Clinical trial NCT04345471
Conditions: Major Depressive Disorder
Sponsor: Mochida Pharmaceutical Company, Ltd.
Start date: 2020-05-18; Completion date: 2022-09-14
Enrollment: 615 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to verify the efficacy and evaluate the safety of 8-week once-daily oral administration of MD-120 in Japanese patients with depression.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None
Interventions: intervention 1: Desvenlafaxine 100 mg intervention 2: Desvenlafaxine 50 mg intervention 3: Placebo
Intervention descriptions: intervention 1: once daily dosing for 8 weeks intervention 2: once daily dosing for 8 weeks intervention 3: once daily dosing for 8 weeks

Protocol documents:
Prot_000.pdf: 
A Placebo-controlled Study of MD-120 in 
Depression Patients 
Study Protocol 
Mochida Pharmaceutical Co., Ltd.
Protocol code: 
MD120101 
Date of Creation: March 2, 2020 
Version Number: Version 1.0
ClinicalTrials.gov Identifier: NCT04345471 
CONFIDENTIAL 




Protocol synopsis 
i 
 
[Abbreviations used in this study protocol] 
Abbreviations 
English terms 
ALP 
Alkaline phosphatase 
ALT (GPT) 
Alanine aminotransferase (glutamic-pyruvic transaminase) 
AST (GOT) 
Aspartate aminotransferase (glutamic-oxaloacetic transaminase) 
CGI-I 
Clinical Global Impression-Improvement Scale 
CGI-S 
Clinical Global Impression-Severity Scale 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CYP 
Cytochrome P450 
DSM-5 
Diagnostic and Statistical Manual of 
Mental Disorders, 5th edition 
eCOA 
Electronic Clinical Outcome Assessment 
EDC 
Electronic Data Capture 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration (U.S.) 
γ-GTP 
γ-Glutamyl transpeptidase 
HAMD17 
Hamilton Depression Rating Scale, 17 items 
HbA1c 
Glycosylated Hemoglobin 
HDL 
High Density Lipoprotein 
ITT 
Intention-To-Treat 
JAN 
Japanese Accepted Names for Pharmaceuticals 
LDL 
Low Density Lipoprotein 
LOCF 
Last Observation Carried Forward 
MADRS 
Montgomery Åsberg Depression Rating Scale 
MAO 
Monoamine oxidase 
MedDRA/J 
Medical Dictionary for Regulatory Activities/Japanese version 
M.I.N.I. 
Mini International Neuropsychiatric Interview 
NaSSA 
Noradrenergic and Specific Serotonergic Antidepressant 
PPS 
Per Protocol Set 
QIDS16-SR-J 
The 16-item Quick Inventory of Depressive Symptomatology self-report version 
SDS 
Sheehan Disability Scale 
SNRI 
Serotonin Noradrenaline Reuptake Inhibitor 
SSRI 
Selective Serotonin Reuptake Inhibitor 
TMS 
Transcranial Magnetic Stimulation 
 


Protocol synopsis 
ii 
 
[Terms in this study protocol] 
Terms 
Explanations 
MD-120 
Development code of the investigational drug of this clinical study 
 
Nonproprietary name: Desvenlafaxine succinate hydrate (JAN) 
Overseas proprietary name: PRISTIQ® 
Screening period 
Period from “the start of any observation or test scheduled at the initial 
registration” to “the day of the second registration,” when the subject eligibility 
is reviewed. 
Run-in period 
Period from “the next day of the second registration” to “the day of 
randomization” or “the time of completion of all observation and tests 
scheduled at the visit at the time of premature termination”, when the subject’s 
stability of symptom and compliance are checked. 
Treatment period 
Period from “the next day of randomization” to “the day of the Week 8 visit 
during treatment period” or “the visit at premature termination”, when the 
efficacy and safety are evaluated. 
Follow-up period 
Period from “the next day of the Week 8 visit during treatment period” or  
“the visit at the time of premature termination” to “the time of completion of all 
observation and tests scheduled at the end of follow-up period” or “the time of 
completion of all observation and tests scheduled at the visit at the time of 
premature termination during follow-up period*”, when the post-treatment safety 
is evaluated. 
Baseline 
At the end of run-in period 
Amount of change 
(Score at evaluation timepoint) - (Baseline score) 
Response  
[MADRS] 
Criteria for response: “Total MADRS score at evaluation timepoint is ≤50% of 
baseline score.” 
[HAMD17] 
Criteria for response: “Total HAMD17 score at evaluation timepoint is ≤50% 
of baseline score.” 
[CGI-I] 
Criteria for response: “Evaluated as “1. Very much improved” or “2. Much 
improved” at evaluation timepoint” 
Remission 
[MADRS] 
Criteria for remission: “Total MADRS score at evaluation timepoint is ≤10.” 
[HAMD17] 
Criteria for remission: “Total HAMD17 score at evaluation timepoint is ≤7.” 
* The time of premature termination before Week 1 visit during follow-up period. 
 
 




Protocol synopsis 
iv 
 
 
(3) Follow-up period 
[Placebo group] 
• 
The subjects will receive the placebo (2 placebo tablets) from the 
start to Week 1 visit of follow-up period. 
[MD-120 50 mg group] 
• 
The subjects will receive the placebo (2 placebo tablets) from the 
start to Week 1 visit of follow-up period. 
[MD-120 100 mg group] 
• 
The subjects will receive MD-120 50 mg (1 MD-120 50 mg tablet) 
and the placebo (1 placebo tablet) from the start to Week 1 visit of 
follow-up period. 
Primary endpoint 
(1) Efficacy 
Change in total MADRS score from baseline to Week 8 visit during 
treatment period 
(2) Safety 
Adverse events during treatment period and follow-up period 
Secondary endpoint 
(1) Efficacy 
• 
Response evaluated by total MADRS score at Week 8 visit 
during treatment period 
(Criteria for response: “Total MADRS score at Week 8 visit 
during treatment period is ≤50% of baseline score.”) 
• 
Remission evaluated by total MADRS score at Week 8 visit 
during treatment period 
(Criteria for remission: “Total MADRS score at Week 8 visit 
during treatment period is ≤10.”) 
• 
Change in total HAMD17 score from baseline to Week 8 visit 
during treatment period 
• 
Response evaluated by total HAMD17 score at Week 8 visit 
during treatment period 
(Criteria for response: “Total HAMD17 score at Week 8 visit 
during treatment period is ≤50% of baseline score.”) 
• 
Remission evaluated by total HAMD17 score at Week 8 visit 
during treatment period 
(Criteria for remission: “Total HAMD17 score at Week 8 visit 
during treatment period is ≤7.”) 
• 
CGI-I at Week 8 of the treatment period 
• 
Response evaluated by CGI-I at Week 8 visit during treatment 
period 
(Criteria for response: “Evaluated as “1. Very much improved” 
or “2. Much improved” at Week 8 visit during treatment 
period”) 
• 
Change in CGI-S from baseline to Week 8 visit during treatment 
period 
• 
Change in total QIDS16-SR-J score from baseline to Week 8 
visit during treatment period 
• 
Change in total SDS score from baseline to Week 8 visit during 
treatment period 


Protocol synopsis 
v 
 
(2) Safety 
1) 
Adverse drug reactions (ADRs) during treatment period and 
follow-up period 
2) 
Adverse events and ADRs during treatment period 
3) 
Adverse events and ADRs during follow-up period 
Inclusion criteria 
(At the initial registration) 
(1) Patients who have consented in writing to participate in this clinical 
study 
(2) Outpatients aged ≥20 at the time of informed consent 
(3) Patients with "depression" who have experienced non-psychotic or 
non-mixed single or repeated episode, which has been diagnosed 
according to DSM-5 (for DSM-5-based diagnosis, Mini-
International Neuropsychiatric Interview [M.I.N.I.] version 7.0.2 
will be used as a diagnostic aid tool) 
(4) Patients in whom the current depressive episode has persisted for ≥3 
months and ≤18 months if it is single or for ≥1 months and ≤18 
months if it is recurrent, according to DSM-5 
(5) Patients with the total score of ≥20 in Hamilton Depression Rating 
Scale (HAMD) 17 and the sub-score of ≥2 for Item 1 (depressed 
mood) 
(6) Patients with the score of ≥4 in CGI-S 
(7) Patients with the total score of ≥16 in Quick Inventory of Depressive 
Symptomatology (QIDS)16-SR-J 
Exclusion criteria 
(At the initial registration) 
(1) Patients judged by the (sub-)investigator to have any of the 
following disorders classified according to DSM-5 (using a 
diagnostic aid tool of M.I.N.I. version 7.0.2 if appropriate) 
• 
Intellectual disabilities 
• 
Autism spectrum syndrome/Autism spectrum disorder 
• 
Attention deficit and hyperkinesia/Attention deficit and 
hyperactivity disorder 
• 
Schizophrenia spectrum disorder and other psychotic disorders 
• 
Bipolar and related disorders 
• 
Obsessive disorder syndrome and related syndromes/Obsessive 
compulsive disorder and related disorders 
• 
Psychic trauma and stress-related disorders 
• 
Disassociation syndrome/dissociative disorders 
• 
Eating behavior disorders and eating disorders 
• 
Substance-related disorders (except for those caused by tobacco 
or caffeine) 
• 
Neurocognitive deficiency 
• 
Personality disorders 
(2) Patients concurrently with any of the following disorders classified 
according to DSM-5, which is also positioned as the main disorder 
by the (sub-)investigator (using a diagnostic aid tool of M.I.N.I. 
version 7.0.2 if appropriate) 
• 
Anxiety/Anxiety disorders 
(3) Patients judged by the (sub-)investigator to have a past history of 
any of the following disorders classified according to DSM-5 (using 
a diagnostic aid tool of M.I.N.I. version 7.0.2 if appropriate) 


Protocol synopsis 
vi 
 
• 
Schizophrenia spectrum disorder and other psychotic disorders 
• 
Bipolar and related disorders 
• 
Substance-related disorders (except for those caused by tobacco 
or caffeine) 
(4) Patients meeting any of the followings: 
• 
Patients who presented a certain form of followings “suicidal 
behavior” (suicide attempt, interrupted suicide attempt, 
withdrawn suicide attempt, and preparatory behavior) within 1 
year before the start of the screening period as assessed 
according to Columbia-Suicide Severity Rating Scale (C-SSRS) 
• 
Patients meeting B14 or B16 under “B. Suicidal ideation, Self-
injurious and Suicidal behavior” or B18 within past 12 months 
in M.I.N.I. version 7.0.2 
• 
Patients with the sub-score of ≥3 for Item 11 (suicide) in 
HAMD17 
• 
Patients with the sub-score of ≥5 for Item 10 (Thought of Death 
or Suicide) in Montgomery-Asberg Depression Scale (MADRS) 
• 
Patients with the sub-score of ≥3 for Item 12 (Suicidal ideation) 
in QIDS16-SR-J 
• 
Patients judged by the (sub-)investigator to be at a high risk of 
suicide 
(5) Patients who have a first-degree relative (parent, sibling, and child) 
with bipolar and related disorders 
(6) Patients with a past history of or co-existing convulsive disorder 
such as epilepsy (excluding fever seizure) 
(7) Patients with a past history of or co-existing acute angle closure 
glaucoma or elevated intraocular pressure 
(8) Patients who have received desvenlafaxine 
(9) Patients who received venlafaxine for the current depressive episode 
(10) Patients with serious drug allergy or hypersensitivity, or 
hypersensitivity to venlafaxine or desvenlafaxine 
(11) Patients who received other investigational drugs within 16 weeks 
before the start of the screening period 
(12) Patients who received but were not responsive to two or more 
antidepressants given at an adequate dose (in the range of approved 
dose excluding initial low dose, and doctors who treat the patients 
judged to be adequate) for at least 4 weeks for the current or past 
depressive episode 
(13) Patients who have undergone electroconvulsive therapy or 
transcranial magnetic stimulation (TMS) therapy 
(14) Patients with a history of hospitalization owing to psychiatric 
disorders excluding depression 
(15) Patients who received any antipsychotics within 2 weeks before the 
start of screening period (or within 6 months for a depot 
formulation) 
(16) Patients who received a hypnotic/sedative (excluding zopiclone, 
zolpidem, and eszopiclone) within 2 weeks before the start of 
screening period 


Protocol synopsis 
vii 
 
(17) Patients with a co-existing serious hepatic, renal, hematological, 
respiratory, gastrointestinal, or cardiovascular disease, or 
metabolism/electrolytes abnormality 
(18) Female patients who are or may be pregnant, are breast-feeding, or 
male and female patients who are intend to conceive during the 
study period 
(19) Patients who are otherwise judged by the (sub-) investigator to be 
ineligible for this clinical study 
Inclusion criteria 
(At the second registration) 
(1) Patients whose depressive episode at the time of the initial 
registration persists 
(2) Patients with the total score of ≥20 in Hamilton Depression Rating 
Scale (HAMD) 17 and the sub-score of ≥2 for Item 1 (depressed 
mood) 
(3) Patients with the score of ≥4 in CGI-S 
(4) Patients with the total score of ≥16 in Quick Inventory of Depressive 
Symptomatology (QIDS)16-SR-J 
Exclusion criteria 
(At the second registration) 
(1) Patients meeting any of the followings: 
• 
Patients who presented a certain form of followings “suicidal 
behavior” (suicide attempt, interrupted suicide attempt, 
withdrawn suicide attempt, and preparatory behavior) between 
the initial and second registrations as assessed according to C-
SSRS 
• 
Patients with the sub-score of ≥3 for Item 11 (suicide) in 
HAMD17 
• 
Patients with the sub-score of ≥5 for Item 10 (Suicidal 
Thoughts) in Montgomery-Asberg Depression Scale (MADRS) 
• 
Patients with the sub-score of ≥3 for Item 12 (Thought of Death 
or Suicide) in QIDS16-SR-J 
• 
Patients judged by the (sub-)investigator to be at a high risk of 
suicide 
(2) Patients who have received a concomitant drug or therapy prohibited 
from the start of screening period 
(3) Patients who have deviated from the conditions for concomitant use 
of hypnotic/sedative that are allowed for use from the start of 
screening period 
(4)  Patients determined by the (sub-)investigator to be ineligible for the 
study based on the result of diagnosis confirmation by the Clinical 
data analytics committee regarding the assessment at the time of the 
initial registration by the (sub-)investigator for the diagnosis 
(5) Patients who are otherwise judged by the (sub-) investigator to be 
ineligible for this clinical study 
Inclusion criteria 
(At randomization) 
(1) Patients whose depressive episode at the time of the initial 
registration persists 
(2) Patients with the total score of ≥20 in Hamilton Depression Rating 
Scale (HAMD) 17 and the sub-score of ≥2 for Item 1 (depressed 
mood) 
(3) Patients with the score of ≥4 in CGI-S 


Protocol synopsis 
viii 
 
(4) Patients with the total score of ≥16 in Quick Inventory of Depressive 
Symptomatology (QIDS)16-SR-J 
Exclusion criteria 
(At randomization) 
(1) Patients meeting any of the followings: 
• 
Patients who presented a certain form of followings “suicidal 
behavior” (suicide attempt, interrupted suicide attempt, 
withdrawn suicide attempt, and preparatory behavior) between 
the second registration and randomization as assessed 
according to C-SSRS 
• 
Patients with the sub-score of ≥3 for Item 11 (suicide) in 
HAMD17 
• 
Patients with the sub-score of ≥5 for Item 10 (Suicidal 
Thoughts) in Montgomery-Asberg Depression Scale (MADRS) 
• 
Patients with the sub-score of ≥3 for Item 12 (Thought of Death 
or Suicide) in QIDS16-SR-J 
• 
Patients judged by the (sub-)investigator to be at a high risk of 
suicide 
(2) Patients whose total score in HAMD17 deteriorated or improved by 
≥25% from the second registration 
(3) Patients who missed taking the investigational drug on ≥2 days 
during run-in period 
(4) Patients who have received a concomitant drug or therapy prohibited 
from the start of screening period 
(5) Patients who have deviated from the conditions for concomitant use 
of hypnotic/sedative that are allowed for use from the start of 
screening period 
(6) Patients determined by the (sub-)investigator to be ineligible for the 
study based on the result of diagnosis confirmation by the Clinical 
data analytics committee regarding the assessment at the time of the 
initial registration by the (sub-)investigator for the diagnosis  
(7) Patients who are otherwise judged by the (sub-) investigator to be 
ineligible for this clinical study 
Prohibited concomitant drugs 
Concomitant drugs prohibited from the start of screening period to the end 
of follow-up period 
(1) 
MAO inhibitors 
(2) 
Investigational drugs other than MD-120 
(3) 
Desvenlafaxine and venlafaxine other than MD-120 
Concomitant drugs prohibited from the start of screening period to the 
completion of all observation and tests scheduled at the end of treatment 
period 
(4) 
Antipsychotic drugs 
(5) 
Antianxiety drugs 
(6) 
Hypnotic/sedative drugs (excluding zopiclone, zolpidem, and 
eszopiclone) 
(7) 
Hypnotic drugs 
(8) 
Antidepressant drugs 
(9) 
Antimanic drugs 
(10) Antiepileptic drugs 
(11) Antiparkinson drugs 


Protocol synopsis 
ix 
 
(12) Chinese medicines indicated for treatment of anxiety, insomnia, and 
depressed mood 
(13) Drugs 
containing 
serotonin 
precursor 
(L-tryptophan, 
5-
hydroxytryptophan, etc.) 
(14) Drugs containing tramadol 
(15) Triptan drugs 
Prohibited concomitant 
therapies 
Concomitant therapies prohibited from the start of screening period to the 
end of follow-up period 
(1) 
Electroconvulsive therapy 
(2) 
Transcranial magnetic stimulation (TMS) therapy 
(3) 
Supplement containing St. John 's Wort as the active ingredient 
Concomitant therapies prohibited from the start of screening period to the 
completion of all observation and tests scheduled at the end of treatment 
period 
(4) 
Systematized psychotherapies (including cognitive behavior 
therapies) 
Allowed concomitant drugs 
Subjects receiving zopiclone, zolpidem, or eszopiclone, at 2 weeks 
before the start of the screening period will be allowed to concomitantly 
use such hypnotics/sedatives. They will be allowed to use only 1 drug 
from the start of screening period to the completion of all observation and 
tests scheduled at the end of treatment period when needed and on ≤3 
days per week, but prohibited to use it within 24 hours before each 
scheduled visit. The dosage shall not exceed 7.5 mg/night for zopiclone, 
5 mg/night for zolpidem, and 2 mg/night for eszopiclone.  
Statistical analysis 
Analysis of the primary efficacy endpoint: 
• 
The efficacy analysis will be mainly performed on the full analysis 
set (FAS).  
• 
A Mixed-effects Model for Repeated Measures (MMRM) will be 
used for the main analysis of the primary efficacy endpoint. The 
analytical model will use the change in total MADRS score from 
baseline to each evaluation timepoint as a response variable; the 
treatment group, assessment timepoint, and the interaction between 
the treatment group and assessment timepoint as fixed effects, the 
total MADRS score at the baseline as a covariate, the structure of  
error variance as Unstructured, and Kenward Roger as degrees of 
freedom adjustment. Based on this analytical model, changes in total 
MADRS score from the baseline to Week 8 visit during treatment 
period in the MD-120 50 mg and 100 mg groups will be compared 
to that in the placebo group. For missing data on the response 
variable, no data will be substituted. 
• 
Adjustment of multiplicity will be performed in the main analysis on 
the efficacy primary endpoint according to a closed testing 
procedure. Results on the efficacy primary endpoint will be firstly 
compared between the placebo group and MD-120 50 mg group 
with a significance level of 5%. Only when Hypothesis 1 is verified, 
a comparison between the placebo group and MD-120 100 mg group 
will be made with significance level of 5%. 
[Hypothesis 1] Superiority of the MD-120 50 mg group to the 


Protocol synopsis 
x 
 
 placebo group 
[Hypothesis 2] Superiority of the MD-120 100 mg group to the  
placebo group 
 
 
 
 
 
 
 
 
 
 
 
Study period 
April 2020 to December 2022 
 








Table of Contents 
 
 
Table of Contents 
1. Study objective ..................................................................................................................... 1 
2. Background information ..................................................................................................... 2 
2.1 
Name and explanation of the investigational drug ............................................. 2 
2.2 
Background for this clinical study ........................................................................ 2 
2.3 
Summary of known and potential risks and benefits in the subjects ............... 4 
3. Study design ....................................................................................................................... 12 
3.1 
Study type .............................................................................................................. 12 
3.2 
Anticipated period of study participation .......................................................... 12 
3.3 
Treatment groups ................................................................................................. 14 
3.4 
Dosage and administration .................................................................................. 14 
3.5 
Endpoints ............................................................................................................... 16 
4. Inclusion and exclusion criteria of subjects ................................................................... 18 
4.1 
Target ..................................................................................................................... 18 
4.2 
Inclusion and exclusion criteria .......................................................................... 18 
5. Clinical study procedures ................................................................................................. 24 
5.1 
Informed consent .................................................................................................. 24 
5.2 
Observation and test, and evaluation schedule ................................................ 25 
6. Investigational drug ........................................................................................................... 31 
6.1 
Dosage form and content of investigational drug ............................................ 31 
6.2 
Procedures for management of the investigational drug ................................ 31 
6.3 
Method for randomization and blinding ............................................................. 31 
6.4 
Procedure for unblinding with the investigational drug assignment table .... 33 
7. Treatment and instructions for subjects ......................................................................... 34 
7.1 
Prohibited and allowed therapies ....................................................................... 34 
7.2 
Instructions for subjects ...................................................................................... 36 
8. Withdrawal criteria and procedures for individual subjects ......................................... 38 
8.1 
Withdrawal criteria for individual subjects ........................................................ 38 
8.2 
Withdrawal procedures for individual subjects ................................................ 39 
9. Efficacy evaluation............................................................................................................. 41 
9.1 
Efficacy endpoints ................................................................................................ 41 
9.2 
Timing and method of efficacy evaluation ......................................................... 41 
10. Safety evaluation.............................................................................................................. 43 


Table of Contents 
 
 
10.1 Safety endpoints ................................................................................................... 43 
10.2 Timing and method of safety evaluation ............................................................ 43 
11. Equalization of evaluation, and Clinical data analytics ............................................... 45 
11.1 Equalization of evaliation ..................................................................................... 45 
11.2 Clinical data analytics .......................................................................................... 45 
12. Adverse events ................................................................................................................. 46 
12.1 Definition of adverse events ................................................................................ 46 
12.2 Survey period and items for adverse events ..................................................... 46 
12.3 Definition of serious adverse events and procedures for collecting, 
recording, and reporting such events ................................................................ 47 
12.4 Follow-up survey for serious adverse events and adverse events causally 
related to the investigational drug ...................................................................... 48 
13. Other survey and evaluation items ................................................................................ 49 
13.1 Subject baseline characteristics ......................................................................... 49 
13.2 Concomitant treatment ......................................................................................... 49 
13.3 Comorbidities ........................................................................................................ 49 
13.4 Pharmacokinetic evaluation ................................................................................ 50 
13.5 Pregnancy test ...................................................................................................... 50 
13.6 Use status of the investigational drug ............................................................... 50 
14. Preparation, correction, and retention of case report forms, etc. .............................. 51 
14.1 Target necessary for preparation of case report form ..................................... 51 
14.2 Structure of case report form .............................................................................. 51 
14.3 Preparation of case report form .......................................................................... 51 
14.4 Retention of case report forms ........................................................................... 51 
14.5 Direct access to source documents ................................................................... 51 
14.6 Identification of data that are directly entered in the case report form and 
should be classified into source documents..................................................... 52 
15. Statistical analysis ........................................................................................................... 53 
15.1 Purpose of the analysis and summary ............................................................... 53 
15.2 Analysis sets ......................................................................................................... 53 
15.3 Statistical analysis methodology ........................................................................ 54 
15.4 Target sample size and its rationale ................................................................... 57 
15.5 Significance level and confidence interval ........................................................ 57 
15.6 Data adoption period and conditions ................................................................. 57 
15.7 Handling of missing data and abnormal specimens ........................................ 57 
15.8 Analysis plan ......................................................................................................... 58 


Table of Contents 
 
 
15.9 Procedure for reporting a change or deviation from the initial statistical 
analysis plan .......................................................................................................... 58 
16. Compliance with and deviations from the study protocol as well as revision ......... 59 
16.1 Compliance with and deviations from the study protocol ............................... 59 
16.2 Revision of study protocol................................................................................... 59 
17. Ethical matters ................................................................................................................. 60 
17.1 Compensation for study-related injuries ........................................................... 60 
17.2 Protection of subjects’ privacy ........................................................................... 60 
17.3 Handling of measurement specimens ................................................................ 60 
18. Criteria for prematurely terminating a part and the whole of the clinical study and 
the procedures ....................................................................................................................... 61 
19. Quality, retention, and publication of information ....................................................... 61 
19.1 Quality control and assurance of clinical study ................................................ 61 
19.2 Data handling and record retention .................................................................... 61 
19.3 Laws, regulations, standards, etc. to be complied with for conduct of this 
clinical study ......................................................................................................... 62 
19.4 Agreement regarding publication ....................................................................... 62 
20. Payment and insurance ................................................................................................... 63 
20.1 Payment ................................................................................................................. 63 
20.2 Insurance ............................................................................................................... 63 
21. Study period ..................................................................................................................... 63 
22. Study administrative structure ....................................................................................... 63 
22.1 Name of sponsor, address, and telephone number.......................................... 63 
22.2 Person authorized to put the signature on the study protocol as a 
representative of the sponsor ............................................................................. 63 
22.3 Clinical study conducting manager, monitoring manager, pharmacokinetic 
analysis manager, data management manager, statistical analysis manager, 
safety information manager, and audit manager .............................................. 63 
22.4 Medical expert on the sponsor ............................................................................ 64 
22.5 Study center and investigator ............................................................................. 64 
22.6 Registration center ............................................................................................... 64 
22.7 Randomization registration center ..................................................................... 65 
22.8 Laboratory for general laboratory tests ............................................................. 65 
22.9 Laboratory for drug concentration measurement ............................................. 65 
 


Table of Contents 
 
 
22.10 Reviewer training, and Clinical data analyst...................................................... 65 
22.11 Monitoring contract research organization ....................................................... 66 
23. References ........................................................................................................................ 67 
 
 




1. Study objective 
1 
1. Study objective 
To verify the efficacy and evaluate the safety of 8-week once-daily oral administration of MD-120 (50 
mg and 100 mg) in Japanese patients with depression. 


2. Background information 
2 
2. Background information 
2.1 Name and explanation of the investigational drug 
[Investigational ingredient code]  
MD-120 
 
[Nonproprietary name (active ingredient) ] 
Desvenlafaxine succinate hydrate (JAN) 
 
[Chemical name] 
RS-4-[2-dimethylamino-1-(1-hydroxycyclohexyl)ethyl] phenol (free base) 
 
[Structural formula] 
 
 
[Molecular formula and weight] 
Molecular formula: C16H25NO2 (free base), C16H25NO2•C4H6O4•H2O (succinate monohydrate) 
Molecular weight: 
263.38 (free base), 399.48 (succinate monohydrate) 
 
[Storage method] 
Store it away from direct sunlight at room temperature 
 
[Dosage form and appearance] 
Extended-release tablet: A pale red square-shaped film-coated tablet with a pyramidal shape on one side 
 
2.2 Background for this clinical study 
2.2.1 
Background of and treatment method for the target disorder 
Depression is a psychiatric disorder which causes the degradation of the quality of life associated with 
psychiatric symptoms such as depressed mood or loss of interest or joy and somatic symptoms such as 
weight decreased or sleeplessness. The life-time morbidity rate of depression is 6% in Japan and twice 
higher in females than in males1). Depression is common not only among young adults but also among 
middle-aged and senior citizens in Japan1). According to the MHLW patient survey in 2017, 0.495 million 
men and 0.781 million female receive treatment for their mood disorder including depression, and most 
common in the 40s of all age brackets2). 


2. Background information 
3 
As basic treatment policies for depression, basic intervention are performed by supportive psychiatric 
therapy and psychological training at first, then drug therapy, somatic therapy, and psychiatric therapy are 
started as appropriate for the symptoms, for any severity of depression, mild, moderate, and severe. Drug 
therapy plays the central role for moderate to severe depression3).  
Conventional drugs such as tricyclic and tetracyclic antidepressants and novel antidepressants such as 
SSRI, SNRI, and NaSSA are used as drug therapy for depression. According to the Japanese Society of 
Mood Disorders Guideline (hereinafter, the “JSMD Guideline”), novel antidepressants are primarily used 
as the first-line drugs in many cases from the aspect of tolerability3. Also, antidepressants are not used in 
combination unless otherwise specified and are switched to other antidepressants if an antidepressant used 
at an adequate dose for an adequate period is not adequately effective3). Furthermore, depression treatment 
processes are classified into three phases, the acute phase when pathological depressed state attenuates to 
remission, the continuation phase when remission state is maintained for 3-6 months followed by recovery, 
and the maintenance phase following recovery. It is considered desirable to follow the patients for 
approximately 8 weeks to evaluate the treatment response to drug therapy in the acute phase treatment3). 
 
2.2.2 
Significance of development of MD-120 
MD-120 is a preparation containing desvenlafaxine succinate, which is a succinate of metabolite of 
venlafaxine (Effexor®), and made to release the active ingredient slowly by the modification of 
desvenlafaxine succinate. MD-120 is classified as a SNRI like venlafaxine. As of May 2019, MD-120 is 
approved in 44 countries including the U.S., Canada, Australia, and South Korea for the treatment of major 
depressive disorder (MDD) at the recommended dose of 50 mg/day. 
In Japan, 3 SNRIs (milnacipran hydrochloride, duloxetine hydrochloride, and venlafaxine hydrochloride) 
have been marketed; all of which need to be started with low dose and gradually increased to the 
conventional dose4)-6). On the other hand, MD-120 is recommended to use at the clinically recommended 
dose from the first administration in overseas package insert7).  
MD-120 whose main metabolic pathway is glucuronate conjugation is considered to have a lower risk of 
drug interaction than venlafaxine which is metabolized to desvenlafaxine via CYP2D6. Furthermore, the 
overseas package insert specifies that the dose of venlafaxine whose dose needs to be halved or less in 
patients with mild to severe hepatic function disorder because its blood concentration is increased as 
hepatic function disorder becomes severer8). On the other hand, MD-120 showed no increase in its blood 
concentration according to the severity of hepatic function disorder in a clinical study in patients with 
hepatic function disorder, by which no dose adjustment is required, unlike venlafaxine7). 
A U.S. clinical guideline recommends SSRI, SNRI, mirtazapine, and bupropion as drug therapies for 
depression and a Canadian clinical guideline recommends SNRI along with SSRI including duloxetine, 
venlafaxine, and MD-120 as the first-line drugs for depression treatment9), 10).  
It has been reported that about 20% to 40% of depression patients receiving antidepressant medications 
obtain only partial improvement of their symptoms or no improvement at all11), as described in “2.2.1 
Background of and treatment method for the target disorder”, the antidepressant treatment procedures 
recommends to switch an antidepressant drug to other antidepressant drug if not responded well; therefore, 




2. Background information 
5 
2.3.1.1 Overseas Phase I study (Study 1200-US) 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
2.3.1.2 Global clinical Phase III study (Study 3359-ww) 
The placebo, MD-120 25 mg/day, and MD-120 50 mg/day were administered for 8 weeks after 10-day 
placebo run-in period in 699 patients with MDD including Japanese patients. 
The incidence rate of adverse events during treatment period was 59.3% (137/231), 63.4% (147/232), 
and 68.6% (162/236), respectively, in the placebo group, 25 mg group, and 50 mg group. Adverse events 
observed at the incidence rate of ≥5% in any of the groups were nasopharyngitis, nausea, headache, 
dizziness, somnolence, and dry mouth (Table 2.3-2). Of these events, nasopharyngitis (1 subject) in the 25 
mg group and dizziness and headache (each in 1 subject) in the 50 mg group were rated as severe. The 
other adverse events were rated mild or moderate. 
No death was observed. 
The incidence rate of serious adverse events other than death during run-in period, treatment period, and 
follow-up period was 1.3% (3/231), 0.4% (1/232), and 2.1% (5/236), respectively, in the placebo group, 25 
mg group, and 50 mg group. Serious adverse events other than death were depression in 3 subjects (1 
subject in the run-in period, 1 subject each in the placebo group and the 50 mg group in the treatment 
period), chest discomfort (1 subject in the run-in period), grand mal convulsion and pneumothorax (1 
subject for each in the placebo group), post procedural complication (post-hernia surgery recurrence of 
right side inguinal hernia, 1 subject in the 25 mg group), peritonsillar abscess, pancreatic neuroendocrine 
tumour metastatic, hallucination, auditory, homicidal ideation, suicidal ideation, and suicide attempt (1 


2. Background information 
6 
subject for each in the 50 mg group). All were severe in severity except chest discomfort, grand mal 
convulsion, and post procedural complication that were moderate in severity. The outcome was recovery 
for all except pancreatic neuroendocrine tumour metastatic. 
The incidence rate of adverse events during run-in period, treatment period, and follow-up period was 
2.6% (6/231), 3.4% (8/232), and 3.4% (8/236), respectively, in the placebo group, 25 mg group, and 50 mg 
group. Adverse event that required withdrawal of the clinical trial, which occurred in ≥2 subjects, was 
depression in 7 subjects (1 during run-in period and 2, 3, and 1 subject, respectively, in the placebo group, 
the 25 mg group, and the 50 mg group during treatment period), nausea in 3 subjects (1 during run-in 
period and 1 subject each in the 25 mg and 50 mg groups during treatment period), vomiting in 2 subjects 
(1 subject each in the placebo and 25 mg groups), and anxiety in 2 subjects (1 subject each in the 25 mg 
and 50 mg groups). All of these adverse events were rated either mild or moderate for except for depression 
as serious adverse events other than death, which occurred in 3 subjects (1 during run-in period and 1 each 
in placebo and 50 mg groups during treatment period). Also, outcomes were recovery in all subjects except 
for 2 with depression in the 25 mg group. 
 
Table 2.3-2  Adverse events that occurred in ≥5% of subjects in any of the groups 
(Study 3359-ww, during treatment period) 
Adverse events 
Placebo group 
(n=231) 
25 mg group 
(n=232) 
50 mg group 
(n=236) 
Nasopharyngitis 
25 (10.8) 
17 ( 7.3) 
26 (11.0) 
Nausea 
10 ( 4.3) 
15 ( 6.5) 
26 (11.0) 
Headache 
16 ( 6.9) 
19 ( 8.2) 
19 ( 8.1) 
Dizziness 
 5 ( 2.2) 
11 ( 4.7) 
17 ( 7.2) 
Somnolence 
 9 ( 3.9) 
 8 ( 3.4) 
13 ( 5.5) 
Dry mouth 
 8 ( 3.5) 
13 ( 5.6) 
 6 ( 2.5) 
Percentage of subjects with adverse events (%) 
 
2.3.1.3 Japanese long-term dosing study (Study 3350) 
MD-120 was administered at a flexible dose of 25–100 mg/day for 10 months to 304 Japanese subjects 
who completed Study 3359-ww. 
The incidence rate of adverse events during treatment period was 78.9% (240/304). Adverse events that 
occurred in ≥5% of subjects were nasopharyngitis, somnolence, headache, nausea, diarrhea, dizziness, 
abdominal pain upper, weight increased, back pain, and constipation (Table 2.3-3). Of these events, 
somnolence (1 subject) was the only severe event, and the other adverse events were rated mild or 
moderate. 
1 subject who had suicide and died, which was judged by the clinical investigator to be causally 
unrelated with the investigational drug. 
The incidence rate of serious adverse events other than death, which occurred during treatment period 
and follow-up period was 2.3% (7/304). Serious adverse events other than death were infectious 
mononucleosis, gastroenteritis, contusion, diabetes mellitus, intervertebral disc protrusion, colon cancer, 
and sleep apnoea syndrome in 1 subject for each. Of these, infectious mononucleosis, intervertebral disc 


2. Background information 
7 
protrusion, and colon cancer were severe adverse events. The outcome was recovery for all except sleep 
apnoea syndrome. 
The incidence rate of adverse events which were observed during treatment period and follow-up period 
and required withdrawal of the clinical study was 4.6% (14/304). Adverse events which were observed in 2 
or more subjects and required withdrawal of the clinical study were pregnancy, depression, and suicidal 
ideation (2 subjects each). Of these adverse events, pregnancy (2 subjects) and depression (1 subject) were 
severe. Also, outcomes were recovery for all events except for depression and suicidal ideation (1 subject 
each, the same subject). Moreover, outcomes for pregnancy (2 subjects) were abortion spontaneous and 
normal delivery. 
 
Table 2.3-3  Adverse events observed at the incidence rate of ≥5% (Study 3350, during 
treatment period) 
Adverse events 
MD-120 
(n=304) 
Nasopharyngitis 
113 (37.2) 
Somnolence 
 35 (11.5) 
Headache 
 32 (10.5) 
Nausea 
 31 (10.2) 
Diarrhoea 
 24 ( 7.9) 
Dizziness 
 23 ( 7.6) 
Abdominal pain upper 
 19 ( 6.3) 
Weight increased 
 19 ( 6.3) 
Back pain 
 17 ( 5.6) 
Constipation 
 16 ( 5.3) 
Percentage of subjects with adverse events (%) 
 
2.3.1.4  Overseas Post-Marketing Safety Data 
The overseas post-marketing safety data have suggested no safety concerns, which supports the safety 
profile that has already been assessed and indicates a favorable benefit-risk profile. 
 
2.3.2 
Summary of benefits 
The following are main efficacy-related study results from 3 overseas placebo-controlled studies in 
which MD-120 50 mg/day or 100 mg/day were examined (Study 332-US, Study 333-EU, and Study 335-
US) and a global clinical Phase III study in patients with MDD including Japanese patients (Study 3359-
ww). See “MD-120 Investigator’s Brochure” for details about the efficacy-related study results from each 
of the studies and other clinical studies. 
 
2.3.2.1 3 overseas Phase III placebo-controlled studies (Study 332-US, Study 333-EU, and 
Study 335-US) 
The placebo, MD-120 50 mg/day, and MD-120 100 mg/day were administered for 8 weeks to patients 
with MDD (447, 483, and 615 patients, respectively, in Study 332-US, Study 333-EU, and Study 335-US). 
In Study 335-US, duloxetine 60 mg/day was also administered for 8 weeks. 


2. Background information 
8 
In all these studies, the superiority of the MD-120 50 mg group or MD-120 100 mg group to the placebo 
group was verified for the primary endpoint, the amount of change in the total HAMD17 score (ITT, 
LOCF) from the baseline to Week 8 visit during treatment period (Table 2.3-4). 
Furthermore, the difference in the amount of change in the total MADRS score (ITT, LOCF) from the 
baseline to Week 8 visit during treatment period, the secondary endpoint, between the MD-120 50 mg 
group or MD-120 100 mg group and the placebo group was taken to be statistically significant as is for the 
primary endpoint (Table 2.3-5). 
 
Table 2.3-4  Amount of change in the total HAMD17 score in 3 overseas Phase III placebo-
controlled studies 
(Week 8 visit during treatment period, LOCF, ANCOVA) 
Study code 
Treatment 
period 
Treatment 
groups 
Number 
of 
subjects 
Amount of change in 
HAMD17 from the 
baseline 
(Adjusted mean [SE]) 
Difference from the 
placebo group 
(Adjusted mean 
[95%CI]) 
P value 
332-US 
Week 8 
Placebo 
150 
 −9 53 [0.58] 
- 
- 
50 mg 
150 
 −11.5 [0.58] 
1.9 [ 0.3, 3.5] 
0.018 
100 mg 
147 
 −11.0 [0.59] 
1 5 [-0.1, 3.1] 
0.065 
333-EU 
Week 8 
Placebo 
161 
 −10.7 [0.61] 
- 
- 
50 mg 
164 
 −13.2 [0.60] 
2.5 [ 0 9, 4.1] 
0.002 
100 mg 
158 
 −13.7 [0.61] 
3.0 [ 1.4, 4.7] 
<0.001 
335-US 
Week 8 
Placebo 
160 
 −8.68 [0.58] 
- 
- 
50 mg 
148 
 −9.75 [0.60] 
1 1 [-0.6, 2.7] 
0.198 
100 mg 
150 
−10.50 [0.60] 
1.8 [ 0.2, 3.4] 
0.028 
Duloxetine 
60 mg 
157 
−10.30 [0.60] 
1.7 [ 0.0, 3.4] 
0.047 
 
Table 2.3-5  Amount of change in the total MADRS score in 3 overseas Phase III placebo-
controlled studies 
(Week 8 visit during treatment period, LOCF, ANCOVA) 
Study code 
Treatment 
period 
Treatment 
groups 
Number 
of 
subjects 
Amount of change in 
MADRS from the 
baseline 
(Adjusted mean [SE]) 
Difference from the 
placebo group 
(Adjusted mean 
[95%CI]) 
P value 
332-US 
Week 8 
Placebo 
150 
−12 3 [0.85] 
- 
- 
50 mg 
148 
−15.0 [0.85] 
2.7 [ 0.4, 5.0] 
0.022 
100 mg 
142 
−14 3 [0.87] 
2.0 [−0.3, 4.4] 
0.095 
333-EU 
Week 8 
Placebo 
161 
−13 3 [0.79] 
- 
- 
50 mg 
164 
−16.4 [0.78] 
3.1 [ 1.0, 5.2] 
0.004 
100 mg 
157 
−17 5 [0.79] 
4.2 [ 2.1, 6.3] 
<0.001 
335-US 
Week 8 
Placebo 
156 
−11.0 [0.82] 
- 
- 
50 mg 
143 
−12.7 [0.85] 
1.7 [−0.6, 4.0] 
0.149 
100 mg 
145 
−14.4 [0.84] 
3.3 [ 1.1, 5.6] 
0.004 
Duloxetine 
60 mg 
152 
−14.4 [0.87] 
3.4 [ 1.1, 5.8] 
0.005 
 




2. Background information 
10 
Table 2.3-7  Amount of change in the total MADRS score in Study 3359-ww 
(Week 8 visit during treatment period, LOCF, Analysis of covariance) 
Treatment 
period 
Treatment 
groups 
Number of 
subjects 
Amount of change in 
MADRS from the 
baseline 
(Adjusted mean 
[SE]) 
Difference from the 
placebo group 
(Adjusted mean 
[95%CI]) 
P value 
Week 8 
Placebo 
229 
 −9.23 [0.61] 
- 
- 
25 mg 
231 
−10.23 [0.60] 
1.00 [−0.68, 2.68] 
0.242 
50 mg 
235 
−11.29 [0.60] 
2.06 [ 0.39, 3.73] 
0.016 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


2. Background information 
11 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.3.3 
Efficacy and Safety in the Elderly 
In an overseas clinical pharmacology study in 48 healthy adults aged ≥18 years (Study 175-US) where a 
single dose of MD-120 was administered (at 300 mg to the first 10 subjects and at 200 mg to the remaining 
38 subjects), the pharmacokinetics of MD-120 was not significantly different between the elderly (aged 
≥65 years, 32 subjects) and non-elderly subjects (aged 18 and 45 years, 16 subjects). The overseas package 
insert describes that patients aged ≥65 years who had received MD-120 developed orthostatic systolic 
hypotension more often than patients aged <65 years; however, it also states that the efficacy and safety 
profile are not generally different between patients aged ≥65 years and patients aged <65 years7). 
Furthermore, it specifies that the dose in the elderly should be determined in consideration to the possibility 
of decreased renal clearance. However, dose adjustment only according to the age is not required7). 
 




3. Study design 
13 
the time of premature termination during follow-up 
period*.” 
Period when the post-treatment safety is evaluated. 
* The time of premature termination after Week 1 visit during follow-up period. 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 




3. Study design 
15 
All subjects will receive the placebo (2 placebo tablets) from the start to the end of run-in period. 
 
(2) Treatment period 
[Placebo group] 
• 
The subjects will receive the placebo (2 placebo tablets) from the start to the end of treatment period. 
[MD-120 50 mg group] 
• 
The subjects will receive MD-120 50 mg (1 MD-120 50 mg tablet) and the placebo (1 placebo tablet) 
from the start to the end of treatment period. 
[MD-120 100 mg group] 
• 
The subjects will receive MD-120 50 mg (1 MD-120 50 mg tablet) and the placebo (1 placebo tablet) 
from the start to Week 1 visit during treatment period. 
• 
The subjects will receive MD-120 100 mg (2 MD-120 50 mg tablet) from the day following the Week 
1 visit during treatment period to the end of treatment period. 
 
(3) Follow-up period 
[Placebo group] 
• 
The subjects will receive the placebo (2 placebo tablets) from the start to Week 1 visit during follow-
up period. 
[MD-120 50 mg group] 
• 
The subjects will receive the placebo (2 placebo tablets) from the start to Week 1 visit during follow-
up period. 
[MD-120 100 mg group] 
• 
The subjects will receive MD-120 50 mg (1 MD-120 50 mg tablet) and the placebo (1 placebo tablet) 
from the start to Week 1 visit during follow-up period. 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
  
 
 


3. Study design 
16 
 
 
 
 
 
 
 
 
 
3.5 Endpoints 
3.5.1 
Primary endpoint 
(1) Efficacy evaluation 
Change in total MADRS score from baseline to Week 8 visit during treatment period 
(2) Safety evaluation 
Adverse events during treatment period and follow-up period 
 
[Rationale for the design] 
(1) Efficacy evaluation 
The Clinical Evaluation Guideline recommends to use HAMD or MADRS as the main 
endpoints12). There is a correlation between the evaluations based on HAMD and MADRS, but 
MADRS is prepared to be more sensitive to the change in the severity of depression. Unlike HAMD, 
MADRS, which enables the unidimensional evaluation of psychiatric symptoms eliminating the 
impact of somatic symptoms, is considered to more correctly determine antidepressant effects in the 
comparison of the efficacy of antidepressants13). There was significant difference in the amount of 
change in the total MADRS score (ITT, LOCF) from the baseline to Week 8, between the MD-120 
50 mg/day group and the placebo group as is for the primary endpoint (the amount of change in the 
total HAMD17 score from the baseline to Week 8) in Study 3359-ww in which all population 
including the Japanese population that use MADRS as the secondary endpoint (See “2.3.2 Summary 
of benefits”). 
It has been concluded, based on these reasons, that MADRS is appropriate as the primary endpoint 
for efficacy evaluation in this clinical study. 
 
(2) Safety evaluation 
Since collecting safety information during and after the administration of MD-120 in patients with 
depression is one of the purposes of this clinical study, adverse events during treatment period and 
follow-up period were determined as the endpoints. 
 
3.5.2 
Secondary endpoint 
(1) Efficacy evaluation 


3. Study design 
17 
1) Response evaluated by total MADRS score at Week 8 visit during treatment period 
(Criteria for response: “Total MADRS score at Week 8 visit during treatment period is ≤50% of 
baseline score.”) 
2) Remission evaluated by total MADRS score at Week 8 visit during treatment period 
(Criteria for remission: “Total MADRS score at Week 8 visit during treatment period is ≤10.”) 
3) Change in total HAMD17 score from baseline to Week 8 visit during treatment period 
4) Response evaluated by total HAMD17 score at Week 8 visit during treatment period 
(Criteria for response: “Total HAMD17 score at Week 8 visit during treatment period is ≤50% of 
baseline score.”) 
5) Remission evaluated by total HAMD17 score at Week 8 visit during treatment period 
(Criteria for remission: “Total HAMD17 score at Week 8 visit during treatment period is ≤7.”) 
6) CGI-I at Week 8 visit during treatment period 
7) Response evaluated by CGI-I at Week 8 visit during treatment period 
(Criteria for response: “Evaluated as “1. Very much improved” or “2. Much improved” at Week 
8 visit during treatment period”) 
8) Change in CGI-S from baseline to Week 8 visit during treatment period 
9) Change in total QIDS16-SR-J score from baseline to Week 8 visit during treatment period 
10) Change in total SDS score from baseline to Week 8 visit during treatment period 
 
(2) Safety evaluation 
1) 
ADRs during treatment period and follow-up period 
2) 
Adverse events and ADRs during treatment period 
3) 
Adverse events and ADRs during follow-up period 
 
 


4. Inclusion and exclusion criteria of subjects 
18 
4. Inclusion and exclusion criteria of subjects 
4.1 Target 
Patients with depression 
4.2 Inclusion and exclusion criteria 
4.2.1 
Initial registration 
4.2.1.1 Inclusion criteria 
At the initial registration, patients meeting all of the following inclusion criteria will be included in this 
clinical study. 
(1) Patients who have consented in writing to participate in this clinical study 
(2) Outpatients aged ≥20 years at the time of informed consent 
(3) Patients with "depression" who have experienced non-psychotic or non-mixed single or repeated 
episode, which has been diagnosed according to DSM-5 (for DSM-5-based diagnosis, Mini-
International Neuropsychiatric Interview [M.I.N.I.] version 7.0.2 will be used as a diagnostic aid tool) 
(4) Patients in whom the current depressive episode has persisted for ≥3 months and ≤18 months if it is 
single or for ≥1 months and ≤18 months if it is recurrent, according to DSM-5 
(5) Patients with the total score of ≥20 in Hamilton Depression Rating Scale (HAMD) 17 and the sub-
score of ≥2 for Item 1 (depressed mood) 
(6) Patients with the score of ≥4 in CGI-S 
(7) Patients with the total score of ≥16 in Quick Inventory of Depressive Symptomatology (QIDS)16-SR-J 
 
[Rationale for the establishment] 
(1) It was established as the basic matter for the clinical study. 
(2) The lower age limit of 20 years was established in consideration of ability in making decision of 
consent.  
(3) For diagnosis of depression based on standardized criteria, the sponsor selected DSM-5, which is 
generally used as diagnostic criteria for mental disorder. To support diagnosis using DSM-5, 
M.I.N.I., a structured interview form for mental disorder, was selected as a tool for diagnostic aid.  
(4) It was established to ensure appropriate efficacy and safety evaluation of MD-120 in patients with 
depression. 
(5) - (7) In light of the criteria in Study 3359-ww, 3 overseas placebo-controlled studies, and clinical 
studies of the other antidepressant drugs, it was established to select patients with moderate or 
severe depression in this clinical study, which is intended to appropriately evaluate the efficacy of 
MD-120 for treatment of depression. 
 


4. Inclusion and exclusion criteria of subjects 
19 
4.2.1.2 Exclusion criteria 
At the initial registration, individuals who meet any of the following exclusion criteria will be excluded 
from this clinical study. 
(1) Patients judged by the (sub-)investigator to have any of the following disorders classified according to 
DSM-5 (using a diagnostic aid tool of M.I.N.I. version 7.0.2 if appropriate) 
• 
Intellectual disabilities 
• 
Autism spectrum syndrome/Autism spectrum disorder 
• 
Attention deficit and hyperkinesia/Attention deficit and hyperactivity disorder 
• 
Schizophrenia spectrum disorder and other psychotic disorders 
• 
Bipolar and related disorders 
• 
Obsessive disorder syndrome and related syndromes/Obsessive compulsive disorder and related 
disorders 
• 
Psychic trauma and stress-related disorders 
• 
Disassociation syndrome/dissociative disorders 
• 
Eating behavior disorders and eating disorders 
• 
Substance-related disorders (except for those caused by tobacco or caffeine) 
• 
Neurocognitive deficiency 
• 
Personality disorders 
(2) Patients concurrently with any of the following disorders classified according to DSM-5, which is also 
positioned as the main disorder by the (sub-)investigator (using a diagnostic aid tool of M.I.N.I. 
version 7.0.2 if appropriate) 
• 
Anxiety/Anxiety disorders 
(3) Patients judged by the (sub-)investigator to have a past history of any of the following disorder 
classified according to DSM-5 (using a diagnostic aid tool of M.I.N.I. version 7.0.2 if appropriate) 
• 
Schizophrenia spectrum disorder and other psychotic disorders 
• 
Bipolar and related disorders 
• 
Substance-related disorders (except for those caused by tobacco or caffeine) 
(4) Patients meeting any of the followings: 
• 
Patients who presented a certain form of followings “suicidal behavior” (suicide attempt, 
interrupted suicide attempt, withdrawn suicide attempt, and preparatory behavior) within 1 year 
before the start of the screening period as assessed according to Columbia-Suicide Severity Rating 
Scale (C-SSRS) 
• 
Patients meeting any of B14 or B16 under “B. Suicidal ideation, Self-injurious and Suicidal 
behavior” or B18 within past 12 months in M.I.N.I. version 7.0.2 
• 
Patients with the sub-score of ≥3 for Item 11 (suicide) in HAMD17 
• 
Patients with the sub-score of ≥5 for Item 10 (Thought of Death or Suicide) in Montgomery-
Asberg Depression Scale (MADRS) 
• 
Patients with the sub-score of ≥3 for Item 12 (Suicidal ideation) in QIDS16-SR-J 
• 
Patients judged by the (sub-)investigator to be at a high risk of suicide 
(5) Patients who have a first-degree relative (parent, sibling, and child) with bipolar and related disorders 


4. Inclusion and exclusion criteria of subjects 
20 
(6) Patients with a past history of or co-existing convulsive disorder such as epilepsy (excluding fever 
seizure) 
(7) Patients with a past history of or co-existing acute angle closure glaucoma or elevated intraocular 
pressure 
(8) Patients who have received desvenlafaxine 
(9) Patients who received venlafaxine for the current depressive episode 
(10) Patients with serious drug allergy or hypersensitivity, or hypersensitivity to venlafaxine or 
desvenlafaxine 
(11) Patients who received other investigational drugs within 16 weeks before the start of the screening 
period 
(12) Patients who received but were not responsive to two or more antidepressants given at an adequate 
dose (in the range of approved dose excluding initial low dose, and doctors who treat the patients 
judged to be adequate) for at least 4 weeks for the current or past depressive episode 
(13) Patients who have undergone electroconvulsive therapy or transcranial magnetic stimulation (TMS) 
therapy 
(14) Patients with a history of hospitalization owing to psychiatric disorder excluding depression 
(15) Patients who received any antipsychotics within 2 weeks before the start of the screening period (or 
within 6 months for a depot formulation) 
(16) Patients who received a hypnotic/sedative (excluding zopiclone, zolpidem, and eszopiclone) within 2 
weeks before the start of the screening period 
(17) Patients with a co-existing serious hepatic, renal, hematological, respiratory, gastrointestinal, or 
cardiovascular disease, or metabolism/electrolytes abnormality 
(18) Female patients who are or may be pregnant, are breast-feeding, or male and female patients who are 
intend to conceive during the study period 
(19) Patients who are otherwise judged by the (sub-) investigator to be ineligible for this clinical study 
 
[Rationale for the design] 
(1) - (3) These items were established, because these may affect appropriate evaluation of the efficacy 
and safety of MD-120 in patients with depression. 
(4) It was established to ensure the safety of subjects. 
(5) It was established, because the subject potentially has a bipolar disorder owing to such genetic 
background, which may affect appropriate evaluation of the efficacy and safety. 
(6) - (7) It was established to ensure the safety of subjects, because overseas package insert 
recommends that “should use cautiously” or “should avoid using” for these disorders and 
symptoms in “WARNING AND PRECAUTIONS”. 
(8) - (9) These items were established, because these may affect appropriate evaluation of the efficacy 
and safety of MD-120. 
(10) It was established to ensure the safety of subjects. 
(11) It was established as the basic matter for the clinical study. 


4. Inclusion and exclusion criteria of subjects 
21 
(12) It was established, because patients resistant to antidepressant drugs may not be appropriately 
evaluated for the efficacy and safety of MD-120 for depression treatment. 
(13) - (14) These items were established, because such subjects may concurrently have a severe 
psychiatric disorder other than depression, and thus may not be appropriately evaluated for the 
efficacy and safety of MD-120 for depression treatment. 
(15) - (16) These items were established, because these may affect appropriate evaluation of the 
efficacy and safety of MD-120. 
(17) It was established to ensure the safety of subjects. 
(18) It was established to ensure the safety of subjects and partner of male subjects. 
(19) It was established as the basic matter for the clinical study. 
 
4.2.2 
Second registration 
4.2.2.1 Inclusion criteria 
At the second registration, subjects meeting all of the following inclusion criteria will be included in 
this clinical study. 
(1) Patients in whom the depressive episode at the time of the initial registration persists 
(2) Patients with the total score of ≥20 in Hamilton Depression Rating Scale (HAMD) 17 and the sub-
score of ≥2 for Item 1 (depressed mood) 
(3) Patients with the score of ≥4 in CGI-S 
(4) Patients with the total score of ≥16 in Quick Inventory of Depressive Symptomatology (QIDS)16-SR-J 
 
[Rationale for the design] 
The above criteria were established as explained in [Rationale for the establishment] for “4.2.1.1 
Inclusion criteria (initial registration).” 
 
4.2.2.2 Exclusion criteria 
At the second registration, subjects who meet any of the following exclusion criteria will be excluded 
from this clinical study. 
(1) Patients meeting any of the followings: 
• 
Patients who presented a certain form of followings “suicidal behavior” (suicide attempt, 
interrupted suicide attempt, withdrawn suicide attempt, and preparatory behavior) between the 
initial and second registrations as assessed according to C-SSRS 
• 
Patients with the sub-score of ≥3 for Item 11 (suicide) in HAMD17 
• 
Patients with the sub-score of ≥5 for Item 10 (Suicidal Thoughts) in Montgomery-Asberg 
Depression Scale (MADRS) 
• 
Patients with the sub-score of ≥3 for Item 12 (Thought of Death or Suicide) in QIDS16-SR-J 
• 
Patients judged by the (sub-)investigator to be at a high risk of suicide 
(2) Patients who received a drug or therapy prohibited for concomitant use from the start of screening 
period 


4. Inclusion and exclusion criteria of subjects 
22 
(3) Patients who deviated from the conditions for concomitant use of hypnotics/sedatives allowed for use 
from the start of screening period 
(4)  Patients determined by the (sub-)investigator to be ineligible for the study based on the result of 
diagnosis confirmation by the Clinical data analytics committee regarding the assessment at the time 
of the initial registration by the (sub-)investigator for the diagnosis 
(5) Patients who are otherwise not eligible for this clinical study as determined by the (sub-)investigator  
 
[Rationale for the design] 
(1) It was established to ensure the safety of subjects. 
(2) It was established, because these may affect appropriate evaluation of the efficacy and safety of 
MD-120 in patients with depression and to ensure the safety of subjects. 
(3) These items were established because subjects may deviate from the conditions for concomitant 
use of hypnotics/sedatives during treatment period, and also the items may affect appropriate 
evaluation of the efficacy and safety of MD-120. 
(4) This item was set out since subjects thereto applicable would not be appropriate for the efficacy 
and safety evaluation of MD-120. 
(5) It was established as the basic matter for the clinical study. 
 
4.2.3 
Randomization registration 
4.2.3.1 Inclusion criteria 
At the randomization registration, subjects meeting all of the following inclusion criteria will be 
included in this clinical study. 
(1) Patients in whom the depressive episode at the time of the initial registration persists 
(2) Patients with the total score of ≥20 in Hamilton Depression Rating Scale (HAMD) 17 and the sub-
score of ≥2 for Item 1 (depressed mood) 
(3) Patients with the score of ≥4 in CGI-S 
(4) Patients with the total score of ≥16 in Quick Inventory of Depressive Symptomatology (QIDS)16-SR-J 
 
[Rationale for the design] 
The above criteria were established as explained in [Rationale for the establishment] for “4.2.1.1 
Inclusion criteria (initial registration).” 
 
4.2.3.2 Exclusion criteria 
At the randomization registration, subjects who meet any of the following exclusion criteria will be 
excluded from this clinical study. 
(1) Patients meeting any of the followings: 
• 
Patients who presented a certain form of followings “suicidal behavior” (suicide attempt, 
interrupted suicide attempt, withdrawn suicide attempt, and preparatory behavior) between the 
second registration and randomization as assessed according to C-SSRS 


4. Inclusion and exclusion criteria of subjects 
23 
• 
Patients with the sub-score of ≥3 for Item 11 (suicide) in HAMD17 
• 
Patients with the sub-score of ≥5 for Item 10 (Suicidal Thoughts) in MADRS 
• 
Patients with the sub-score of ≥3 for Item 12 (Thought of Death or Suicide) in QIDS16-SR-J 
• 
Patients judged by the (sub-)investigator to be at a high risk of suicide 
(2) Patients whose total score in HAMD17 deteriorated or improved by ≥25% from the second 
registration 
(3) Patients who missed taking the investigational drug on ≥2 days during run-in period 
(4) Patients who have received a concomitant drug or therapy prohibited from the start of screening period 
(5) Patients who deviated from the conditions for concomitant use of hypnotics/sedatives allowed for use 
from the start of screening period 
(6) Patients determined by the (sub-)investigator to be ineligible for the study based on the result of 
diagnosis confirmation by the Clinical data analytics committee regarding the assessment at the time 
of the initial registration by the (sub-)investigator for the diagnosis 
(7) Patients who are otherwise judged by the (sub-) investigator to be ineligible for this clinical study 
 
[Rationale for the design] 
(1) It was established to ensure the safety of subjects. 
(2) It was established, because subjects who have responded to the placebo or marked exacerbation of 
symptoms during the period are not appropriate for the efficacy and safety evaluation of MD-120. 
(3) It was established, because subjects who have failed compliance during such period can not be 
expected to keep the compliance during treatment and subsequent periods, interfering with 
appropriate evaluation of the efficacy and safety of MD-120. 
(4) It was established, because these may affect appropriate evaluation of the efficacy and safety of 
MD-120 in patients with depression and to ensure the safety of subjects. 
(5) These items were established, because they may also be deviated during treatment period, or 
affect the appropriate evaluation of the efficacy and safety of MD-120. 
(6) This item was set out since subjects thereto applicable would not be appropriate for the efficacy 
and safety evaluation of MD-120. 
(7) It was established as the basic matter for the clinical study.. 
 


5. Clinical study procedures 
24 
5. Clinical study procedures 
5.1 Informed consent 
5.1.1 
Preparation of informed consent form and written patient information 
The investigator will prepare an informed consent form used to obtain patient’s consent to participation 
in the clinical study based on “Written patient information for trials of MD-120 (draft)” provided by the 
sponsor. The written patient information shall include matters specified in the Good Clinical Practice 
(GCP). The investigator will submit the prepared written patient information to the head of the study 
center, obtain the approval from the institutional review board, and then submit the approved document to 
the sponsor. 
 
5.1.2 
Selection of subjects, explanation of the clinical study with written information, and 
obtaining informed consent 
(1) The (sub-)investigator will give a patient the written patient information and explain the content to 
him or her before the start of the clinical study. 
(2) After confirming that the patient has understood the content of the written patient information, the 
(sub-)investigator will obtain the voluntary consent to participation in the clinical study from the 
patient. 
(3) The (sub-)investigator and patient will sign the informed consent and enter the respective dates. 
The clinical research coordinator will also sign it and enter the respective date if he or she has 
given supplementary explanation. 
(4) The patient will be defined as a subject by signing the informed consent and entering the respective 
date. 
(5) The (sub-)investigator will retain the original copy of the signed written informed consent in a 
duplicate form with the original medical records (medical charts, etc.) and deliver the duplicate 
copy to the subject. 
(6) The (sub-)investigator will record the concerned delivery of the written patient information and the 
duplicate copy of the written informed consent. 
 
5.1.3 
Information provision after informed consent 
(1) If the sponsor provides new information that may affect the subject’s willingness to continue 
participation in the clinical study, the (sub-)investigator will promptly convey that information to 
the subject, check whether he or she wishes to continue participation in the clinical study again, 
and record practice and result of the check in the original medical record. 
(2) The investigator will promptly revise the written patient information when recognizing such 
necessity. The investigator will submit the revised written patient information to the head of the 


5. Clinical study procedures 
25 
study center, obtain the approval from the institutional review board, and then submit the approved 
document to the sponsor. 
(3) Upon revision of the written patient information, the (sub-)investigator will give explanation again 
using the revised written patient information in accordance with “5.1.2 Selection of subjects, 
explanation of the clinical study with written information, and obtaining informed consent.” In 
addition, the (sub-)investigator will obtain voluntary written re-consent to continued participation 
in the clinical study from the subject. 
5.2 Observation and test, and evaluation schedule 
Table 5.2-1 shows the observation and test, Table 5.2-2 shows planned day for visits and acceptable 
window, and Table 5.2-3 shows evaluation schedule as well as details of the general laboratory test and 
vital signs. 
 






5. Clinical study procedures 
28 
5.2.1 
Initial registration 
The (sub-)investigator will perform observation, tests and evaluation necessary for eligibility assessment 
on the patient with the written informed consent in accordance with “Table 5.2-1 Observation and test, and 
evaluation schedule” and proceed with the initial registration in accordance with the procedure as shown in 
Table 5.2-4. 
 
Table 5.2-4  Procedure and description of the initial registration 
Procedure 
Description 
Eligibility assessment 
↓ 
• 
Inspect if the patient meets each of the inclusion criteria and 
exclusion criteria for the initial registration 
• 
Assess the eligibility for the initial registration 
Application of the initial 
registration 
↓ 
• 
Enter required information in the subject registration system, and 
apply case registration to the subject registration center 
Result of the initial 
registration 
↓ 
• 
Check the eligibility assessment result provided by the subject 
registration center 
Notifying subject of the 
registration result 
↓ 
• 
If the subject registration center provides an “eligible” result to the 
subject in the eligibility assessment, notify him or her of that 
matter. 
• 
If the subject registration center provides an “ineligible” result to 
the subject in the eligibility assessment, notify him or her of that 
matter and terminate the clinical study for him or her. 
Continuation of clinical 
study 
• 
Perform general clinical laboratory tests as scheduled at the start of 
screening period. 
• 
Schedule the next visit with the subject 
• 
Hand the drug-use diary. 
 
5.2.2 
Second registration 
The (sub-)investigator will perform observation, tests, and evaluation in accordance with “Table 5.2-1 
Observation and test, and evaluation schedule.” The (sub-)investigator will proceed with the second 
registration in accordance with the procedure as shown in Table 5.2-5 and dispense the investigational drug 
to eligible subjects. 
When a subject meets “8.1.1 Withdrawal criteria in the screening period and run-in period,“ the 
(sub-)investigator will withdraw him or her from the clinical study in accordance with the procedure as 
shown in “8.2-1 Withdrawal in screening period.” 
 
Table 5.2-5  Procedure and description of the second registration 
Procedure 
Description 
Observation and evaluation at 
the end of screening period 
 
• 
Inspect if the subject meets each of the inclusion criteria and 
exclusion criteria for the second registration 
• 
Assess the eligibility for the second registration 


5. Clinical study procedures 
29 
Application of the second 
registration 
 
• 
Enter required information in the subject registration system, and 
apply case registration to the subject registration center 
Result of the second registration 
 
• 
Check the eligibility assessment result provided by the subject 
registration center 
Notifying subject of the 
registration result 
 
• 
If the subject registration center provides an “eligible” result to 
the subject in the eligibility assessment, notify him or her of that 
matter. 
• 
If the subject registration center provides an “ineligible” result to 
the subject in the eligibility assessment, notify him or her of that 
matter and terminate the clinical study for him or her. 
Continuation of clinical study 
• 
Schedule the next visit with the subject 
• 
Dispense the investigational drug 
 
5.2.3 Randomization registration 
The (sub-)investigator will perform observation, tests, and evaluation in accordance with “Table 5.2-1 
Observation and test, and evaluation schedule.” The (sub-)investigator will proceed with the randomization 
registration in accordance with the procedure as shown in Table 5.2-6 and dispense the investigational drug 
to eligible subjects. 
When a subject meets “8.1.1 Withdrawal criteria in the screening period and run-in period,“ the 
(sub-)investigator will withdraw him or her from the clinical study in accordance with the procedure as 
shown in “8.2-2 Withdrawal in run-in period.” 
 
Table 5.2-6  Procedure and description of the randomization registration 
Procedure 
Description 
Observation and evaluation at 
the end of run-in period 
 
• 
Inspect if the subject meets each of the inclusion criteria and 
exclusion criteria for the randomization registration 
• 
Assess the eligibility for the randomization registration 
Application of the 
randomization registration 
 
• 
Enter required information in the subject registration system, and 
apply randomization registration to the subject registration center 
Result of the randomization 
registration 
 
• 
Check the eligibility assessment result provided by the subject 
registration center 
Notifying subject of the 
registration result 
 
• 
If the subject registration center provides an “eligible” result to 
the subject in the eligibility assessment, notify him or her of that 
matter. 
• 
If the subject registration center provides an “ineligible” result to 
the subject in the eligibility assessment, notify him or her of that 
matter and terminate the clinical study for him or her. 
Continuation of clinical study 
• 
Schedule the next visit with the subject 
• 
Dispense the investigational drug 
 


5. Clinical study procedures 
30 
5.2.4 
Treatment period 
The (sub-)investigator will perform observation, tests, and evaluation in accordance with “Table5.2-1 
Observation and test, and evaluation schedule.” The (sub-)investigator will schedule the next visit and then 
dispense an appropriate amount of the investigational drug as needed until the next visit. 
When a subject meets “8.1.2 Withdrawal criteria in the treatment period,“ the (sub-)investigator will take 
actions in accordance with “8.2 Withdrawal procedures for individual subjects.“ 
 
5.2.5 
Follow-up period 
The (sub-)investigator will perform observation, tests, and evaluation in accordance with “Table5.2-1 
Observation and test, and evaluation schedule.” 
When a subject meets “8.1.3 Withdrawal criteria in the follow-up period,“ the (sub-)investigator will 
take actions in accordance with the procedure as shown in “8.2-4 Withdrawal in follow-up period .“ 
 


6. Investigational drug 
31 
6. Investigational drug 
6.1 Dosage form and content of investigational drug 
In this clinical study, the investigational drug described in Table 6.1-1 will be used. 
 
Table 6.1-1  Dosage form, appearance ,and content of investigational drug 
Investigational drug 
Dosage form and appearance 
Content 
MD-120 50 mg tablet 
Extended-release tablet: Pale 
red square-shaped film-coated 
tablet with a pyramidal shape 
on one side 
Each tablet contains 50 mg of desvenlafaxine  
Placebo tablet 
Extended-release tablet: Pale 
red square-shaped film-coated 
tablet with a pyramidal shape 
on one side 
No desvenlafaxine contained 
 
6.2 Procedures for management of the investigational drug 
The investigational drug storage manager will keep and retain the records on receipt of the 
investigational drug provided by the sponsor, its incoming and outgoing amounts at the pharmacy of the 
study center, use status for each subject, and return of the remaining investigational drug in accordance 
with “Written procedure for management of the investigational drug“ and “Written instructions for 
handling the investigational drug“ provided by the sponsor and written standard operation procedures at the 
study center. 
6.3 Method for randomization and blinding 
6.3.1 
Blinding in run-in period 
The (sub-)investigator shall not inform any subject that he or she is supposed to take the placebo during  
run-in period. 
 
6.3.2 
Randomization registration 
The person responsible for investigational drug randomization will randomize the investigational drug by 
the permuted block method in which the study center is defined as a block in accordance with separately 
prepared “Written specifications for randomization. Subjects assessed to be eligible at the randomization 
registration will be randomly assigned to any of the three groups at a ratio of 1:1:1. 
 


6. Investigational drug 
32 
6.3.3 
Maintenance of blindness 
6.3.3.1 Handling of investigational drug randomization table 
(1) After the end of the randomization, the person responsible for investigational drug randomization 
will separately seal the original copy and one duplicate copy of the following investigational drug 
randomization tables. The person responsible for investigational drug randomization and sponsor 
will retain the original copy and one duplicate copy, respectively, until unblinding after the 
completion of the clinical study. Also, the person responsible for the subject registration will 
incorporated the information in the investigational drug randomization table in the subject 
registration system which will be used for emergency unblinding described in section 6.4.1, and 
verification of treatment groups to which each subject has been randomized at the drug 
concentration measurement laboratory as described in section 6.3.3.2. 
(2) Unblinding will be implemented in accordance with “6.4Procedure for unblinding with the 
investigational drug assignment table,“ where necessary. 
(3) If the sponsor retrieves the investigational drug before unblinding, the investigational drug storage 
manager will check the quantity of the remainder of the investigational drug and seal the outer box. 
Unopened boxes, if any, will be retrieved without sealing. 
 
6.3.3.2 Maintenance of unblindness at the drug concentration measurement laboratory 
(1) In this study, blood sampling will be performed for all subjects randomized for the investigational 
drug; however, drug concentration measurement is performed only for the MD-120 groups (50 mg 
group and 100 mg group). Therefore, the drug concentration measurement laboratory will be 
unblinded since it needs to verify the treatment group to which each subject will be randomized 
pertinent to measurement of drug concentration. The person responsible for the subject registration 
will provide the drug concentration measurement laboratory with an unblineded accecc to the 
subject registration system. The drug concentration measurement laboratory will verify the 
treatment group on the subject registration system in accordance with the procedures separately 
prepared by the drug concentration measurement laboratory. The information concerning the 
unblinded accounts and treatment groups should be handled appropriately in accordance with the 
procedures. 
(2) The drug concentration measurement laboratory will store the account of unblineded, the 
information of the treatment group and the measurement results properly in accordance with the 
procedures separately prepared. 
 


6. Investigational drug 
33 
6.4 Procedure for unblinding with the investigational drug assignment table 
6.4.1 
Unblinding with investigational drug assignment table for emergency unblinding during the 
study period 
(1) The (sub-)investigator will promptly communicate with the sponsor and request the emergency 
unblinding if he or she considers it necessary to know of which group the investigational drug was 
administered (for instance, in the case where such unblinding is considered urgently necessary 
because actions have to be taken on a serious adverse event). 
(2) Even in a case other than (1), the sponsor can decide emergency unblinding in consultation with 
the (sub-)investigator if they consider it necessary to know of which group the investigational drug 
was administered. 
(3) For emergency unblinding described in (1) or (2), the sponsor will access the subject registration 
system and unblind the information for each subject in accordance with the “Written procedure for 
unblinding with investigational drug assignment table for emergency unblinding” separately 
prepared by the sponsor. 
(4) The sponsor will provide the investigational drug randomization information to the concerned 
(sub-)investigator. 
(5) If measurements of drug concentration are required pertinent to an emergency unblinding, the 
sponsor will notify the drug concentration measurement laboratory and request the measurements 
of drug concentration on the subject, and in turn, the drug concentration measurement laboratory 
will submit to the sponsor the measurements of drug concentration on the subject in accordance 
with the procedures separately prepared. 
 
6.4.2 
Unblinding after lock of database 
6.4.2.1 Lock of database 
After the end of the follow-up period for all the subjects, the sponsor will determine handling of the data 
in all the subjects in analyses as specified in this study protocol (See “15.2 Analysis sets”) and lock the 
database. For the above determination, advices from medical experts may be sought where necessary. 
 
6.4.2.2 Unblinding 
Unblinding shall be performed in accordance with separately prepared “Written procedure for 
investigational drug randomization.“ 


7. Treatment and instructions for subjects 
34 
7. Treatment and instructions for subjects 
7.1 Prohibited and allowed therapies 
7.1.1 
Prohibited concomitant drugs 
Table 7.1-1 shows prohibited concomitant treatment drugs in this clinical study (See “Annex 4 List of 
prohibited concomitant drugs“). If the prohibited concomitant treatment becomes unavoidable owing to 
exacerbation of the target disorder or adverse events, and the subject meets “8.1 Withdrawal criteria for 
individual subjects,“ he or she will be withdrawn from the clinical study in accordance with “8.2 
Withdrawal procedures for individual subjects,” and then appropriate treatment will be given. 
 
Table 7.1-1  Prohibited concomitant drugs 
Concomitant drugs prohibited from the start of screening period to the end of follow-up period 
(1) 
MAO inhibitors* 
(2) 
Investigational drugs other than MD-120 
(3) 
Desvenlafaxine and venlafaxine other than MD-120 
Concomitant drugs prohibited from the start of screening period to the completion of all observation and 
tests scheduled at the visit at the end of treatment period 
(4) 
Antipsychotic drugs 
(5) 
Antianxiety drugs 
(6) 
Hypnotic/sedative drugs (excluding zopiclone, zolpidem, and eszopiclone) 
(7) 
Hypnotic drugs 
(8) 
Antidepressant drugs 
(9) 
Antimanic drugs 
(10) 
Antiepileptic drugs 
(11) 
Antiparkinson drugs 
(12) 
Chinese medicines indicated for treatment of anxiety, insomnia, and depressed mood 
(13) 
Drugs containing serotonin precursor (L-tryptophan, 5-hydroxytryptophan, etc.) 
(14) 
Drugs containing tramadol 
(15) 
Triptan drugs 
*If MAO inhibitors are administered after the end of treatment with MD-120, there must be an interval of 
at least 7 days. 
 
[Rationale for the establishment of prohibited concomitant drugs] 
(1) It was established to ensure the safety of subjects, because their concomitant use with MD-120 may 
lead to onset of serotonin syndrome. 
(2) It was established as a basic requirement for a clinical trial. 
(3) - (12) These items were established, because these are considered to affect appropriate evaluation of 
the efficacy and safety of MD-120. 


7. Treatment and instructions for subjects 
35 
(13) - (15) These items were established, because concomitant use of these drugs with MD-120 may 
enhance the serotonergic action, potentially affecting appropriate evaluation of the efficacy and 
safety of MD-120. 
 
7.1.2 
Prohibited concomitant therapies 
Table7.1-2 shows prohibited concomitant therapies in this clinical study. If the prohibited concomitant 
therapy becomes unavoidable owing to exacerbation of the target disorder or adverse events, and the 
subject meets “8.1. Withdrawal criteria for individual subjects,“ he or she will be withdrawn from the 
clinical study in accordance with “8.2 Withdrawal procedures for individual subjects,” and then appropriate 
treatment will be given. 
 
Table7.1-2  Prohibited concomitant therapies 
Concomitant therapies prohibited from the start of screening period to the end of follow-up period 
(1) Electroconvulsive therapy 
(2) Transcranial magnetic stimulation (TMS) therapy 
(3) Supplement containing St. John 's Wort as the active ingredient 
Concomitant therapies prohibited from the start of screening period to the completion of all observation 
and tests scheduled at the end of treatment period 
(4) Systematized psychotherapies (including cognitive behavior therapies) 
 
[Rationale for the establishment of prohibited concomitant therapies] 
(1)-(4) These items were established, because these may affect appropriate evaluation of the efficacy and 
safety of MD-120. 
 
7.1.3 
Allowed concomitant drugs 
Concomitant use of hypnotic/sedative drugs is allowed only when their use is as specified in (1) to (3). 
Table7.1-3 shows allowed concomitant hypnotic/sedative drugs. If the use of drugs that deviates from the 
regulations of allowed concomitant drugs becomes unavoidable owing to exacerbation of the target disease 
or adverse events, and the subject meets “8.1 Withdrawal criteria for individual subjects,” he or she will be 
withdrawn from the clinical study in according with “8.2 Withdrawal procedures for individual subjects,” 
and then appropriate treatment will be given. 
 
(1) 
Concomitant use of the hypnotic/sedative drugs listed in Table 7.1-3 are allowed from the start of 
screening period to the completion of all observation and tests scheduled at the end of treatment 
period only for the subjects who were using these drugs as of 2 weeks before the start of the 
screening period. 


7. Treatment and instructions for subjects 
36 
(2) 
During screening, run-in, and treatment period, use of only 1 drug is allowed as a single dose up to 
3 days a week (use for up to 3 days per 7-day time frame starting from the start of screening 
period is allowed), but prohibited within 24 hours before visit specified in "Table 5.2-1 
Observation and test, and evaluation schedule.".  
(3) 
The maximum dose should be 7.5 mg/night for zopiclone, 5 mg/night for zolpidem, and 2 
mg/night for eszopiclone. 
 
After all the observations, tests, and evaluations at the end of treatment period are completed, the above 
(2) and (3) will not apply. Concomitant drugs may be used at the discretion of the (sub-)investigator. 
 
Table7.1-3  Allowed concomitant hypnotic/sedative drugs 
Allowed concomitant hypnotic/sedative drugs 
(1) 
Zopiclone 
(2) 
Zolpidem 
(3) 
Eszopiclone 
 
[Rationale for the establishment of allowed concomitant drugs] 
To treat sleep disorder associated with depression, concomitant use of hypnotic/sedative drugs is 
allowed in ethical consideration of the subjects. To minimize an impact of the efficacy evaluation of MD-
120, types of the drugs and regimens are restricted considering that the Clinical Assessment Guideline 
recommends to set out a rule to not change the dosage regimen of a psychotropics during clinical studies 
and also to limit the concomitant use of hypnotics/sedatives to those of super-short action since 
concomitant use of antianxiety, hypnotics/sedatives or mental treatment may affect the efficacy and 
safety assessments
12)
. 
 
7.2 Instructions for subjects 
7.2.1 
Dose compliance of investigational drug 
The (sub-)investigator will verify subjects' dose compliance at each visit and instruct them on dose 
compliance, and also, at the time of the prescription, instruct subjects to: 
(1) Administer the investigational drug according to the (sub-)investigator's instruction; 
(2) Administer the investigational drug at around the same time every day whether with food or not, 
while the time of dose can be at any time; 
(3) Not bite on, crack, or crush the investigational drug, and administer it without any modification; 
(4) Administer the investigational drug before the following visits; the visit of the end of run-in period, 
the Week 8 visit or the visit at the time of premature termination during treatment period, and Week 
1 visit or the visit at the time of premature termination during follow-up period. 
(5) Bring any remaining drugs at each visit, and return them to the (sub-)investigator; and 


7. Treatment and instructions for subjects 
37 
(6) Notify the (sub-)investigator or study coordinator promptly upon facing difficulties continuing 
receiving the investigational drug. 
 
7.2.2 
Keeping drug-use diary 
The (sub-)investigator will instruct subjects to:  
(1) Enter the following information in the “drug-use diary“ every day: 
 
All subjects: Use status of investigational drug (run-in, treatment, and follow-up periods) 
 
Subfects who are allowed to use concomitant drugs: Use status of hypnotic/sedative drugs 
(screening, run-in, and treatment periods) 
(2) Bring the "drug-use diary" to each visit, and submit it to the (sub-)investigator 
 
7.2.3 
Contraception 
The (sub-)investigator will instruct subjects to prevent conception, using condom or with placement of 
an intrauterine device for females and in an appropriate manner such as use of condom for males. 
Childbearing potential female subjects and male subjects whose partner is childbearing potential will be 
instructed to communicate with the (sub-)investigator when the contraception is deemed uncertain. If 
female subject is confirmed to be pregnant from the screening period to Week 1 of the follow-up period, 
the (sub-)investigator will withdraw her from the screening, run-in, treatment, or follow-up period in 
accordance with “8.2 Withdrawal procedures for individual subjects.“ In addition, if female subject or male 
subject whose partner is childbearing potential is confirmed to be pregnant during treatment or follow-up 
period, the survey for outcome of the pregnancy will be conducted according to “12.3 Definition of serious 
adverse events and procedures for collecting, recording, and reporting such events” and “12.4 Follow-up 
survey for serious adverse events and adverse events causally related to the investigational drug.” 
 
7.2.4 
Other cautions 
The (sub-)investigator will instruct subjects to: 
(1) Notify the (sub-)investigator before receiving treatment given by other doctor; 
(2) Avoid consuming alcohol; and 
(3) Avoid using over-the-counter drugs and supplements with actions to improve sleep. 
(4) Be careful when engaging in operations of machinery involving risks such as driving a car, etc. 
 
 


8. Withdrawal criteria and procedures for individual subjects 
38 
8. Withdrawal criteria and procedures for individual subjects 
8.1 Withdrawal criteria for individual subjects 
When any of the following withdrawal criteria is met, the (sub-)investigator will take actions in 
accordance with “8.2 Withdrawal procedures for individual subjects.“ 
 
8.1.1 
Withdrawal criteria in the screening and run-in periods 
(1) 
Inclusion and exclusion criteria: If the (sub-)investigator finds that any of the inclusion criteria is 
not met or any of the exclusion criteria is met (See “4. Inclusion and exclusion criteria of 
subjects”) 
(2) 
Adverse events: If the (sub-)investigator considers it difficult to continue the clinical study owing 
to the adverse event or if the subject wishes to discontinue the clinical study because of the 
adverse event 
(3) 
Convenience of the subject: If it is difficult to continue the clinical study for convenience of the 
subject 
(4) 
Others: For others, if the (sub-)investigator considers that the subject should be withdrawn from 
the clinical study 
 
8.1.2 
Withdrawal criteria in the treatment period 
(1) 
Inclusion and exclusion criteria: If the (sub-)investigator finds after-the-fact that any of the 
inclusion criteria had not been met or any of the exclusion criteria has been met (See “4. Inclusion 
and exclusion criteria of subjects”). 
(2) 
Adverse events: If the (sub-)investigator considers it difficult to continue the clinical study owing 
to the adverse event or if the subject wishes to discontinue the study treatment because of the 
adverse event 
(3) 
Convenience of the subject: If it is difficult to continue the clinical study for convenience of the 
subject 
(4) 
Concomitant drugs: If a drug falling under “7.1.1 Prohibited concomitant drugs” has been 
indicated or administered, or a therapy falling under “7.1.2 Prohibited concomitant therapies” has 
been indicated, and the (sub-)investigator considers it difficult to discontinue the concerned 
therapy. 
(5) 
Allowed concomitant drugs: If an allowed concomitant drug has been used in a manner falling out 
of provisions in “7.1.3 Allowed concomitant drugs,“ and the (sub-)investigator considers it 
difficult to ensure compliance of the concerned treatment with the provisions 
(6) 
Inadequate response: The effect of the investigational drug is not sufficient and the 
(sub-)investigator determines that the study should be terminated. 
(7) 
Number of days on dose: If the subject has taken the investigational drug on 3 days or fewer 
during the first week of treatment period 


8. Withdrawal criteria and procedures for individual subjects 
39 
(8) 
Suicidal behavior: If a certain form of followings “suicidal behavior” (suicide attempt, and 
interrupted suicide attempt) has occurred as assessed according to C-SSRS 
(9) 
Pregnancy: If the subject becomes pregnant 
(10) 
Others: For others, if the (sub-)investigator considers that the subject should be withdrawn from 
the clinical study 
 
8.1.3 
Withdrawal criteria in the follow-up period 
(1) 
Adverse events: If the (sub-)investigator considers it difficult to continue the clinical study owing 
to the adverse event or if the subject wishes withdrawal from the clinical study because of the 
adverse event 
(2) 
Convenience of the subject: If it is difficult to continue the clinical study for convenience of the 
subject 
(3) 
Pregnancy: If the subject becomes pregnant by Week 1 visit during follow-up period. 
(4) 
Others: For others, if the (sub-)investigator considers that the subject should be withdrawn from 
the clinical study 
 
8.2 Withdrawal procedures for individual subjects 
If a case meeting any item of “8.1 Withdrawal criteria for individual subjects“ occurs after the initial 
registration, the (sub-)investigator will promptly communicate with the sponsor and proceed with the 
following procedures.  
 
8.2.1 
Withdrawal in screening period 
(1) 
The clinical study for the subject will be terminated without transition to follow-up period. 
(2) 
The (sub-)investigator will enter presence or absence of withdrawal, date of withdrawal (date on 
which withdrawal is determined), and reason for the withdrawal in the case report form. 
 
8.2.2 
Withdrawal in run-in period 
(1) 
In accordance with “Table 5.2-1 Observation and test, and evaluation schedule,“ observation and 
evaluation scheduled at the visit at the time of premature termination in run-in period will be 
conducted, and the clinical study for the subject will be terminated without transition to follow-up 
period. 
(2) 
The (sub-)investigator will enter presence or absence of withdrawal, date of withdrawal (date on 
which withdrawal is determined), and reason for the withdrawal in the case report form. 
 


8. Withdrawal criteria and procedures for individual subjects 
40 
8.2.3 
Withdrawal in treatment period 
(1) 
In accordance with “Table 5.2-1 Observation and test, and evaluation schedule,“ observation and 
evaluation scheduled at the visit at the time of premature termination in treatment period will be 
conducted, and the subject will enter follow-up period. 
(2) 
The (sub-)investigator will enter presence or absence of withdrawal, date of withdrawal (date on 
which withdrawal is determined), and reason for the withdrawal in the case report form. 
 
8.2.4 
Withdrawal in follow-up period 
8.2.4.1  Before Week 1 visit during follow-up period 
(1) 
In accordance with “Table 5.2-1 Observation and test, and evaluation schedule,“ observation and 
evaluation scheduled at the visit at the time of premature termination before Week 1 visit during 
follow-up period will be conducted, and the clinical study for the subject will be terminated. 
(2) 
The (sub-)investigator will enter presence or absence of withdrawal, date of withdrawal (date on 
which withdrawal is determined), and reason for the withdrawal in the case report form. 
 
8.2.4.2  After Week 1 visit during follow-up period 
(1) 
In accordance with “Table 5.2-1 Observation and test, and evaluation schedule,“ observation and 
evaluation scheduled at the visit at the time of premature termination after Week 1 visit during 
follow-up period will be conducted, and the clinical study for the subject will be terminated. 
(2) 
The (sub-)investigator will enter presence or absence of withdrawal, date of withdrawal (date on 
which withdrawal is determined), and reason for the withdrawal in the case report form. 
 
8.2.5 
Other points to note 
If the visit is not available for the subject’s convenience, and observation, tests, and evaluation in the 
above section 8.2.2, 8.2.3, or 8.2.4 are not possible, the (sub-)investigator will check existence of the 
subject by telephone, etc. wherever possible, and enter the check result (contact is successful or not) and 
date of the check. In addition, the (sub-)investigator will instruct the subject to return the remainder of the 
investigational drug and “drug-use diary“ to the study center if he or she has these on hand. 
 
 


9. Efficacy evaluation 
41 
9. Efficacy evaluation 
9.1 Efficacy endpoints 
The efficacy endpoints are as follows: 
(1) MADRS 
(2) HAMD17 
(3) CGI-S 
(4) CGI-I 
(5) QIDS16-SR-J 
(6) SDS 
9.2 Timing and method of efficacy evaluation 
Each efficacy endpoints of evaluation by the (sub-)investigator will be evaluated in accordance with 
“Table 5.2-1 Observation and test, and evaluation schedule. Diagnosis and evaluation in a subject will be 
performed by the same persons throughout the clinical study period wherever possible. 
The eCOA system will be used for each efficacy evaluation by the (sub-)investigator and subjects. After 
study completion, the Clinical data analytics committee will store the evaluation result of each efficacy 
endpoints collected using eCOA system (including audit trail) in an electronic recording media (CD-ROM 
etc.), and provide it to the study center. 
The detailed evaluation method and the method to provide electronic data to the sponsor are separately 
specified in the procedures. 
 
9.2.1 
MADRS 
The (sub-)investigator will evaluate each subject’s symptoms based on 10 MADRS items in  
accordance with “MADRS structured interview guide (SIGMA).“  
 
9.2.2 
HAMD17 
The (sub-)investigator will evaluate each subject’s symptoms based on 17 HAMD17 items in accordance 
with “HAM-D structured interview guide (SIGH-D)“.  
 
9.2.3 
CGI-S 
The (sub-)investigator will evaluate each subject’s general severity of depression using CGI-S. 
 
9.2.4 
CGI-I 
The (sub-)investigator will evaluate each subject’s general improvement of depression compared with 
baseline symptoms using CGI-I.  


9. Efficacy evaluation 
42 
 
9.2.5 
QIDS16-SR-J 
Each subject will self-evaluate his/her own symptoms of depression on 16 QIDS16-SR-J items.  
 
9.2.6 
SDS 
Each subject will self-evaluate his/her social disability on 5 SDS items.  
 
 


10. Safety evaluation 
43 
10. Safety evaluation 
10.1 Safety endpoints 
The safety endpoints are as follows: 
(1) Adverse events 
(2) General laboratory test 
Hematology test: White blood cell count (WBC), red blood cell count (RBC), hemoglobin, 
hematocrit, and platelet count 
Chemistry test: 
AST(GOT), ALT(GPT), ALP, gamma-GTP, LDH, total bilirubin, total protein, 
albumin, urea nitrogen, creatinine, total cholesterol, triglyceride, HDL-
cholesterol, LDL-cholesterol, blood glucose, HbA1c, sodium, potassium, and 
chloride 
Urinalysis (qualitative): Urine protein, urine glucose, and occult blood in urine 
(3) vital signs:Sitting blood pressures (systolic/diastolic), and pulse rates 
(4) Body weight 
(5) Standard 12-lead ECG 
(6) C-SSRS 
 
10.2 Timing and method of safety evaluation 
The (sub-)investigator will perform observation, tests, and evaluation on adverse events, general 
laboratory test items, vital signs, body weight, standard 12-lead ECG, and C-SSRS in accordance with “5.2 
Observation and test, and evaluation schedule.“ 
 
10.2.1 Adverse events 
See “12. Adverse events.“ 
 
10.2.2 General laboratory test 
The (sub-)investigator will collect subjects’ blood and urine samples (See "Annex 5 Sample collection 
procedures" for the volume of blood and urine samples to be collected at each visit) in accordance with 
“Table 5.2-1 Observation and test, and evaluation schedule.” Specimens will be processed, and submitted 
to the central laboratory for general laboratory tests in accordance with "Annex 5 Sample collection 
procedures." The central laboratory will report the test results to the sponsor and study center. 
The (sub-)investigator will check the test results and retain these with the original medical record 
(medical chart, etc.) at the study center. 
 


10. Safety evaluation 
44 
10.2.3 Vital signs 
The (sub-)investigator will measure sitting blood pressures (systolic/diastolic) and pulse rates in 
accordance with “Table 5.2-1 Observation and test, and evaluation schedule“ and enter the date of 
measurement and measured values in the case report form. 
 
10.2.4 Body weight 
The (sub-)investigator will measure body weight in accordance with “Table 5.2-1 Observation and test, 
and evaluation schedule“ and enter the date of measurement and measured value in the case report form. 
 
10.2.5 Standard 12-lead ECG 
The (sub-)investigator will measure standard 12-lead ECG on the subject at rest in the supine position in 
accordance with “Table 5.2-1 Observation and test, and evaluation schedule,“ and enter the date of 
measurement, the presence or absence of abnormal findings, and the contents of the abnormal findings if 
present, in the case report form.  
 
10.2.6 C-SSRS 
The (sub-)investigator will assess suicidality of the subject using C-SSRS and the eCOA system in 
accordance with “Table 5.2-1 Observation and test, and evaluation schedule. After study completion, the 
Clinical data analytics committee will store the evaluation result of each C-SSRS collected using eCOA 
system (including audit trail) in an electronic recording media (CD-ROM etc.), and provide it to the study 
center. The principal investigator will retain the results as source documents. 
The detailed evaluation method and the method to provide electronic data to the sponsor are separately 
specified in the procedures. 
 
 


11. Rater training and Clinical data analytics 
45 
11. Rater training and Clinical data analytics  
11.1 Rater training 
The sponsor will assign a training vendor to provide reviewer training to (sub-)investigators to equalize 
methods for evaluation in (1) to (6) and instruction to subjects in (7) and (8) as shown below. Only the 
(sub-)investigators certified by the training vendor will be qualified to make assessments in (1) to (6), and 
subjects instruction in (7) and (8). The (sub-)investigators certified by the training vendor shall retain the 
training record at the study center. Detailed equalization are separately specified in the written procedures. 
 
(1) Diagnosis using M.I.N.I. 
(2) MADRS 
(3) HAMD17 
(4) CGI-S 
(5) CGI-I 
(6) C-SSRS 
(7) QIDS16-SR-J 
(8) SDS 
 
11.2 Clinical data analytics  
11.2.1 Efficacy endpoints (From the start of screening period to Week 8 visit during treatment 
period) 
The Clinical data analytics committee will use eCOA system to obtain the efficacy assessments (See 
“9.2 Timing and method of efficacy evaluation”). The Clinical data analytics committee will perform the 
blinded review on the assessments, and report to the (sub-)investigator any dispute regarding the 
assessments. Also, the Clinical data analytics committee will as necessary discuss the review method with 
the (sub-)investigator, but in no event provide an instruction to correct the assessments; provided that the 
(sub-)investigator is allowed to reconsider assessments at his/her discretion based on the Clinical data 
analytics committee's review results. The details of the review method will be set out separately in the 
operating procedures. 
 
11.2.2 Subjects' diagnosis (at the initial registration) 
The (sub-)investigator will use the cCOA system to evaluate subjects' diagnosis confirmation at the 
initial registration. The Clinical data analytics committee will use eCOA system to obtain this assessments 
results. The Clinical data analytics committee will perform the blinded review on the subjects' diagnosis 
confirmation and report to the (sub-)investigator's. The details of the review method will be set out 
separately in the operating procedures. 


12. Adverse events 
46 
12. Adverse events 
12.1 Definition of adverse events 
An adverse event is any undesirable or unintended sign (including abnormal findings in general 
laboratory tests,vital signs, body weight, and standard 12-lead ECG), symptom, or disorder in a subject 
given the investigational drug, irrespective of the causal relationship to the investigational drug. An adverse 
event which is judged to be causally related to the investigational drug is defined as an adverse drug 
reaction (ADR). In addition, any abnormal general laboratory test value meeting the following criteria is 
classified as an adverse event. 
(1) A change in laboratory test value meets definition of serious adverse events 
(2) A change in laboratory test value requires suspension or discontinuation of the investigational drug 
(3) A change in laboratory test value requires medication or action for the treatment 
(4) A change in laboratory test value leads to surgical intervention. 
(5) Although the change in laboratory test value does not fall under the above cases, the 
(sub-)investigator considers the change as a medically noteworthy finding. 
 
12.2 Survey period and items for adverse events 
The (sub-)investigator will survey the following items in subjects given the investigational drug for 
adverse events that have occurred from the first dose of the investigational drug in treatment period to the 
end of follow-up period and enter the contents in the case report form. 
If an adverse event has recurred after resolution of the same event but different judgements for the causal 
relationship to the investigational drug are given to these events, or if an adverse event that occurred before 
the first dose of the investigational drug has been exacerbated after that, events of the same medical term 
that have occurred at different timings will be entered in the case report form as separate adverse events. 
(1) Name of adverse event (enter the diagnostic term where possible) 
(2) Date of onset 
(3) Date of resolution or date of confirmation of outcome 
(4) Outcome (recovered/resolved, recovering/resolving, not recovered/not resolved, 
recovered/resolved with sequelae, died) 
(5) Severity (mild, moderate, severe) 
(6) Serious adverse event (yes or no) 
(7) Action on the investigational drug (unchanged, discontinued [no re-treatment], interrupted 
[temporal suspension], not applicable [after the last dose of the investigational drug]) 
(8) Causal relationship to the investigational drug (related or unrelated) 
If a serious adverse event occurs, the (sub-)investigator will prepare a “Report on serious adverse events” 
in accordance with “12.3 Definition of serious adverse events and procedures for collecting, recording, and 
reporting such events” and enter the content in the case report form. Severity and seriousness of adverse 


12. Adverse events 
47 
events will be determined in accordance with “Severity/seriousness classification criteria of adverse drug 
reactions (PAB/PCSD Notification No. 80 dated June 29, 1992) or Common Terminology Criteria for 
Adverse Events v5.0 JCOG Japanese version.” 
12.3 Definition of serious adverse events and procedures for collecting, recording, 
and reporting such events 
An adverse event falling under any of (1) to (6) below irrespective of the causal relationship to the 
investigational drug is defined as a serious adverse event. Actions on serious adverse events are described 
below (See “Figure 12.3-1 Outline of procedures for reporting serious adverse events“). 
(1) Event leading to death 
(2) Life-threatening event 
(3) Event requiring hospitalization or prolongation of hospitalization for treatment 
(4) Event resulting in disability 
(5) Congenital disorder or anomaly in the subsequent generations 
(6) Serious event equivalent to (1) to (5) 
 
Figure 12.3-1  Outline of procedures for reporting serious adverse events 
 
If a serious adverse event occurs, the investigator will take necessary actions on the concerned subject 
such as discontinuation of the investigational drug and treatment of the adverse event and proceed with the 
following procedures (See “Figure 12.3-1 Outline of procedures for reporting serious adverse events“). 
(1) Promptly communicate the onset of the serious adverse event to the sponsor. 
(2) Prepare a “Report on serious adverse events“ and submit it to the sponsor and the head of study 
center at the earliest possible within 7 days after communication with the sponsor. 
(3) Retain a duplicate copy of the submitted report with the original medical record. 
(in line with the category of reporting to PMDA) 
Reporting 
Information provision 
and seeking for advices 
where necessary 
• 
Prompt communication (sponsor) 
Sponsor
Medical experts
Pharmaceuticals and Medical 
Devices Agency (PMDA) 
Investigator at each study 
center 
Head of study center 
• 
Submission of “Report on serious adverse events“ at 
the earliest possible within 7 days 
(head of study center and sponsor) 
Investigator at the 
concerned study 
center 
Head of supervising study center 


12. Adverse events 
48 
(4) Even after that, try to collect further detailed data, and report new information, if any, to the sponsor 
and study center. 
12.4 Follow-up survey for serious adverse events and adverse events causally 
related to the investigational drug 
(1) 
A follow-up survey will be conduced for the serious adverse event irrespective of the causal 
relationship to the investigational drug or the adverse event causally related to the investigational 
drug that does not resolve by the end of follow-up period, if any. 
(2) 
The follow-up survey shall be continued until the target event resolves in principle. For any 
adverse event that does not resolve at 12 weeks after the end of follow-up period, the follow-up 
survey may be terminated, except for serious adverse events causally related to the 
investigational drug and adverse events causally related to the investigational drug for which the 
follow-up is considered necessary by the sponsor and (sub-)investigator. For these exceptional 
events, the follow-up survey should be continued wherever possible. 
(3) 
The follow-up survey results obtained after the end of follow-up period may be recorded in a 
separate document, “Follow-up survey record on adverse events,“ without being entered in the 
case report form and reported to the sponsor. 
 


13. Other survey and evaluation items 
49 
13. Other survey and evaluation items 
13.1 Subject baseline characteristics 
The (sub-)investigator will investigate the following items at the start of screening period and enter the 
obtained information in the case report form. 
(1) Sex 
(2) Race 
(3) Date of birth 
(4) Date of informed consent 
(5) Height 
(6) Time of onset of depression 
(7) Number of depressive episodes 
(8) Time of onset of the current depressive episode 
(9) Applicability of each of the 9 depression symptoms to DSM-5 criteria 
(10) Prior treatment with antidepressant drugs for current and past depressive episodes 
1) Presence/absence of a history of treatment 
2) Name of drugs 
(11) A history of treatment with hypnotics/sedatives (within 2 months before the initial registration) 
1) Presence/absence of a history of treatment 
2) Name of drugs 
(12) Presence/absence of a history of treatment with antianxiety drug (within 2 months before the initial 
registration) 
13.2 Concomitant treatment 
The (sub-)investigator will survey use status of concomitant drugs and therapies throughout the clinical 
study period (from the start of the screening period to the end of the follow-up period). For concomitant 
drugs, the name, administration route, treatment duration (date of the first dose and date of the last dose), 
and purpose for the use will be entered in the case report form. In addition, for non-drug treatment, if 
applicable, the details, treatment duration (date of start of the treatment and date of end of the treatment), 
and the purpose will be entered in the case report form. 
13.3 Comorbidities 
The (sub-)investigator will survey the subject for comorbidities at each visit from the screening period to 
the run-in period and enter presence or absence of comorbidities and the details (if present) in the case 
report form. 


13. Other survey and evaluation items 
50 
13.4 Pharmacokinetic evaluation 
The endpoint of pharmacokinetics is the plasma desvenlafaxine concentration. The (sub-)investigator 
will collect blood from subjects in accordance with “Table 5.2-1 Observation and test, and evaluation 
schedule“ and enter, in the case report forms, the time and date of each blood collection and of the 3 
nearest doses of the investigational drug pre-blood draw, as well as the presence/absence of meal within 2 
hours before and after dose. Specimens will be submitted to the central laboratory for general laboratory 
tests, and then, from the central laboratory for general laboratory tests to the laboratory for drug 
concentration measurement. The laboratory for drug concentration measurement will measure the plasma 
desvenlafaxine concentration in the MD-120 group (50 mg and 100 mg groups) according to the separate 
operating procedures, and report the measurement results to the sponsor and study center after unblinding 
upon study completion. 
13.5 Pregnancy test 
The (sub-)investigator will collect urine from any premenopausal female subject at the study center in 
accordance with “Table 5.2-1 Observation and test, and evaluation schedule“ and perform pregnancy test to 
check if she is pregnant or not. 
13.6 Use status of the investigational drug 
The (sub-)investigator will check the drug-use status through the “drug-use diary” and interview at each 
visit during run-in, treatment, and follow-up periods (before Week 1 visit) and at the time of premature 
termination and enter the date of the first dose of the investigational drug and date of the last dose (or 
treatment discontinuation), and number of tablets used between the previous visit and current visit in the 
case report form. 
 


14. Preparation, correction, and retention of case report forms, etc. 
51 
14. Preparation, correction, and retention of case report forms, 
etc. 
14.1 Target necessary for preparation of case report form 
The (sub-)investigator and clinical research coordinator will prepare case report forms for subjects 
deemed “eligible” at the initial registration. 
14.2 Structure of case report form 
The case report form in this clinical study will be prepared in an electronic data capture (EDC) system. 
14.3 Preparation of case report form 
(1) Issuance of account for preparation of case report form 
The sponsor (or person designated by the sponsor) will provide training to the (sub-)investigators 
and clinical research coordinators for use and entry methods of the EDC system and issue an account 
to such trained professional. 
(2) Preparation by (sub-)investigators and clinical research coordinators 
The (sub-)investigator and clinical research coordinator will prepare a case report form within an 
authorized range in the EDC system in accordance with the manual provided by the sponsor. 
(3) Correction by (sub-)investigators and clinical research coordinators 
The (sub-)investigator or clinical research coordinator will correct the content in a case report 
form in the EDC system if he or she consider it necessary and enter the reason. In addition, the 
corrected content, correcting person, and date of correct will be automatically recorded as electronic 
information. 
(4) Electronic signature by investigator 
The investigator will inspect the content in the case report form, confirm absence of any problem, 
and put the electronic signature in the EDC system. 
14.4 Retention of case report forms 
The investigator will retain electromagnetic media (CD-ROM, etc.) on the content of case report forms 
(including audit trails) provided by the sponsor. 
14.5 Direct access to source documents 
The study center and investigator will allow direct access to all the clinical study records such as source 
documents at monitoring and audit sessions of the sponsor as well as inspections of regulatory authorities 
in and outside Japan in a manner previously determined under agreement with the sponsor. In addition, the 
sponsor shall have a duty of confidentiality on the obtained information. 
The source documents in this clinical study will be as follows: 


14. Preparation, correction, and retention of case report forms, etc. 
52 
(1) Original medical record (including written informed consent, test reports, and ECG charts, etc.) 
(2) All the documents related to the subject registration (including the screening list) 
(3) All the documents related to diagnosis and evaluation (M.I.N.I. diagnosis results*, MADRS 
evaluation results*, HAMD17 evaluation results*, CGI-S and CGI-I evaluation results*, QIDS16-
SR-J evaluation results*, SDS evaluation results*, C-SSRS questionnaire results*, and diagnosis 
confirmation results*) 
 
*M.I.N.I diagnostic results, MADRS, HAMD17, CGI-S, CGI-I, QIDS16-SR-J, SDS,C-SSRS, and 
diagnosis confirmation results, which are directly entered in the eCOA device shall be deemed as 
source materials. 
(4) Drug-use diary 
(5) Documents related to storage of the investigational drug (including investigational drug storage 
table, investigational drug delivery note, and investigational drug retrieval note) 
14.6 Identification of data that are directly entered in the case report form and should 
be classified into source documents 
Not applicable in this clinical study 
 


15. Statistical analysis 
53 
15. Statistical analysis 
15.1 Purpose of the analysis and summary 
The purpose of the analysis is to evaluate the efficacy of 8-week treatment with MD-120 in Japanese 
patients with depression and investigate the safety. 
The efficacy will be analyzed by comparing changes in total MADRS score from the baseline to Week 8 
visit during treatment period, the primary endpoint, in the MD-120 50 mg and 100 mg groups to that in the 
placebo group. 
The safety will be analyzed based on the incidence of adverse events during treatment and follow-up 
periods, the primary endpoint, in each dose group. 
15.2 Analysis sets 
The following analysis sets will be used. The efficacy analysis set will be mainly performed on the full 
analysis set (FAS). The safety analysis set will be mainly performed on the safety analysis set during 
treatment period. 
 
15.2.1 Efficacy analysis set 
15.2.1.1 FAS 
Of subjects registered for randomization, those meeting all the following items will be included in the 
above analysis set. 
(1) Subjects who have received the investigational drug at least once during treatment period 
(2) Subjects who have evaluated for the total MADRS score at the baseline and at least one timepoint 
after the start of treatment period 
 
15.2.1.2 PPS 
Of subjects included in the FAS, those meeting all the following items will be included in the per 
protocol set (PPS). 
(1) 
Subjects who meet the inclusion criteria and do not fall under the exclusion criteria 
(2) 
Subjects who have not violated “7.1.1 Prohibited concomitant drugs“ or “7.1.2 Prohibited 
concomitant therapies“ from the start of screening period to the end of treatment period 
(3) 
Subjects who have used hypnotic/sedative drugs in compliance with provisions in “7.1.3 Allowed 
concomitant drugs“ from the start of sreening period to the end of treatment period 
(4) 
Subjects in whom the study treatment period or the number of days from the first dose of the 
investigational drug to the last dose in the treatment period is 42 days or longer, and the drug-use 
rate during the study treatment period is 75% or higher 
 


15. Statistical analysis 
54 
15.2.2 Safety analysis set 
15.2.2.1 Safety analysis set in run-in period 
Subjects meeting all the following items will be included in the above analysis set. 
(1) Subjects who have received the investigational drug at least once during run-in period 
(2) Subjects in whom the safety evaluation data in run-in period are available 
 
15.2.2.2 Safety analysis set in treatment period 
Of subjects registered for randomization, those meeting all the following items will be included in the 
above analysis set. 
(1) Subjects who have received the investigational drug at least once during treatment period 
(2) Subjects in whom the safety evaluation data after the dose of the investigational drug in treatment 
period are available 
 
15.2.2.3 Safety analysis set in follow-up period 
Subjects meeting all the following items will be included in the above analysis set. 
(1) Subjects included in the “Safety analysis set in treatment period” 
(2) Subjects in whom the safety evaluation data in follow-up period are available 
 
15.2.3 Pharmacokinetic analysis set 
Subjects meeting all the following items at the same time will be included in the above analysis set. 
(1) Subjects who have received the investigational drug at least once during treatment period 
(2) Subjects in whom the drug concentration evaluation data after the dose of the investigational drug 
in treatment period are available 
 
15.3 Statistical analysis methodology 
15.3.1 Features of demographic variables and other reference values 
Features of demographic variables and other reference values are summarized as follows: 
(1) Demographic variables 
Sex, race, age (informed consent), height, body weight (at the start of screening period), and BMI 
(2) Other factors 
1) 
Age at the onset of depression 
2) 
Period from onset of depression 
3) 
Number of depressive episodes 
4) 
Duration of current depressive episode 
5) 
Presence/absence of prior treatment with antidepressant drugs for current and past depressive 
episodes 
6) 
Presence/absence of concomitant use of hypnotic/sedative drugs and narcoleptics (within 2 
months before the initial registration) 


15. Statistical analysis 
55 
7) 
Presence/absence of a history of treatment with antianxiety drug (within 2 months before the 
initial registration) 
8) 
Presence or absence of comorbidities 
9) 
Total MADRS score, total HAMD17 score, CGI-S, and total QIDS16-SR-J score at the baseline 
 
15.3.2 Efficacy analysis 
15.3.2.1 Analysis on primary endpoint 
(1) Primary endpoint 
Change in total MADRS score from baseline Week 8 visit during treatment period) 
 
(2) Main analysis on primary endpoint 
A Mixed-effects Model for Repeated Measures (MMRM) will be used for the main analysis of 
the primary efficacy endpoint. The analytical model will use a change in total MADRS score from 
baseline to each evaluation timepoint as a response variable; the treatment group, assessment 
timepoint, and the interaction between the treatment group and assessment timepoint as fixed 
effects, and the total MADRS score at the baseline as a covariate the structure of error variance as 
Unstructured, and Kenward Roger as degrees of freedom adjustment. Based on this analytical 
model, changes in total MADRS score from the baseline to Week 8 visit during treatment period in 
the MD-120 50 mg and 100 mg groups will be compared to that in the placebo group. For missing 
data on the response variable, no data will be substituted. 
 
Adjustment of multiplicity will be performed in the main analysis on the efficacy primary 
endpoint according to a closed testing procedure. Results on the efficacy primary endpoint will be 
firstly compared between the placebo group and MD-120 50 mg group with a significance level of 
5%. Only when Hypothesis 1 is verified, a comparison between the placebo group and MD-120 
100 mg group will be made with significance level of 5%. 
[Hypothesis 1] Superiority of the MD-120 50 mg group to the placebo group 
[Hypothesis 2] Superiority of the MD-120 100 mg group to the placebo group 
 
(3) Secondary analysis on primary endpoint 
An analysis of covariance will be performed on the primary endpoint by comparing relevant 
results in the MD-120 50 mg group and 100 mg group to that in the placebo group. The analytical 
model will use a change in total MADRS score from baseline to Week 8 visit during treatment 
period as a response variable; the treatment group as a fixed effect, and the total MADRS score at 
the baseline as a covariate. For missing data on the response variable, data will be substituted in a 
last observation carried forward (LOCF) manner. 
 
15.3.2.2 Analysis on secondary endpoints 
The analysis will be performed on the following endpoints. 


15. Statistical analysis 
56 
(1) 
Response evaluated by total MADRS score at Week 8 visit during treatment period 
(2) 
Remission evaluated by total MADRS score at Week 8 visit during treatment period 
(3) 
Change in total HAMD17 score from baseline to Week 8 visit during treatment period 
(4) 
Response evaluated by total HAMD17 score at Week 8 visit during treatment period 
(5) 
Remission evaluated by total HAMD17 score at Week 8 visit during treatment period 
(6) 
CGI-I at Week 8 visit during treatment period 
(7) 
Response evaluated by CGI-I at Week 8 visit during treatment period  
(8) 
Change in CGI-S from baseline to Week 8 visit during treatment period 
(9) 
Change in total QIDS16-SR-J score from baseline to Week 8 visit during treatment period 
(10) Change in total SDS score from baseline to Week 8 visit during treatment period 
 
15.3.3 Safety analysis 
Data on adverse events will be tabulated using preferred terms (PTs) of MedDRA/J. 
 
15.3.3.1 Analysis on primary endpoint 
An incidence of adverse events during treatment and follow-up periods in each dose group will be 
calculated. 
 
15.3.3.2 Analysis on secondary endpoints 
The incidence on the following endpoint in each dose group will be calculated. 
(1) Adverse drug reactions (ADRs) during treatment period and follow-up period 
(2) Adverse events and ADRs during treatment period 
(3) Adverse events and ADRs during follow-up period 
 
15.3.3.3 Analysis on other endpoints 
The analysis will be performed on the following endpoints. 
(1) General laboratory test 
(2) Vital signs 
(3) Body weight 
(4) Standard 12-lead ECG 
(5) C-SSRS 
 
15.3.4 Pharmacokinetic analysis 
Plasma desvenlafaxine concentration at each evaluation timepoint during treatment period will be 
summarized for each dose group. 


15. Statistical analysis 
57 
15.4 Target sample size and its rationale 
A total of 594 subjects (n = 198 per group) will be included in the FAS. 
 
 
  
 
 
 
 
 
 
 
 
15.5 Significance level and confidence interval 
Tests on endpoints will be performed with a two-sided significance level of 5%. Interval estimation will 
be performed with a confidence coefficient of 0.95, and thus a two-sided 95% confidence interval will be 
used. 
15.6 Data adoption period and conditions 
Data adoption period and conditions are specified in separately prepared “Handling plan.” 
15.7 Handling of missing data and abnormal specimens 
15.7.1 Handling of missing data 
Data missing for the analysis of the primary efficacy endpoint will be handled in accordance with the 
procedures specified in "15.3.2.1 Analysis on primary endpoint." 
Data missing for the analysis of the secondary efficacy endpoint will be handled in accordance with the 
procedures specified in the "analysis plan" to be separately preprared. 
For missing evaluation data other than the safety and pharmacokinetics, data at the other observation or 
measurement timepoint will not be substituted. 
 
15.7.2 Handling of abnormal specimens 
Abnormal specimens in general laboratory tests will be excluded from the analysis. In the individual data 
list, however, the relevant data will be used with a note of “Abnormal specimen.” 
 


15. Statistical analysis 
58 
15.8 Analysis plan 
Technical details related to the statistical analysis and other analyses performed where necessary are 
specified in separately prepared “Analysis plan.” 
 
15.9 Procedure for reporting a change or deviation from the initial statistical analysis 
plan 
All the changes and deviations from the initial statistical plan described in “15. Statistical analysis“ will 
be described in the final study report. 


16. Compliance with and deviations from the study protocol as well as revision 
59 
16. Compliance with and deviations from the study protocol as 
well as revision 
16.1 Compliance with and deviations from the study protocol 
This clinical study will be conducted in compliance with the study protocol under agreement between the 
investigator and sponsor. The sponsor and investigator will consult about the study protocol and put their 
signature or name and their seal on duplicate copies (2 copies) of the study protocol or equivalent 
document, and the investigator will enter the date. Furthermore, such protocol shall be approved by the 
institutional review board. 
The (sub-)investigator is not allowed to make a deviation or change from the study protocol without the 
prior written agreement with the sponsor and prior approval of the institutional review board. This, 
however, will not apply to medically unavoidable cases (emergency deviation) such as a deviation for 
avoidance of an emergent risk in a subject. In a case of emergency deviation, the investigator will submit 
the emergency deviation report to the sponsor and the head of study center for agreement of the sponsor 
and approval of the institutional review board. The (sub-)investigator will record the content and reason for 
a deviation from the study protocol, if any. 
16.2 Revision of study protocol 
When any of the following cases is applicable, the sponsor shall revise the study protocol as necessary. 
(1) When any of matters related to the quality, efficacy, and safety of the investigational drug and 
other information relevant to proper conduct of the clinical study becomes available 
(2) When the study protocol has to be changed owing to medically unavoidable situation 
(3) When the head of a study center directs correction based on comments from the institutional 
review board 
 
The sponsor and investigator will consult about the revised study protocol and put their signature or 
name and their seal on duplicate copies (2 copies) of the study protocol or equivalent document, and the 
investigator will enter the date. Furthermore, such protocol shall be approved by the institutional review 
board. 
After preparation of this study protocol, the following changes on Annex 1, Annex 3, and Annex 4 will 
be reported to the head of the study center and investigator by attaching the concerned annex as necessary, 
and changes on Annex 2 will be reported to the head of the study center and investigator by attaching a part 
of the concerned annex only including the information specific to the study center. 
(1) “Administrative structure chart of the sponsor“(Annex 1) 
(2) “List of study centers and investigators“ (Annex 2) 
(3) “List of contract research organizations“(Annex 3) 
(4) “List of prohibited concomitant drugs“(Annex 4) 


17. Ethical matters 
60 
17. Ethical matters 
17.1 Compensation for study-related injuries 
If any study-related injury occurs in a subject, the sponsor will appropriately compensate for the injury. 
17.2 Protection of subjects’ privacy 
Adequate considerations will be given to protection of subjects’ privacy, and subject identification code 
will be used instead of the name if a subject is identified in the case report form, etc. The prepared case 
report forms will be used only for this clinical study. 
17.3 Handling of measurement specimens 
Measurement specimens will be used only for purposes specified in this study protocol. Measurement 
specimens will be appropriately destroyed in accordance with the operation procedure at the laboratory or 
study center after end of measurement or end of storage period. 
 
 


18. Criteria for prematurely terminating a part and the whole of the clinical study and the procedures 
61 
18. Criteria for prematurely terminating a part and the whole of 
the clinical study and the procedures 
(1) If the sponsor becomes aware of information that this investigational drug may harm subjects, the 
company shall consider prematurely terminating a part or the whole of the clinical study in 
consultation with medical experts. 
(2) If the sponsor decides to prematurely terminate a part or the whole of the clinical study, the 
company shall promptly report the above premature termination and the reason to the heads of all 
the study centers involved in the clinical study and PMDA in writing. 
(3) Upon receipt of the report of the premature termination from the sponsor, the head of the study 
center will promptly notify the investigator and institutional review board of that matter in writing 
and give detailed explanation to them. 
(4) If the clinical study is prematurely terminated, the (sub-)investigator will promptly notify the 
subjects of that matter, provide appropriate medical practices, and take other necessary actions. 
 
19. Quality, retention, and publication of information 
19.1 Quality control and assurance of clinical study 
The quality control and assurance of the clinical study at the study center will be implemented in 
accordance with written procedures related to conduct of the clinical study specified by the head of the 
study center. In addition, any study center will accept monitoring and audit of the sponsor. 
19.2 Data handling and record retention 
19.2.1 Documents and records to be retained 
“Documents or records related to clinical study” that should be retained at the study center will be as 
specified in the Good Clinical Practice (GCP) and internal provisions at the study center. 
 
19.2.2 Retention period 
The head of the study center will retain “Documents or records related to clinical study” that should be 
retained until the date of 1) or 2) below, whichever comes later. 
(1) Date when marketing of the investigational drug is approved (or date when 3 years have elapsed 
since the discontinuation of development.) 
(2) Date when 3 years have elapsed since premature termination or completion of the clinical study 
In addition, if the sponsor requires extension of the above retention period, the head of the study center 
will consult with the sponsor about the retention period and method. For retention of the records, a 


19. Quality, retention, and publication of information 
62 
responsible person shall be appointed for each type of the records. In addition, when the sponsor no longer 
requires such retention, the company will notify the head of the study center or administrator of the 
institutional review board of that matter. 
19.3 Laws, regulations, standards, etc. to be complied with for conduct of this clinical 
study 
This clinical study will be conducted in compliance with the following laws, regulations, standards, etc. 
(1) “Ethical principles based on Declaration of Helsinki“ 
(2) “Paragraph 3 of Article 14 and Article 80-2 of the Act on Securing Quality, Efficacy and Safety of 
Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products, Gene Therapy 
Products, and Cosmetics“ (Law No. 145 of 1960) 
(3) “Ministerial Ordinance for Enforcement of the Act on Securing Quality, Efficacy and Safety of 
Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products, Gene Therapy 
Products, and Cosmetics“ (MHW Ordinance No. 1 of 1961) 
(4) “Ministerial Ordinance on Good Clinical Practice for Drugs“ (MHW Ordinance No.28 of March 
27, 1997) 
19.4 Agreement regarding publication 
Publication and authors of the article will be determined through consultation between the sponsor and 
medical experts. 
 


20. Payment and insurance 
63 
20. Payment and insurance 
20.1 Payment 
Actions to reduce burden of a subject associated with participation in the clinical study may be specified 
in writing through consultation at each study center, if such actions are taken. Matters regarding the other 
necessary expenses will be specified in writing through consultation separately at each study center. 
20.2 Insurance 
The sponsor will take actions such as insurance to ensure compensation for cost of treatment for study-
related injuries and other damage incurred in the subject. 
 
21. Study period 
April 2020 to December 2022 
 
22. Study administrative structure 
22.1 Name of sponsor, address, and telephone number 
Mochida Pharmaceutical Co., Ltd. 
 
 
22.2 Person authorized to put the signature on the study protocol as a representative 
of the sponsor 
 
 
 
 
 
22.3 Clinical study conducting manager, monitoring manager, pharmacokinetic 
analysis manager, data management manager, statistical analysis manager, 
safety information manager, and audit manager 
See Annex 1 


22. Study administrative structure 
64 
22.4 Medical expert on the sponsor 
 
 
[Roles] 
(1) Advice regarding preparation of the study protocol, investigator’s brochure, and final study 
report 
(2) Advice regarding proceeding of this clinical study, safety and efficacy evaluation, etc 
(3) Assessment of causal relationship to the investigational drug and future actions for serious 
adverse events 
(4) Advice regarding communication of revision of the study protocol, etc. or new information about 
this investigational drug and direction methods 
(5) Advice regarding data handling 
(6) Duties related to preparation of articles of this clinical study 
(7) Advice regarding statistical analysis 
(8) Other duties associated with (1) to (7) 
22.5 Study center and investigator 
See Annex 2 
22.6 Registration center 
 
 
[Roles] 
(1) 
Preparation of written registration procedure 
(2) 
Eligibility assessment of subject candidates for the initial registration based on the inclusion 
criteria and exclusion criteria for the initial registration 
(3) 
Initial registration of subjects assessed to be eligible for the initial registration 
(4) 
Eligibility assessment of subject candidates for second registration based on the inclusion 
criteria and exclusion criteria for the second registration 
(5) 
Second registration of subjects assessed to be eligible for the second registration 
(6) 
Eligibility assessment of subject candidates for randomization registration based on the 
inclusion criteria and exclusion criteria for the randomization registration 
(7) 
Randomization registration of subjects assessed to be eligible for the randomization 
registration 


22. Study administrative structure 
65 
22.7 Randomization registration center 
 
 
 
[Roles] 
(1) 
Preparation of written procedure for investigational drug randomization 
(2) 
Preparation and storage of investigational drug assignment table for randomization and 
blinding of the investigational drug 
(3) 
Preparation and storage of the investigational drug assignment table for emergency unblinding 
available for individual unblinding 
(4) 
Assignment of the investigational drug (See “6.3.2 Randomization registration”) 
(5) 
Sampling of investigational drug for indistinguishability test of the investigational drug, 
confirmatory test after assignment of the investigational drug, assessment for conformity in 
approval review document 
(6) 
Confirmation of indistinguishability at the start (after assignment of the investigational drug) 
and completion (after end of the follow-up period for all the subjects) of the clinical study 
(7) 
Preparation of indistinguishability test report 
(8) 
Duties related to unblinding (See “6.4 Procedure for unblinding with the investigational drug 
assignment table“) 
22.8 Laboratory for general laboratory tests 
 
 
[Roles] 
(1) 
Collection of measurement specimens for hematology test, blood biochemistry test, and 
urinalysis 
(2) 
Conducting and reporting of hematology test, blood biochemistry test, and urinalysis 
(3) 
Provision of electronic data of test results 
(4) 
Primary storage of specimens for drug concentration measurement and their shipping 
arrangement to laboratory 
22.9 Laboratory for drug concentration measurement 
 
 
[Roles] 
(1) 
Validation of measurement method of plasma desvenlafaxine concentration 
(2) 
Measurement of plasma desvenlafaxine concentrations for this clinical study 
22.10 Reviewer training, and Clinical data analyst 
 


22. Study administrative structure 
66 
 
[Roles] 
(1) 
Training and qualification of reviewers 
(2) 
Preparation and management of eCOA 
(3) 
Obtaining the license to use the copyright for the assessment criteria 
(4) 
Clinical data analytics of the efficacy endpoints 
(5) 
Clinical data analytics of subjects' diagnosis confirmation 
 
22.11 Monitoring contract research organization 
 
 
[Roles] 
(1) 
Conducting of monitoring in accordance with the study protocol 
 


23. References 
67 
23. References 
1) 
Norio Ozaki. Chapter 13 Depression and bipolar disorder, B Epidemiology,Standard of 
psychiatrics (Standard textbook) Version 7 edited by Norio Ozaki, Masaru Mimura, Masafumi 
Mizuno, Toshiya Murai: Igaku-Shoin Ltd. (Tokyo); 2018. p. 341-71. 
2) 
Outline of patient survey results (2017) [Internet]. Ministry of Health, Labour and Welfare 
(Tokyo); [cited 2019 November 7]:  
Available from: https://www.mhlw.go.jp/toukei/saikin/hw/kanja/17/. 
3) 
Clinical Practice Guideline of Japanese Society of Mood Disorders II, Depression (DSM-5)/Major 
depressive disorder 2016 [Internet] dated July 24, 2019, prepared by Guideline Preparation 
Committee for Clinical Practice Guideline for Mood Disorders, Japanese Society of Mood [cited 
2019 November 7].  
Available from: https://www.secretariat.ne.jp/jsmd/iinkai/katsudou/data/20190724.pdf  
4) 
Asahi Kasei Pharma Corporation. Toledomin Tablets®12.5 mg, 15 mg, 25 mg, and 50 mg Package 
Insert revised in March 2019 (version 26). 
5) 
Shionogi & Co., Ltd.. Cymbalta® Capsules 20 mg and 30 mg Package Insert revised in April 2019 
(version 1). 
6) 
Pfizer Japan Inc.. Effexor® SR Capsules 37.5 mg and 75 mg Package Insert revised in October 
2019 (version 1). 
7)  Pfizer Inc. PRISTIQ® Label. Revised: 2018 November. 
8)  Pfizer Inc. EFFEXOR XR® Label. Revised: 2018 December. 
9) 
Practice guideline for the treatment of patients with major depressive disorder 3rd ed. [Internet]. 
American Psychiatric Association; 2010 October [cited 2019 November 12]; Available from: 
https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/mdd.pdf. 
10) Kennedy SH, Lam RW, McIntyre RS, Tourjman SV, Bhat V, Blier P, et al. Canadian Network for 
Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of 
Adults with Major Depressive Disorder, Section 3. Pharmacological Treatments. Can J Psychiatry. 
2016 Sep;61(9):540-60. 
11) Cognitive-behavioral therapy for refractory depression, edited by Shigenobu Kanba, Arcmedia 
(Tokyo);2013;p.75-85 
12) Note for “Guideline for Clinical Evaluation Methods of Antidepressant Drugs“ PFSB/ELD 
Notification No. 1116-1 of the Evaluation and Licensing Division, Pharmaceutical and Food Safety 
Bureau, Ministry of Health, Labour and Welfare, dated November 16, 2010 
13) Full-use of MADRS: Clinical evaluation of depression based on MADRS Japanese version using 
SIGMA Revised version 3, edited by Toshiya Inada: Jiho Inc. (Tokyo); 2013. Chapter 1, 
Montgomery Åsberg Depression Rating Scale (MADRS); p.1-14. 
14) Tourian KA, Padmanabhan SK, Groark J, Brisard C, Farrington D. Desvenlafaxine 50 and 100 
mg/d in the Treatment of Major Depressive Disorder: An 8-week, Phase III, Multicenter, 


23. References 
68 
Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Trial and a Post Hoc Pooled 
Analysis of Three Studies. Clin Ther. 2009 Jun;31 Pt 1:1405-23. 
 

SAP_001.pdf: 
MD120101 
MOCHIDA PHARMACEUTICAL CO., LTD. 
Statistical analysis plan 
1 
A Placebo-controlled Study of MD-120 in 
Depression Patients 
Statistical Analysis Plan 
Mochida Pharmaceutical Co., Ltd. 
Protocol Code: 
MD120101 
Date of Creation: 
September 14, 2022 
Version No.:  
2.0 
ClinicalTrials.gov Identifier: NCT04345471


MD120101 
MOCHIDA PHARMACEUTICAL CO., LTD. 
Statistical analysis plan 
 
【Confidentiality】 
The information contained in this statistical analysis plan is intended to be presented and disclosed 
only to the parties involved in the study. It may not be reprinted or reproduced without the 
permission of Mochida Pharmaceutical Co., Ltd. 
 
 
 
2 
 
Version History 
Version 
Date Created or 
Amended 
Reasons for Amendments 
Prepared By 
Comment 
1.0 
2020/4/1 
- 
 
 
Initial 
version 
2.0 
2022/9/14 
Refer to revision history 
 
 
Finalized 
 
 


MD120101 
MOCHIDA PHARMACEUTICAL CO., LTD. 
Statistical analysis plan 
 
3 
Table of contents 
Definition of Terms ....................................................................................................................... 9 
1 
Study Director and Team .................................................................................................... 10 
1.1 
Study Director .......................................................................................................... 10 
1.2 
Person Responsible for Monitoring.......................................................................... 10 
1.3 
Person Responsible for Statistical Analysis ............................................................. 10 
1.4 
Person Responsible for Data Management .............................................................. 10 
1.5 
Person Responsible for Safety Information Management ........................................ 10 
1.6 
Person Responsible for pharmacokinetic analysis ................................................... 10 
1.7 
Statistical Analysis Team ......................................................................................... 10 
2 
Objectives, Eligible Subjects and Study Design ................................................................. 11 
2.1 
Study Objective ........................................................................................................ 11 
2.2 
Eligible Subject ........................................................................................................ 11 
2.3 
Study Drug ............................................................................................................... 11 
2.4 
Treatment group ....................................................................................................... 11 
2.5 
Study Design ............................................................................................................ 11 
2.6 
Target Sample Size and Rationale for Selection of Sample Size ............................. 11 
2.6.1 
Target Sample Size ........................................................................................... 11 
2.6.2 
Sample Size Rationale ...................................................................................... 11 
3 
Analysis Sets ....................................................................................................................... 13 
3.1 
Efficacy Analysis Population ................................................................................... 13 
3.1.1 
FAS ................................................................................................................... 13 
3.1.2 
PPS ................................................................................................................... 13 
3.2 
Safety Analysis Population ...................................................................................... 13 
3.2.1 
Safety analysis set in the run-in period (SAF in the run-in period) .................. 13 
3.2.2 
Safety analysis set in the treatment period (SAF) ............................................ 13 
3.2.3 
Safety analysis set in the follow-up period (SAF in the follow-up period) ...... 14 
3.3 
Other Analysis Population ....................................................................................... 14 
3.3.1 
Pharmacokinetic analysis set ............................................................................ 14 
4 
Data Used in Analysis ......................................................................................................... 15 
4.1 
Analysis Data Set ..................................................................................................... 15 


MD120101 
MOCHIDA PHARMACEUTICAL CO., LTD. 
Statistical analysis plan 
 
4 
4.1.1 
Format of Analysis Data Set ............................................................................. 15 
4.1.2 
Contents of the Analysis Data Set .................................................................... 15 
4.2 
Data Sets Other Than the Analysis Data Set ............................................................ 15 
4.2.1 
Data Sets Obtained before Unblinding ............................................................. 15 
4.2.2 
Data Sets Obtained on or after Unblinding....................................................... 15 
5 
Assessment Time................................................................................................................. 16 
5.1 
Assessment Time Definitions .................................................................................. 16 
5.1.1 
Assessments by Time Point .............................................................................. 16 
5.1.2 
Assessments by period...................................................................................... 16 
5.1.3 
Assessments Not Dependent on the Time Point or period ............................... 17 
5.2 
Handling of Data ...................................................................................................... 17 
5.2.1 
Assessments Performed for Each Time Point .................................................. 17 
5.2.2 
Assessments Performed for Each period .......................................................... 17 
6 
Definition of Prognostic Factors (Explanatory Variables) .................................................. 18 
6.1 
Background Factors ................................................................................................. 18 
6.1.1 
Demographic variables ..................................................................................... 18 
6.1.2 
Other factors ..................................................................................................... 18 
6.1.3 
Baseline ............................................................................................................ 19 
6.2 
Covariates measured after randomization ................................................................ 19 
6.2.1 
Extent of Exposure to the investigational drug ................................................. 19 
6.2.2 
Concomitant Drugs and Therapies ................................................................... 19 
7 
Endpoint (dependent variable) Definitions ......................................................................... 20 
7.1 
Efficacy endpoints .................................................................................................... 20 
7.1.1 
Total MADRS score ......................................................................................... 20 
7.1.2 
Change in total MADRS score from baseline .................................................. 20 
7.1.3 
Response evaluated by total MADRS score ..................................................... 20 
7.1.4 
Remission evaluated by total MADRS score ................................................... 20 
7.1.5 
Total HAMD17 score ....................................................................................... 21 
7.1.6 
Change in total HAMD17 score from baseline ................................................ 21 
7.1.7 
Response evaluated by total HAMD17 score ................................................... 21 
7.1.8 
Remission evaluated by total HAMD17 score ................................................. 21 


MD120101 
MOCHIDA PHARMACEUTICAL CO., LTD. 
Statistical analysis plan 
 
5 
7.1.9 
CGI-I................................................................................................................. 22 
7.1.10 
Response evaluated by CGI-I ........................................................................... 22 
7.1.11 
CGI-S ................................................................................................................ 22 
7.1.12 
Change in CGI-S from baseline ........................................................................ 22 
7.1.13 
Total QIDS16-SR-J score .................................................................................. 22 
7.1.14 
Change in total QIDS16-SR-J score from baseline ............................................ 23 
7.1.15 
Total SDS score ................................................................................................ 23 
7.1.16 
Change in total SDS score from baseline ......................................................... 23 
7.1.17 
SDS subscale .................................................................................................... 23 
7.1.18 
Change in SDS subscale from baseline ............................................................ 24 
7.2 
Withdrawal ............................................................................................................... 24 
7.2.1 
Number of Days to Withdrawal of Administration (days) ............................... 24 
7.2.2 
Timing of withdrawal of treatment ................................................................... 24 
7.3 
Adverse events ......................................................................................................... 24 
7.3.1 
Adverse Events Resulting in Death .................................................................. 24 
7.3.2 
SAEs Excluding Death ..................................................................................... 25 
7.3.3 
Adverse Events Resulting in Treatment Withdrawal ....................................... 25 
7.3.4 
Adverse Events Resulting in Treatment Interrupted ........................................ 25 
7.3.5 
Common Adverse Events ................................................................................. 25 
7.3.6 
AEs of Interest .................................................................................................. 25 
7.3.7 
Number of Days to Adverse Event Onset (days) .............................................. 25 
7.3.8 
Time of onset of the AE ................................................................................... 26 
7.3.9 
Duration of adverse events (days) .................................................................... 26 
7.3.10 
Outcome of Adverse Events ............................................................................. 26 
7.4 
General laboratory tests ............................................................................................ 26 
7.4.1 
Laboratory Measurements ................................................................................ 27 
7.4.2 
Change in laboratory values ............................................................................. 27 
7.4.3 
Clinical test value abnormality ......................................................................... 27 
7.5 
Vital signs and body weight ..................................................................................... 27 
7.5.1 
Vital signs and body weight ............................................................................. 27 
7.5.2 
Changes in vital signs and body weight ........................................................... 27 


MD120101 
MOCHIDA PHARMACEUTICAL CO., LTD. 
Statistical analysis plan 
 
6 
7.6 
ECG .......................................................................................................................... 28 
7.6.1 
12-lead ECG abnormal ..................................................................................... 28 
7.7 
C-SSRS .................................................................................................................... 28 
7.7.1 
C-SSRS ............................................................................................................. 28 
7.8 
Pharmacokinetics ..................................................................................................... 28 
7.8.1 
Plasma desvenlafaxine concentration (ng/mL) ................................................. 28 
8 
Primary analysis .................................................................................................................. 30 
8.1 
Efficacy .................................................................................................................... 30 
8.1.1 
Definitions of Primary Endpoint ...................................................................... 30 
8.1.2 
Primary analysis on primary endpoint .............................................................. 30 
8.1.3 
Secondary Analysis on primary endpoint ......................................................... 30 
8.1.4 
Sensitivity analysis of the primary analysis...................................................... 31 
8.2 
Safety ....................................................................................................................... 31 
8.2.1 
Definitions of Primary Endpoint ...................................................................... 31 
8.2.2 
Analysis on primary endpoint ........................................................................... 31 
8.3 
Interim analysis ........................................................................................................ 31 
8.4 
Multiple Comparison / Multiplicity ......................................................................... 32 
9 
General Considerations Regarding the Details of the Planned Analyses ............................ 33 
9.1 
Definitions of Notations in Planned Analyses ......................................................... 33 
9.1.1 
Definitions of Figure and Table Titles.............................................................. 33 
9.1.2 
Statistical Tests and Calculations of CI in Figures and Tables ......................... 35 
9.1.3 
Details of Exploratory Statistical Tests ............................................................ 35 
9.2 
Supplementary Matters Concerning How to Impute Missing Values ...................... 37 
9.2.1 
LOCF method ................................................................................................... 37 
9.3 
Rounding of Digits in Analysis ................................................................................ 37 
9.4 
Software Used for Analysis ..................................................................................... 37 
9.5 
Other Precautions ..................................................................................................... 37 
9.6 
Relevant Publications, Guidelines............................................................................ 37 
10 Study Subjects ..................................................................................................................... 39 
11 Efficacy Evaluation ............................................................................................................. 39 
12 Safety Evaluation ................................................................................................................ 39 


MD120101 
MOCHIDA PHARMACEUTICAL CO., LTD. 
Statistical analysis plan 
 
7 
13 Discussion and Overall Conclusions ................................................................................... 39 
14 Analysis Figures and Tables ............................................................................................... 40 
14.1 
Disposition of Subjects and Distributions of Prognostic Factors ............................. 40 
14.1.1 
Disposition of Subjects ..................................................................................... 40 
14.1.2 
Demographic and Other Baseline Characteristics ............................................ 42 
14.1.3 
Extent of Exposure to Study Drugs .................................................................. 43 
14.2 
Efficacy .................................................................................................................... 43 
14.2.1 
Total MADRS score ......................................................................................... 43 
14.2.2 
Response evaluated by total MADRS score ..................................................... 47 
14.2.3 
Remission evaluated by total MADRS score ................................................... 49 
14.2.4 
Total HAMD17 score ....................................................................................... 49 
14.2.5 
Response evaluated by total HAMD17 score ................................................... 53 
14.2.6 
Remission evaluated by total HAMD17 score ................................................. 53 
14.2.7 
CGI-I................................................................................................................. 54 
14.2.8 
Response evaluated by CGI-I ........................................................................... 56 
14.2.9 
CGI-S ................................................................................................................ 56 
14.2.10 
Total QIDS16-SR-J score .................................................................................. 57 
14.2.11 
Total SDS score ................................................................................................ 58 
14.3 
Safety ....................................................................................................................... 60 
14.3.1 
Adverse events .................................................................................................. 60 
14.3.2 
Deaths, Other Serious Adverse Events, and Other Significant Adverse Events
 
63 
14.3.3 
Descriptions of Deaths, Other Serious Adverse Events and Other Significant 
Adverse Events .................................................................................................................... 63 
14.3.4 
Laboratory Measurements ................................................................................ 64 
14.3.5 
Vital Signs and Body Weight ........................................................................... 64 
14.3.6 
ECG .................................................................................................................. 65 
14.3.7 
C-SSRS ............................................................................................................. 65 
14.3.8 
Concomitant Drugs ........................................................................................... 65 
14.4 
Pharmacokinetics ..................................................................................................... 65 
14.4.1 
Pharmacokinetics .............................................................................................. 66 


MD120101 
MOCHIDA PHARMACEUTICAL CO., LTD. 
Statistical analysis plan 
 
8 
15 Reference List ..................................................................................................................... 66 
16 Appendix ............................................................................................................................. 67 
16.1 
Study Information .................................................................................................... 67 
16.2 
Subject Data Listings ............................................................................................... 67 
16.2.1 
Withdrawn Subjects .......................................................................................... 67 
16.2.2 
Protocol Deviations .......................................................................................... 67 
16.2.3 
Subjects Excluded From the Efficacy Analysis................................................ 67 
16.2.4 
Background Factors .......................................................................................... 67 
16.2.5 
Covariates Measured after Randomization ....................................................... 67 
16.2.6 
Individual Efficacy Response Data .................................................................. 67 
16.2.7 
Adverse events .................................................................................................. 67 
16.2.8 
Laboratory Measurements ................................................................................ 67 
16.2.9 
Vital Signs and Body Weight ........................................................................... 67 
16.2.10 
ECG .................................................................................................................. 68 
16.2.11 
C-SSRS ............................................................................................................. 68 
16.2.12 
Pharmacokinetics .............................................................................................. 68 
 


MD120101 
MOCHIDA PHARMACEUTICAL CO., LTD. 
Statistical analysis plan 
 
9 
 
 
 
 
Definition of Terms 
The definitions of the main terms used in this SAP are as follows. 
 
Term 
Description 
Analysis Data set 
See the GCP SOPs 
 
 
CMH test 
Abbreviation for Cochran-Mantel-Haenszel test. 
FAS 
Abbreviation for Full Analysis Set. 
GEE analysis 
Abbreviation for analysis using Generalized Estimating Equations. 
Handling plan 
See the GCP SOPs 
 
 
IWRS 
Abbreviation for Interactive Web Response System. 
LOCF 
Abbreviation for Last Observation Carried Forward. One way to 
impute missing data. An imputation method that replaces missing 
data with the last observed value. 
MAR 
Abbreviation for Missing At Random. A missing mechanism that 
the probability of being missing at a given time point is related to 
the value of the endpoint observed at a previous time point. 
MCMC method 
Abbreviation for Markov-Chain Monte Carlo method. 
MMRM analysis 
Abbreviation for analysis using Mixed-effects Model for Repeated 
Measures. 
Monotone missing 
Missing patterns that an endpoint is observed up to a certain time 
point, but missing at later time points. 
Non-monotone missing 
Missing patterns that an endpoint is missing at once but is observed 
again at a later time point. 
OC 
Abbreviation for Observed Cases. Refers to not imputing. 
PPS 
Abbreviation for Per Protocol Set. 
PT 
Abbreviation for Preferred Term in MedDRA. 
SAS 
Abbreviation for Statistical Analysis System. Software used for 
analysis. 
SOC 
Abbreviation for System Organ Class in MedDRA. 
Tipping Point Analysis 
A method of sensitivity analysis for missing mechanisms. 
 
 
 


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1 
Study Director and Team 
1.1 
Study Director 
 
 
 
1.2 
Person Responsible for Monitoring 
 
 
 
1.3 
Person Responsible for Statistical Analysis 
 
 
 
 
 
1.4 
Person Responsible for Data Management 
 
 
 
 
 
1.5 
Person Responsible for Safety Information Management 
 
 
 
 
1.6 
Person Responsible for pharmacokinetic analysis 
 
 
 
1.7 
Statistical Analysis Team 
 
 
 
 
 
 
 
 


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2 
Objectives, Eligible Subjects and Study Design 
2.1 
Study Objective 
To verify the efficacy and evaluate the safety of 8-week once-daily oral administration of MD-120 
(50 mg and 100 mg) in Japanese patients with depression. 
 
2.2 
Eligible Subject 
Patients with depression 
 
2.3 
Study Drug 
Investigational drug 
・ MD-120 50 mg tablet 
Comparator 
・ Placebo tablet 
 
2.4 
Treatment group 
MD-120 50 mg group 
MD-120 100 mg group 
Placebo group 
 
2.5 
Study Design 
A randomized, parallel-group, multicenter, double-blind, placebo-controlled study 
 
2.6 
Target Sample Size and Rationale for Selection of Sample Size 
2.6.1 
Target Sample Size 
594 subjects as FAS (198 subjects per group) 
 
2.6.2 
Sample Size Rationale 
 
 
 
 
 
 
 
 


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3 
Analysis Sets 
3.1 
Efficacy Analysis Population 
3.1.1 
FAS 
Of subjects registered for randomization, those meeting all the following items will be included in 
the above analysis set. 
 Subjects who have received the investigational drug at least once during treatment period 
 Subjects who have evaluated for the total MADRS score at the baseline and at least one 
timepoint after the start of treatment period 
 
3.1.2 
PPS 
Of subjects included in the FAS, those meeting all the following items will be included in the per 
protocol set (PPS). 
 Subjects who meet the inclusion criteria and do not fall under the exclusion criteria 
 Subjects who have not violated the Protocol “7.1.1 Prohibited concomitant drugs“ or the 
Protocol “7.1.2 Prohibited concomitant therapies“ from the start of screening period to the 
end of treatment period 
 Subjects who have used hypnotic/sedative drugs in compliance with provisions in the 
Protocol “7.1.3 Allowed concomitant drugs“ from the start of screening period to the end of 
treatment period 
 Subjects in whom the study treatment period or the number of days from the first dose of the 
investigational drug to the last dose in the treatment period is 42 days or longer, and the 
drug-use rate during the study treatment period is 75% or higher 
 
3.2 
Safety Analysis Population 
3.2.1 
Safety analysis set in the run-in period (SAF in the run-in period) 
Subjects meeting all the following items will be included in the above analysis set. 
 Subjects who have received the investigational drug at least once during run-in period 
 Subjects in whom the safety evaluation data in the run-in period are available 
 
3.2.2 
Safety analysis set in the treatment period (SAF) 
Of subjects registered for randomization, those meeting all the following items will be included in 
the above analysis set. 
 Subjects who have received the investigational drug at least once during treatment period 
 Subjects in whom the safety evaluation data after the dose of the investigational drug in the 
treatment period are available 


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3.2.3 
Safety analysis set in the follow-up period (SAF in the follow-up period) 
Subjects meeting all the following items will be included in the above analysis set. 
 Subjects included in the “Safety analysis set in the treatment period” 
 Subjects in whom the safety evaluation data in the follow-up period are available 
 
3.3 
Other Analysis Population 
3.3.1 
Pharmacokinetic analysis set 
Subjects meeting all the following items at the same time will be included in the above analysis 
set. 
 Subjects who have received the investigational drug at least once during treatment period 
 Subjects in whom the drug concentration evaluation data after the dose of the investigational 
drug in the treatment period are available 
 
 


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4 
Data Used in Analysis 
4.1 
Analysis Data Set 
4.1.1 
Format of Analysis Data Set 
SAS data set 
 
4.1.2 
Contents of the Analysis Data Set 
 Data reflecting subject and data handling performed in accordance with the Handling Plan, 
and conforming to GCP SOPs 
 
・ CRF data (including eCOA data) 
・ Laboratory Tests data 
 Analysis population flags and reasons for exclusion 
 Concomitant Drug Code (WHO-DDs) 
 Concurrent Diseases and Adverse Event Codes (MedDRA) 
 Protocol Deviation Case Data 
 Other data and flags required for analysis 
・ Flags for sample abnormalities 
・ Flags for AEs of Interest 
・ Inclusion/Exclusion criteria data (IWRS data) 
 
4.2 
Data Sets Other Than the Analysis Data Set 
4.2.1 
Data Sets Obtained before Unblinding 
Not applicable 
 
4.2.2 
Data Sets Obtained on or after Unblinding 
 Key data 
・ Received from the person responsible for Study Drug Allocation 
 Drug concentration data 
・ Received from the person responsible for pharmacokinetic analysis 
 
 


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5 
Assessment Time 
5.1 
Assessment Time Definitions 
5.1.1 
Assessments by Time Point 
The following table shows each assessment time points for the parameters assessed. 
Assessment Time 
Definition 
Start of screening period, End of screening 
period, Start of run-in period (no visit), End of 
run-in period or the time of premature 
termination, Week 1 visit during treatment 
period, …, Week 8 visit during treatment 
period, …, Week 8 visit during treatment period 
or the time of premature termination, Week 1 
visit during follow-up period, Week 1 visit 
during follow-up period or the time of 
premature termination, End of follow-up period 
or the time of premature termination 
See the protocol 
 
For convenience, the assessment time points shown above are replaced as follows. 
Assessment Time (before replacing the 
terms) 
Assessment Time (after replacing the terms) 
End of run-in period or the time of 
premature termination 
Baseline 
Week 1,..., Week 8 visit during treatment 
period 
Week 1,..., Week 8 
Week 8 visit during treatment period or 
the time of premature termination 
End of treatment period (EOT) 
Week 1 visit during follow-up period 
Follow-up Week 1 
 
5.1.2 
Assessments by period 
The assessment time of the items to be evaluated for each period shows as follows. 
Evaluation period 
Definitions 
Screening period 
Period from the start of any observation or test scheduled at the initial 
registration to the second registration. 
Period when the subject eligibility is reviewed. 


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Run-in period 
Period from the next day of the second registration to the day of 
randomization or the time of completion of all observation and tests 
scheduled at the visit at the time of premature termination. 
Period when the subject’s stability of symptom and compliance are 
checked. 
Treatment period 
Period from the next day of randomization to the day of the Week 8 
visit during treatment period or the visit at the time of premature 
termination. 
Period when the efficacy and safety are evaluated. 
Follow-up period 
Period from the next day of the Week 8 visit during treatment period or 
the next day of the visit at the time of premature termination to the time 
of completion of all observation and tests scheduled at completion or 
the visit at the time of premature termination during follow-up period*. 
Period when the post-treatment safety is evaluated. 
* The time of premature termination after Week 1 visit during follow-
up period. 
 
5.1.3 
Assessments Not Dependent on the Time Point or period 
When analyses are to be performed throughout the entire term of the study (e.g., analysis of 
survival data, laboratory abnormalities), all data including unscheduled measurements will be used 
for the analysis unless otherwise specified. 
 
5.2 
Handling of Data 
The handling of the data for each endpoint is defined in the Handling Plan. This section defines 
the handling of data not described in the Handling Plan. 
 
5.2.1 
Assessments Performed for Each Time Point 
Not applicable 
 
5.2.2 
Assessments Performed for Each period 
5.2.2.1. 
Handling of Adverse Events 
This should be handled based on onset date of adverse events according to Section 5.1.2. 
 
5.2.2.2. 
Handling of withdrawal 
This should be handled according to the CRF. 
 


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6 
Definition of Prognostic Factors (Explanatory 
Variables) 
The definitions of prognostic factors is as follows. Otherwise, the definitions are defined 
separately for each analysis item. For details, see Appendix 1. 
 
6.1 
Background Factors 
6.1.1 
Demographic variables 
 Sex 
 Race 
 Age (years) 
・ Age at informed consent 
 Height (cm) 
 Body weight (kg) (at the start of the screening period) 
 BMI (kg/m2) (at the start of the screening period) 
・ Body weight (kg) (at the start of the screening period) / (height (cm) / 100) 2 
 
6.1.2 
Other factors 
 Age at the onset of depression (year) 
・ Age at the date of depression* 
*: Definition of the date of onset of depression 
・ If the day of time of onset of depression is missing then impute the missing 
part as 15th. 
・ If the month and the day of time of onset of depression is missing then 
impute the missing part as July, 1st. 
 Period from onset of depression (month) 
・ (Date of informed consent - Date of onset of depression) / 30 
However, if it becomes negative, it is replaced with 0 
 Number of depressive episodes (times) 
 Duration of current depressive episode (month) 
・ (Date of informed consent - date of onset of the current depressive episode*) / 30 
If it becomes negative, it is replaced with 0 
* Impute the day of the time of onset of depression as 15th. 
 Presence/absence of prior treatment with antidepressant drugs for current and past 
depressive episodes 


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 Presence/absence of concomitant use of hypnotic/sedative drugs and narcoleptics (within 2 
months before the initial registration) 
 Presence/absence of a history of treatment with antianxiety drug (within 2 months before the 
initial registration) 
 Presence or absence of comorbidities 
 
6.1.3 
Baseline 
 Total MADRS score (baseline) 
 Total HAMD17 score (baseline) 
 CGI-S (baseline) 
 Total QIDS16-SR-J score (baseline) 
 Total SDS score (baseline) 
 
6.2 
Covariates measured after randomization 
6.2.1 
Extent of Exposure to the investigational drug 
 Duration of exposure of the investigational drug (days) (treatment period) 
・ date of the last dose of the investigational drug in the treatment period - date of the first 
dose of the investigational drug in the treatment period + 1 
 Compliance rate of the investigational drug (%) (treatment period) 
・ Total number of tablets taken from Week 1 to EOT (tablets) / [duration of exposure of 
the investigational drug (days) (treatment period)× 2 ] × 100 
 Total exposure of the investigational drug (mg) (treatment period) 
・ Placebo group: 0 
・ MD-120 50 mg group: Total number of tablets taken from Week 1 to EOT × 25 
・ MD-120 100 mg group: Number of tablets taken on Week 1 × 25 + Total number of 
tablets taken from Week 2 to EOT × 50 
※When the subject discontinued before Week 1, Total number of tablets taken on 
EOT × 25 
 
6.2.2 
Concomitant Drugs and Therapies 
Not applicable 
 
 


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7 
Endpoint (dependent variable) Definitions 
Missing data will be handled as follows. 
・ Imputation rules of Efficacy endpoints are defined individually. 
・ Others will not be imputed in principle. If specific imputation rules are defined for 
individual endpoints, they will be imputed accordingly. 
 
7.1 
Efficacy endpoints 
7.1.1 
Total MADRS score 
 Definition of a formula or derivation 
・ Sum of MADRS 10 items 
 Assessment time 
・ Baseline, Week 1, 2, 4, 6, and 8 
 Imputation method 
・ If imputing missing values, LOCF method will be used 
 
7.1.2 
Change in total MADRS score from baseline 
 Definition of a formula or derivation 
・ Total MADRS score at each time point - total MADRS score (Baseline) 
 Assessment time 
・ Week 1, 2, 4, 6, and 8 
 Imputation method 
・ If imputing missing values, LOCF method will be used 
 
7.1.3 
Response evaluated by total MADRS score 
 Definition of a formula or derivation 
・ Response if the total MADRS score at each time point is ≤50% from baseline score 
 Assessment time 
・ Weeks 1, 2, 4, 6, and 8 
 Imputation method 
・ If imputing missing values, LOCF method will be used (only at Week 8) 
 
7.1.4 
Remission evaluated by total MADRS score 
 Definition of a formula or derivation 
・ Remission if the total MADRS score at each time point is ≤10 
 Assessment time 


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・ Weeks 1, 2, 4, 6, and 8 
 Imputation method 
・ If imputing missing values, LOCF method will be used (only at Week 8) 
 
7.1.5 
Total HAMD17 score 
 Definition of a formula or derivation 
・ Sum of HAMD 17 items 
 Assessment time 
・ Baseline, Week 2, 4, and 8 
 Imputation method 
・ If imputing missing values, LOCF method will be used 
 
7.1.6 
Change in total HAMD17 score from baseline 
 Definition of a formula or derivation 
・ Total HAMD17 score at each time point - total HAMD17 score (Baseline) 
 Assessment time 
・ Week 2, 4, and 8 
 Imputation method 
・ If imputing missing values, LOCF method will be used 
 
7.1.7 
Response evaluated by total HAMD17 score 
 Definition of a formula or derivation 
・ Response if the total HAMD17 score at each time point is ≤50% from baseline score 
 Assessment time 
・ Week 2, 4, and 8 
 Imputation method 
・ If imputing missing values, LOCF method will be used (only at Week 8) 
 
7.1.8 
Remission evaluated by total HAMD17 score 
 Definition of a formula or derivation 
・ Remission if the total HAMD17 score at each time point is ≤7 
 Assessment time 
・ Week 2, 4, and 8 
 Imputation method 
・ If imputing missing values, LOCF method will be used (only at Week 8) 
 


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7.1.9 
CGI-I 
 Definition of a formula or derivation 
・ Measured values will be used. 
 Assessment time 
・ Week 1, 2, 4, 6, and 8 
 Imputation method 
・ If imputing missing values, LOCF method will be used (only at Week 8) 
 
7.1.10 
Response evaluated by CGI-I 
 Definition of a formula or derivation 
・ Response if CGI-I at each time point is 1 or 2 
 Assessment time 
・ Week 1, 2, 4, 6, and 8 
 Imputation method 
・ If imputing missing values, LOCF method will be used (only at Week 8) 
 
7.1.11 
CGI-S 
 Definition of a formula or derivation 
・ Measured values will be used. 
 Assessment time 
・ Baseline, Week 1, 2, 4, 6, and 8 
 Imputation method 
・ If imputing missing values, LOCF method will be used (only at Week 8) 
 
7.1.12 
Change in CGI-S from baseline 
 Definition of a formula or derivation 
・ CGI-S at each time point – CGI-S (Baseline) 
 Assessment time 
・ Week 1, 2, 4, 6, and 8 
 Imputation method 
・ If imputing missing values, LOCF method will be used (only at Week 8) 
 
7.1.13 
Total QIDS16-SR-J score 
 Definition of a formula or derivation 
・ Sum of the following nine values 
・ Maximum value of sleep items (item 1-4) 


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・ Maximum value of appetite/weight items (item 6-9) 
・ Maximum value of items related to psychomotor status (item 15 and 16) 
・ Values for each of the 6 items (item 5 and 10-14) other than the above 
 Assessment time 
・ Baseline, Week 1, 2, 4, 6, and 8 
 Imputation method 
・ If imputing missing values, LOCF method will be used (only at Week 8) 
 
7.1.14 
Change in total QIDS16-SR-J score from baseline 
 Definition of a formula or derivation 
・ Total QIDS16-SR-J score at each time point - total QIDS16-SR-J score (Baseline) 
 Assessment time 
・ Week 1, 2, 4, 6, and 8 
 Imputation method 
・ If imputing missing values, LOCF method will be used (only at Week 8) 
 
7.1.15 
Total SDS score 
 Definition of a formula or derivation 
・ Sum of SDS 3 items 
・ If “I have not worked/studied at all during the past week for reasons unrelated to the 
disorder” is selected, total SDS score will be handled as a missing value 
 Assessment time 
・ Baseline, Week 4 and 8 
 Imputation method 
・ If imputing missing values, LOCF method will be used (only at Week 8) 
 
7.1.16 
Change in total SDS score from baseline 
 Definition of a formula or derivation 
・ Total SDS score at each time point - total SDS score (Baseline) 
 Assessment time 
・ Week 4 and 8 
 Imputation method 
・ If imputing missing values, LOCF method will be used (only at Week 8) 
 
7.1.17 
SDS subscale 
 Definition of a formula or derivation 


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・ Each of SDS 3 items will be used 
・ WORK/SCHOOL 
・ SOCIAL LIFE 
・ FAMILY LIFE/HOME RESPONSIBILITIES 
 Assessment time 
・ Baseline, Week 4 and 8 
 Imputation method 
・ If imputing missing values, LOCF method will be used (only at Week 8) 
 
7.1.18 
Change in SDS subscale from baseline 
 Definition of a formula or derivation 
・ SDS subscale at each time point - SDS subscale (Baseline) 
 Assessment time 
・ Week 4 and 8 
 Imputation method 
・ If imputing missing values, LOCF method will be used (only at Week 8) 
 
7.2 
Withdrawal 
7.2.1 
Number of Days to Withdrawal of Administration (days) 
 Definition of a formula or derivation 
・ Date of withdrawal (date on which withdrawal is determined) - Date of the first dose of 
the investigational drug in the treatment period + 1 
 
7.2.2 
Timing of withdrawal of treatment 
 Definition of a formula or derivation 
・ In subjects who discontinued the treatment period, 7.2.1 is divided as follows 
・ Day 1-7, Day 8-14, Day 15-28, Day 29-42, Day 43-56, Day 57 or more, Not 
administered 
 
 
7.3 
Adverse events 
7.3.1 
Adverse Events Resulting in Death 
 Definition of formula or calculation 
・ Adverse Events for which "fatal" was selected in outcome 
 


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7.3.2 
SAEs Excluding Death 
 Definition of formula or calculation 
・ SAEs other than those resulting in death 
 
7.3.3 
Adverse Events Resulting in Treatment Withdrawal 
 Definition of formula or calculation 
・ Adverse events for which “discontinued (no re-treatment)" was selected in action with 
the study drug. 
 
7.3.4 
Adverse Events Resulting in Treatment Interrupted 
 Definition of formula or calculation 
・ Adverse events for which “interrupted (temporal suspension)"was selected in action 
with the study drug. 
 
7.3.5 
Common Adverse Events 
 Definition of a formula or derivation 
・ Adverse events (PT) that occurred in 5% or more of either treatment group during the 
aggregation period* 
* See 14.3.1.7. 
 
7.3.6 
AEs of Interest 
 Definition of a formula or derivation 
・ Adverse events (PT) identified as "AEs of Interest" according to “4.1.2 Contents of the 
Analysis Data Set (6)” 
※ The following event groups are defined as "AEs of Interest" 
・ Suicide-related adverse events 
・ Cardiovascular adverse events 
 
7.3.7 
Number of Days to Adverse Event Onset (days) 
 Definition of formula or calculation 
・ Adverse events that occurred prior to the date of the first dose of the investigational 
drug in the treatment period 
・ Date of onset - date of the first dose of the investigational drug in treatment 
period 
・ Adverse events that occurred on or after the date of the first dose of the investigational 
drug in the treatment period 


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・ Date of onset - date of the first dose of the investigational drug in the treatment 
period + 1 
 
7.3.8 
Time of onset of the AE 
 Definition of a formula or derivation 
・ Adverse events occurring during treatment period: "7.3.7 Number of Days to Adverse 
Event Onset (days)" are divided as follows 
・ Day 1-7, Day 8-14, Day 15-28, Day 29-42, Day 43-56, Day 57 or more 
・ Adverse events occurring during the follow-up period: The Number of Days from the 
date of the first dose of the investigational drug in the follow-up period to adverse 
event onset * is divided as follows 
・ Day 1-7, Day 8 or more 
*: Calculated as "Date of onset - date of the first dose of the investigational drug in the 
follow-up period + 1". The date of the first dose of the investigational drug in the 
follow-up period will be the next day of the last dose of the investigational drug in the 
treatment period 
 
7.3.9 
Duration of adverse events (days) 
 Definition of a formula or derivation 
・ Date of resolution or date of confirmation of outcome – date of onset of adverse event 
+ 1 
 
7.3.10 
Outcome of Adverse Events 
 Definition of a formula or derivation 
・ Resolved: if outcome of the adverse event is " recovered/resolved" 
・ Unresolved: if outcome of the adverse event is either "recovering/resolving “, "not 
recovered/not resolved “, "recovered/resolved with sequelae “, or "fatal." 
 
7.4 
General laboratory tests 
Data will be handled as follows. 
・ Missing data are not imputed in principle 
・ Abnormalities obtained from general laboratory tests will be excluded from the analysis. In 
the individual data list, however, the relevant data will be used with a note of “Abnormal 
specimen.” 
・ If the value is greater than or equal to the upper limit of quantitation, or less than the lower 
limit of quantitation, the limits are used as a measured value in the aggregation 


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7.4.1 
Laboratory Measurements 
 Definition of a formula or derivation 
・ Measured values will be used 
 Assessment time 
・ Start of screening period, Week 2, 4, 8, and EOT 
 
7.4.2 
Change in laboratory values 
 Definition of a formula or derivation 
・ Value at each time point - Value at the start of screening period 
 Assessment time 
・ Week 2, 4, 8, and EOT 
 
7.4.3 
Clinical test value abnormality 
 Definition of a formula or derivation 
The following categories will be used, depending on the relationship between the 
measured value and the corresponding reference value. 
・ Within the reference range 
Lower reference value ≤ Measured value ≤ Upper reference value 
・ Greater than the upper limit of the reference value 
Upper reference value < Measured value 
・ Less than the lower limit of the reference value 
Measured value < Lower reference values 
 
7.5 
Vital signs and body weight 
7.5.1 
Vital signs and body weight 
 Definition of a formula or derivation 
・ Measured values will be used. 
 Assessment time 
・ Baseline, Week 1, 2, 4, 6, 8, EOT, and Follow-up Week 1 
 
7.5.2 
Changes in vital signs and body weight 
 Definition of a formula or derivation 
・ Value at each time point - Value (Baseline) 
 Assessment time 
・ Week 1, 2, 4, 6, 8, EOT, and Follow-up Week 1 


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7.6 
ECG 
7.6.1 
12-lead ECG abnormal 
 Definition of a formula or derivation 
・ When "Yes" is selected for the presence or absence of abnormal findings. 
 Assessment time 
・ Baseline and EOT 
 
7.7 
C-SSRS 
7.7.1 
C-SSRS 
 Definition of a formula or derivation 
・ Definition of a formula or derivation 
・ Suicidal ideation 
When "Yes" is selected for any item 
・ 1: Wish to be Dead 
・ 2: Non-Specific Active Suicidal Thoughts 
・ 3: Active Suicidal Ideation with Any Methods (Not Plan) without Intent to 
Act 
・ 4: Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
・ 5: Active Suicidal Ideation with Specific Plan and Intent 
・ Suicidal behavior 
When "Yes" is selected for any item 
・ Actual Attempt 
・ Interrupted Attempt 
・ Aborted Attempt or Self-Interrupted Attempt 
・ Preparatory Acts or Behavior 
・ Suicide 
・ Suicidal ideation or behavior 
・ When either suicidal ideation or suicidal behavior is "yes" 
 
7.8 
Pharmacokinetics 
7.8.1 
Plasma desvenlafaxine concentration (ng/mL) 
Data will be handled as follows. 
・ Missing data are not imputed in principle 
・ If the value is no quantitative, it its handled as missing in aggregation 


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・ If the value is below the lower limit of quantitation, it is handled as 0 in aggregation. The 
value will be shown as BLQ in the listing of concentration and the lower limit of quantitation 
will be shown in a footnote. 
 Definition of a formula or derivation 
・ Measured values will be used (*Placebo group is excluded.). 
 Assessment time 
・ Week 2, 4, and 8, and EOT 
 
 


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8 
Primary analysis 
8.1 
Efficacy 
8.1.1 
Definitions of Primary Endpoint 
Change in total MADRS score from baseline to Week 8 
 
8.1.2 
Primary analysis on primary endpoint 
A Mixed-effects Model for Repeated Measures (MMRM) will be used for the main analysis of the 
primary efficacy endpoint. The analytical model will use a change in total MADRS score from 
baseline to each assessment timepoint as a response variable; the treatment group, assessment 
timepoint, and the interaction between the treatment group and assessment timepoint as fixed effects, 
and the total MADRS score at the baseline as a covariate the structure of error variance as 
Unstructured, and Kenward Roger as degrees of freedom adjustment. Based on this analytical model, 
changes in total MADRS score from the baseline to Week 8 visit during treatment period in the MD-
120 50 mg and 100 mg groups will be compared to that in the placebo group. For missing data on 
the response variable, no data will be substituted. 
 
Adjustment of multiplicity will be performed in the main analysis on the efficacy primary 
endpoint according to a closed testing procedure. Results on the efficacy primary endpoint will be 
firstly compared between the placebo group and MD-120 50 mg group with a significance level of 
5%. Only when Hypothesis 1 is verified, a comparison between the placebo group and MD-120 100 
mg group will be made with significance level of 5%. 
[Hypothesis 1] Superiority of the MD-120 50 mg group to the placebo group 
[Hypothesis 2] Superiority of the MD-120 100 mg group to the placebo group 
 
For more information on the statistics to be calculated, see “14.2.1.1.1 MMRM Analysis of 
Change in total MADRS score from baseline”. See Appendix 2 for a sample SAS program.  
 
8.1.3 
Secondary Analysis on primary endpoint 
An analysis of covariance will be performed on the primary endpoint by comparing relevant 
results in the MD-120 50 mg group and 100 mg group to that in the placebo group. The analytical 
model will use a change in total MADRS score from baseline to Week 8 visit during treatment 
period as a response variable; the treatment group as a fixed effect, and the total MADRS score at 
the baseline as a covariate. For missing data on the response variable, data will be substituted in a 
last observation carried forward (LOCF) manner. 


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For more information on the statistics to be calculated, see “14.2.1.1.6 ANCOVA Analysis of 
Change in total MADRS score from baseline”. 
 
8.1.4 
Sensitivity analysis of the primary analysis 
The following analysis is performed as a sensitivity analysis for the primary analysis. 
 
8.1.4.1. 
Tipping Point Analysis of Change in total MADRS score from baseline 
The use of MMRM for the primary efficacy analysis is based on the MAR assumption. As a 
sensitivity analysis for the missing mechanism assumption, Tipping Point Analysis which is based 
on the MNAR assumptions is performed. The procedure is as follows. 
1. 
Non-monotone missing values of change in total MADRS score are imputed using multiple 
imputation MCMC method by each treatment group. The number of imputations will be 10, 
and the random seed will be set to 2970. 
2. 
Monotone missing values of change in total MADRS score in the 10 dataset created in step 1 
are imputed using multiple substitution regression method. After imputation, the sensitivity 
parameter Δ is added to the imputed value. The number of imputations will be 1, and the seed 
will be set to 8229. 
3. 
The 10 pseudo-complete data generated in step 2 will be compared between MD-120 group 
and placebo group using the same model as the primary analysis. 
4. 
The 10 obtained analysis results are combined. 
The sensitivity parameter Δ is incremented by 1 from 0 to 5. 
 
For more information on the statistics to be calculated, see “14.2.1.1.2 Tipping Point Analysis of 
Change in total MADRS score from baseline”. See Appendix 2 for a sample SAS program. 
 
8.2 
Safety 
8.2.1 
Definitions of Primary Endpoint 
Adverse events during the treatment and follow-up periods 
 
8.2.2 
Analysis on primary endpoint 
An incidence of adverse events during treatment and follow-up periods in each dose group will be 
calculated. 
 
8.3 
Interim analysis 
Not implemented. 
 


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8.4 
Multiple Comparison / Multiplicity 
See 8.1.2 
 
 
 


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9 
General Considerations Regarding the Details of the 
Planned Analyses 
9.1 
Definitions of Notations in Planned Analyses 
9.1.1 
Definitions of Figure and Table Titles 
For the planned analyses described from Chapter 10, only the Figure and Table titles are presented 
as a rule. The titles is defined by the following rule. 
・ Rule: Analysis method of Tabulated variable (subgroup) (category of tabulation other than 
subgroup) (assessment time point) (data imputation method) (data set analyzed) 
・ Example: Descriptive statistics of Systolic Blood Pressure (age) (Week 8) (LOCF) (FAS) 
This indicates the calculation of the descriptive statistics for systolic blood pressure at Week 8, 
with missing data imputed by LOCF, for each age category (e.g., age < 60 years, age ≥ 60 years) in 
the FAS. 
 
Details of the above rules are as follows. 
 Identification of analysis method 
Unless otherwise specified, the analysis will be performed as described below. 
Supplemental information about the details of the analysis will be provided separately after 
the title. 
Analysis method 
displayed in the title 
The analysis that will be performed. 
Descriptive statistics 
Descriptive statistics will be calculated for each treatment group. 
Descriptive statistics include, unless otherwise specified, the 
number of subjects, mean, standard deviation, minimum, median, 
and maximum. 
Summary 
The number of subjects (N) in the data set analyzed, and the 
number of subjects (n) and the proportion of subjects will be 
calculated for each treatment group. Subjects for which the 
dependent variable for aggregation is missing and are not 
imputed will not be included in the analysis, and will therefore 
not be included in the denominator of the ratio calculation. 
Summary 
(adverse events) 
The number of subjects (N) in the data set analyzed, the number 
of subjects with the events (n) and the incidence rates of the 
events will be calculated for each treatment group. When 
summarizing by event, in principle, the summary on entire events 


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Analysis method 
displayed in the title 
The analysis that will be performed. 
will be performed similarly. When data after exposure to the 
study drug are included, adverse drug reactions should be 
tabulated similarly as a rule. For events specific to each gender, 
the number of subjects of that gender will be used for the 
denominator of the rate. 
Profiles 
Plot graphs using appropriate statistics, such as the mean value, 
for each treatment group. 
Shift table 
A contingency table comparing the results at the baseline with 
the results at each assessment time point will be prepared for 
each treatment group. 
Disposition 
The number of subjects will be calculated for each treatment 
group. 
Distribution 
For continuous variables, descriptive statistics will be calculated 
for each treatment group. Unless otherwise stated, descriptive 
statistics include the number of subjects (N) in the data set 
analyzed, mean, standard deviation, minimum, median, and 
maximum. For discrete variables (including qualitative 
variables), the number of subjects (N) in the data set analyzed , 
the number of subjects (n), and the proportion will be calculated 
for each treatment group. For subjects with missing variables are 
included in the analysis and also in the denominator of the ratio 
calculation. 
Listings 
Listings will be prepared. 
Other 
The analyses corresponding to the titles will be performed. The 
details will be described in the SAP to the extent that the analysis 
can be performed. 
 
 Specification of subgroups 
・ See Appendix 1 for the factors used in subgroup analyses. 
・ If not specified, the analysis is performed without considering the subgroup. 
 
 Specification of tabulation categories other than subgroups 
・ The categories are specified in detail (e.g., severity, time of onset). 
 


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(4) Specification of Assessment time 
・ The assessment time defined in Chapter 7 corresponding to the Tabulated variable is 
specified. 
・ When the assessment time is not specified, all of the assessment time defined in 
Chapter 7 corresponding to the Tabulated variable will be used for analyses. 
 
(5) Specification of the data imputation method 
・ The data imputation method is specified when multiple imputation methods are defined 
in Chapter 7. 
・ When no data imputation method is specified, data will be replaced according to the 
data imputation method defined in Chapter 7.Endpoint (dependent variable) 
Definitions 
 
(6) Specification of the data set analyzed 
・ The data set analyzed is specified 
 
9.1.2 
Statistical Tests and Calculations of CI in Figures and Tables 
The tests and calculations of CIs will be described separately, after the title. Unless otherwise 
specified, statistical tests and calculations of CIs will not be performed. 
 
9.1.3 
Details of Exploratory Statistical Tests 
The details of statistical tests are as follows. 
 
9.1.3.1. 
Efficacy 
Defined in each figure and table 
 
9.1.3.2. 
Adverse events 
(1) Fisher's exact test 
The following tests will be performed. 
・ Test of contingency table for adverse events and treatment groups 
(2 levels: MD-120 50 mg group and Placebo group) 
・ Test of contingency table for adverse events and treatment groups 
(2 levels: MD-120 100 mg group and Placebo group) 
・ Test of contingency table for adverse events and treatment groups 
(2 levels: MD-120 50 mg group and MD-120 100 mg group) 
 


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9.1.3.3. 
Clinical Laboratory Values 
Changes from baseline will be calculated in accordance with Section 7.4.2 and statistical tests will 
be performed. For qualitative values, the measured values will be converted into integers and done in 
the same way as quantitative values. 
 Wilcoxon 2 sample test 
The following tests will be performed. 
・ Tests comparing changes between MD-120 50 mg group and Placebo group for each 
assessment time point and for each laboratory parameter 
・ Tests comparing changes between MD-120 100 mg group and Placebo group for each 
assessment time point and for each laboratory parameter 
・ Tests comparing changes between MD-120 50 mg group and MD-120 100 mg group 
for each assessment time point and for each laboratory parameter 
 
9.1.3.4. 
Vital signs and weight 
 Wilcoxon 2 sample test 
The following tests will be performed. 
・ Tests comparing changes between MD-120 50 mg group and Placebo group for each 
assessment time point and for each parameter 
・ Tests comparing changes between MD-120 100 mg group and Placebo group for each 
assessment time point and for each parameter 
・ Tests comparing changes between MD-120 50 mg group and MD-120 100 mg group 
for each assessment time point and for each parameter 
 
9.1.3.5. 
ECG 
 Fisher's exact test 
The following tests will be performed. 
・ Tests in contingency tables for the presence or absence of abnormal ECG findings and 
treatment groups 
(2 levels: MD-120 50 mg group and Placebo group) 
・ Tests in contingency tables for the presence or absence of abnormal ECG findings and 
treatment groups 
(2 levels: MD-120 100 mg group and Placebo group) 
・ Tests in contingency tables for the presence or absence of abnormal ECG findings and 
treatment groups 
(2 levels: MD-120 50 mg group and MD-120 100 mg group 
 


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9.2 
Supplementary Matters Concerning How to Impute Missing Values 
9.2.1 
LOCF method 
If the value at each time point shown in Section 7.1 is missing, the closest value prior to the 
planned day of the evaluation will be used for the LOCF imputation. The value used to LOCF 
imputation will include all data that meet the data adoption conditions from the date of the first dose 
of the investigational drug in the treatment period (including the same day), regardless of whether or 
not they are included in the data adoption period. 
At the start of the screening period and at baseline, no LOCF imputation will be performed. 
 
The data adoption period and data adoption conditions including the planned day for each time 
point will be specified in the Handling Plan. 
 
9.3 
Rounding of Digits in Analysis 
・ In principle, rounding will not be performed at all during calculation processes. 
・ When a nonparametric test based on ranks is performed, the test will be performed after 
rounding off the variables to 10 decimal places immediately before performing the test. 
 
9.4 
Software Used for Analysis 
SAS Release 9.4 or later 
 
9.5 
Other Precautions 
・ From Chapter 10 of this SAP, and for chapter numbers for the results of the analyses to be 
prepared, see the “Structure and Content of Clinical Study Reports” 
・ This SAP will be reviewed after the database is locked and before unblinding, and the 
appropriateness of the analysis method in the SAP and the necessity for each analysis are 
assessed. 
 
9.6 
Relevant Publications, Guidelines 
Statistical Principles for Clinical Studies Iyakushin No. 1047 (November 30, 1998) 
Guidance No. 494 for Investigation of Dose-Response Relationships Needed for Approval of New 
Drugs (July 25, 1994) 
Selection of Control Groups in Clinical Trials and Related Problems Iyakushin Notification No. 
136 (February 27, 2001) 
Guideline on the Structure and Content of the Study General Report No. 335 (May 1, 1996) 
Yutaka Matsuyama, "Analysis of Missing Data in Longitudinal Studies: A Review", Jpn J Biomet, 
vol. 25, no. 2, pp. 89-116, 2004 


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Xu Yan, Shiowjen Lee, and Ning Lee, "Missing Data Handling Methods in Medical Device 
Clinical Trials", Journal of biopharmaceutical statistics, vol. 19, pp. 1085-98, 2009 
 
 
 


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10 
Study Subjects 
See chapter 14. 
 
11 
Efficacy Evaluation 
See chapter 14. 
 
12 
Safety Evaluation 
See chapter 14. 
 
13 
Discussion and Overall Conclusions 
Not applicable to the SAP 
 
 
 


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14 
Analysis Figures and Tables 
14.1 
Disposition of Subjects and Distributions of Prognostic Factors 
14.1.1 
Disposition of Subjects 
14.1.1.1. 
Disposition of Subjects 
Table 14.1.1.1.1 
Disposition of Subjects in the Study (1st enrolled subjects) 
・ Classification is as follows. Aggregation by reason for discontinuation 
is also performed 
・ 1st enrolled, 2nd enrolled, started run-in period, randomized, 
started treatment period, completed treatment period*, and 
completed follow-up period† 
*: Subjects who completed without discontinuing the treatment 
period 
†: Subjects who completed without discontinuing the follow-up 
period 
・ Discontinued screening period, discontinued run-in period, 
discontinued treatment period, and discontinued follow-up period 
(Before Week 1 visit, After Week 1 visit) 
 
Table 14.1.1.1.2 
Summary of Discontinuation of Treatment Period by timing of occurrence 
(subjects who discontinued treatment period) 
・ Summarize discontinuation in the treatment period based on 7.2.2 
Timing of withdrawal of treatment. Aggregation by reason for 
discontinuation is also performed. 
 
14.1.1.2. 
Protocol Deviation 
Table 14.1.1.2.1 
Summary of Significant Deviations by Category (1st enrolled subjects) 
・ The numbers of subjects and the numbers of deviations will be 
calculated. 
・ The following categories will be used. 
(1) When the subject is enrolled in the study despite violations of 
GCP or failure to satisfy inclusion criteria 
(2) When the subject meets the criteria for discontinuation during 
the study but is not discontinued 
(3) When then subject violates the rules about dose 
(administration regulations) 


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(4) When the subject uses prohibited concomitant therapies 
(5) When the subject does not receive observations, 
examinations, and assessment about primary endpoints 
(6) When any other important problems occur  
 
14.1.1.3. 
Structure of Efficacy Analysis Populations 
Table 14.1.1.3.1 
Structure of Efficacy Analysis Populations (randomized subjects) 
・ The following categories will be used. 
・ Randomized subjects 
・ FAS, subjects excluded from the FAS  
・ PPS, subjects excluded from the PPS  
 
Table 14.1.1.3.2 
Subjects Excluded from Efficacy Analysis Populations (randomized subjects) 
・ Only the number of subjects will be calculated 
・ The following categories will be used. 
・ Subjects excluded from the FAS 
(1) No investigational drug was administered during the 
treatment period. 
(2) No baseline or post-treatment value of total MADRS score 
・ Subjects excluded from the PPS 
(1) Did not meet the inclusion or exclusion criteria 
(2) Violated protocol “7.1.1 Prohibited concomitant drugs“ or 
“7.1.2 Prohibited concomitant therapies“ from the start of 
screening period to the end of treatment period 
(3) used hypnotic/sedative drugs in violation of provisions in 
protocol “7.1.3 Allowed concomitant drugs“ from the start 
of screening period to the end of treatment period 
(4) Duration of exposure of the investigational drug was less 
than 42 days or compliance rate was less than 75% in the 
treatment period 
 
14.1.1.4. 
Structure of Safety Analysis Populations 
Table 14.1.1.4.1 
Structure of Safety Analysis Population (2nd enrolled subjects) 
・ Classification is as follows 
・ 2nd enrolled subjects 


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・ SAF in the run-in period, subjects excluded from SAF in the run-
in period 
・ Randomized subjects 
・ SAF, subjects excluded from SAF 
・ SAF in the follow-up period, subjects excluded from SAF in the 
follow-up period 
 
14.1.1.5. 
Structure of Pharmacokinetic Analysis Population 
Table 14.1.1.5.1 
Structure of Pharmacokinetic Analysis Population (randomized subjects) 
・ Classification is as follows 
・ Example of assignment registration 
・ Pharmacokinetic analysis set, subjects excluded from 
Pharmacokinetic analysis set 
※ Placebo group is excluded from the tabulation. 
 
14.1.2 
Demographic and Other Baseline Characteristics 
14.1.2.1. 
Demographic and Other Baseline Characteristics (Demographic Variables) 
Table 14.1.2.1.1 
Demographic and Other Baseline Characteristics (Demographic Variables) 
(FAS) 
Table 14.1.2.1.2 
Demographic and Other Baseline Characteristics (Demographic Variables) 
(PPS) 
Table 14.1.2.1.3 
Demographic and Other Baseline Characteristics (Demographic Variables) 
(SAF) 
 
14.1.2.2. 
Demographic and Other Baseline Characteristics (Other Factors) 
Table 14.1.2.2.1 
Demographic and Other Baseline Characteristics (Other Factors) (FAS) 
Table 14.1.2.2.2 
Demographic and Other Baseline Characteristics (Other Factors) (PPS) 
Table 14.1.2.2.3 
Demographic and Other Baseline Characteristics (Other Factors) (SAF) 
 
14.1.2.3. 
Demographic and Other Baseline Characteristics (Baseline) 
Table 14.1.2.3.1 
Demographic and Other Baseline Characteristics (Baseline) (FAS) 
Table 14.1.2.3.2 
Demographic and Other Baseline Characteristics (Baseline) (PPS) 
Table 14.1.2.3.3 
Demographic and Other Baseline Characteristics (Baseline) (SAF) 
 
 


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14.1.3 
Extent of Exposure to Study Drugs 
14.1.3.1. 
Extent of Exposure to Study Drugs 
Table 14.1.3.1.1 
Extent of Exposure to Study Drugs (FAS) 
Table 14.1.3.1.2 
Extent of Exposure to Study Drugs (PPS) 
Table 14.1.3.1.3 
Extent of Exposure to Study Drugs (SAF) 
 
14.2 
Efficacy 
14.2.1 
Total MADRS score 
14.2.1.1. 
Analysis of total MADRS score 
14.2.1.1.1. 
MMRM Analysis of Change in total MADRS score from baseline 
The following analyses are performed. 
・ Model description 
・ Response variable: Change in total MADRS score from baseline  
・ Fixed effect: treatment group, time point, interaction between 
treatment group and time point 
・ Covariate(s): Total MADRS score (baseline) 
・ Covariance Structure: Unstructured 
・ Approximation for the degrees of freedom: Kenward Roger 
・ Time point included in the analysis: Week 1, 2, 4, 6, and 8 
・ The following statistics will be calculated: 
・ Adjusted mean (for each treatment group) 
・ Adjusted mean difference from placebo and its two-sided 95% CI 
・ Test for Fixed effect (for each treatment group): p-value 
・ Comparison 
・ MD-120 50 mg group vs Placebo group 
・ MD-120 100 mg group vs Placebo group 
※ Data from the three groups will be used to estimate differences 
between groups at each time point using a contrast factor. 
※ Analysis using the response variable as Total MADRS score will be 
performed in the same way. 
Table 14.2.1.1.1.1 MMRM Analysis of Change in total MADRS score from baseline (OC) 
(FAS) 
Table 14.2.1.1.1.2 MMRM Analysis of Change in total MADRS score from baseline (OC) (PPS) 
 
14.2.1.1.2. 
Tipping Point Analysis of Change in total MADRS score from baseline 
The model and the statistics to be calculated are the same as in 14.2.1.1.1 


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Table 14.2.1.1.2.1 Tipping Point Analysis of Change in total MADRS score from baseline (OC) 
(Week 8) (FAS) 
 
14.2.1.1.3. 
MMRM Analysis of Change in total MADRS score from baseline (Stratified 
Analysis) 
For the model used in 14.2.1.1.1, one background factor is added and the 
same analysis is performed 
Table 14.2.1.1.3.1 MMRM Analysis of Change in total MADRS score from baseline (Week 8) 
(Stratification: Demographic variables) (OC) (FAS) 
Table 14.2.1.1.3.2 MMRM Analysis of Change in total MADRS score from baseline (Week 8) 
(Stratification: Other factors) (OC) (FAS) 
 
14.2.1.1.4. 
MMRM Analysis of Change in total MADRS score from baseline (Subgroup 
Analysis) 
The model and the statistics to be calculated are the same as in 14.2.1.1.1 
※ If fewer than 10 subjects are in any of the subgroups, no analysis will be 
performed in that subgroup. 
Table 14.2.1.1.4.1 MMRM Analysis of Change in total MADRS score from baseline (Week 8) 
(Subgroup: Demographic variables) (OC) (FAS) 
Table 14.2.1.1.4.2 MMRM Analysis of Change in total MADRS score from baseline (Week 8) 
(Subgroup: Other factors) (OC) (FAS) 
Table 14.2.1.1.4.3 MMRM Analysis of Change in total MADRS score from baseline (Week 8) 
(Subgroup: Baseline) (OC) (FAS) 
 
14.2.1.1.5. 
MMRM(Overall) Analysis of Change in total MADRS score from baseline 
The following analyses are performed. 
・ Model description 
・ Response variable: Change in total MADRS score from baseline 
・ Fixed effect: treatment group, time point 
・ Covariate(s): Total MADRS score (baseline) 
・ Covariance Structure: Unstructured 
・ Approximation for the degrees of freedom: Kenward Roger 
・ Time point included in the analysis: Week 1, 2, 4, 6, and 8 
・ The following statistics will be calculated: 
・ Adjusted mean (for each treatment group) 
・ Adjusted mean difference from placebo and its two-sided 95% CI 


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・ Test for Fixed effect (for each treatment group): p-value 
・ Comparison 
・ MD-120 50 mg group vs Placebo group 
・ MD-120 100 mg group vs Placebo group 
※ Data from the three groups will be used to estimate 
differences between groups across the overall treatment period 
using a contrast factor. 
Table 14.2.1.1.5.1 MMRM(Overall) Analysis of Change in total MADRS score from baseline 
(OC) (FAS) 
 
14.2.1.1.6. 
ANCOVA Analysis of Change in total MADRS score from baseline 
The following analyses will be performed. 
・ Model description 
・ Dependent variable: Change in total MADRS score from baseline 
・ Fixed effect: treatment group 
・ Covariate(s): Total MADRS score (baseline) 
・ The following statistics will be calculated: 
・ Adjusted mean (for each treatment group) 
・ Adjusted mean difference from placebo and its two-sided 95% CI 
・ Test for Fixed effect (for each treatment group): p-value 
・ Comparison 
・ MD-120 50 mg group vs Placebo group 
・ MD-120 100 mg group vs Placebo group 
※ Data from the three groups will be used to estimate 
differences between groups at each time point using a contrast 
factor. 
※ Analysis using the response variable as Total MADRS score will be 
performed in the same way. 
Table 14.2.1.1.6.1 ANCOVA Analysis of Change in total MADRS score from baseline (LOCF) 
(FAS) 
Table 14.2.1.1.6.2 ANCOVA Analysis of Change in total MADRS score from baseline (OC) 
(FAS) 
Table 14.2.1.1.6.3 ANCOVA Analysis of Change in total MADRS score from baseline (LOCF) 
(PPS) 
Table 14.2.1.1.6.4 ANCOVA Analysis of Change in total MADRS score from baseline (OC) 
(PPS) 


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14.2.1.1.7. 
ANCOVA Analysis of Change in total MADRS score from baseline (Subgroup 
Analysis) 
The model and the statistics to be calculated are the same as in 14.2.1.1.1 
※ If fewer than 10 subjects are in any of the subgroups, no analysis will be 
performed in that subgroup. 
Table 14.2.1.1.7.1 ANCOVA Analysis of Change in total MADRS score from baseline (Week 8) 
(Subgroup: Demographic variables) (LOCF) (FAS) 
Table 14.2.1.1.7.2 ANCOVA Analysis of Change in total MADRS score from baseline (Week 8) 
(Subgroup: Other factors) (LOCF) (FAS) 
Table 14.2.1.1.7.3 ANCOVA Analysis of Change in total MADRS score from baseline (Week 8) 
(Subgroup: Baseline) (LOCF) (FAS) 
 
14.2.1.2. 
Description of total MADRS score 
14.2.1.2.1. 
Descriptive Statistics of total MADRS score and Change in total MADRS score 
from baseline 
・ The following statistics will be calculated: 
・ Mean and its two-sided 95% CI 
Table 14.2.1.2.1.1 Descriptive Statistics of total MADRS score and Change in total MADRS 
score from baseline (LOCF) (FAS) 
Table 14.2.1.2.1.2 Descriptive Statistics of total MADRS score and Change in total MADRS 
score from baseline (OC) (FAS) 
Table 14.2.1.2.1.3 Descriptive Statistics of total MADRS score and Change in total MADRS 
score from baseline (LOCF) (PPS) 
Table 14.2.1.2.1.4 Descriptive Statistics of total MADRS score and Change in total MADRS 
score from baseline (OC) (PPS) 
 
14.2.1.2.2. 
Descriptive Statistics of total MADRS score and Change in total MADRS score 
from baseline (Subgroup Analysis) 
・ The following statistics will be calculated: 
・ Mean and its two-sided 95% CI 
Table 14.2.1.2.2.1 Descriptive Statistics of total MADRS score and Change in total MADRS 
score from baseline (Subgroup: Demographic variables) (Week 8) (LOCF) 
(FAS) 
Table 14.2.1.2.2.2 Descriptive Statistics of total MADRS score and Change in total MADRS 
score from baseline (Subgroup: Other factors) (Week 8) (LOCF) (FAS) 


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Table 14.2.1.2.2.3 Descriptive Statistics of total MADRS score and Change in total MADRS 
score from baseline (Subgroup: Baseline) (Week 8) (LOCF) (FAS) 
Table 14.2.1.2.2.4 Descriptive Statistics of total MADRS score and Change in total MADRS 
score from baseline (Subgroup: Study Center) (Week 8) (LOCF) (FAS) 
 
14.2.1.3. 
Graphs of total MADRS score 
14.2.1.3.1. 
Profiles of total MADRS score and Change in total MADRS score from 
baseline (MMRM Analysis) 
See 14.2.1.1.1 
Figure 14.2.1.3.1.1 Profiles of total MADRS score and Change in total MADRS score from 
baseline (MMRM Analysis) (OC) (FAS) 
 
14.2.1.3.2. 
Profiles of total MADRS score and Change in total MADRS score from 
baseline (ANCOVA Analysis) 
See 14.2.1.1.6 
Figure 14.2.1.3.2.1 Profiles of total MADRS score and Change in total MADRS score from 
baseline (ANCOVA Analysis) (OC/LOCF at Week 8) (FAS) 
 
 
14.2.2 
Response evaluated by total MADRS score 
14.2.2.1. 
Analysis of response evaluated by total MADRS score 
14.2.2.1.1. 
GEE analysis of response evaluated by total MADRS score 
The following analyses are performed. 
・ Model description 
・ Response variable: Response evaluated by total MADRS score 
(Link Function: logit) 
・ Fixed effect: treatment group, time point, interaction between 
treatment group and time point 
・ Covariate(s): Total MADRS score (baseline) 
・ Covariance Structure: Unstructured 
・ Time point included in the analysis: Week 1, 2, 4, 6, and 8 
・ The following statistics will be calculated: 
・ Odds ratio and its two-sided 95% CI versus placebo group 
・ Test for Fixed effect (for each treatment group): p-value 
※If at least one of the two groups being compared has no 
response cases, these statistics are not calculated. 


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・ Comparison 
・ MD-120 50 mg group and Placebo group 
・ MD-120 100 mg group and Placebo group 
※Data from the three groups will be used to estimate differences 
between groups at each time point. 
Table 14.2.2.1.1.1 GEE analysis of response evaluated by total MADRS score (OC) (FAS) 
 
14.2.2.1.2. 
Logistic regression of response evaluated by total MADRS score 
The following analyses are performed. 
・ Model description 
・ Response variable: response evaluated by total MADRS score 
・ Fixed effect: treatment group 
・ Covariate(s): Total MADRS score (baseline) 
・ The following statistics will be calculated: 
・ Odds ratio and its two-sided 95% CI versus placebo group 
・ Test for Fixed effect (for each treatment group): p-value 
※If at least one of the two groups being compared has no 
response cases, these statistics are not calculated. 
・ Comparison 
・ MD-120 50 mg group and Placebo group 
・ MD-120 100 mg group and Placebo group 
※Data from the three groups will be used to estimate differences 
between groups at each time point. 
Table 14.2.2.1.2.1 Logistic regression of response evaluated by total MADRS score (OC/LOCF 
at Week 8) (FAS) 
 
14.2.2.1.3. 
Comparison of response evaluated by total MADRS score 
The following analyses are performed. 
・ The following statistics will be calculated: 
・ Fisher’s Exact Test: p-value 
・ Comparison 
・ MD-120 50 mg group and Placebo group 
・ MD-120 100 mg group and Placebo group 
Table 14.2.2.1.3.1 Comparison of response evaluated by total MADRS score (OC/LOCF at 
Week 8) (FAS) 
 


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14.2.2.2. 
Description of response evaluated by total MADRS score 
14.2.2.2.1. 
Aggregation of response evaluated by total MADRS score 
Not applicable 
 
14.2.2.3. 
Graphs of response evaluated by total MADRS score 
Not applicable 
 
 
14.2.3 
Remission evaluated by total MADRS score 
14.2.3.1. 
Analysis of remission evaluated by total MADRS score 
14.2.3.1.1. 
GEE analysis of remission evaluated by total MADRS score 
The model and the statistics to be calculated will conform to 14.2.2.1.1 
Table 14.2.3.1.1.1 GEE analysis of remission evaluated by total MADRS score (OC) (FAS) 
 
14.2.3.1.2. 
Logistic regression of remission evaluated by total MADRS score 
The model and the statistics to be calculated will conform to 14.2.2.1.2 
Table 14.2.3.1.2.1 Logistic regression of remission evaluated by total MADRS score (OC/LOCF 
at Week 8) (FAS) 
 
14.2.3.1.3. 
Comparison of remission evaluated by total MADRS score 
Table 14.2.3.1.3.1 Comparison of remission evaluated by total MADRS score (OC/LOCF at 
Week 8) (FAS) 
 
14.2.3.2. 
Description of remission evaluated by total MADRS score 
14.2.3.2.1. 
Aggregation of remission evaluated by total MADRS score 
Not applicable 
 
14.2.3.3. 
Graphs of remission evaluated by total MADRS score 
Not applicable 
 
 
14.2.4 
Total HAMD17 score 
14.2.4.1. 
Analysis of total HAMD17 score 
14.2.4.1.1. 
MMRM Analysis of Change in total HAMD17 score from baseline 
The model and the statistics to be calculated will conform to 14.2.1.1.1 


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Table 14.2.4.1.1.1 MMRM Analysis of Change in total HAMD17 score from baseline (OC) 
(FAS) 
Table 14.2.4.1.1.2 MMRM Analysis of Change in total HAMD17 score from baseline (OC) 
(PPS) 
 
14.2.4.1.2. 
MMRM Analysis of Change in total HAMD17 score from baseline (Stratified 
Analysis) 
For the model used in 14.2.4.1.1, one background factor is added and the 
same analysis is performed 
Table 14.2.4.1.2.1 MMRM Analysis of Change in total HAMD17 score from baseline (Week 8) 
(Stratification: Demographic variables) (OC) (FAS) 
Table 14.2.4.1.2.2 MMRM Analysis of Change in total HAMD17 score from baseline (Week 8) 
(Stratification: Other factors) (OC) (FAS) 
 
14.2.4.1.3. 
MMRM Analysis of Change in total HAMD17 score from baseline (Subgroup 
Analysis) 
The model and the statistics to be calculated are the same as in 14.2.4.1.1 
※ If fewer than 10 subjects are in any of the subgroups, no analysis will be 
performed in that subgroup. 
Table 14.2.4.1.3.1 MMRM Analysis of Change in total HAMD17 score from baseline (Week 8) 
(Subgroup: Demographic variables) (OC) (FAS) 
Table 14.2.4.1.3.2 MMRM Analysis of Change in total HAMD17 score from baseline (Week 8) 
(Subgroup: Other factors) (OC) (FAS) 
Table 14.2.4.1.3.3 MMRM Analysis of Change in total HAMD17 score from baseline (Week 8) 
(Subgroup: Baseline) (OC) (FAS) 
 
14.2.4.1.4. 
MMRM(Overall) Analysis of Change in total HAMD17 score from baseline 
The model and the statistics to be calculated will conform to 14.2.1.1.5 
Table 14.2.4.1.4.1 MMRM(Overall) Analysis of Change in total HAMD17 score from baseline 
(OC) (FAS) 
 
14.2.4.1.5. 
ANCOVA Analysis of Change in total HAMD17 score from baseline 
The model and the statistics to be calculated will conform to 14.2.1.1.6 
Table 14.2.4.1.5.1 ANCOVA Analysis of Change in total HAMD17 score from baseline (LOCF) 
(FAS) 


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Table 14.2.4.1.5.2 ANCOVA Analysis of Change in total HAMD17 score from baseline (OC) 
(FAS) 
Table 14.2.4.1.5.3 ANCOVA Analysis of Change in total HAMD17 score from baseline (LOCF) 
(PPS) 
Table 14.2.4.1.5.4 ANCOVA Analysis of Change in total HAMD17 score from baseline (OC) 
(PPS) 
 
14.2.4.1.6. 
ANCOVA Analysis of Change in total HAMD17 score from baseline 
(Subgroup Analysis) 
The model and the statistics to be calculated are the same as in 14.2.4.1.5 
※ If fewer than 10 subjects are in any of the subgroups, no analysis will be 
performed in that subgroup. 
Table 14.2.4.1.6.1 ANCOVA Analysis of Change in total HAMD17 score from baseline (Week 
8) (Subgroup: Demographic variables) (LOCF) (FAS) 
Table 14.2.4.1.6.2 ANCOVA Analysis of Change in total HAMD17 score from baseline (Week 
8) (Subgroup: Other factors) (LOCF) (FAS) 
Table 14.2.4.1.6.3 ANCOVA Analysis of Change in total HAMD17 score from baseline (Week 
8) (Subgroup: Baseline) (LOCF) (FAS) 
 
14.2.4.2. 
Description of total HAMD17 score 
14.2.4.2.1. 
Descriptive Statistics of total HAMD17 score and Change in total HAMD17 
score from baseline 
・ Statistics to be calculated 
・ Mean and its two-sided 95% CI 
Table 14.2.4.2.1.1 Descriptive Statistics of total HAMD17 score and Change in total HAMD17 
score from baseline (LOCF) (FAS) 
Table 14.2.4.2.1.2 Descriptive Statistics of total HAMD17 score and Change in total HAMD17 
score from baseline (OC) (FAS) 
Table 14.2.4.2.1.3 Descriptive Statistics of total HAMD17 score and Change in total HAMD17 
score from baseline (LOCF) (PPS) 
Table 14.2.4.2.1.4 Descriptive Statistics of total HAMD17 score and Change in total HAMD17 
score from baseline (OC) (PPS) 
 
14.2.4.2.2. 
Descriptive Statistics of total HAMD17 score and Change in total HAMD17 
score from baseline (Subgroup Analysis) 
・ Statistics to be calculated 


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・ Mean and its two-sided 95% CI 
Table 14.2.4.2.2.1 Descriptive Statistics of total HAMD17 score and Change in total HAMD17 
score from baseline (Subgroup: Demographic variables) (Week 8) (LOCF) 
(FAS) 
Table 14.2.4.2.2.2 Descriptive Statistics of total HAMD17 score and Change in total HAMD17 
score from baseline (Subgroup: Other factors) (Week 8) (LOCF) (FAS) 
Table 14.2.4.2.2.3 Descriptive Statistics of total HAMD17 score and Change in total HAMD17 
score from baseline (Subgroup: Baseline) (Week 8) (LOCF) (FAS) 
Table 14.2.4.2.2.4 Descriptive Statistics of total HAMD17 score and Change in total HAMD17 
score from baseline (Subgroup: Study Center) (Week 8) (LOCF) (FAS) 
 
14.2.4.3. 
Graphs of total HAMD17 score 
14.2.4.3.1. 
Profiles of total HAMD17 score and Change in total HAMD17 score from 
baseline (MMRM analysis) 
See 14.2.4.1.1 
Figure 14.2.4.3.1.1 Profiles of total HAMD17 score and Change in total HAMD17 score from 
baseline (MMRM analysis) (OC) (FAS) 
 
14.2.4.3.2. 
Profiles of total HAMD17 score and Change in total HAMD17 score from 
baseline (ANCOVA Analysis) 
See 14.2.4.1.5 
Figure 14.2.4.3.2.1 Profiles of total HAMD17 score and Change in total HAMD17 score from 
baseline (ANCOVA Analysis) (OC/LOCF at Week 8) (FAS) 
 
14.2.4.3.3. 
Correlation between total HAMD17 score and total MADRS score 
・ The following statistics will be calculated: 
・ Correlation coefficient (Pearson’s product moment correlation 
coefficient) 
・ Test of no correlation: p-value 
Figure 14.2.4.3.3.1 Correlation between total HAMD17 score and total MADRS score (Week 8) 
(LOCF) (FAS) 
Figure 14.2.4.3.3.2 Correlation between change in total HAMD17 score and change in total 
MADRS score (Week 8) (LOCF) (FAS) 
 
 


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14.2.5 
Response evaluated by total HAMD17 score 
14.2.5.1. 
Analysis of response evaluated by total HAMD17 score 
14.2.5.1.1. 
GEE analysis of response evaluated by total HAMD17 score 
The model and the statistics to be calculated will conform to 14.2.2.1.1 
Table 14.2.5.1.1.1 GEE analysis of response evaluated by total HAMD17 score (OC) (FAS) 
 
14.2.5.1.2. 
Logistic regression of response evaluated by total HAMD17 score 
The model and the statistics to be calculated will conform to 14.2.2.1.2 
Table 14.2.5.1.2.1 Logistic regression of response evaluated by total HAMD17 score (OC/LOCF 
at Week 8) (FAS) 
 
14.2.5.1.3. 
Comparison of response evaluated by total HAMD17 score 
Table 14.2.5.1.3.1 Comparison of response evaluated by total HAMD17 score (OC/LOCF at 
Week 8) (FAS) 
 
14.2.5.2. 
Description of response evaluated by total HAMD17 score 
14.2.5.2.1. 
Aggregation of response evaluated by total HAMD17 score 
Not applicable 
 
14.2.5.3. 
Graphs of remission evaluated by total HAMD17 score 
Not applicable 
 
14.2.6 
Remission evaluated by total HAMD17 score 
14.2.6.1. 
Analysis of remission evaluated by total HAMD17 score 
14.2.6.1.1. 
GEE analysis of remission evaluated by total HAMD17 score 
The model and the statistics to be calculated will conform to 14.2.2.1.1 
Table 14.2.6.1.1.1 GEE analysis of remission evaluated by total HAMD17 score (OC) (FAS) 
 
14.2.6.1.2. 
Logistic regression of remission evaluated by total MADRS score 
The model and the statistics to be calculated will conform to 14.2.2.1.2 
Table 14.2.6.1.2.1 Logistic regression of remission evaluated by total HAMD17 score 
(OC/LOCF at Week 8) (FAS) 
 
14.2.6.1.3. 
Comparison of remission evaluated by total HAMD17 score 
Table 14.2.6.1.3.1 Comparison of remission evaluated by total HAMD17 score (OC/LOCF at 
Week 8) (FAS) 


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14.2.6.2. 
Description of remission evaluated by total HAMD17 score 
14.2.6.2.1. 
Aggregation of remission evaluated by total HAMD17 score 
Not applicable 
 
14.2.6.3. 
Graphs of remission evaluated by total HAMD17 score 
Not applicable 
 
 
14.2.7 
CGI-I 
14.2.7.1. 
Analysis of CGI-I 
14.2.7.1.1. 
MMRM Analysis of CGI-I 
The following analyses are performed. 
・ Model description 
・ Response variable: CGI-I 
・ Fixed effect: treatment group, time point, interaction between 
treatment group and time point 
・ Covariance Structure: Unstructured 
・ Approximation for the degrees of freedom: Kenward Roger 
・ Time point included in the analysis: Week 1, 2, 4, 6, and 8 
・ The following statistics will be calculated: 
・ Adjusted mean (for each treatment group) 
・ Adjusted mean difference from placebo and its two-sided 95% CI 
・ Test for Fixed effect (for each treatment group): p-value 
・ Comparison 
・ MD-120 50 mg group vs Placebo group 
・ MD-120 100 mg group vs Placebo group 
※ Data from the three groups will be used to estimate differences 
between groups at each time point using a contrast factor. 
 
Table 14.2.7.1.1.1 MMRM Analysis of CGI-I (OC) (FAS) 
 
14.2.7.1.2. 
ANOVA Analysis of CGI-I 
The following analyses are performed. 
・ Model description 
・ Response variable: CGI-I 


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・ Fixed effect: treatment group 
・ The following statistics will be calculated: 
・ Adjusted mean (for each treatment group) 
・ Adjusted mean difference from placebo and its two-sided 95% CI 
・ Test for Fixed effect (for each treatment group): p-value 
・ Comparison 
・ MD-120 50 mg group vs Placebo group 
・ MD-120 100 mg group vs Placebo group 
※ Data from the three groups will be used to estimate differences 
between groups at each time point using a contrast factor. 
Table 14.2.7.1.2.1 ANOVA Analysis of CGI-I (OC/LOCF at Week 8) (FAS) 
 
14.2.7.1.3. 
CMH test of CGI-I 
The following analyses are performed. 
・ Model 
・ Row variable: Treatment group (*Only 2 groups to be compared 
are used) 
・ Column variable: CGI-I 
・ Stratification Variables: None 
・ Comparison 
・ MD-120 50 mg group vs Placebo group 
・ MD-120 100 mg group vs Placebo group 
・ The following statistics will be calculated: 
・ ANOVA statistic (ridit score): p-value 
Table 14.2.7.1.3.1 CMH test of CGI-I (OC/LOCF at Week 8) (FAS) 
 
14.2.7.2. 
Description of CGI-I 
14.2.7.2.1. 
Descriptive Statistics of CGI-I 
・ The following statistics will be calculated: 
・ Mean and its two-sided 95% CI 
Table 14.2.7.2.1.1 Descriptive Statistics of CGI-I (OC/LOCF at Week 8) (FAS) 
 
14.2.7.3. 
Graphs of CGI-I 
14.2.7.3.1. 
Profiles of CGI-I (MMRM analysis) 
・ See 14.2.7.1.1 
Figure 14.2.7.3.1.1 Profiles of CGI-I (MMRM analysis) (OC) (FAS) 


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14.2.8 
Response evaluated by CGI-I 
14.2.8.1. 
Analysis of response evaluated by CGI-I 
14.2.8.1.1. 
GEE Analysis of response evaluated by CGI-I 
The model and the statistics to be calculated are in accordance with 
14.2.2.1.1 (* Baseline adjustment will not be performed.)  
Table 14.2.8.1.1.1 GEE Analysis of response evaluated by CGI-I (OC) (FAS) 
 
14.2.8.1.2. 
Logistic regression of response evaluated by CGI-I 
The model and the statistics to be calculated are in accordance with 
14.2.2.1.2 (* Baseline adjustment will not be performed.)  
Table 14.2.8.1.2.1 Logistic regression of response evaluated by CGI-I (OC/LOCF at Week 8) 
(FAS) 
 
14.2.8.1.3. 
Comparison of responses in CGI-I 
Table 14.2.8.1.3.1 Comparison of responses in CGI-I (OC/LOCF at Week 8) (FAS) 
 
 
14.2.8.2. 
Description of response in CGI-I 
14.2.8.2.1. 
Aggregation of response evaluated by CGI-I 
Not applicable 
 
14.2.8.3. 
Graphs of responses in CGI-I 
Not applicable 
 
 
14.2.9 
CGI-S 
14.2.9.1. 
Analysis of CGI-S 
14.2.9.1.1. 
MMRM Analysis of Change in CGI-S from baseline 
The model and the statistics to be calculated will conform to 14.2.1.1.1 
Table 14.2.9.1.1.1 MMRM Analysis of Change in CGI-S from baseline (OC) (FAS) 
 
14.2.9.1.2. 
ANCOVA Analysis of Change in CGI-S from baseline 
The model and the statistics to be calculated will conform to 14.2.1.1.6 


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Table 14.2.9.1.2.1 ANCOVA Analysis of Change in CGI-S from baseline (OC/LOCF at Week 
8) (FAS) 
 
14.2.9.2. 
Description of CGI-S 
14.2.9.2.1. 
Descriptive Statistics of CGI-S and Change in CGI-S from baseline 
・ The following statistics will be calculated: 
・ Mean and its two-sided 95% CI 
Table 14.2.9.2.1.1 Descriptive Statistics of CGI-S and Change in CGI-S from baseline 
(OC/LOCF at Week 8) (FAS) 
 
14.2.9.2.2. 
Aggregation of CGI-S 
Table 14.2.9.2.2.1 Aggregation of CGI-S (OC/LOCF at Week 8) (FAS) 
 
14.2.9.3. 
Graphs of CGI-S 
14.2.9.3.1. 
Profiles of CGI-S and Change in CGI-S from baseline (MMRM analysis) 
See 14.2.9.1.1 
Figure 14.2.9.3.1.1 Profiles of CGI-S and Change in CGI-S from baseline (MMRM Analysis) 
(OC) (FAS) 
 
 
14.2.10 Total QIDS16-SR-J score 
14.2.10.1. 
Analysis of Total QIDS16-SR-J score 
14.2.10.1.1. 
MMRM Analysis of Change in total QIDS16-SR-J score from baseline 
The model and the statistics to be calculated will conform to 14.2.1.1.1 
Table 14.2.10.1.1.1 MMRM Analysis of Change in total QIDS16-SR-J score from baseline (OC) 
(FAS) 
 
14.2.10.1.2. 
ANCOVA Analysis of Change in total QIDS16-SR-J score from baseline 
The model and the statistics to be calculated will conform to 14.2.1.1.6 
Table 14.2.10.1.2.1 ANCOVA Analysis of Change in total QIDS16-SR-J score from baseline 
(OC/LOCF at Week 8) (FAS) 
 
14.2.10.2. 
Description of total QIDS16-SR-J score 
14.2.10.2.1. 
Descriptive Statistics of total QIDS16-SR-J score and Change in total QIDS16-
SR-J score from baseline 
・ The following statistics will be calculated: 


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・ Mean and its two-sided 95% CI 
Table 14.2.10.2.1.1 Descriptive Statistics of total QIDS16-SR-J score and Change in total QIDS16-
SR-J score from baseline (OC/LOCF at Week 8) (FAS) 
 
14.2.10.3. 
Graphs of total QIDS16-SR-J score 
14.2.10.3.1. 
Profiles of total QIDS16-SR-J score and Change in total QIDS16-SR-J score 
from baseline (MMRM analysis) 
See 14.2.10.1.1 
Figure 14.2.10.3.1.1 
Profiles of total QIDS16-SR-J score and Change in total QIDS16-SR-J 
score from baseline (MMRM Analysis) (OC) (FAS) 
 
 
14.2.11 Total SDS score 
14.2.11.1. 
Analysis of Total SDS score 
14.2.11.1.1. 
MMRM Analysis of Change in total SDS score from baseline 
The model and the statistics to be calculated will conform to 14.2.1.1.1 
Table 14.2.11.1.1.1 MMRM Analysis of Change in total SDS score from baseline (OC) (FAS) 
Table 14.2.11.1.1.2 MMRM Analysis of Change in SDS (WORK/SCHOOL) from baseline (OC) 
(FAS) 
Table 14.2.11.1.1.3 MMRM Analysis of Change in SDS (SOCIAL LIFE) from baseline (OC) 
(FAS) 
Table 14.2.11.1.1.4 MMRM Analysis of Change in SDS (FAMILY LIFE/HOME 
RESPONSIBILITIES) from baseline (OC) (FAS) 
 
14.2.11.1.2. 
ANCOVA Analysis of Change in total SDS score from baseline 
The model and the statistics to be calculated will conform to 14.2.1.1.6 
Table 14.2.11.1.2.1 ANCOVA Analysis of Change in total SDS score from baseline (OC/LOCF at 
Week 8) (FAS) 
Table 14.2.11.1.2.2 ANCOVA Analysis of Change in SDS (WORK/SCHOOL) from baseline 
(OC/LOCF at Week 8) (FAS) 
Table 14.2.11.1.2.3 ANCOVA Analysis of Change in SDS (SOCIAL LIFE) from baseline 
(OC/LOCF at Week 8) (FAS) 
Table 14.2.11.1.2.4 ANCOVA Analysis of Change in SDS (FAMILY LIFE/HOME 
RESPONSIBILITIES) from baseline (OC/LOCF at Week 8) (FAS) 
 


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14.2.11.2. 
Description of total SDS score 
14.2.11.2.1. 
Descriptive Statistics of total SDS score and Change in total SDS score from 
baseline 
・ The following statistics will be calculated: 
・ Mean and its two-sided 95% CI 
Table 14.2.11.2.1.1 Descriptive Statistics of total SDS score and Change in total SDS score from 
baseline (OC/LOCF at Week 8) (FAS) 
Table 14.2.11.2.1.2 Descriptive Statistics of SDS subscale and Change in SDS subscale from 
baseline (OC/LOCF at Week 8) (FAS) 
 
14.2.11.3. 
Graphs of total SDS score 
14.2.11.3.1. 
Profiles of total SDS score and Change in total SDS score from baseline 
(MMRM analysis) 
See 14.2.11.1.1 
Figure 14.2.11.3.1.1 
Profiles of total SDS score and Change in total SDS score from 
baseline (MMRM Analysis) (OC) (FAS) 
 
 
 


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14.3 
Safety 
14.3.1 
Adverse events 
14.3.1.1. 
Brief Summary of Adverse Events 
The number of subjects with the following events and the incidence rate are 
calculated. Adverse reactions are also summarized. 
・ Adverse events 
・ Severe adverse events 
・ Adverse events leading to death 
・ Serious adverse events excluding death 
・ Adverse events leading to treatment withdrawal 
Table 14.3.1.1.1 
Brief Summary of Adverse Events (Treatment and Follow-up period) (SAF) 
Table 14.3.1.1.2 
Brief Summary of Adverse Events (Treatment period) (SAF) 
Table 14.3.1.1.3 
Brief Summary of Adverse Events (Follow-up period) (SAF in the follow-up 
period) 
Table 14.3.1.1.4 
Brief Summary of Adverse Events (Run-in period) (SAF in the run-in period) 
 
14.3.1.2. 
Summary of Adverse Events (Subgroup Analysis) 
Table 14.3.1.2.1 
Summary of Adverse Events (Subgroup: Demographic Variables) (Treatment 
and Follow-up period) (SAF) 
Table 14.3.1.2.2 
Summary of Adverse Events (Subgroup: Other Factors) (Treatment and 
Follow-up period) (SAF) 
Table 14.3.1.2.3 
Summary of Adverse Events (Subgroup: Baseline) (Treatment and Follow-up 
period) (SAF) 
 
14.3.1.3. 
Summary of Adverse Events by SOC and PT 
Table 14.3.1.3.1 
Summary of Adverse Events by SOC and PT (Treatment and Follow-up 
period) (SAF) 
・ Fisher's exact test 
Table 14.3.1.3.2 
Summary of Adverse Events by SOC and PT (Treatment period) (SAF) 
・ Fisher's exact test 
Table 14.3.1.3.3 
Summary of Adverse Events by SOC and PT (Follow-up period) (SAF in the 
Follow-up period) 
・ Fisher's exact test 
Table 14.3.1.3.4 
Summary of Adverse Events by SOC and PT (Run-in period) (SAF in the run-
in period) 
 


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14.3.1.4. 
Summary of Adverse Events by SOC and PT (Subgroup Analysis) 
Table 14.3.1.4.1 
Summary of Adverse Events by SOC and PT (Subgroup: Sex) (Treatment and 
Follow-up period) (SAF) 
Table 14.3.1.4.2 
Summary of Adverse Events by SOC and PT s (Subgroup: Age) (Treatment 
and Follow-up period) (SAF) 
 
14.3.1.5. 
Summary of Adverse Events by SOC and PT by severity 
Table 14.3.1.5.1 
Summary of Adverse Events by SOC and PT by severity (Treatment and 
Follow-up period) (SAF) 
When a single subject experiences multiple episodes of the same event, 
only the most severe episode will be counted. 
 
14.3.1.6. 
Summary of Adverse Events by SOC and PT by timing of occurrence 
The incidence rate is defined as follows. 
・ Number of subjects with event/Number of subjects * ×100 
The number of subjects * is defined as follows 
・ For each category (day X ≦ Number of Days to Adverse Event 
Onset (days) ≦ day Y (see "7.3.8 Time of onset of the AE")), 
only subjects meeting the following conditions are included in the 
denominator.  
・ Number of days to completion of follow-up # ≧ Lower 
limit (day X) of the number of days to the event included in 
the summary 
# Number of days to completion of follow-up will be 
defined as (date of completion of follow-up - date of the 
first dose of the investigational drug in the treatment period 
or follow-up period + 1). The date of completion of follow-
up will be the latest date of week 1 visit during follow-up 
period or the time of premature termination, end of follow-
up period or the time of premature termination, or existence 
of the subject. Subjects with missing follow-up will always 
be included in the denominator. Adverse events for which 
the time of onset is missing will be excluded from the 
tabulation. 
Table 14.3.1.6.1 
Summary of Adverse Events by SOC and PT by timing of occurrence 
(Treatment and Follow-up period) (SAF) 


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14.3.1.7. 
Common Adverse Events 
Table 14.3.1.7.1 
Summary of Common Adverse Events by PT (Treatment and Follow-up 
period) (SAF) 
・ The following statistics will be calculated: 
・ Differences in the incidence rates of the events and its two-sided 
95% CI 
・ Comparison 
・ MD-120 50 mg group vs Placebo group 
・ MD-120 100 mg group vs Placebo group 
・ MD-120 100 mg group vs MD-120 50 mg group 
 
Table 14.3.1.7.2 
Descriptive Statistics of Number of Days to Onset of Common Adverse 
Events Treatment and Follow-up period) (SAF) 
When a single subject experiences multiple episodes of the same event, 
only the first occurrence of the event will be used. 
Table 14.3.1.7.3 
Descriptive Statistics of Duration of Relatively Frequent Adverse Events 
Treatment and Follow-up period) (SAF) 
When a single subject experiences multiple episodes of the same event, 
only the episode with the longest duration will be counted. Only the 
recovered/resolved events will be considered. 
Table 14.3.1.7.4 
Summary of Outcomes of Relatively Frequent Adverse Events Treatment and 
Follow-up period) (SAF) 
When a single subject experiences multiple episodes of the same event, 
only the unrecovered/unresolved episode will be counted. 
Table 14.3.1.7.5 
Summary of Common Adverse Events by PT (Follow-up period) (SAF in the 
follow-up period) 
 
14.3.1.8. 
AEs of Interest 
・ The following statistics will be calculated: 
・ Differences in the incidence rates of the events and its two-sided 
95% CI 
・ Comparison 
・ MD-120 50 mg group vs Placebo group 
・ MD-120 100 mg group vs Placebo group 
・ MD-120 100 mg group vs MD-120 50 mg group 


MD120101 
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Statistical analysis plan 
 
63 
 
 
 
 
Table 14.3.1.8.1 
Summary of Suicide-related Adverse Events by PT (Treatment and Follow-up 
period) (SAF) 
Table 14.3.1.8.2 
Summary of Cardiovascular Adverse Events by PT (Treatment and Follow-up 
period) (SAF) 
 
14.3.2 
Deaths, Other Serious Adverse Events, and Other Significant Adverse Events 
14.3.2.1. 
Adverse Events Resulting in Death 
Table 14.3.2.1.1 
Listing of Adverse Events Resulting in Death 
List all adverse events that occurred in subjects who experienced adverse 
events resulting in death. 
 
14.3.2.2. 
SAEs Excluding Death 
Table 14.3.2.2.1 
Listing of SAEs Excluding Death 
List all adverse events that occurred in subjects who experienced SAEs 
excluding death. 
Table 14.3.2.2.2 
Summary of SAEs Excluding Death by SOC and PT (Treatment and follow-
up period) (SAF) 
 
14.3.2.3. 
Adverse Events Resulting in the treatment Withdrawal 
Table 14.3.2.3.1 
Listing of Adverse Events Resulting in Treatment Withdrawal 
List all adverse events that occurred in subjects who experienced adverse 
events resulting in treatment withdrawal. 
Table 14.3.2.3.2 
Summary of Adverse Events Resulting in Treatment Withdrawal by SOC and 
PT (Treatment period) (SAF) 
 
14.3.2.4. 
Adverse Events Resulting in Treatment Interrupted 
Table 14.3.2.4.1 
Listing of Adverse Events Resulting in Treatment Interrupted 
List all adverse events that occurred in subjects who experienced adverse 
events resulting in treatment Interrupted. 
Table 14.3.2.4.2 
Summary of Adverse Events Resulting in Treatment Interrupted by SOC and 
PT (Treatment period) (SAF) 
 
14.3.3 
Descriptions of Deaths, Other Serious Adverse Events and Other Significant Adverse 
Events 
Not applicable to the SAP 
 


MD120101 
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Statistical analysis plan 
 
64 
 
 
 
 
 
14.3.4 
Laboratory Measurements 
14.3.4.1. 
Laboratory Measurements 
Table 14.3.4.1.1 
Descriptive Statistics of Laboratory Measurement (Quantitative Value) (SAF) 
・ Wilcoxon 2-sample test  
Table 14.3.4.1.2 
Shift Table of Laboratory Measurement (Qualitative Value) (SAF) 
・ Wilcoxon 2-sample test  
 
14.3.4.2. 
Laboratory Abnormalities 
Table 14.3.4.2.1 
Shift Table of Laboratory Abnormalities (SAF) 
The following variables will be classified and summarized according to 
"7.4.3 Clinical test value abnormality” 
・ Row Variable: Measurements at the Start of Screening period 
・ Column variables: Minimum and maximum values after administration 
in the treatment period 
 
14.3.4.3. 
Laboratory box plots 
Figure 14.3.4.3.1 
Box plots of Laboratory Measurements (SAF) 
Only for parameters for which the reference values are the same for both 
males and females 
Figure 14.3.4.3.2 
Box plots of Laboratory Measurements (Subgroup: Sex) (SAF) 
Only for parameters for which the reference values are different for males 
and females 
 
 
14.3.5 
Vital Signs and Body Weight 
14.3.5.1. 
Descriptive Statistics of Vital Sign and Body Weight 
Table 14.3.5.1.1 
Descriptive Statistics of Vital Sign and Body Weight (SAF) 
・ Wilcoxon 2-sample test 
 
14.3.5.2. 
Box plots of Vital Sign and Body Weight 
Figure 14.3.5.2.1 
Box plots of Vital Sign and Body Weight (SAF) 
 
 


MD120101 
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Statistical analysis plan 
 
65 
 
 
 
 
14.3.6 
ECG 
14.3.6.1. 
Summary of 12-lead ECG Abnormalities 
Table 14.3.6.1.1 
Summary of 12-lead ECG Abnormalities (SAF) 
・ Fisher's exact test 
 
14.3.6.2. 
Shift Table of ECG Abnormalities 
Table 14.3.6.2.1 
Shift Table of 12-lead ECG Abnormalities (SAF) 
 
14.3.7 
C-SSRS 
14.3.7.1. 
Summary of C-SSRS 
For the following items, the number of subjects who became "yes" at least 
once after administration in the treatment period is totaled. 
・ Suicidal ideation 
・ Suicidal behavior 
・ Suicidal ideation or behavior 
Table 14.3.7.1.1 
Summary of C-SSRS (SAF) 
 
14.3.7.2. 
Shift Table of C-SSRS 
The following items are summarized. The evaluation will be "yes" if it 
becomes "yes" at least once after administration in the treatment period. 
・ No suicidal ideation or behavior 
・ Suicidal ideation * 
・ Suicidal behavior * 
*: If both are “yes”, "Suicidal behavior" is assumed. 
Table 14.3.7.2.1 
Shift Table of C-SSRS (SAF) 
 
14.3.8 
Concomitant Drugs 
14.3.8.1. 
Summary of Concomitant Drugs 
Concomitant Drugs are summarized by ATC level 2 and Preferred Name in 
WHO-DDs. 
Table 14.3.8.1.1 
Summary of Concomitant Drugs (SAF) 
 
14.4 
Pharmacokinetics 


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Statistical analysis plan 
 
66 
 
 
 
 
14.4.1 
Pharmacokinetics 
14.4.1.1. 
Descriptive Statistics of Plasma desvenlafaxine concentration 
Table 14.4.1.1.1 
Descriptive Statistics of Plasma desvenlafaxine concentration (OC) 
(Pharmacokinetic analysis set) 
 
 
15 
Reference List 
Not applicable to the SAP 
 
 
 
 


MD120101 
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Statistical analysis plan 
 
67 
 
 
 
 
16 
Appendix 
16.1 
Study Information 
Not applicable to the SAP 
 
16.2 
Subject Data Listings 
16.2.1 
Withdrawn Subjects 
Table 16.2.1.1 
Listing of Withdrawals 
 
16.2.2 
Protocol Deviations 
Table 16.2.2.1 
Listing of Protocol Deviations 
 
16.2.3 
Subjects Excluded From the Efficacy Analysis 
Table 16.2.3.1 
Listing of Subjects Excluded From the FAS and PPS  
 
16.2.4 
Background Factors 
Table 16.2.4.1 
Listing of Background Factors 
 
16.2.5 
Covariates Measured after Randomization 
Table 16.2.5.1 
Listing of Extent of Exposure to Study Drug  
Table 16.2.5.2 
Listing of Concomitant Drugs 
Table 16.2.5.3 
Listing of Concomitant Therapies 
 
16.2.6 
Individual Efficacy Response Data 
Table 16.2.6.1 
Listing of Efficacy Endpoints 
 
16.2.7 
Adverse events 
Table 16.2.7.1 
Adverse Event Reclassification Table  
Table 16.2.7.2 
List of Adverse Events (Treatment and Follow-up period) 
Table 16.2.7.3 
List of Adverse Events (Run-in period) 
 
16.2.8 
Laboratory Measurements 
Table 16.2.8.1 
Listing of Laboratory Measurements 
 
16.2.9 
Vital Signs and Body Weight 
Table 16.2.9.1 
Listing of Vital Signs and Body Weight 


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Statistical analysis plan 
 
68 
 
 
 
 
 
16.2.10 ECG 
Table 16.2.10.1 
Listing of 12-lead ECG Abnormalities 
 
16.2.11 C-SSRS 
Table 16.2.11.1 
Listing of C-SSRS 
 
16.2.12 Pharmacokinetics 
Table 16.2.12.1 
Listing of Plasma desvenlafaxine concentration 
 
 


Appendix1：List of factors used for Subgroup/Stratification Analysis
 (d  indicates discrete variables  and c  indicates continuous variables )
Factors
Stratification
Analysis
14.2.1.1.4.1-3
14.2.1.1.7.1-3
14.2.1.2.2.1-3
14.2.4.1.3.1-3
14.2.4.1.6.1-3
14.2.4.2.2.1-3
14.3.1.2.1-3
14.3.1.4.1-2
14.2.1.1.3.1-2
14.2.4.1.2.1-2
6.1.1 Demographic Variables
Sex (Male, Female)
d
d
d
Race (AMERICAN INDIAN OR ALASKA NATIVE, ASIAN(JAPANESE, NON-JAPANESE), BLACK
OR AFRICAN AMERICAN, NATIVE HAWAIIAN OR OTHER PACIFIC ISLANDER, WHITE,
MULTIPLE)
Age (years)
c
Age (years)(20-29, 30-39, 40-49, 50-59, 60-64, 65<=)
Age (years)(20-50, 51<=)
d
Age (years)(20-64, 65<=)
d
d
Height(cm)
Body weight (kg) (at the start of the screening period)
c
BMI (kg/m2) (at the start of the screening period)
c
6.1.2 Other Factors
Age at the onset of depression (year)
c
Period from onset of depression (month)
c
Number of depressive episodes (times)
c
Number of depressive episodes (times)(1, 2<=, unspecified)
d
Duration of current depressive episode (month)
c
Duration of current depressive episode (month)(<6, 6 - <12, 12-18)
d
Presence/absence of prior treatment with antidepressant drugs for current and past depressive episodes (No,
Yes)
d
d
Presence/absence of concomitant use of hypnotic/sedative drugs and narcoleptics (within 2 months before the
initial registration) (No, Yes)
d
d
Presence/absence of a history of treatment with antianxiety drug (within 2 months before the initial
registration) (No, Yes)
d
d
Presence or absence of comorbidities (No, Yes)
6.1.3 Baseline
Total MADRS score (baseline)
Total MADRS score (baseline)(<=30, 31<=)
d
Total HAMD17 score (baseline)
CGI-S (baseline)
Total QIDS16-SR-J score (baseline)
Total SDS score (baseline)
6.2.1 Extent of Exposure to the investigational drug
Duration of exposure of the investigational drug (days) (treatment period)
Duration of exposure of the investigational drug (days) (treatment period)(1-7, 8-14, 15-28, 29-42, 43-56,
57<=)
Compliance rate of the investigational drug (%) (treatment period)
Compliance rate of the investigational drug (%) (treatment period)(<75%, 75%<=)
Total exposure of the investigational drug (mg) (treatment period)
Subgroup
Analysis


 
Appendix 2：sample SAS Program 
Notes 
In principle, variable names in the program below confirm to CDISC ADaM standard. Parts of 
program that are unrelated to the analysis algorithm, such as processing and sorting of the data set 
and outputting to the TLFs, are omitted. 
The dataset structure, variable names, populated value, etc. may differ from the actual analysis 
dataset. 
 
 Table 14.2.1.1.1.1 MMRM Analysis of Change in total MADRS score from baseline (OC) 
(FAS) 
*Program for comparison only at Week 8 is shown below. 
 
 
*-TRT02PN：Treatment grp(1: 50mg grp, 2： 100 mg grp, 3： Placebo grp); 
proc mixed data=ADEFF; 
where PARAMCD="MADRSTOT" and AVISITN in(1,2,4,6,8) and FASFL="Y" and 
DTYPE="OC"; 
class TRT02PN AVISITN USUBJID; 
model CHG=BASE AVISITN TRT02PN TRT02PN*AVISITN/ddfm=kr; 
lsmeans TRT02PN*AVISITN; 
estimate "MD-120 50 mg grp – Placebo grp at Week 8" 
TRT02PN*AVISITN 
0 0 0 0 1 
0 0 0 0 0 
0 0 0 0 -1  
TRT02PN 1 0 -1/ cl; 
estimate "MD-120 100 mg grp – Placebo grp at Week 8" 
TRT02PN*AVISITN 
0 0 0 0 0 
0 0 0 0 1 
0 0 0 0 -1  
TRT02PN 0 1 -1/ cl; 
repeated AVISITN/subject=USUBJID type=un; 
run;quit; 


 
 Table 14.2.1.1.2.1 Tipping Point Analysis of Change in total MADRS score from baseline 
(OC) (Week 8) (FAS) 
*-step 1：Imputing non-monotone missing values; 
*-tr_MADRS：transposed dataset as 1 observation for each subject; 
proc mi data=tr_MADRS seed=2970 nimpute=10 out=tr_MADRS_mono; 
 
by TRT02PN; 
 
mcmc impute=monotone; 
 
var v1 v2 v4 v6 v8; *-v1 v2 v4 v6 v8：total MADRS score at each timepoint; 
run; 
 
*-create flag variables for identifying monotone missing values 
*-v1miss： (1：missing、0：observed); 
data tr_MADRS_mono; 
 
set tr_MADRS_mono; 
 
if v1=. then v1miss=1; else v1miss=0; 
 
if v2=. then v2miss=1; else v2miss=0; 
 
if v4=. then v4miss=1; else v4miss=0; 
 
if v6=. then v6miss=1; else v6miss=0; 
 
if v8=. then v8miss=1; else v8miss=0; 
run; 
 
%macro tpa(sp); 
 
*-Specifying sensitivity parameter (&sp.) from 0 to 5; 
%do sp=0 %to 5; 
 
*-step 2-1：Imputing monotone missing values; 
proc mi data=tr_MADRS_mono seed=8229 nimpute=1 out=tr_MADRS_imp; 
 
class TRT02PN; 
 
monotone reg(/detail); 
 
var TRT02PN v0 v1 v2 v4 v6 v8; 
run; 
 
*-step 2-2：add sensitivity parameter to the imputed value; 
data tr_MADRS_adj; 
 
set tr_MADRS_imp; 
 
if v1miss=1 then v1=v1+&sp.; 
 
if v2miss=1 then v2=v2+&sp.; 
 
if v4miss=1 then v4=v4+&sp.; 
 
if v6miss=1 then v6=v6+&sp.; 
 
if v8miss=1 then v8=v8+&sp.; 
run; 
 
*-Converting transposed dataset into Basic Data Structure and calculating change 
in total MADRS score (the program is omitted); 


 
 
 
*-step 3：Applying the same MMRM model as the Primary Analysis ; 
ods output Estimates=tpa_diff01; 
proc mixed data=ADEFF_tpa; 
 
by _Imputation_; 
 
class TRT02PN AVISITN USUBJID; 
 
model CHG=BASE AVISITN TRT02PN TRT02PN*AVISITN/ddfm=kr; 
 
lsmeans TRT02PN*AVISITN; 
estimate "MD-120 50 mg grp – Placebo grp at Week 8" 
TRT02PN*AVISITN 
0 0 0 0 1 
0 0 0 0 0 
0 0 0 0 -1  
TRT02PN 1 0 -1/ cl; 
estimate "MD-120 100 mg grp – Placebo grp at Week 8" 
TRT02PN*AVISITN 
0 0 0 0 0 
0 0 0 0 1 
0 0 0 0 -1  
TRT02PN 0 1 -1/ cl; 
 
repeated AVISITN/subject=USUBJID type=un; 
run;quit; 
 
proc sort data=tpa_diff01; 
 
by Label; 
run; 
 
*-step 3：Combining estimates of adjusted mean differences; 
proc mianalyze data=tpa_diff01; 
by Label; 
 modeleffects Estimate; 
stderr StdErr; 
run; 
%end; 
%mend; 
 
%tpa; 


Statistical Analysis Plan: Revision History (A Placebo-controlled Study of MD-120 in Depression Patients)
Date of change
Version
Person who
changed
Change
No.
Section
Changes and Reasons
2022/9/14
Ver1.0 → ver2.0
※
1
1 Study Director and Team
Changed people responsible
The study director and the Person Responsible for Data Management were changed.
[Reason] Responding to changes in the person responsible for the preparation of the SAP.
2
2.6.2 Sample Size Rationale
Corrected minor error
Hypothesis 1/Hypothesis 2 was added.
[Reason] To correct omissions from the protocol.
3
4.2.2 Data Sets Obtained on or after
Unblinding
Corrected minor error
The section name in 4.2.2 was changed from "Data Sets Obtained after Unblinding" to "Data Sets Obtained on
or after Unblinding".
[Reason] To correct minor errors.
4
6.1 Background Factors
6.2 Covariates measured after
randomization
Corrected minor error
The unit was replaced before the assessment time point.
[Reason] To correct minor errors.
5
6.2.1 Extent of Exposure to the
investigational drug
Appendix 1
Removed analysis
"Number of days of the investigational drug administration" was deleted.
[Reason] It couldn't be identified from the CRF.
6
6.2.1 Extent of Exposure to the
investigational drug
Changed derivation
The derivation for "compliance rate of the investigational drug" and "total exposure of the investigational
drug" were changed.
[Reason] In conjunction with the data collection methods of this study.
Unless otherwise noted, the section numbers given in the main text shall be the most recent version (ver2.0).


Statistical Analysis Plan: Revision History (A Placebo-controlled Study of MD-120 in Depression Patients)
Date of change
Version
Person who
changed
Change
No.
Section
Changes and Reasons
7
7.1.15 Total SDS score
Changed definition
The following rule was added to "(1) Definition of a formula or derivation".
・If “I have not worked/studied at all during the past week for reasons unrelated to the disorder” is selected,
total SDS score will be handled as a missing value
[Reason] To consider for use in CSR.
8
7.1.17 SDS subscale
7.1.18 Change in SDS subscale from
baseline
Added endpoint
SDS subscales and their changes from baseline were added to endpoints.
[Reason] To consider for use in CSR.
9
7.2.2 Timing of withdrawal of
treatment
Added category of endpoint
"Not administered" was added to the category of "Timing of withdrawal of treatment."
[Reason] To consider for use in CSR.
10
7.3.4 Adverse Events Resulting in
Treatment Interrupted
Added endpoint
"Adverse Events Resulting in Treatment Interrupted" was added.
[Reason] To consider for use in CSR.
11
7.3.5 Common Adverse Events
Changed definition of endpoint
The definition was changed as follows.
(Before change) Adverse events (PT) that occurred in 5% or more of either group during the treatment and
follow-up periods
(After change) Adverse events (PT) that occurred in 5% or more of either group during the aggregation
period
[Reason] To consider for use in CSR.
12
7.5 Vital signs and body weight
Added analysis
For measured values and changes in vital signs and body weight, the assessment at Week 1 of the follow-up
period was added.
[Reason] To consider for use in CSR.


Statistical Analysis Plan: Revision History (A Placebo-controlled Study of MD-120 in Depression Patients)
Date of change
Version
Person who
changed
Change
No.
Section
Changes and Reasons
13
7.8.1 Plasma desvenlafaxine
concentration (ng/mL)
Changed analysis method
The handling for values below the lower limit of quantification was changed from "handled as missing" to
"handled as 0."
[Reason] To consider for use in CSR.
Corrected minor error
Unit (ng/mL) were added to the section title.
[Reason] To correct omissions.
14
9.2.1 LOCF method
Changed analysis method
The target of LOCF imputation was changed as follows.
The value used to LOCF imputation will include ...
(Before change) all data that meet the data adoption conditions from the date of the first dose of the
investigational drug in the treatment period ( not included on the same day ), regardless of whether or not
they are included in the data adoption period.
(After change) all data that meet the data adoption conditions from the date of the first dose of the
investigational drug in the treatment period ( including the same day ), regardless of whether or not they are
included in the data adoption period.
[Reason] To ensure consistency with the protocol and the handling plan.
15
14.1.1.1. Disposition of Subjects
14.1.1.4. Structure of Safety Analysis
Populations
Changed analysis method
In "Table 14.1.1.1.1 Disposition of Subjects in the Study (1st enrolled subjects)", the tabulation of
"discontinued screening period" was added. In addition, the tabulation of "discontinued follow-up period" was
divided into (Before Week 1 visit) and (After Week 1 visit).
In Table 14.1.1.4.1 Structure of Safety Analysis Population (2nd enrolled subjects), the tabulation of
"Randomized subjects" was added.
[Reason] To consider for use in CSR.


Statistical Analysis Plan: Revision History (A Placebo-controlled Study of MD-120 in Depression Patients)
Date of change
Version
Person who
changed
Change
No.
Section
Changes and Reasons
16
14.2.2.1.1. GEE analysis of response
evaluated by total MADRS score
14.2.2.1.2. Logistic regression of
response evaluated by total MADRS
score
Added annotation
In the statistics to be calculated, a sentence "※If at least one of the two groups being compared has no
response cases, these statistics are not calculated." was added.
[Reason] To consider the situation in which the estimation is impossible.
17
14.2.7.1.1. MMRM Analysis of CGI-I Deleted analysis
The analysis of the change from baseline in CGI-I was deleted.
[Reason] It couldn't be calculated.
18
14.2.11.1.1. MMRM Analysis of
Change in total SDS score from
baseline
14.2.11.1.2. ANCOVA Analysis of
Change in total SDS score from
baseline
14.2.11.2.1. Descriptive Statistics of
total SDS score and Change in total
SDS score from baseline
Added analysis
An analysis of SDS subscale was added.
[Reason] To consider for use in CSR.
19
14.3.1.6. Summary of Adverse Events
by SOC and PT by timing of
occurrence
Changed analysis
The reference date used to derive the number of days to completion of follow-up was changed from "date of
the first dose of the investigational drug in treatment period" to "date of the first dose of the investigational
drug in treatment period or follow-up period."
[Reason] To perform the tabulation according to the onset time in the follow-up period.
20
14.3.1.7. Common Adverse Events
Added analysis
Difference in incidence rates (3 ways) and two-sided 95% CI were added to Calculated statistics.
Table 14.3.1.7.5 Summary of Common Adverse Events by PT (Follow-up period) (SAF in Follow-up period)
was added.
[Reason] To consider for use in CSR.


Statistical Analysis Plan: Revision History (A Placebo-controlled Study of MD-120 in Depression Patients)
Date of change
Version
Person who
changed
Change
No.
Section
Changes and Reasons
21
14.3.1.8. Notable Adverse Events
Added analysis
Difference in incidence rates (3 ways) and their two-sided 95 CI were added to Calculated statistics.
[Reason] To consider for use in CSR.
22
14.3.2 Deaths, Other Serious Adverse
Events, and Other Significant Adverse
Events
14.3.2.3. Adverse Events Resulting in
Treatment Withdrawal
Changed analysis title
The analysis title was changed as follows.
<Not applicable for the english version of SAP>
[Reason] To consider for use in CSR.
23
14.3.2.4. Adverse Events Resulting in
Treatment Interrupted
Added analysis
The following analysis was added.
Table 14.3.2.4.1 Listing of Adverse Events Resulting in Treatment Interrupted
Table 14.3.2.4.2 Summary of Adverse Events Resulting in Treatment Interrupted by SOC and PT (Treatment
period) (SAF)
[Reason] To consider for use in CSR.
24
14.3.4.2. Laboratory Abnormalities
Corrected minor error
The analysis method of "Table 14.3.4.2.1 Shift Table of Laboratory Abnormalities (SAF)" was changed as
follows.
(Before change) Column variables: Minimum and maximum values after administration
(After change) Column variables: Minimum and maximum values after administration in the treatment period
[Reason] To clarify the analysis method.
25
14.3.6.1. Summary of 12-lead ECG
Abnormalities
Added analysis
For Table 14.3.6.1.1 Summary of 12-lead ECG Abnormalities (SAF), Fisher exact test was added.
[Reason] To correct omissions.


Statistical Analysis Plan: Revision History (A Placebo-controlled Study of MD-120 in Depression Patients)
Date of change
Version
Person who
changed
Change
No.
Section
Changes and Reasons
26
14.3.7.1. Summary of C-SSRS
Corrected minor error
The analysis method was changed as follows.
(Before change) The number of subjects who became "yes" at least once after administration is totaled.
(After change) The number of subjects who became "yes" at least once after administration in the treatment
period  is totaled.
[Reason] To clarify the analysis method.
27
14.3.7.2. Shift Table of C-SSRS
Corrected minor error
The analysis method was changed as follows.
(Before change) The evaluation shall be "yes" if it becomes "yes" at least once after administration.
(After change) The evaluation shall be "yes" if it becomes "yes" at least once after administration in the
treatment period .
[Reason] To clarify the analysis method.
28
14.3.8.1. Summary of Concomitant
Drugs
Added analysis
The following analysis was added.
Table 14.3.8.1.1 Summary of Concomitant Drugs ( SAF)
[Reason] To consider for use in CSR.
29
Other minor changes were made.