rating Scale (MADRS) total score with change from 
baseline will be listed by subject number [Listing 16.2.6.1.1]. A descriptive statistics summary 
table will be presented for MADRS total score and total score change from baseline by treatment 
and visit [Table 14.2.2.1]. Baseline for calculating total score change will be the Visit 3 
assessment. Each MADRS item will be listed by subject number [Listing 16.2.6.1.2] and 
MADRS item frequency counts will be presented in a summary table by treatment and visit 
[Table 14.2.2.2] for the Intent to Treat Population. 


 
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Treatment group mean (+/- SE) MADRS total score and total score change from baseline will 
be plotted versus treatment [Figure 14.2.2.1 and Figure 14.2.2.2]. 
To evaluate the efficacy of TS-121 compared to placebo on MDD symptoms as measured by 
the MADRS scale, 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 from baseline in MADRS score) depending on the distribution of the 
data. The baseline MADRS total score will be included as a covariate. Comparisons of TS-121 
10 mg versus placebo and TS-121 50 mg versus placebo will be evaluated at each timepoint. 
The following is example SAS programming code that will be used to fit the MMRM model 
and evaluate treatment mean differences: 
Proc Mixed Method = REML; 
 
Class GROUP Subject_ID VISIT; 
 
Model Change = Baseline GROUP VISIT GROUP*VISIT  
/ solution ddfm=kenwardroger; 
  
repeated VISIT / sub=Subject_ID type= UN; 
lsmeans GROUP*VISIT / pdiff alpha=0.05 cl; 
  
ods output lsmeans=lsm covparms=cp tests3=t3 diffs=diffs; 
run; quit; 
In case the repeated measures model with unstructured covariance matrix (type = UN) fails to 
converge then the compound symmetry model (type = CS) will be used. 
Least squares treatment group mean differences with 95% confidence intervals will be reported 
for TS-121 10 mg versus placebo and for TS-121 50 mg versus placebo evaluated at Visits 4, 
5, 6/EOT and 7. The primary endpoints for analysis are treatment mean differences at Week 
6/EOT [Table 14.2.2.3]. Statistical significance of Type 3 tests and model variance terms will 
be reported separately [Table 14.2.2.4].  
The primary analysis will assess treatment mean differences at Week 6/EOT. An assessment of 
time on treatment will be performed as an analysis of covariance on the latest assessment of the 
primary endpoint, change in MADRS score. The model will include all patients in the specified 
population and may include patients with the baseline assessment and no post-baseline efficacy 
data. In this model, where TIME will be included as a continuous predictor in this model, a 


 
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statistically significant GROUP*TIME interaction effect, with greater reductions in MADRS 
scores in the TS-121 groups compared to placebo, will be interpreted as indicating efficacy. 
The following is example SAS programming code that will be used to fit the analysis of 
covariance model: 
Proc Mixed Method = REML; 
 
Class GROUP; 
 
Model Change = Baseline GROUP TIME GROUP*TIME  
/ solution ddfm=kenwardroger; 
lsmeans GROUP / pdiff alpha=0.05 cl; 
  
ods output lsmeans=lsm2 tests3=t3 solution; 
run; quit; 
Treatment least squares means with 95% confidence intervals will be reported and also slope 
estimates for the baseline and TIME covariates [Table 14.2.2.5]. Model details will be presented 
in a statistical appendix. 
6.3.13.2 Secondary Endpoints 
The MADRS responder status, indicating ≥ 50% reduction in total score from baseline (Visit 3 
assessment) will be listed [Listing 16.2.6.1.1] and the number and percentage responders will 
be summarized by treatment and visit [Table 14.2.2.6]. Percentage responders at each visit will 
be calculated relative to number of patients evaluated. 
The Clinical Global Impression Severity (CGI-S) and CGI Improvement (CGI-I) will be 
presented in a listing with CGI-S change from baseline and CGI-I-Improver status, indicating 
(“Very much improved” or “Much improved”) [Listing 16.2.6.2]. The CGI-S score and score 
change from baseline will be presented in a descriptive summary table [Table 14.2.3.1]. The 
CGI-I summary by treatment group and visit will include score frequencies and the mean and 
median CGI-I scores [Table 14.2.3.2]. 
Treatment group mean (+/- SE) CGI-S score and score change from baseline will be plotted 
versus treatment [Figure 14.2.3.1 and Figure 14.2.3.2]. 
Hamilton Anxiety Scale (HAM-A) total score, total score change from baseline and item scores 
will be presented in a listing [Listing 16.2.6.3]. A descriptive summary table will be presented 


 
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for HAM-A total score and total score change from baseline (n, mean, SD, SE, CV%, minimum, 
median and maximum) by treatment and visit [Table 14.2.4.1].  A summary table will be 
presented for each item response of HAM-A, with score frequencies and the mean and median 
scores [Table 14.2.4.2]. Treatment group mean (+/- SE) HAM-A observed and change from 
baseline will be plotted versus treatment [Figure 14.2.4.1 and Figure 14.2.4.2]. 
Symptoms of Depression Questionnaire (SDQ) total score, total score change from baseline and 
item scores will be listed [Listing 16.2.6.4]. A descriptive summary table will be presented of 
total score observed and change from baseline results [Table 14.2.5.1] and a summary table of 
each item with the mean and median scores [Table 14.2.5.2]. Treatment group mean (+/- SE) 
SDQ total score and change from baseline will be plotted versus treatment [Figure 14.2.5.1 and 
Figure 14.2.5.2]. 
With respect to the secondary qualitative outcome variables, the MMRM/non-parametric 
methods described above will also be used to compare the difference among the three treatment 
groups for each secondary endpoint depending on the distribution of the data. 
Changes from Baseline (Visit 3) to Week 6/EOT will be assessed for the following: 
• CGI-S score [Table 14.2.3.3 LSmeans, Table 14.2.3.4 Type 3 tests] 
• HAM-A total score [Table 14.2.4.3 LSmeans, Table 14.2.4.4 Type 3 tests] 
• SDQ score [Table 14.2.5.3 LSmeans, Table 14.2.5.4 Type 3 tests] 
The Pearson Chi-square test will be used to compare the difference between active treatment 
groups and the placebo group for the following secondary endpoints evaluated at Week 6/EOT. 
The 95% confidence interval (asymptotic calculation) for each treatment difference, 
TS-121 - Placebo, of percentage responders will also be reported. 
• Percentage of MADRS responders (≥ 50% reduction in total score) [Table 14.2.2.6] 
• Percentage of CGI-I improvers (“Very much improved” or “Much improved”) 
[Table 14.2.3.2] 
6.3.13.3 Multiple Imputation for Missing Visits 
Multiple imputation method for missing visits will be performed for primary and secondary 
efficacy endpoints and the summary of treatment differences at Week 6/EOT will be presented 
as a sensitivity analysis.  


 
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The following example SAS programming multiple imputation (MI) code will be used to assess 
pattern of missing visits: 
Proc MI Nimpute=0; 
Var GROUP TRT10 TRT50 BASE WEEK2 WEEK4 WEEK6 FOLLOW; 
run; 
The indicator variables TRT10 (1 for TS-121 10 mg and otherwise 0) and TRT50 (1 for TS-121 
10 mg and otherwise 0) are equivalent to the GROUP treatment classification variables. 
The following MI code will be used to create a set of imputation data sets. 
 
Proc MI Seed=xxxxx Nimpute=x out=impute_1 round= . . . .1 .1 .1 .1 ; 
 
EM INITIAL = AC MAXITER=25 CONVERGE=0.00001; 
 
Var TRT10 TRT50 BASE WEEK2 WEEK4 WEEK6 FOLLOW; 
run; 
The number of imputed data sets (Nimpute) will be set to have relative efficiency > 95% for 
each imputed variable. This number is expected to be < 10.  
The MMRM of Section 6.3.13.1 is then run by imputation number to generate two data sets: 
The model parameters (solutionF, solution for model fixed effects) and the treatment by visit 
mean differences. Only the set of treatment mean differences used to evaluate the Week 6/EOT 
treatment mean differences (GROUPDIF1-GROUPDIF2: D50-placebo, D10-placebo, D50-
D10) will be sorted by GROUPDIF1, GROUPDIF2 and imputation number. 
The following example SAS programming code will be used to evaluate the Week 6/EOT 
treatment mean differences (D50-placebo, D10-placebo, D50-10):  
Proc Mianalyze Data=Diff(keep=GROUPDIF1 GROUPDIF2 Est_diff SE_diff) Edf=xx; 
 By GROUPDIF1 GROUPDIF1; 
 Modeleffects Est_diff; 
 Stderr SE_diff; 
 Ods Output Parameterestimates=Est_diff1 VarianceInfo = SE_diff1; 
run; 
The following example SAS programming code will be used to evaluate the solution for model 
fixed effects.  


 
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Proc Mianalyze  Parms(classvar=full)= solutionF; 
Class GROUPDIF TIME; 
Modeleffects BASE GROUP TIME GROUP*TIME; 
run; 
The sensitivity analysis for MADRS treatment mean differences at Week 6/EOT will be 
presented [Table 14.2.2.3.1] and the MI analysis for MMRM fixed effects will be reported 
separately [Table 14.2.2.4.1]. Details of the MI analysis will be presented in a statistical 
appendix. 
Supplementary summary tables and statistical appendices will also be presented for the MI 
analysis for MMRM fit to secondary endpoints. 
6.3.14 
Pharmacodynamic (PD) Analysis 
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, as, for example, urine volume and concentration used to calculate 8h 
urinary cortisol. 
6.3.14.1 Plasma Copeptin 
Plasma copeptin and change from baseline will be presented in a listing [Listing 16.2.6.5] and 
summarized [Table 14.2.6.1]. Change from baseline to Visit 6 will be compared between 
TS-121 treatments and placebo using an analysis of covariance. The following is example SAS 
programming code that will be used to fit the model and evaluate treatment mean differences: 
Proc Mixed Method = REML; 
 
Class GROUP Subject_ID; 
 
Model Change = Baseline GROUP baseline*GROUP / ddfm=kenwardroger; 
 
Random subject_ID; 
lsmeans GROUP / pdiff alpha=0.05 cl; 
  
ods output lsmeans=lsm diffs=diffs; 
run; quit; 
Least squares mean differences with 95% confidence intervals for TS-121 10 mg versus placebo 
and for TS-121 50 mg versus placebo evaluated at Visit 6 will be presented [Table 14.2.6.2]. 


 
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Statistical significance of the baseline*Group interaction will be noted. In case this has p<0.1 
then the distribution of baseline plasma copeptin across treatment groups will be examined and 
a different model for comparing plasma copeptin change from baseline across treatment groups 
may be assessed. 
The association between baseline plasma copeptin and baseline MADRS total score will be 
presented in a scatter plot of MADRS baseline total score versus baseline plasma copeptin 
[Figure 14.2.6.1.1] for the intent to treat population. The association between biomarker 
response to treatment and treatment efficacy will be presented in a scatter plot of MADRS total 
score change from baseline versus plasma copeptin change from baseline [Figure 14.2.6.1.2] 
for the intent to treat population. 
6.3.14.2 Inflammatory Markers 
Inflammatory markers (IL-1, IL-6, HS-CRP, and TNF-α) and change from baseline will be 
presented in a listing [Listing 16.2.6.6] and summarized [Table 14.2.7.1]. Change from baseline 
at Visit 6 will be compared between TS-121 treatments and placebo using an analysis of 
covariance for change dependent on baseline, treatment and baseline by treatment interaction. 
Least squares mean differences with 95% confidence intervals for TS-121 10 mg versus placebo 
and for TS-121 50 mg versus placebo evaluated at Visit 6 [Table 14.2.7.2]. 
The association between inflammatory markers at baseline and baseline MADRS total score 
will be presented in separate scatter plots of MADRS baseline total score versus each 
inflammatory marker for the intent to treat population [Figure 14.2.6.2.1]. The association 
between biomarker response to treatment and treatment efficacy will be presented in separate 
scatter plots of MADRS total score change from baseline versus each inflammatory marker 
change from baseline [Figure 14.2.6.2.2] for the intent to treat population. 
6.3.14.3 Cortisol 
Pharmacodynamic biomarkers (salivary cortisol, hair cortisol and 8h urinary cortisol) will be 
presented in listings [Listing16.2.6.7.1, Listing16.2.6.7.2 and Listing 16.2.6.7.3] and 
summarized [Table 14.2.8.1]. 
The association between cortisol assessments at baseline and baseline MADRS total score will 
be presented in a separate scatter plots for the intent to treat population [Figure 14.2.6.3]. 


 
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6.3.15 
Subgroup Analysis for Primary Endpoint 
The association between MADRS total score change from baseline to Visit 6 and the following 
demographic or anthropometric information, baseline severity, baseline PD biomarkers or other 
background information will be explored using descriptive subgroup analysis of MADRS total 
score from baseline and scatter plots. Factors and covariates in the analysis, as well as the 
MADRS total score change will be presented in a listing for the intent to treat population 
[Listing 16.2.6.8] including any pooled groups and subgroup categories used in the analysis: 
• Gender (Male, Female) 
• Age 
• BMI  
• Race (White, Other) 
• Baseline MADRS score 
• HAM-D score at Visit 1.1 
• Concomitant ADT (SSRI, Other) 
• Age at MDD diagnosis 
• MDD duration 
• Baseline PD biomarkers 
o Cortisol (salivary cortisol morning and evening and the ratio of morning to 
evening, hair cortisol, 8h urinary cortisol) 
o Plasma copeptin 
o Inflammatory markers (IL-1, IL-6, HS-CRP, TNF- α) 
Subgroup categories will be determined based on clinical preference or derived from the data 
based on the sample median or quartiles. 
Descriptive summaries by treatment will be presented of MADRS total score change from Visit 
3 to Visit 6 in selected subgroup categories for the intent to treat population [Table 14.2.9.1]. 
The MADRS total score change will be presented in scatter plots versus subgroup categories or 
the underlying ungrouped covariate corresponding to tabulated subgroup categories [Figure 
14.2.7.1]. 
6.3.16 
Safety Analysis 
The analysis of the safety variables will be based on the safety analysis population. Safety will 
be assessed based on reported adverse events, abnormal findings from physical and 


 
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ophthalmological examinations, body weight, vital sign measurements, 12-lead ECGs, C- SSRS 
score and clinical laboratory assessment results. 
6.3.16.1 Adverse Events 
The following AE listings will be produced: 
 All AEs [Listing 16.2.7.1]  
 SAEs [Listing 16.2.7.2]  
 AEs leading to Study Drug Discontinuation [Listing 16.2.7.3]  
 EOCSs [Listing 16.2.7.4] 
 Overdose [Listing 16.2.7.5] 
The following information will be included in AE listings: Subject number, age, sex and race, 
treatment group, verbatim term, MedDRA preferred term (PT), system organ class (SOC), SAE 
indicator flag, AE onset date (and time) and study day, AE end date (and time), duration (days), 
severity, relationship to study drug, action taken for study drug, action taken to treat, AE 
outcome, and treatment emergent (TEAE) flag. Adverse events with onset date on or later than 
date of first dose of the randomized treatment, which also meet one of the following two criteria, 
will be considered TEAE. 
• The AE was not present prior to the first dose of study drug for the treatment period 
• The AE was present prior to the first dose of study drug for the treatment period and 
increased in severity 
Each summary tabulation of AEs will include the number and percentage of patients who 
experienced TEAEs grouped to treatment (TS-121 10 mg, TS-121 50 mg and placebo) and the 
number and percentage of all patients who experienced AEs during placebo lead-in.  
The overview of AEs includes the number and percentage of patients with at least one AE, with 
any SAE or with an AE that led to study discontinuation [Table 14.3.1.1].  
Tables of number (and percentage) of patients with AEs summarized by SOC, PT and maximum 
severity [Table 14.3.1.2] and by SOC, PT and relationship to investigational product [Table 
14.3.1.3] will be presented by treatment group for the safety analysis population. Treatment 
related AEs include those that are marked as “possibly”, “probably” or “definitely related to 


 
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study drug”.  In the case of multiple occurrences of the same AEs (at the same SOC and PT 
level) in an individual patient, the AE with the greatest severity will be reported in Table 
14.3.1.2 and the AE with the greatest relationship to study drug will be reported in Table 
14.3.1.3. 
Serious AEs and EOCSs, if any occur, will be summarized [Table 14.3.2.1 and Table 14.3.2.2]. 
6.3.16.2 Clinical Safety Laboratory Tests (Biochemistry, 
Hematology and Urinalysis) 
Clinical laboratory biochemistry and hematology results will be presented, using conventional 
units (original units, received from the laboratory are consistent with CDISC standards) and 
standard international (SI) units, will be listed by subject number and study time point 
[Listing 16.2.8.1.1 through Listing 16.2.8.2.2]. Laboratory analyses will utilize scheduled Visit 
3 assessments as baseline values. Only if scheduled Visit 3 result is missing will the latest 
predose assessment be used as the baseline for that patient and test. Change from baseline will 
be calculated only for laboratory tests with at least one recorded pre-dose assessment. 
Certain hematology test samples were assessed by certain sites’ local laboratory and these will 
be listed together with the corresponding central laboratory results. 
Clinical urinalysis and urinalysis microscopic tests will be listed using conventional units 
[Listing 16.2.8.3]. 
Laboratory reference ranges, in conventional and SI units will be listed [Listing 16.2.8.4]. 
All values outside the clinical reference ranges will be flagged in the data listings. The 
quantitative abnormal values will be flagged with ‘L’ for values below the lower limit of the 
clinical reference range and ‘H’ for values above the upper limit of the clinical reference range 
and included in the listings. In addition, certain qualitative tests may be flagged abnormal ‘A’. 
The Investigator will assess whether the values outside the clinical reference range are clinically 
significant and laboratory values outside the reference ranges will be reported as abnormal not 
clinically significant (NCS) or abnormal clinically significant (CS). Clinically significant 
laboratory values will be recorded by the Investigator as AEs. 
Abnormal laboratory values ordered by test category (biochemistry, hematology and 
urinalysis), randomized treatment, subject number, laboratory test, date and time will be listed 
using conventional and SI units [Listing 16.2.8.5.1 and Listing 16.2.8.5.2]. Abnormal CS 


 
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laboratory values ordered by test category (biochemistry, hematology and urinalysis), 
randomized treatment, subject number, laboratory test, date and time will be listed using 
conventional and SI units [Table 14.3.4.1 and Table 14.3.4.2].  
Descriptive statistics (n, mean, SD, SE, CV%, minimum, median and maximum) for non-
categorical data including biochemistry, hematology and any quantitative urinalysis will be 
presented by treatment group and time point for both observed values and changes from baseline 
in conventional units [Table 14.3.5.1.1] and in SI units [Table 14.3.5.1.2]. Urinalysis categorical 
results (normal or abnormal) will also be tabulated [Table 14.3.5.2].  
Biochemistry, hematology and urinalysis shift tables will be constructed that show the change 
in quantitative laboratory values (or urinalysis normal/abnormal) from baseline to end of 
treatment [Table 14.3.5.3.1 through Table 14.3.5.3.3].  
Critical ranges for clinically significant laboratory outlier criteria (attached Appendix A) and 
clinically noteworthy changes (Appendix B) will be used to identify values and trends of 
potential medical importance. A summary of the number and percentage of patients with 
clinically significant laboratory outliers, based on Appendix A, for each specified laboratory 
test will be presented [Table 14.3.5.4.1]. The summary will present across scheduled and 
unscheduled tests after first dose in Visit 3 and across scheduled and unscheduled test during 
placebo lead-in period. Clinical laboratory outlier values of individual patients will be presented 
in a listing [Table 14.3.5.4.2].  Similar analyses will be performed for clinically noteworthy 
changes from baseline [Table 14.3.5.5.1 and Table 14.3.5.5.2]. 
Evaluation of Drug-Induced Serious Hepatotoxicity 
The evaluation of drug-induced serious hepatoxicity (eDISH) will be based on a tabulation by 
subject number [Table 14.3.4.3] and scatter plot figure. The table will present all scheduled and 
unscheduled ALT, AST, ALP and TBL of any patient with AST or ALT > 3x ULN or TBL > 2 
x ULN. This table will be assessed to identify any incidence of  
1. Three-fold or greater elevations above the ULN of ALT or AST and 
2. Among patients showing such AT elevations, any patient with elevation of serum TBL to 
>2xULN and without initial finding of cholestasis (elevated serum ALP). 
Side by side scatter plots will be presented of time-matched ALT versus TBL [Figure 14.3.1.1] 
and time-matched AST versus TBL [Figure 14.3.1.2] grouped to combined TS-121 treatment 


 
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groups and placebo. These plots will be presented using ×ULN units and logarithmic scale. The 
ALT versus TBL and AST versus TBL plots will also be presented using each patient’s post-
baseline maximum value [Figure 14.3.2.1 and Figure 14.3.2.2]. 
6.3.16.3 Vital Signs 
Vital signs will be listed [Listing 16.2.9.1.1]. Vital signs change from baseline will also be listed 
[Listing 16.2.9.1.2]. Baseline is defined as the scheduled predose assessment of Visit 3. Only if 
scheduled Visit 3 result is missing, will the latest predose assessment be used as the baseline for 
that subject number and test. Change from baseline will be calculated only for vital signs 
evaluated post-baseline and with at least one recorded pre-dose assessment. 
Descriptive summaries (n, mean, SD, SE, CV%, minimum, median and maximum) of vital signs 
(by parameter) and oral body temperature measurements observed values and change from 
baseline will be presented by treatment and time point [Table 14.3.6.1.1 and Table 14.3.6.1.2].  
6.3.16.4 12-Lead Electrocardiogram 
Electrocardiogram data (ventricular rate, RR, PR, QT, QTcB and QTcF interval data, QRS 
duration) will be listed [Listing 16.2.9.2.1] with the Investigator interpretation.  Any QTcF or 
QTcB >500 msec will be flagged in the listing.  Electrocardiogram data change from baseline 
will be listed [Listing 16.2.9.2.2] and each flagged to distinguish QTc change from baseline 30 
to 60 msec or >60 msec. 
Descriptive summaries (n, mean, SD, SE, CV%, minimum, median and maximum) of interval 
data observed values and change from baseline will be presented by treatment and time point 
[Table 14.3.6.2.1 and Table 14.3.6.2.2]. Baseline is defined as the scheduled predose 
assessment of Visit 3. Only if scheduled Visit 3 result is missing, will the latest predose 
assessment be used as the baseline for that subject number and test. 
The categorical analysis of QTcB and QTcF will be presented in a frequency table of patients 
categorized based on maximum post-baseline QTc (<= 500 msec or >500 msec) and maximum 
change from baseline (<30 msec, 30 to 60 msec, and >60 msec) [Table 14.3.6.2.3]. 
The incidence of abnormalities, based on the clinical interpretations from the Investigator, will 
be enumerated by treatment group and visit [Table 14.3.6.2.4].  


 
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6.3.16.5 Body Weight  
All body weight (kg) measurements and change from baseline will be listed [Listing 16.2.9.3]. 
Descriptive summaries (n, mean, SD, SE, CV%, minimum, median and maximum) of body 
weight and change from baseline will be presented by treatment and time point [Table 14.3.6.3.1 
and Table 14.3.6.3.2]. Baseline is defined as the scheduled predose assessment of Visit 3. Only 
if scheduled Visit 3 result is missing, will the latest predose assessment be used as the baseline 
for that subject number and test. 
6.3.16.6 Ophthalmological Examinations 
The observed and change from baseline LOCS III grading scores and best corrected visual 
acuity scores will be listed [Listing 16.2.9.4]. Any LOCS III grade increase from baseline >=0.5 
or >= 0.8 will be flagged. The flagged records will also be interpreted and annotated based on 
the definition of 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)]. Any record of Class I 
lens events will be listed [Table 14.3.6.4.1].  
Descriptive statistics (n, mean, SD, SE, CV%, minimum, median and maximum) of LOCS III 
grading items and best corrected visual acuity score and change from baseline will be presented 
by treatment and time point [Table 14.3.6.4.2 and Table 14.3.6.4.3]. Baseline is defined as the 
latest predose assessment of Visit 2. 
6.3.16.7 Columbia Suicidal Severity Rating Scale (C-SSRS) 
Responses to C-SSRS suicidal ideation questions 1 through 5, the suicidal ideation score and 
score change from baseline will be listed by treatment, subject number and visit 
[Listing 16.2.9.5.1]. All reported responses to Suicidal Ideation Item 1 (Wish to be dead) and 
Item 2 (Non-Specific Active Suicidal Thoughts), any positive response to Item 3 Item 4 Item 5 
and the suicidal ideation score with change from baseline will be listed.  
A shift table of suicidal ideation items 1 and 2 evaluated at baseline (Visit 3) and at Week 2, 
Week 4, Week 6/EOT, and Follow-up will be presented [Table 14.3.6.5.1]. A descriptive 
summary (n, mean, SD, SE, min, median, max) by treatment and visit will be presented of 
observed and change from baseline suicidal ideation score [Table 14.3.6.5.2]. 
The suicidal ideation intensity rating, including rating 0, any reported intensity of suicidal 
ideation and any reported suicidal behavior will be listed [Listing 16.2.9.5.2]. 


 
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7. 
REFERENCES 
1. SAS® Version 9.2 of the SAS System for Unix. Copyright © 2002-2003. SAS Institute Inc. SAS and 
all other SAS Institute Inc. product or service names are registered trademarks or trademarks of SAS 
Institute Inc., Cary, NC, USA. 
2. U. S. Food and Drug Administration/Center for Drug Evaluation and Research. (2012). Guidance 
for Industry Suicidal Ideation and Behavior:  Prospective Assessment of Occurrence in 
Clinical Trials.  
3. Columbia Suicide Severity Rating Scale Scoring and Data Analysis Guide. 
http://www.cssrs.columbia.edu. 
 
 


 
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Table 2 
Tables to be Included in Section 14 of the Clinical Study Report 
Note: Top line tables are indicated * 
SECTION 14.1: 
Demographic Data 
*Table 14.1.1.1 
Patient Disposition by Treatment Group and Overall (All Randomized Patients) 
Table 14.1.1.2 
Patient Disposition by Treatment Group and Overall (Safety Analysis Population) 
Table 14.1.1.3 
Patient Disposition Through End of Placebo Lead-in (All Consented Patients) 
Table 14.1.2.1 
Demographics and Baseline Characteristics including Screening Height, Weight 
and Body Mass Index (Safety Analysis Population) 
*Table 14.1.2.2 
Hamilton Depression Scale HAM-D Total Score at Screening and Baseline 
(Safety Analysis Population) 
*Table 14.1.3 
Baseline Major Depressive Disorder Characteristics (Safety Analysis Population) 
Table 14.1.4 
Medical History and Psychiatric History (Safety Analysis Population) 
Table 14.1.5 
Concomitant Medications (Safety Analysis Population) 
SECTION 14.2:  
Treatment Compliance, PK, Efficacy and PD Data 
Table 14.2.1 
Treatment Dose Compliance (Safety Analysis Population) 
*Table 14.2.2.1 
Montgomery-Asberg Depression Rating Scale (MADRS) Total Score Observed 
and Change from Baseline by Treatment and Visit (Intent to Treat Population) 
Table 14.2.2.2 
Montgomery-Asberg Depression Rating Scale (MADRS) Item Response 
Frequency by Treatment and Visit (Intent to Treat Population) 
*Table 14.2.2.3 
Analysis of Montgomery-Asberg Depression Rating Scale (MADRS) Total Score 
Change from Baseline Least Squares Treatment Mean Differences by Visit (Intent 
to Treat Population) 
Table 14.2.2.3.1 
Multiple Imputation Method for Missing Visits Analysis of Montgomery-Asberg 
Depression Rating Scale (MADRS) Total Score Change from Baseline Least 
Squares Treatment Mean Differences by Visit (Intent to Treat Population) 
*Table 14.2.2.4 
Analysis of Montgomery-Asberg Depression Rating Scale (MADRS) Total Score 
Change from Baseline Model Summary (Intent to Treat Population) 
Table 14.2.2.4.1 
Multiple Imputation Method for Missing Visits Analysis of Montgomery-Asberg 
Depression Rating Scale (MADRS) Total Score Change from Baseline Model 
Summary (Intent to Treat Population) 
*Table 14.2.2.5 
Analysis of Montgomery-Asberg Depression Rating Scale (MADRS) Total Score 
Change from Baseline at Week 6/EOT (Intent to Treat Population) 
Table 14.2.2.6 
Montgomery-Asberg 
Depression 
Rating 
Scale 
(MADRS) 
Responders 
Comparison of TS-121 Treatment versus Placebo at Week 6/EOT (Intent to Treat 
Population) 
Table 14.2.3.1  
Clinical Global Impression Severity (CGI-S) Score Observed and Change from 
Baseline by Treatment and Visit (Intent to Treat Population) 


 
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Table 14.2.3.2  
Summary and Analysis of Clinical Global Impression Improvement (CGI-I) Score 
Frequency, CGI-I Summary Scores and CGI-I Improver Frequency by Treatment 
and Visit (Intent to Treat Population) 
Table 14.2.3.3 
Analysis of Clinical Global Impression Severity (CGI-S) Score Least Squares 
Treatment Mean Differences by Visit (Intent to Treat Population) 
Table 14.2.3.3.1 
Multiple Imputation Method for Missing Visits Analysis of Clinical Global 
Impression Severity (CGI-S) Score Least Squares Treatment Mean Differences 
by Visit (Intent to Treat Population) 
Table 14.2.3.4 
Analysis of Clinical Global Impression Severity (CGI-S) Score Change from 
Baseline Model Summary (Intent to Treat Population) 
Table 14.2.3.4.1 
Multiple Imputation Method for Missing Visits Analysis of Clinical Global 
Impression Severity (CGI-S) Score Change from Baseline Model Summary 
(Intent to Treat Population) 
Table 14.2.4.1  
Hamilton Anxiety Scale (HAM-A) Total Score Observed and Change from 
Baseline by Treatment and Visit (Intent to Treat Population) 
Table 14.2.4.2 
Hamilton Anxiety Scale (HAM-A) Item Scores Response Frequency by 
Treatment and Visit (Intent to Treat Population) 
Table 14.2.4.3 
Analysis of Hamilton Anxiety Scale (HAM-A) Least Squares Treatment Mean 
Differences by Visit (Intent to Treat Population) 
Table 14.2.4.3.1 
Multiple Imputation Method for Missing Visits Analysis of Hamilton Anxiety 
Scale (HAM-A) Least Squares Treatment Mean Differences by Visit (Intent to 
Treat Population) 
Table 14.2.4.4 
Analysis of Hamilton Anxiety Scale (HAM-A) Change from Baseline Model 
Summary (Intent to Treat Population) 
Table 14.2.4.4.1 
Multiple Imputation Method for Missing Visits Analysis of Hamilton Anxiety 
Scale (HAM-A) Change from Baseline Model Summary (Intent to Treat 
Population) 
Table 14.2.5.1 
Symptoms of Depression Questionnaire (SDQ) Total Score Observed and Change 
from Baseline by Treatment and Visit (Intent to Treat Population) 
Table 14.2.5.2 
Symptoms of Depression Questionnaire (SDQ) Item Response by Treatment and 
Visit (Intent to Treat Population) 
Table 14.2.5.3 
Analysis of Symptoms of Depression Questionnaire (SDQ) Total Score Change 
from Baseline Least Squares Treatment Mean Differences by Visit (Intent to Treat 
Population) 
Table 14.2.5.3.1 
Multiple Imputation Method for Missing Visits Analysis of Symptoms of 
Depression Questionnaire (SDQ) Total Score Change from Baseline Least 
Squares Treatment Mean Differences by Visit (Intent to Treat Population) 
Table 14.2.5.4 
Analysis of Symptoms of Depression Questionnaire (SDQ) Total Score Change 
from Baseline Model Summary (Intent to Treat Population) 


 
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Table 14.2.5.4.1 
Multiple Imputation Method for Missing Visits Analysis of Symptoms of 
Depression Questionnaire (SDQ) Total Score Change from Baseline Model 
Summary (Intent to Treat Population) 
Table 14.2.6.1 
Plasma Copeptin and Change from Baseline (Exploratory PD Analysis 
Population) 
Table 14.2.6.2 
Analysis of Plasma Copeptin and Change from Baseline at Week 6 (Exploratory 
PD Analysis Population) 
Table 14.2.7.1 
Inflammatory Markers (IL-1, IL-6, HS-CRP, and TNF-α) and Change from 
Baseline (Intent to Treat Population) 
Table 14.2.7.2 
Analysis of Inflammatory Markers Change from Baseline at Visit 6 (Intent to 
Treat Population) 
Table 14.2.8.1 
Pharmacodynamic Biomarkers, Cortisol in Saliva, Hair and Plasma, Observed 
and Change from Baseline (Intent to Treat Population) 
Table 14.2.9.1 
MADRS Total Score Change from Baseline by Patient Characteristic and 
Treatment (Intent to Treat Population) 
SECTION 14.3.1: 
Adverse Events 
*Table 14.3.1.1 
Overall Summary of Adverse Events, Treatment Emergent and with Onset During 
Placebo Lead-in by Treatment (Safety Analysis Population) 
*Table 14.3.1.2 
Summary of Adverse Events by System Organ Class, Preferred Term, Severity 
and Treatment (Safety Analysis Population) 
Table 14.3.1.3 
Summary of Treatment Emergent Adverse Events by System Organ Class, 
Preferred Term, Relationship to Study Drug and Treatment (Safety Analysis 
Population) 
SECTION 14.3.2: 
Deaths, Serious Adverse Events and Events of Clinical Significance 
*Table 14.3.2.1 
Serious Adverse Events (Safety Analysis Population)  
*Table 14.3.2.2 
Events of Clinical Significance (Safety Analysis Population) 
SECTION 14.3.4: 
Laboratory Abnormal Assessments 
Table 14.3.4.1 
Abnormal Clinically Significant Clinical Laboratory Values (in Conventional 
Units) (Safety Analysis Population) 
Table 14.3.4.2 
Abnormal Clinically Significant Clinical Laboratory Values (in Standard 
International Units) (Safety Analysis Population) 
Table 14.3.4.3 
Individual Patients Evaluated for Drug-Induced Serious Hepatoxicity (Safety 
Analysis Population) 
SECTION 14.3.5: 
Laboratory Assessments 
Table 14.3.5.1.1 
Descriptive Statistics for Clinical Laboratory Results (Conventional Units) 
(Safety Analysis Population) 
Table 14.3.5.1.2 
Descriptive Statistics for Clinical Laboratory Results (Standard International 
Units) (Safety Analysis Population) 


 
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Table 14.3.5.2 
Summary of Urinalysis Categorical Results (Safety Analysis Population) 
Table 14.3.5.3.1 
Shift from Baseline to End of Treatment in Biochemistry Laboratory Results 
(Safety Analysis Population) 
Table 14.3.5.3.2 
Shift from Baseline to End of Treatment in Hematology Laboratory Results 
(Safety Analysis Population) 
Table 14.3.5.3.3 
Shift from Baseline to End of Treatment in Urinalysis Laboratory Results (Safety 
Analysis Population) 
Table 14.3.5.4.1 
Number and Percentage of Patients With Clinical Laboratory Outlier Values 
(Safety Analysis Population) (Safety Analysis Population) 
Table 14.3.5.4.2 
Individual Patients with Clinical Laboratory Outlier Values (in Conventional 
Units) (Safety Analysis Population) 
Table 14.3.5.5.1 
Number and Percentage of Patients With Clinically Noteworthy Laboratory 
Changes (Safety Analysis Population) 
Table 14.3.5.5.2 
Individual Patients with Clinically Noteworthy Laboratory Changes (in 
Conventional Units) (Safety Analysis Population) 
SECTION 14.3.6:  
Other Safety Assessments 
Table 14.3.6.1.1 
Vital Signs Observed Values (Safety Analysis Population) 
Table 14.3.6.1.2 
Vital Signs Change from Baseline (Safety Analysis Population) 
Table 14.3.6.2.1 
Quantitative 12-Lead Electrocardiogram Assessments, Observed Values (Safety 
Analysis Population) 
Table 14.3.6.2.2 
Quantitative 12-Lead Electrocardiogram Assessments, Change from Baseline 
(Safety Analysis Population) 
Table 14.3.6.2.3 
Categorical Summary of 12-Lead Electrocardiogram QTc (Safety Analysis 
Population) 
Table 14.3.6.2.4 
Summary of 12-Lead ECG Interpretations (Safety Analysis Population) 
Table 14.3.6.3.1 
Body Weight Observed Values (Safety Analysis Population) 
Table 14.3.6.3.2 
Body Weight Change from Baseline (Safety Analysis Population) 
Table 14.3.6.4.1 
Ophthalmological Examination Class I Lens Events (Safety Analysis Population) 
Table 14.3.6.4.2 
Ophthalmological Examination LOCS III Grading and Best Corrected Visual 
Acuity Score Observed Values (Safety Analysis Population) 
Table 14.3.6.4.3 
Ophthalmological Examination LOCS III Grading and Best Corrected Visual 
Acuity Score Change from Baseline (Safety Analysis Population) 
Table 14.3.6.5.1 
Columbia Suicide Severity Rating Scale (C-SSRS) Shift from Baseline (Safety 
Analysis Population) 
Table 14.3.6.5.2 
Columbia Suicide Severity Rating Scale (C-SSRS) Suicidal Ideation Score 
Observed and Change from Baseline (Safety Analysis Population) 
 


 
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Table 3 
Figures to be Included in Section 14 of the Clinical Study Report 
Note: Top line figures are indicated * 
Figure 14.1.1 
Patient Disposition (All Screened Patients) 
Refer to shells document.  
Figure 14.2.1 
Plasma 
 Concentrations versus Actual Time Post Dose (Pharmacokinetic 
Population)  
Refer to shells document.  
Scatter plot using different symbols for TS-121 10 mg and TS-121 50 mg treatment 
groups. X-axis is actual time post dose. 
*Figure 14.2.2.1 
Montgomery-Asberg Depression Rating Scale (MADRS) Total Score Treatment 
Mean (+/- SE) versus Visit (Intent to Treat Population) 
Refer to shells document.  
Profile plot using different symbols for TS-121 10 mg, TS-121 50 mg and Placebo 
treatment groups. X-axis in weeks from Baseline through follow-up. Plot Week 6 or 
ET at 6 weeks and Follow-up at 10 weeks. 
*Figure 14.2.2.2 
Montgomery-Asberg Depression Rating Scale (MADRS) Total Score Treatment 
Mean (+/- SE) Change from Baseline versus Visit (Intent to Treat Population) 
Refer to shells document.  
Profile plot using different symbols for TS-121 10 mg, TS-121 50 mg and Placebo 
treatment groups. X-axis in weeks from Baseline through follow-up. Plot Week 6 or 
ET at 6 weeks and Follow-up at 10 weeks. Reference line at zero change from 
baseline. 
Figure 14.2.3.1 
Clinical Global Impression Severity (CGI-S) Score Treatment Mean (+/- SE) versus 
Visit (Intent to Treat Population) 
Profile plot using different symbols for TS-121 10 mg, TS-121 50 mg and Placebo 
treatment groups. X-axis in weeks from Baseline through follow-up. Plot Week 6 or 
ET at 6 weeks and Follow-up at 10 weeks. 
Figure 14.2.3.2 
Clinical Global Impression Severity (CGI-S) Score Treatment Mean (+/- SE) 
Change from Baseline versus Visit (Intent to Treat Population) 
Profile plot using different symbols for TS-121 10 mg, TS-121 50 mg and Placebo 
treatment groups. X-axis in weeks from Baseline through follow-up. Plot Week 6 or 
ET at 6 weeks and Follow-up at 10 weeks. Reference line at zero change from 
baseline. 
Figure 14.2.4.1 
Hamilton Anxiety Scale (HAM-A) Treatment Mean (+/- SE) versus Visit (Intent to 
Treat Population) 
Profile plot using different symbols for TS-121 10 mg, TS-121 50 mg and Placebo 
treatment groups. X-axis in weeks from Baseline through follow-up. Plot Week 6 or 
ET at 6 weeks and Follow-up at 10 weeks. 


 
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Figure 14.2.4.2 
Hamilton Anxiety Scale (HAM-A) Treatment Mean (+/- SE) Change from Baseline 
versus Visit (Intent to Treat Population) 
Profile plot using different symbols for TS-121 10 mg, TS-121 50 mg and Placebo 
treatment groups. X-axis in weeks from Baseline through follow-up. Plot Week 6 or 
ET at 6 weeks and Follow-up at 10 weeks. Reference line at zero change from 
baseline. 
Figure 14.2.5.1 
Symptoms of Depression Questionnaire (SDQ) Total Score Treatment Mean (+/- 
SE) versus Visit (Intent to Treat Population) 
Profile plot using different symbols for TS-121 10 mg, TS-121 50 mg and Placebo 
treatment groups. X-axis in weeks from Baseline through follow-up. Plot Week 6 or 
ET at 6 weeks and Follow-up at 10 weeks. 
Figure 14.2.5.2 
Symptoms of Depression Questionnaire (SDQ) Total Score Treatment Mean (+/- 
SE) Change from Baseline versus Visit (Intent to Treat Population) 
Profile plot using different symbols for TS-121 10 mg, TS-121 50 mg and Placebo 
treatment groups. X-axis in weeks from Baseline through follow-up. Plot Week 6 or 
ET at 6 weeks and Follow-up at 10 weeks. Reference line at zero change from 
baseline. 
Figure 14.2.6.1.1 
Baseline Montgomery-Asberg Depression Rating Scale (MADRS) Total Score 
versus Baseline Plasma Copeptin  (Intent to Treat Population) 
Refer to shells document.  
Scatter plot using different symbols for TS-121 10 mg, TS-121 50 mg and Placebo 
treatment groups. X-axis is baseline plasma copeptin. Plot baseline MADRS total 
score. 
Figure 14.2.6.1.2 
Montgomery-Asberg Depression Rating Scale (MADRS) Total Score Change from 
Baseline versus Plasma Copeptin Change from Baseline (Intent to Treat Population) 
Scatter plot using different symbols for TS-121 10 mg, TS-121 50 mg and Placebo 
treatment groups. X-axis is plasma copeptin change. Plot MADRS total score 
change. 
Figure 14.2.6.2.1 
Baseline Montgomery-Asberg Depression Rating Scale (MADRS) Total Score 
versus Baseline Inflammatory Markers (IL-1, IL-6, HS-CRP, and TNF-α) (Intent to 
Treat Population) 
Scatter plot, one pager per marker using different symbols for TS-121 10 mg, TS-
121 50 mg and Placebo treatment groups. X-axis is baseline Marker. Plot baseline 
MADRS total score. 
Figure 14.2.6.2.2 
Montgomery-Asberg Depression Rating Scale (MADRS) Total Score Change from 
Baseline versus Inflammatory Markers (IL-1, IL-6, HS-CRP, and TNF-α) Change 
from Baseline (Intent to Treat Population) 
Scatter plot using different symbols for TS-121 10 mg, TS-121 50 mg and Placebo 
treatment groups. X-axis is inflammatory marker. Plot MADRS total score change. 


 
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Figure 14.2.6.3 
Baseline Montgomery-Asberg Depression Rating Scale (MADRS) Total Score 
versus Baseline Pharmacodynamic Biomarkers  (Intent to Treat Population) 
One page each for salivary cortisol, hair cortisol and 8h urinary cortisol. Scatter 
plot using different symbols for TS-121 10 mg, TS-121 50 mg and Placebo treatment 
groups. X-axis is baseline Pharmacodynamic Biomarker (Cortisol level). Plot 
baseline MADRS total score. 
Figure 14.2.7.1 
Montgomery-Asberg Depression Rating Scale (MADRS) Total Score Change from 
Baseline versus Baseline Patient Characteristics  (Intent to Treat Population) 
Refer to shells document.  
One page per ‘patient characteristic’ in Listing 16.2.6.8. Scatter plot using different 
symbols for TS-121 10 mg, TS-121 50 mg and Placebo treatment groups. X-axis is 
baseline Patient Characteristic (may be group score). Plot MADRS total score 
change from baseline. In case of grouped scores in only 2 or 3 groups then present 
overlay box plots (median with 25th to 75th percentiles) of the MADRS Total score 
change per group and treatment. 
Figure 14.3.1.1 
Time-matched Post-Baseline Alanine Aminotransferase versus Total Bilirubin 
(Safety Analysis Population) 
 
Refer to shells document.  
One page, two panels. Left is Placebo Group and right is Overall TS-121 Groups. 
Include scheduled and unscheduled post-baseline assessments. Units are ×ULN for 
horizontal and vertical axes and scale is logarithmic. 
Figure 14.3.1.2 
Time-matched Post-Baseline Aspartate Aminotransferase versus Total Bilirubin 
(Safety Analysis Population) 
 
As Figure 14.3.1.1. 
Figure 14.3.2.1 
Peak Post-Baseline Alanine Aminotransferase versus Peak Total Bilirubin (Safety 
Analysis Population) 
 
As Figure 14.3.1.1, one point per patient and unmatched unscheduled results are 
included. 
Figure 14.3.2.2 
Peak Post-Baseline Aspartate Aminotransferase versus Peak Total Bilirubin 
(Safety Analysis Population) 
 
As Figure 14.3.1.1, one point per patient and unmatched unscheduled results are 
included. 
 


 
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Table 4  
Listings to be Included in Section 16 of the Clinical Study Report 
Note: Listings that support top line tables or figures are indicated * 
 
Study Information 
 
Listing 16.1.7 
Randomization and Interactive Response Technology (IRT) Record 
 
Documentation Of Statistical Methods 
Appendix 16.1.9.2.1 
Statistical Analysis Details of Table 14.2.2.3 and Table 14.2.2.4 Analysis of 
Montgomery-Asberg Depression Rating Scale (MADRS) Total Score Change from 
Baseline 
Appendix 16.1.9.2.2 
Statistical Analysis Details of Table 14.2.2.5 Analysis of Montgomery-Asberg 
Depression Rating Scale (MADRS) Total Score Change from Baseline at Week 
6/EOT 
Appendix 16.1.9.2.3 
Statistical Analysis Details of Table 14.2.2.6 Montgomery-Asberg Depression 
Rating Scale (MADRS) Responders Comparison of TS-121 Treatment versus 
Placebo at Visit 6 (Intent to Treat Population) 
Appendix 16.1.9.2.4 
Statistical Analysis Details of Table 14.2.3.2 Summary and Analysis of Clinical 
Global Impression Improvement (CGI-I) Score Frequency, CGI-I Summary Scores 
and CGI-I Improver Frequency by Treatment and Visit (Intent to Treat Population) 
Appendix 16.1.9.2.5 
Statistical Analysis Details of Table 14.2.3.3 and Table 14.2.3.4 Analysis of Clinical 
Global Impression Severity (CGI-S) Score Change from Baseline (Intent to Treat 
Population) 
Appendix 16.1.9.2.6 
Statistical Analysis Details of Table 14.2.4.2 and Table 14.2.4.3 Analysis of 
Hamilton Anxiety Scale (HAM-A) Change from Baseline (Intent to Treat 
Population) 
Appendix 16.1.9.2.7 
Statistical Analysis Details of Table 14.2.5.3 and Table 14.2.5.4 Analysis of 
Symptoms of Depression Questionnaire (SDQ) Total Score Change from Baseline 
(Intent to Treat Population) 
Appendix 16.1.9.2.8 
Statistical Analysis Details of Table 14.2.7.2 Analysis of Inflammatory Markers 
Change from Baseline at Visit 6 (Intent to Treat Population) 
Appendix 16.1.9.2.9 
Multiple Imputation Method for Missing Visits Statistical Analysis Details of 
Table 14.2.2.3.1 and Table 14.2.2.4.1 Analysis of Montgomery-Asberg Depression 
Rating Scale (MADRS) Total Score Change from Baseline 
Appendix 16.1.9.2.10 Multiple Imputation Method for Missing Visits Statistical Analysis Details of 
Table 14.2.2.5.1 Analysis of Montgomery-Asberg Depression Rating Scale 
(MADRS) Total Score Change from Baseline at Week 6/EOT 
Appendix 16.1.9.2.11 Multiple Imputation Method for Missing Visits Statistical Analysis Details of 
Table 14.2.2.6.1 Montgomery-Asberg Depression Rating Scale (MADRS) 
Responders Comparison of TS-121 Treatment versus Placebo at Visit 6 (Intent to 
Treat Population) 
Appendix 16.1.9.2.12 Multiple Imputation Method for Missing Visits Statistical Analysis Details of 
Table 14.2.3.2.1 Summary and Analysis of Clinical Global Impression Improvement 


 
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(CGI-I) Score Frequency, CGI-I Summary Scores and CGI-I Improver Frequency 
by Treatment and Visit (Intent to Treat Population) 
Appendix 16.1.9.2.13 Multiple Imputation Method for Missing Visits Statistical Analysis Details of 
Table 14.2.3.3.1 and Table 14.2.3.4.1 Analysis of Clinical Global Impression 
Severity (CGI-S) Score Change from Baseline (Intent to Treat Population) 
Appendix 16.1.9.2.14 Multiple Imputation Method for Missing Visits Statistical Analysis Details of 
Table 14.2.4.2.1 and Table 14.2.4.3.1 Analysis of Hamilton Anxiety Scale (HAM-
A) Change from Baseline (Intent to Treat Population) 
Appendix 16.1.9.2.15 Multiple Imputation Method for Missing Visits Statistical Analysis Details of 
Table 14.2.5.3.1 and Table 14.2.5.4.1 Analysis of Symptoms of Depression 
Questionnaire (SDQ) Total Score Change from Baseline (Intent to Treat Population) 
Appendix 16.1.9.2.16 Multiple Imputation Method for Missing Visits Statistical Analysis Details of 
Table 14.2.7.2.1 Analysis of Inflammatory Markers Change from Baseline at Visit 
6 (Intent to Treat Population) 
SECTION 16.2.1: Disposition 
*Listing 16.2.1.1 
Study Disposition (All Screened Patients) 
SECTION 16.2.2: Protocol Deviations 
 Listing 16.2.2.1 
Protocol Deviations  
SECTION 16.2.3: Analysis Sets 
 Listing 16.2.3.1 
Assignment to Analysis Populations (Safety Analysis Population) 
SECTION 16.2.4: Demographics And Baseline Characteristics 
*Listing 16.2.4.1 
Demographics (Safety Analysis Population) 
Listing 16.2.4.2.1 
Screening and Baseline 17 Items Hamilton Rating Scale (HAM-D) (All Screened 
Patients) 
Listing 16.2.4.2.2 
Baseline Major Depressive Disorder Characteristics (Intent to Treat Population) 
Listing 16.2.4.3 
Medical and Psychiatric History (Safety Analysis Population) 
Listing 16.2.4.4 
Concomitant Medications (Safety Analysis Population) 
Listing 16.2.4.5 
Prior Antidepressant Therapy (Safety Analysis Population) 
Listing 16.2.4.6.1 
Drug Screening Results (Safety Analysis Population) 
Listing 16.2.4.6.2 
Serology Screen Results (Safety Analysis Population) 
Listing 16.2.4.6.3 
Pregnancy Test Results (Safety Analysis Population) 
SECTION 16.2.5: Exposure/Compliance/Drug Concentration 
Listing 16.2.5.1 
Investigational Product Dose Compliance (Safety Analysis Population) 
Listing 16.2.5.2 
Pharmacokinetic 
Sample 
Times 
and 
Plasma 
 
Concentrations 
(Pharmacokinetic Analysis Population) 


 
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SECTION 16.2.6:  Efficacy and Pharmacodynamic Data 
*Listing 16.2.6.1.1 
Montgomery-Asberg Depression Rating Scale (MADRS) Total Score, Total Score 
Change from Baseline and Responder Status (Intent to Treat Population) 
Listing 16.2.6.1.2 
Montgomery-Asberg Depression Rating Scale (MADRS) Item Responses (Intent to 
Treat Population) 
Listing 16.2.6.2 
Clinical Global Impression Severity (CGI-S) and CGI Improvement (CGI-I) (Intent 
to Treat Population) 
Listing 16.2.6.3 
Hamilton Anxiety Scale (HAM-A) (Intent to Treat Population) 
Listing 16.2.6.4 
Symptoms of Depression Questionnaire (SDQ) (Intent to Treat Population) 
Listing 16.2.6.5 
Plasma Copeptin Observed and Change from Baseline (Intent to Treat Population) 
Listing 16.2.6.6 
Inflammatory Markers, IL-1, IL-6, HS-CRP, and TNF-α (Intent to Treat Population) 
Listing 16.2.6.7.1 
Salivary Cortisol (Intent to Treat Population) 
Listing 16.2.6.7.2 
Hair Cortisol (Intent to Treat Population) 
Listing 16.2.6.7.3 
Urinary Cortisol (Intent to Treat Population) 
Listing 16.2.6.8 
Patient Characteristics, Demographic and Baseline Pharmacodynamic Biomarkers, 
Listed with Montgomery-Asberg Depression Rating Scale (MADRS) Total Score 
Baseline and Change from Baseline (Intent to Treat Population)  
SECTION 16.2.7: Adverse Events 
*Listing 16.2.7.1 
Adverse Events (Safety Analysis Population) 
*Listing 16.2.7.2 
Serious Adverse Events (SAEs) (Safety Analysis Population) 
Listing 16.2.7.3 
Adverse Events Associated with Study Drug Discontinued (Safety Analysis 
Population) 
*Listing 16.2.7.4 
Events of Clinical Significance (Safety Analysis Population) 
Listing 16.2.7.5 
Overdose Events  (Safety Analysis Population) 
SECTION 16.2.8:  Listing of Individual Laboratory Measurements by Subject Number 
Listing 16.2.8.1.1 
Clinical Laboratory Results (Conventional Units): Biochemistry (Safety Analysis 
Population) 
Listing 16.2.8.1.2 
Clinical Laboratory Results (Standard International Units): Biochemistry (Safety 
Analysis Population) 
Listing 16.2.8.2.1 
Clinical Laboratory Results (Conventional Units): Hematology (Safety Analysis 
Population) 
Listing 16.2.8.2.2 
Clinical Laboratory Results (Standard International Units): Hematology (Safety 
Analysis Population) 
Listing 16.2.8.2.3 
Local Clinical Laboratory Results and Corresponding Central Laboratory Results 
(Conventional Units): Hematology (Safety Analysis Population) 
Listing 16.2.8.3 
Clinical Laboratory Results: Urinalysis (Safety Analysis Population) 


 
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Listing 16.2.8.4 
Clinical Laboratory Reference Ranges 
Listing 16.2.8.5.1 
Abnormal Clinical Laboratory Values (in Conventional Units) (Safety Analysis 
Population) 
Listing 16.2.8.5.2 
Abnormal Clinical Laboratory Values (Standard International Units) (Safety 
Analysis Population) 
SECTION 16.2.9: Vital Signs, Physical Findings And Other Observations Related To 
Safety 
Listing 16.2.9.1.1 
Vital Signs - Observed Values (Safety Analysis Population) 
Listing 16.2.9.1.2 
Vital Signs – Change from Baseline (Safety Analysis Population) 
Listing 16.2.9.2.1 
12-Lead Electrocardiogram – Observed Values and Investigator Interpretation 
(Safety Analysis Population) 
Listing 16.2.9.2.2 
12-Lead Electrocardiogram – Change from Baseline Values (Safety Analysis 
Population) 
Listing 16.2.9.3 
Height, Observed and Change from Baseline Weight and BMI (Safety Analysis 
Population) 
Listing 16.2.9.4 
Ophthalmological LOCS III Grading Scores and Best Corrected Visual Acuity 
Scores Observed and Change from Baseline (Safety Analysis Population)  
Listing 16.2.9.5.1 
Columbia-Suicide Severity Rating Scale, Suicidal Ideation (Safety Analysis 
Population) 
Listing 16.2.9.5.2 
Columbia-Suicide Severity Rating Scale, Ideation Intensity and Behavior Detail 
(Safety Analysis Population) 


 
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APPENDIX A: CLINICALLY SIGNIFICANT LABORATORY OUTLIER CRITERIA 
 
Outlier Criteria [a] 
Analyte 
SI Units 
Conventional Units 
HEMATOLOGY 
 
 
Hemoglobin (increase) 
Value >2 mmol/L above the ULN 
Value >2 g/dL above the ULN 
Hemoglobin (decrease) 
Value <6.2 mmol/L 
Value <10 g/dL 
Leukocytes (decrease) 
Value <3.0 x109/L 
Value <3.0 x103/µL 
Lymphocytes (increase) 
Value >4.0 x109/L 
Value >4.0 x103/µL 
Lymphocytes (decrease) 
Value <0.8 x109/L 
Value <0.8 x103/µL 
Neutrophils (decrease) 
Value <1.5 x109/L 
Value <1.5 x103/µL 
Platelets (decrease) 
Value <75 x109/L 
Value <75 x103/µL 
BIOCHEMISTRY 
 
 
Albumin (decrease) 
Value <30 g/L 
Value <3 g/dL 
Alkaline phosphatase (increase) 
Value >2.5 xULN 
Value >2.5 xULN 
ALT (increase) 
Value >2.5 xULN 
Value >2.5 xULN 
AST (increase) 
Value >2.5 xULN 
Value >2.5 xULN 
Bicarbonate (decrease) 
Value <16 mmol/L  
Value <16 mEq/L  
Bilirubin (increase) 
Value >1.5 xULN 
Value >1.5 xULN 
Calcium (decrease) 
Value <2.0 mmol/L 
Value <8.0 mg/dL 
Calcium (increase) 
Value >2.9 mmol/L 
Value >11.5 mg/dL 
Cholesterol (increase) 
Value >7.75 mmol/L 
Value >300 mg/dL 
CPK (increase) 
Value >2.5 xULN 
Value >2.5 xULN 
Creatinine (increase) 
Value >1.5 xULN 
Value >1.5 xULN 
GGT (increase) 
Value >2.5 xULN 
Value >2.5 xULN 
Glucose (decrease) 
Value <3.0 mmol/L 
Value <55 mg/dL 
Glucose (increase) 
Value >8.9 mmol/L 
Value >160 mg/dL 
Magnesium (decrease) 
Value <0.5 mmol/L 
Value <1.2 mg/dL 
Magnesium (increase) 
Value >1.23 mmol/L 
Value >3.0 mg/dL 
Phosphate (decrease) 
Value <0.8 mmol/L 
Value <2.5 mg/dL 
Potassium (decrease) 
Value < 3.0 mmol/L 
Value < 3.0 mEq/L 
Potassium (increase) 
Value >5.5 mmol/L 
Value >5.5 Meq/L 
Sodium (decrease) 
Value <130 mmol/L 
Value <130 mEq/L 
Sodium (increase) 
Value >150 mmol/L 
Value >150 mEq/L 
Triglycerides (increase) 
Value >2.5 xULN 
Value >2.5 xULN 
Uric acid (increase) 
Value >0.59 mmol/L 
Value >10 mg/dL 
URINALYSIS 
 
 
Hemoglobin, urine (increase) 
Present 
Present 
Protein, urine (increase) 
Result of 2+ or 3+ 
Result of 2+ or 3+ 
Notes: 
LLN = lower limit of normal range; ULN = upper limit of normal range; ALT = alanine aminotransferase; AST = 
aspartate aminotransferase; CPK = creatine phosphokinase; GGT = gamma-glutamyl transpeptidase. 
[a] Outlier values based on Grade 2 (moderate) or higher from the Common Toxicity Criteria for Adverse Events v3.0 (CTCAE) 
Publish Date: August 9, 2006. 


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APPENDIX B: CRITERIA FOR CLINICALLY NOTEWORTHY LABORATORY 
CHANGES 
Analyte 
Criteria  
Hemoglobin 
Male: < 0.85 x Baseline value 
Female: < 0.85 x Baseline value 
Hematocrit 
Male: < 0.85 x Baseline value 
Female: < 0.85 x Baseline value 
White Blood Cell Count (WBC) 
if Baseline value is ≤ LLN, < 0.85 x Baseline value or  
if Baseline value is ≥ ULN, > 1.15 x Baseline value or 
if Baseline value is > ULN & a post-treatment value is < LLN or 
if Baseline value is < LLN & a post-treatment value is > ULN 
Neutrophils 
< 0.85 x Baseline value 
Eosinophils 
> 1.5 x Baseline value 
Platelet Count 
if Baseline value is ≤ LLN, < 0.85 x Baseline value 
Alkaline Phosphatase 
> 1.5 x Baseline value 
ALT 
> 1.5 x Baseline value 
AST 
> 1.5 x Baseline value 
CPK 
> 1.5 x Baseline value 
Total Bilirubin 
> 1.25 x Baseline value 
Albumin 
< 0.9 x Baseline value 
Glucose 
if Baseline value is < LLN, < 0.8 x Baseline value or  
if Baseline value is > ULN, > 2 x Baseline value or 
if Baseline value is > ULN & a post-treatment value is < LLN or 
if Baseline value is < LLN & a post-treatment value is > ULN 
Sodium 
if Baseline value is < LLN, < 0.95 x Baseline value or  
if Baseline value is > ULN, > 1.05 x Baseline value or 
if Baseline value is > ULN & a post-treatment value is < LLN or 
if Baseline value is < LLN & a post-treatment value is > ULN 
Potassium 
if Baseline value is < LLN, < 0.9 x Baseline value or  
if Baseline value is > ULN, > 1.1 x Baseline value or 
if Baseline value is > ULN & a post-treatment value is < LLN or 
if Baseline value is < LLN & a post-treatment value is > ULN 
Chloride 
if Baseline value is < LLN, < 0.9 x Baseline value or  
if Baseline value is > ULN, > 1.1 x Baseline value or 
if Baseline value is > ULN & a post-treatment value is < LLN or 
if Baseline value is < LLN & a post-treatment value is > ULN 
Calcium 
if Baseline value is < LLN, < 0.9 x Baseline value or  
if Baseline value is > ULN, > 1.1 x Baseline value or 
if Baseline value is > ULN & a post-treatment value is < LLN or 
if Baseline value is < LLN & a post-treatment value is > ULN 
Blood Urea Nitrogen (BUN) 
> 1.2 x Baseline value 
Creatinine 
> 1.33 x Baseline value 
LDH 
> 1.5 x Baseline value 
Notes: 
LLN = lower limit of normal range; ULN = upper limit of normal range; ALT = alanine aminotransferase; AST = 
aspartate aminotransferase; CPK = creatine phosphokinase; LDH = lactate dehydrogenase.


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APPENDIX C: 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 (AE): 
Exposure 
Is there evidence that the subject/subject 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.) 
 


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Rechallenge 
Was the subject/subject reexposed 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 
Study Drug 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 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.