Conditions: Major Depressive Disorder
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 248
Healthy volunteers: no

Brief summary:
This trial is a 52-week study to assess the safety of long-term use of brexpiprazole as adjunctive therapy in combination with an antidepressant.

Detailed description:

Arms:
arm 1: 2 mg/day (starting dose 1mg/day) of Brexpiprazole will be orally administered once daily

Interventions: intervention 1: Brexpiprazole
Intervention descriptions: intervention 1: 2 mg/day (starting dose 1mg/day) of Brexpiprazole will be orally administered once daily

Protocol document:
Prot_000.pdf: 
 
 
CLINICAL STUDY PROTOCOL 
 
 
 
A multi-center, open-label trial to assess the long-term safety and efficacy of 
brexpiprazole as adjunctive therapy in patients with major depressive disorder 
 
 
 
 
 
NCT Number: NCT03737474 
PRT NO.: 331-102-00059 
Version Date: 23 Jan 2020 (Version 3.0) 


Protocol 331-102-00059 
Confidential - Proprietary Information 
1 
Protocol Version 3.0, 23 Jan 2020 
Otsuka Pharmaceutical Co., Ltd. 
 
Investigational Medicinal Product 
Brexpiprazole 
 
CLINICAL PROTOCOL 
 
A multi-center, open-label trial to assess the long-term safety and efficacy of 
brexpiprazole as adjunctive therapy in patients with major depressive disorder 
 
Protocol No. 331-102-00059 
 
CONFIDENTIAL – PROPRIETARY INFORMATION 
 
Clinical Development Phase:  
3 
 
Sponsor: 
Otsuka Pharmaceutical Co., Ltd. 
 
Immediately Reportable Event: 
Office of Pharmacovigilance Operations, 
Department of Pharmacovigilance,  
Otsuka Pharmaceutical Co., Ltd. 
e-mail address: IRE_331-102-00059@otsuka.jp 
3-2-27, Otedori, Chuo-ku, Osaka, 540-0021, Japan 
 
 
Issue Date: 
23 May 2018 
Amendment 1: 
23 Oct 2018  
Amendment 2: 
23 Jan 2020 
Version No.: 
3.0 


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Protocol Version 3.0, 23 Jan 2020 
Protocol Synopsis 
Name of Sponsor: Otsuka Pharmaceutical 
Co., Ltd. 
Name of Investigational Medicinal Product: 
Brexpiprazole (OPC-34712) 
Protocol No.: 331-102-00059 
 
Protocol Title: 
A multi-center, open-label trial to assess the long-term safety and 
efficacy of brexpiprazole as adjunctive therapy in patients with major 
depressive disorder 
Clinical Phase/ 
Type of Trial: 
Phase 3 
Long-term trial 
Treatment 
Indication: 
Patients with major depressive disorder ("major depressive disorder, 
single episode" or "major depressive disorder, recurrent episode") 
according to the classification criteria of the Diagnostic and 
Statistical Manual of Mental Disorders, fifth edition (DSM-5®) 
Objectives: 
To assess the safety and efficacy of the long-term use of 
brexpiprazole as adjunctive therapy in combination with a 
commercially available antidepressant (selective serotonin reuptake 
inhibitor [SSRI] or serotonin-noradrenaline reuptake inhibitor [SNRI] 
for rollover subjects and SSRI, SNRI, or mirtazapine for new 
subjects) in subjects with major depressive disorder who continue 
receiving the treatment from the double-blind trial (331-102-00058) 
and in newly enrolled patients 65 years or older with major 
depressive disorder. 
Trial Design: 
A multi-center, open-label trial 
Subject 
Population: 
Target subjects will be those continuing on from the double-blind 
trial (331-102-00058) and newly recruited patients 65 years of age or 
older whose condition corresponds to major depressive disorder. 
The target number of subjects to complete 52 weeks of 
administration was set at 100 subjects and the sample size needed to 
assess the safety of brexpiprazole in the elderly was set as 30 subjects 
receiving IMP administration. 
Inclusion/Exclusi
on Criteria: 
Inclusion criteria 
Rollover subjects 
1) Outpatients 
2) Subjects who have completed the double-blind period (Phase 
B) of the double-blind trial (331-102-00058) and can 
commence the treatment period of this trial within 28 days 
from Week 6 of the double-blind period (Phase B) of the 
double-blind trial (331-102-00058) 
3) Subjects who have a level of comprehension sufficient to 
allow them to give written informed consent to all of the 
observation/examination/evaluation items specified in the 
protocol, and who can understand the contents of the trial 
4) Subjects with a DSM-5 classification-based diagnosis of 


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Protocol Version 3.0, 23 Jan 2020 
"major depressive disorder, single episode" or "major 
depressive disorder, recurrent episode" 
New subjects 
5) Outpatients 
6) Male and female patients ≥ 65 years of age (at the time of 
informed consent) 
7) Subjects who have a level of comprehension sufficient to 
allow them to give written informed consent to all of the 
observation/examination/evaluation items specified in the 
protocol, and who can understand the contents of the trial 
8) Patients with a DSM-5 classification-based diagnosis of 
"major depressive disorder, single episode" or "major 
depressive disorder, recurrent episode" whose current episode 
has persisted for at least 8 weeks 
9) Patients who have received 1 to 3 adequate antidepressant 
drug treatments for the current major depressive episode and 
whose response to all of the treatments has been inadequate. 
Definitions of "adequate antidepressant drug treatments" and 
"inadequate response" are provided below. 
Adequate antidepressant drug treatment: 
Treatment with an antidepressant at an approved dose for at 
least 6 weeks (for combination therapy, treatment for at least 
3 weeks) 
Inadequate response: 
With complete recovery from depressive symptoms and not 
the slightest improvement considered as 100% and 0%, 
respectively, patients carry out self-evaluations for 
improvement by antidepressant drug treatments used to date, 
from among 4 grades (< 25% Improvement, 25% to 49% 
Improvement, 50% to < 75% Improvement, and ≥ 75% 
Improvement), with the evaluations corresponding to < 25% 
Improvement or 25% to 49% Improvement classified as 
inadequate response. 
Patients who, among 1 to 3 adequate antidepressant drug 
treatments, have received treatment for ≥ 6 weeks at least 
once (receiving only combination therapies for ≥ 3 weeks 
does not qualify) are eligible for selection. 
10) Patients undergoing treatment with SSRI, SNRI, or 
mirtazapine at the time of informed consent 
Exclusion criteria 
Rollover subjects 
1) Female subjects who are pregnant or breastfeeding or who 
have positive pregnancy test (urine) results at baseline 
2) Sexually active male subjects or sexually active female 
subjects of childbearing potential, who will not agree to 


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practice 2 different methods of birth control or to remain 
abstinent during the trial and for 30 days after the final IMP 
administration. For birth control, 2 of the following methods 
must be used: vasectomy, tubal ligation, vaginal diaphragm, 
intra-uterine contraceptive device (IUD), oral contraceptives, 
or condom with spermicide. 
3) Subjects who experience a change to the manic state in the 
antidepressant treatment period (Phase A) of the double-blind 
trial (331-102-00058) 
4) Subjects who are discovered to not meet the inclusion criteria 
or to fall under any of the exclusion criteria in the double-
blind trial (331-102-00058) 
5) Subjects who showed marked noncompliance with the IMP 
treatment in the double-blind trial (331-102-00058) (subjects 
whose IMP compliance rates are < 65% between prescribed 
visits) 
6) Subjects receiving treatment with antipsychotics and 
psychostimulants for current major depressive episode 
(excluding the use of IMP in the double-blind trial [331-102-
00058] and use of sulpiride for depression/depressive state or 
gastric/duodenal ulcer) 
7) Subjects receiving treatment with monoamine oxidase 
inhibitors (MAO inhibitors) within 2 weeks before baseline 
8) Subjects using benzodiazepines (excluding ultrashort-acting 
sleep inducers) within 1 week before baseline 
9) Subjects hospitalized for the current major depressive episode 
after the antidepressant treatment period (Phase A) of the 
double-blind trial (331-102-00058) 
10) Subjects with a history of electroconvulsive therapy 
11) Subjects with a diagnosis of any of the following diseases 
according to DSM-5 
a) Neurocognitive disorders 
b) Schizophrenia spectrum and other psychotic disorders 
c) Bipolar and related disorders 
d) Feeding and eating disorders 
e) Obsessive-compulsive disorder 
f) Panic disorder 
g) Posttraumatic stress disorder 
12) Subjects with a diagnosis of any personality disorders 
(borderline personality disorder, antisocial personality 
disorder, paranoid personality disorder, schizoid personality 
disorder, schizotypal personality disorder, histrionic 


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personality disorder) according to DSM-5 
13) Subjects experiencing hallucinations or delusions, or showing 
mood-incongruent psychotic features, in the current major 
depressive episode 
14) Subjects with a Montgomery Åsberg Depression Rating Scale 
(MADRS) score of ≥ 5 for Item 10. Suicide, a Hamilton 
Rating Scale for Depression (HAM-D) score for suicide (No. 
11) of ≥ 3, those answering "Yes" to question 4 or 5 of the 
Columbia-Suicide Severity Rating Scale (C-SSRS) at 
baseline, or those who are, based on current psychiatric 
symptoms or past medical history, at high risk of suicide 
during the trial in the opinion of the investigator or 
subinvestigator 
15) Subjects with clinically significant neurological, hepatic, 
renal, metabolic, hematological, immunological, 
cardiovascular, pulmonary, or gastrointestinal disorders; 
subjects can be enrolled if the conditions are mild or well 
controlled and will not hamper assessment of safety and 
efficacy. 
16) Patients meeting any of the following criteria 
• Patients with type 1 diabetes mellitus or patients with type 2 
diabetes mellitus being treated with insulin 
• Patients with type 2 diabetes mellitus who have not been 
maintained on a stable regimen of anti-diabetic medication(s) 
or undergone diet/exercise therapy for at least 28 days prior to 
baseline 
• Patients meeting either of the following criteria for poor 
blood glucose control at Week 6 of the double-blind period 
(Phase B) of the double-blind trial (331-102-00058) 
a) Glycosylated hemoglobin (HbA1c) of ≥ 7.0% according 
to the global standard value [NGSP value] 
b) Fasting blood glucose level of ≥ 126 mg/dL or nonfasting 
blood glucose level of ≥ 200 mg/dL 
17) Subjects with substance abuse or substance dependence, 
including alcohol and benzodiazepines, based on DSM-5 
diagnostic criteria within 180 days prior to informed consent; 
caffeine and nicotine are not included. 
18) Subjects with a complication of hypothyroidism or 
hyperthyroidism at informed consent (excluding those in a 
stable condition due to medications for the previous 90 days 
or longer), or abnormal thyroid stimulating hormone (TSH) 
and free thyroxine (FT4) levels at Week 6 of the double-blind 
period (Phase B) of the double-blind trial (331-102-00058) 
(assessed based on results from the central laboratory) 


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19) Subjects meeting any of the following criteria or showing 
symptoms at baseline 
a) Poorly controlled hypertension (diastolic blood pressure 
of > 95 mmHg) 
b) Hypotension with symptoms 
c) Orthostatic hypotension in which blood pressure after 
3 minutes of standing is ≥ 30 mmHg lower for systolic 
blood pressure or ≥ 20 mmHg lower for diastolic blood 
pressure, compared with pressures in the supine position 
before standing 
20) Subjects with a complication of ischemic heart diseases, 
myocardial infarction, or congestive heart failure (irrespective 
of well or poorly controlled), or subjects with a history of 
angioplasty, stent placement, or coronary artery bypass 
21) Subjects with a history of neuroleptic malignant syndrome or 
serotonin syndrome 
22) Subjects with a history or complication of epilepsy or 
epileptic seizures, excluding pediatric febrile seizures, post-
traumatic seizures, alcohol withdrawal seizures, and other 
seizures 
23) Subjects with a history of hypersensitivity to antidepressants 
24) Subjects with the following clinical laboratory test values or 
electrocardiogram (ECG) parameters at Week 6 of the 
double-blind period (Phase B) of the double-blind trial (331-
102-00058) (assessed based on results from the central 
laboratory and central ECG measurement facility) 
a) Platelet count: ≤ 75,000 /mm3 
b) Hemoglobin: ≤ 9 g/dL 
c) Absolute neutrophil count: ≤ 1000 /mm3 
d) Aspartate aminotransferase (AST): > 2 times the upper 
limit of the reference range 
e) Alanine aminotransferase (ALT): > 2 times the upper 
limit of the reference range 
f) Creatine phosphokinase (CPK): > 3 times the upper limit 
of the reference range 
g) Creatinine: ≥ 2 mg/dL 
h) QT interval as corrected by Fridericia’s formula (QTcF): 
≥ 450 msec 
25) Subjects with a history or complication of allergy to more 
than one medication 
26) The following subjects falling under the contraindications in 
the package insert for brexpiprazole tablet 


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a) Subjects in a coma 
b) Subjects under the strong influence of central nervous 
system depressants including barbiturate 
analogs/anesthetics 
c) Subjects receiving adrenaline 
d) Subjects with a history of hypersensitivity to components 
of brexpiprazole tablet 
27) Subjects who otherwise should not participate in the trial in 
the opinion of the investigator or subinvestigator 
New subjects 
28) Sexually active male subjects who will not agree to practice 2 
different methods of birth control or to remain abstinent 
during the trial and for 30 days after the final IMP 
administration. For birth control, 2 of the following methods 
must be used: vasectomy, tubal ligation, vaginal diaphragm, 
intra-uterine contraceptive device (IUD), oral contraceptives, 
or condom with spermicide. 
29) Patients who have received at least 4 appropriate 
antidepressant drug treatments for the current major 
depressive episode but whose response was inadequate to all 
treatments 
30) Patients receiving treatment with antipsychotics and 
psychostimulants for the current major depressive episode 
(excluding the use of sulpiride for depression/depressive state 
or gastric/duodenal ulcer) 
31) Patients receiving treatment with MAO inhibitors within 2 
weeks before baseline 
32) Patients using benzodiazepines (excluding ultrashort-acting 
sleep inducers) within 1 week before baseline 
33) Patients with a treatment history showing that all 
antidepressants (also including those not used for the current 
major depressive episode) cannot be tolerated 
34) Patients with a history of electroconvulsive therapy 
35) Patients with a diagnosis of any of the following diseases 
according to DSM-5 
a) Neurocognitive disorders 
b) Schizophrenia spectrum and other psychotic disorders 
c) Bipolar and related disorders 
d) Feeding and eating disorders 
e) Obsessive-compulsive disorder 
f) Panic disorder 
g) Posttraumatic stress disorder 


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36) Patients with a diagnosis of any personality disorders 
(borderline personality disorder, antisocial personality 
disorder, paranoid personality disorder, schizoid personality 
disorder, schizotypal personality disorder, and histrionic 
personality disorder) according to DSM-5 
37) Patients experiencing hallucinations or delusions, or showing 
mood-incongruent psychotic features, in the current major 
depressive episode 
38) Patients receiving a new psychotherapy within 6 weeks prior 
to informed consent 
39) Patients who have previously taken brexpiprazole 
40) Patients who have participated in other clinical trials within 
60 days prior to informed consent 
41) Patients answering "Yes" to question 4 or 5 of C-SSRS at 
screening or baseline, or those who are, based on current 
psychiatric symptoms or past medical history, at high risk of 
suicide during the trial in the opinion of the investigator or 
subinvestigator 
42) Patients with clinically significant neurological, hepatic, 
renal, metabolic, hematological, immunological, 
cardiovascular, pulmonary, or gastrointestinal disorders; 
patients can be enrolled if the conditions are mild or well 
controlled and will not hamper assessment of safety and 
efficacy. 
43) Patients meeting any of the following criteria 
• Patients with type 1 diabetes mellitus or patients with type 2 
diabetes mellitus being treated with insulin 
• Patients with type 2 diabetes mellitus who have not been 
maintained on a stable regimen of anti-diabetic medication(s) 
or undergone diet/exercise therapy for at least 28 days prior to 
screening 
• Patients meeting either of the following criteria for poor 
blood glucose control at screening (assessed based on results 
from the central laboratory) 
a) HbA1c of ≥ 8.0% according to the global standard value 
[NGSP value] 
b) Fasting blood glucose level of ≥ 126 mg/dL or non-fasting 
blood glucose level of ≥ 200 mg/dL 
44) Patients with substance abuse or substance dependence, 
including alcohol and benzodiazepines, based on DSM-5 
diagnostic criteria within 180 days prior to informed consent; 
caffeine and nicotine are not included 
45) Patients with a complication of hypothyroidism or 


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hyperthyroidism at informed consent (excluding those in a 
stable condition due to medications for the previous 90 days 
or longer since acquisition of informed consent), or abnormal 
TSH and FT4 levels at screening (assessed based on results 
from the central laboratory) 
46) Patients meeting any of the following criteria or showing 
symptoms at screening or baseline 
a) Poorly controlled hypertension (diastolic blood pressure 
of > 95 mmHg) 
b) Hypotension with symptoms 
c) Orthostatic hypotension in which blood pressure after 3 
minutes of standing is ≥ 30 mmHg lower for systolic 
blood pressure or ≥ 20 mmHg lower for diastolic blood 
pressure, compared with pressures in the supine position 
before standing 
47) Patients with a complication of ischemic heart disease, 
myocardial infarction, or congestive heart failure (irrespective 
of well or poorly controlled), or patients with a history of 
angioplasty, stent placement, or coronary artery bypass 
48) Patients with a history of neuroleptic malignant syndrome or 
serotonin syndrome 
49) Patients with a history or complication of epilepsy or epileptic 
seizures, excluding pediatric febrile seizures, post-traumatic 
seizures, alcohol withdrawal seizures, and other seizures 
50) Patients with the following clinical laboratory test values or 
ECG parameters at screening (assessed based on results from 
the central laboratory and central ECG measurement facility) 
a) Platelet count: ≤ 75,000 /mm3 
b) Hemoglobin: ≤ 9 g/dL 
c) Absolute neutrophil count: ≤ 1000 /mm3 
d) AST: > 2 times the upper limit of the reference range 
e) ALT: > 2 times the upper limit of the reference range 
f) CPK: > 3 times the upper limit of the reference range 
g) Creatinine: ≥ 2 mg/dL 
h) QTcF: ≥ 450 msec 
51) Patients with a history of hypersensitivity to antidepressants 
52) Patients with a history or complication of allergy to more than 
one medication 
53) The following patients falling under the contraindications in 
the package insert for brexpiprazole tablet 
a) Patients in a coma 


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b) Patients under the strong influence of central nervous 
system depressants including barbiturate 
analogs/anesthetics 
c) Patients receiving adrenaline 
d) Patients with a history of hypersensitivity to components 
of brexpiprazole tablet 
54) Patients who otherwise should not participate in the trial in 
the opinion of the investigator or subinvestigator 
Trial Sites: 
170 sites within Japan 
Investigational 
Medicinal 
Products, Dose, 
Dosage Regimen, 
Treatment Period, 
Formulation, 
Mode of 
Administration: 
Treatment period 
1) Drugs, doses, and regimens: 
• Commercially available antidepressant 
For rollover subjects, an antidepressant (SSRI or SNRI) used 
in the double-blind trial (331-102-00058) will continue to be 
used throughout the treatment period, with no changes from 
the final dose and regimen. For new subjects, an 
antidepressant (SSRI, SNRI, or mirtazapine) being used at the 
time of informed consent will continue to be used throughout 
the treatment period, with no changes from the dose and 
regimen at the time of informed consent. 
During the treatment period, dose adjustment within the 
approved dose range is allowed according to the judgement of 
the investigator or subinvestigator, but the dose may not be 
altered at the time of dose escalation of brexpiprazole at 
Week 1. 
• Brexpiprazole 
Administration of brexpiprazole will commence at 1 mg/day 
and subjects will continue to receive a single brexpiprazole 
1 mg tablet once daily by the oral route until the observations, 
examinations, and evaluations at Week 1. Following the 
observations, examinations, and evaluations performed at 
Week 1, subjects will be administered a single brexpiprazole 
2 mg tablet once daily by the oral route. Subjects who cannot 
tolerate doses of 2 mg/day will be withdrawn from the trial. 
2) Treatment period: 52 weeks 
Trial 
Assessments: 
Efficacy: 
MADRS, Clinical Global Impression — Improvement CGI-I, 
Clinical Global Impression — Severity of Illness (CGI-S), HAM-D, 
Sheehan Disability Scale (SDS) 
 
Other: 
EuroQol-5 Dimension 5-level (EQ-5D-5L) questionnaire 
 
Safety: 


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Adverse events, clinical laboratory tests, vital signs (body 
temperature, diastolic blood pressure and systolic blood pressure, and 
pulse rate [supine, sitting, and standing positions]), physical 
examinations, waist circumference, body weight, 12-lead ECG, 
pregnancy test, C-SSRS, Drug-Induced Extrapyramidal Symptom 
Scale (DIEPSS), Abnormal Involuntary Movement Scale (AIMS), 
Barnes Akathisia Rating Scale (BARS) 
 
Screening: 
Subject demographics, height 
 
Pharmacokinetic and Pharmacogenomic Assessments: 
DNA storage (optional) 
Criteria for 
Evaluation 
Safety Endpoints: 
Adverse events, clinical laboratory tests, vital signs (body 
temperature, diastolic blood pressure and systolic blood pressure and 
pulse rate [supine, sitting, and standing positions]), physical 
examination, waist circumference, 12-lead ECG, body weight, body 
mass index, C-SSRS, DIEPSS, AIMS, BARS 
 
Efficacy Endpoints: 
• Mean changes from baseline in MADRS total scores 
• MADRS response rate 
The proportion of subjects in whom MADRS total scores have 
been reduced by at least 50% from baseline 
• MADRS remission rate 
The proportion of subjects in whom MADRS total scores have 
been reduced by at least 50% from baseline, with their resultant 
MADRS total scores being ≤ 10 
• CGI-I improvement rate 
The proportion of subjects who score 1 or 2 on the CGI-I scale 
• Mean changes from baseline in CGI-S 
• Mean changes from baseline in HAM-D 17-item total score 
• Mean changes from baseline in mean SDS score 
 
Other Endpoints: 
EQ-5D-5L 
Statistical 
Methods: 
Safety analysis 
Incidences of treatment-emergent adverse events will be determined. 
Descriptive statistics of actual measurements at each assessment time 
point and the last assessment time point (Week 52 LOCF) as well as 
changes from baseline will be determined. 
 
Efficacy analysis 


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Descriptive statistics of actual measurements at each assessment time 
point and the last assessment time point (Week 52 LOCF) as well as 
changes from baseline will be determined. 
 
Rationale for target number of subjects 
To verify the safety of long-term administration, the target number of 
subjects to complete 52 weeks of administration was set at around 
100 subjects. Due to the availability of data on safety in elderly 
subjects from foreign clinical trials, the sample size needed to assess 
the safety of brexpiprazole in the elderly was set as 30 new subjects 
(elderly subjects of age 65 and above) receiving IMP administration. 
Trial Duration: 
01 Jun 2018 to 31 Jul 2022 
 


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Table of Contents 
Protocol Synopsis ........................................................................................... 2 
Table of Contents ......................................................................................... 13 
List of In-text Tables ................................................................................... 18 
List of In-text Figures .................................................................................. 19 
List of Appendices........................................................................................ 20 
List of Abbreviations and Definitions of Terms ....................................... 21 
1 
Introduction .......................................................................................................23 
1.1 
Nonclinical Data .............................................................................................25 
1.2 
Clinical Data ...................................................................................................27 
1.2.1 
Clinical Data From Japanese Trials in Subjects With Schizophrenia .........27 
1.2.1.1 
Dose-finding Trial in Subjects With Schizophrenia (331-10-002) .........27 
1.2.1.2 
Long-term Trial in Subjects With Schizophrenia (331-10-003) .............28 
1.2.2 
Clinical Data From Non-Japanese Trial in Subjects With Major 
Depressive Disorder ....................................................................................28 
1.2.2.1 
Confirmatory Trial in Subjects With Major Depressive Disorder 
(331-10-227) ............................................................................................28 
1.2.2.2 
Confirmatory Trial in Subjects With Major Depressive Disorder 
(331-10-228) ............................................................................................29 
1.2.2.3 
Confirmatory Trial in Subjects With Major Depressive Disorder 
(331-13-214) ............................................................................................30 
1.2.2.4 
Long-term Trial in Subjects With Major Depressive Disorder (331-
10-238) ....................................................................................................31 
1.2.2.5 
Long-term Trial in Elderly Subjects With Major Depressive 
Disorder (16160A) ...................................................................................31 
1.3 
Known and Potential Risks and Benefits........................................................32 
2 
Trial Rationale and Objectives ..........................................................................32 
2.1 
Trial Rationale ................................................................................................32 
2.2 
Rationale for DNA Storage ............................................................................34 
2.3 
Rationale for Dosing and Regimen .................................................................35 
2.3.1 
Rationale for Regimen ................................................................................35 
2.3.2 
Rationale for Dose.......................................................................................35 
2.3.2.1 
Rationale for Maintenance Dose .............................................................35 


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2.3.2.2 
Rationale for a Starting Dose of 1 mg/day ..............................................36 
2.4 
Trial Objectives ..............................................................................................36 
3 
Trial Design .......................................................................................................36 
3.1 
Type/Design of Trial .......................................................................................36 
3.2 
Trial Treatments ..............................................................................................38 
3.3 
Trial Population ..............................................................................................38 
3.3.1 
Number of Subjects and Trial Population ...................................................38 
3.3.2 
Subject Number Assignment ......................................................................39 
3.4 
Eligibility Criteria ...........................................................................................39 
3.4.1 
Informed Consent ........................................................................................39 
3.4.2 
Inclusion Criteria .........................................................................................40 
3.4.3 
Exclusion Criteria........................................................................................41 
3.5 
Endpoints ........................................................................................................47 
3.5.1 
Safety Endpoints .........................................................................................47 
3.5.2 
Efficacy Endpoints ......................................................................................47 
3.5.3 
Other Endpoints ..........................................................................................48 
3.6 
Measures to Minimize/Avoid Bias .................................................................48 
3.7 
Trial Procedures ..............................................................................................48 
3.7.1 
Schedule of Assessments ............................................................................51 
3.7.1.1 
Informed Consent ....................................................................................51 
3.7.1.2 
Screening (New Subjects Only) ..............................................................51 
3.7.1.3 
Observations/Examinations in the Treatment Period (52 Weeks) ..........52 
3.7.1.4 
Observations/Examinations in the Post-treatment Observation 
Period .......................................................................................................53 
3.7.1.5 
Examinations at Discontinuation .............................................................53 
3.7.1.6 
Acceptable Window for Testing ..............................................................53 
3.7.2 
Efficacy Assessments ..................................................................................54 
3.7.2.1 
Montgomery Åsberg Depression Rating Scale .......................................54 
3.7.2.2 
Clinical Global Impression - Improvement .............................................55 
3.7.2.3 
Clinical Global Impression - Severity of Illness .....................................55 
3.7.2.4 
Hamilton Rating Scale for Depression ....................................................55 
3.7.2.5 
Sheehan Disability Scale .........................................................................56 
3.7.3 
Other Assessments ......................................................................................56 


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3.7.3.1 
EuroQol-5 Dimension .............................................................................56 
3.7.4 
Safety Assessments .....................................................................................57 
3.7.4.1 
Adverse Events ........................................................................................57 
3.7.4.2 
Clinical Laboratory Assessments ............................................................57 
3.7.4.3 
Vital Signs and Physical Examination ....................................................58 
3.7.4.4 
12-Lead Electrocardiography ..................................................................60 
3.7.4.5 
Pregnancy Test ........................................................................................61 
3.7.4.6 
Columbia-Suicide Severity Rating Scale ................................................61 
3.7.4.7 
Drug-induced Extrapyramidal Symptoms Scale .....................................62 
3.7.4.8 
Abnormal Involuntary Movement Scale .................................................62 
3.7.4.9 
Barnes Akathisia Rating Scale ................................................................63 
3.7.5 
Prior and Concomitant Medications and Therapies ....................................63 
3.7.6 
Investigational Medicinal Product ..............................................................64 
3.7.7 
Requisite Concomitant Medication .............................................................65 
3.7.8 
Pharmacogenomic Assessments .................................................................65 
3.7.8.1 
DNA Storage (for New Subjects Only) ...................................................65 
3.7.8.1.1 
Objective of DNA Storage ...................................................................65 
3.7.8.1.2 
Target Subjects of DNA Storage .........................................................65 
3.7.8.1.3 
Timing of Blood Sampling ..................................................................65 
3.7.8.1.4 
Handling of Samples ............................................................................65 
3.7.8.1.5 
Genomic/Genetic Analysis ..................................................................65 
3.7.8.1.6 
Informed Consent for DNA Storage ....................................................66 
3.7.8.1.7 
Disclosure of Genomic/Genetic Analysis Results to Subjects ............66 
3.7.9 
End of Trial .................................................................................................67 
3.8 
Stopping Rules, Withdrawal Criteria, and Procedures ...................................67 
3.8.1 
Entire Trial ..................................................................................................67 
3.8.2 
Individual Site .............................................................................................67 
3.8.3 
Individual Subject Discontinuation .............................................................67 
3.8.3.1 
Treatment Discontinuation ......................................................................67 
3.8.3.2 
Documenting Reasons for Discontinuation .............................................67 
3.8.3.3 
Withdrawal of Consent ............................................................................69 
3.8.3.4 
Procedures to Encourage Continued Trial Participation .........................70 
3.9 
Screen Failures ................................................................................................70 


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3.10 
Definition of Completed Subjects ..................................................................71 
3.11 
Definition of Subjects Lost to Follow-up .......................................................71 
3.12 
Subject Compliance ........................................................................................71 
3.13 
Protocol Deviations ........................................................................................72 
4 
Restrictions ........................................................................................................72 
4.1 
Prohibited Concomitant Medications .............................................................72 
4.2 
Prohibited Concomitant Therapies .................................................................73 
4.3 
Restricted Concomitant Drugs ........................................................................73 
4.4 
Other Restrictions ...........................................................................................74 
5 
Reporting of Adverse Events ............................................................................76 
5.1 
Definitions ......................................................................................................76 
5.2 
Eliciting and Reporting Adverse Events .........................................................78 
5.3 
Immediately Reportable Events ......................................................................78 
5.4 
Potential Drug-induced Liver Injury ..............................................................79 
5.5 
Pregnancy .......................................................................................................79 
5.6 
Procedure for Breaking the Blind ...................................................................80 
5.7 
Follow-up of Adverse Events .........................................................................80 
5.7.1 
Follow-up of Nonserious Adverse Events ..................................................80 
5.7.2 
Follow-up of Serious Adverse Events and Immediately Reportable 
Events ..........................................................................................................81 
5.7.3 
Follow-up and Reporting of Serious Adverse Events and Immediately 
Reportable Events Occurring After the End of Trial Date (Final Day 
of Observation)............................................................................................81 
6 
Pharmacogenomic Analysis ..............................................................................81 
6.1 
Pharmacogenomic Methods ............................................................................81 
7 
Statistical Analysis ............................................................................................82 
7.1 
Sample Size ....................................................................................................82 
7.2 
Datasets for Analysis ......................................................................................82 
7.2.1 
Efficacy Analysis Set ..................................................................................82 
7.2.2 
Safety Analysis Set .....................................................................................82 
7.3 
Handling of Missing Data ...............................................................................82 
7.4 
Efficacy Endpoint Analysis ............................................................................83 
7.5 
Analysis of Other Endpoints ...........................................................................83 


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7.6 
Analysis of Demographic and Baseline Characteristics .................................83 
7.7 
Safety Analysis ...............................................................................................83 
7.7.1 
Adverse Events............................................................................................83 
7.7.2 
Clinical Laboratory Data .............................................................................84 
7.7.3 
Physical Examination and Vital Signs Data................................................84 
7.7.4 
Electrocardiogram Data ..............................................................................84 
7.7.5 
Other Safety Data ........................................................................................85 
8 
Management of Investigational Medicinal Product ..........................................85 
8.1 
Packaging and Labeling ..................................................................................85 
8.2 
Storage ............................................................................................................86 
8.3 
Accountability .................................................................................................86 
8.4 
Returns and Destruction .................................................................................86 
8.5 
Reporting of Product Quality Complaints ......................................................86 
8.5.1 
Eliciting and Reporting Product Quality Complaints .................................87 
8.5.2 
Information Required for Reporting Product Quality Complaints .............87 
8.5.3 
Return Process for Product Quality Complaints .........................................87 
8.5.4 
Assessment/Evaluation ...............................................................................87 
9 
Records Management ........................................................................................88 
9.1 
Source Documents ..........................................................................................88 
9.2 
Data Collection ...............................................................................................88 
9.3 
File Management at the Trial Site ..................................................................89 
9.4 
Record Retention at the Trial Site ..................................................................89 
10 
Quality Control and Quality Assurance ............................................................89 
10.1 
Monitoring ......................................................................................................89 
10.2 
Auditing ..........................................................................................................90 
11 
Ethics and Responsibility ..................................................................................90 
12 
Confidentiality ...................................................................................................90 
13 
Amendment Policy ............................................................................................91 
14 
Publication Authorship Requirements...............................................................91 
15 
References .........................................................................................................93 
 


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List of In-text Tables 
Table 3.4.2-1 
Inclusion Criteria .......................................................................... 40 
Table 3.4.3-1 
Exclusion Criteria ......................................................................... 42 
Table 3.7-1 
Schedule of Assessments .............................................................. 49 
Table 3.7.1.6-1 
Acceptable Window for Examinations/Assessment Period .......... 54 
Table 3.7.4.2-1 
Clinical Laboratory Assessments .................................................. 58 
 
 


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List of In-text Figures 
Figure 3.1-1 
Trial Design .................................................................................. 37 
 
 


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List of Appendices 
Appendix 1 
Handling and Shipping of Bioanalytical Samples ........................ 95 
Appendix 2 
Criteria for Allowing Concomitant Use of Topical CYP2D6 
Inhibitors, CYP3A4 Inhibitors, and CYP3A4 Inducers................ 96 
Appendix 3 
Protocol Amendments/Administrative Changes ........................... 99 
 
 


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List of Abbreviations and Definitions of Terms 
Abbreviation 
Definition 
5-HT 
5-Hydroxytryptamine 
AIMS 
Abnormal Involuntary Movement Scale 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
APTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
BARS 
Barnes Akathisia Rating Scale 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
CGI 
Clinical Global Impression 
CGI-I 
Clinical Global Impression - Improvement 
CGI-S 
Clinical Global Impression - Severity of Illness 
CK 
Creatine kinase 
CPK 
Creatine phosphokinase 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CYP 
Cytochrome P450 
D2 receptor 
Dopamine D2 receptor 
DIEPSS 
Drug Induced Extra-Pyramidal Symptoms Scale 
DILI 
Drug induced liver injury 
DNA 
Deoxyribonucleic acid 
DSM-5 
Diagnostic and statistical manual of mental disorders fifth edition 
EDTA 
Ethylenediaminetetraacetic acid 
EQ-5D-5L 
EuroQol-5 Dimension, 5 response level version 
FT4 
Free thyroxine 
GCP 
Good Clinical Practice 
GOT 
Glutamic-oxaloacetic transaminase 
GPT 
Glutamic-pyruvic transaminase 
HAM-D 
Hamilton Rating Scale for Depression 
HbA1c 
Glycosylated hemoglobin 
HDL 
High-density lipoprotein 
ICH 
The International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use  
ICMJE 
International Committee of Medical Journal Editors 
IRE 
Immediately reportable event 
IRB 
Institutional review board 
IWRS 
Interactive web response system 
JSMD 
Japanese Society of Mood Disorders 
LDH 
Lactate (lactic acid) dehydrogenase 
LDL 
Low-density lipoprotein 
LOCF 
Last observation carried forward 
LSMD 
Least square mean difference 
MADRS 
Montgomery Åsberg Depression Rating Scale 
MAO inhibitor 
Monoamine oxidase inhibitor 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHLW 
Ministry of Health, Labour and Welfare 
NGSP 
The National Glycohemoglobin Standardization Program 
PANSS 
Positive and Negative Syndrome Scale 
PQC 
Product quality complaint 
PT 
Prothrombin time 
PT (INR) 
Prothrombin time (international normalized ratio) 
QTc 
QT corrected for heart rate 
QTcB 
QT corrected for heart rate by Bazett’s formula  


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Abbreviation 
Definition 
QTcF 
QT corrected for heart rate by Fridericia’s formula 
QTcN 
QT corrected for heart rate by FDA Neuropharmacological Division formula 
SDS 
Sheehan Disability Scale 
SIGH-D 
Structured Interview Guide for HAM-D 
SIGMA 
Structured Interview Guide for MADRS 
SNRI 
Serotonin-noradrenaline reuptake inhibitor 
SSRI 
Selective serotonin reuptake inhibitor 
T3/T4 
Triiodothyronine/levothyroxine 
TEAE 
Treatment-emergent adverse event 
TSH 
Thyroid-stimulating hormone 
γ-GTP 
γ-glutamyl transpeptidase 
 


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1 
Introduction 
Depression is a condition that often takes a chronic course, causing significant suffering 
and imposing a burden on the patient. The disease interferes with the daily activities and 
social life of patients, who continue to suffer from decreased social functioning unless the 
disease remits.1 Moreover, depression is one of the major risk factors for suicide and, 
according to a psychological autopsy study, 60% to 70% of those who committed suicide 
had been diagnosed with depression.2 The number of suicides in Japan, even though a 
downward trend has been noted since 2012, was 21897 in 2016,3 which is still high 
compared with other developed countries. According to a published report by the 
Ministry of Health, Labour and Welfare (MHLW), the economic loss from depression 
resulting in leaves of absence from work, loss of employment, or suicide, etc, is estimated 
to be approximately 2.7 trillion yen in 2009.4 Decreased social functioning and increased 
suicide rate attributable to depression have become serious social problems. Under this 
circumstance, treatment of depression plays an important role in society. 
The lifetime and 12-month prevalence of major depressive disorder in Japan were 6.2% 
and 2.1%, respectively, according to “Study on Mental Health Epidemiological Survey,” 
a study supported by the Health and Labour Sciences Research Grants from fiscal year 
2004 to 2006.5 The Treatment Guidelines issued by the Japanese Society of Mood 
Disorders (JSMD) (hereinafter referred to as JSMD Treatment Guidelines)6 list 
pharmacotherapy with antidepressants as the mainstay in the treatment of major 
depressive disorder. As first-line agents, the guidelines recommend the following novel 
antidepressants: selective serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline 
reuptake inhibitors (SNRIs), and mirtazapine, a noradrenergic and specific serotonergic 
antidepressant. However, remission rates in patients treated with these antidepressants are 
as low as 30% to 40%.7 This difficulty in improving or achieving remission of major 
depressive disorder symptoms interferes with social functioning, causing various issues 
including loss of employment, withdrawal from education, and divorce. 
In the JSMD Treatment Guidelines,6 the following therapeutic methods are 
recommended for patients who fail to respond to the initial treatment with first-line 
agents such as SSRIs, SNRIs, and mirtazapine: Increase the dose to a sufficient level 
within the range in which adverse reactions are not clinically problematic; treat at the 
sufficiently increased dose for approximately 4 weeks; and then either change the drug if 
the patient does not respond to the treatment, or perform augmentation therapy if 
improvement is noted only in some of the symptoms of depression. Agents used for 
augmentation therapy include lithium, triiodothyronine/levothyroxine combination 


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(T3/T4), lamotrigine, valproic acid, carbamazepine, and atypical antipsychotics. While 
augmentation therapy with lithium has been reported to potentiate the antidepressant 
effects of drugs in many placebo-controlled studies,8 most of the drugs investigated in 
such studies were tricyclic antidepressants. Therefore, little data are available on 
augmentation of SSRIs or SNRIs at present. As a result of a meta-analysis on lithium 
toxicity profile,9 renal impairment, hypothyroidism, increased blood calcium level, and 
hyperparathyroidism were reported as adverse effects of particular concern. Special 
attention should be paid to the occurrence of these adverse effects during treatment with 
lithium. Concerning augmentation therapy with T3/T4, most of the available data are also 
from studies on tricyclic antidepressants. Furthermore, the efficacy of augmentation 
therapy with lamotrigine, valproic acid, or carbamazepine has not been sufficiently 
investigated. In addition, augmentation therapy with lithium, T3/T4, lamotrigine, valproic 
acid, or carbamazepine has not been approved for the indication of depression. 
Meanwhile, concerning augmentation therapy with atypical antipsychotics mediated by 
the dopaminergic system, aripiprazole is the only antipsychotic agent that has been 
approved in Japan for use as an adjunctive therapy for the treatment of major depressive 
disorder. The efficacy of aripiprazole was confirmed in a Japanese double-blind, placebo-
controlled trial (031-08-001)10 and 3 overseas double-blind trials of aripiprazole.11,12,13 
However, the results of these clinical trials suggest that a certain percentage of patients 
cannot tolerate long-term use of aripiprazole as adjunctive therapy due to adverse events 
(AEs) such as akathisia and insomnia. This drawback of aripiprazole as an adjunctive 
therapy remains a therapeutic issue. 
Brexpiprazole is a new chemical entity discovered by Otsuka Pharmaceutical Co., Ltd. 
Unlike aripiprazole, brexpiprazole, even at a low level of < 1 nM, exhibits serotonin (5-
HT)1A receptor partial agonist activity, 5-HT2A receptor antagonist activity, and 
dopamine D2 receptor (D2 receptor) partial agonist activity with optimal intrinsic activity. 
The pharmacology of brexpiprazole is believed to be mediated by a combination of high 
binding affinity and functional activities at multiple monoaminergic receptors. It 
modulates the serotonergic and dopaminergic systems with its partial agonist activity or 
antagonist activity. In addition, for adrenergic α1B/2C receptors, it also has similar 
subnanomolar binding affinity and antagonist activity. These 5-HT1A/D2 receptor partial 
agonist activities and 5-HT2A and α1B/2C receptor antagonist activities of brexpiprazole 
are thought to contribute to the antipsychotic, antidepressant, and impulse-control effects. 
Having the optimal intrinsic activity for D2 receptors and potent effects on the 
serotonergic system compared with aripiprazole, brexpiprazole is expected to contribute 


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to a reduction in the incidence and severity of adverse reactions, such as akathisia and 
insomnia, which are issues associated with treatment using aripiprazole. 
In Japan, brexpiprazole was investigated in a double-blind, placebo-controlled trial in 
patients with an acute relapse of schizophrenia (331-10-002)14 and in a long-term trial in 
outpatients with schizophrenia (331-10-003).15 Based on the results of these trials as well 
as overseas clinical trials, an application was filed for marketing authorization of 
brexpiprazole for the indication of schizophrenia, which was approved in January 2018.16 
Outside Japan, double-blind, placebo-controlled trials in patients with an acute relapse of 
schizophrenia (331-10-230 and 331-10-231) were performed, and the results confirmed 
the efficacy of brexpiprazole and demonstrated its safety.17,18 In addition, double-blind, 
placebo-controlled trials in patients with major depressive disorder who had insufficient 
responses to SSRIs or SNRIs (331-10-227 and 331-10-228) were performed, and the 
results confirmed the efficacy of brexpiprazole as adjunctive treatment and demonstrated 
its safety in this patient population.19,20 Based on the results of the above clinical trials, 
brexpiprazole was approved in the US not only for the indication of schizophrenia but 
also received approval as adjunctive treatment of major depressive disorder.21 
As shown above, outside Japan, the efficacy of brexpiprazole was demonstrated not only 
in treating schizophrenia but also as adjunctive treatment for major depressive disorder. 
Therefore, brexpiprazole as adjunctive therapy is also likely to be effective in Japanese 
patients with inadequate response to antidepressants. The results of overseas clinical trials 
show that there are no safety-related concerns associated with brexpiprazole as adjunctive 
therapy. Therefore, use of brexpiprazole as adjunctive therapy is expected to reduce the 
incidence of adverse reactions such as akathisia and insomnia, which are issues 
associated with augmentation therapy using aripiprazole, and to enhance treatment 
adherence. 
In conclusion, since brexpiprazole adjunctive therapy may also benefit Japanese patients 
with inadequate response to antidepressants, a placebo-controlled efficacy trial (331-102-
00058) has been planned. Considering that major depressive disorder requires long-term 
treatment including pharmacotherapy, we have decided to conduct this trial to evaluate 
the long-term safety and efficacy of brexpiprazole. 
1.1 
Nonclinical Data 
Brexpiprazole has been investigated in a number of pharmacological studies for its 
efficacy as a potential treatment for schizophrenia, major depressive disorder, cognitive 
impairments, and other psychiatric disorders. 


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In predictive animal models for antipsychotic-like efficacy, brexpiprazole inhibited 
apomorphine-induced hyperlocomotion and stereotyped behavior, and conditioned 
avoidance response in rats, and these effects were more potent than those of aripiprazole. 
Furthermore, brexpiprazole showed dose-dependently inhibited (±)-2,5-dimethoxy-4-
iodoamphetamine (DOI)-induced head twitch response in rats, suggesting 5-HT2A 
receptor antagonism, and the effect was stronger than that of aripiprazole. Moreover, 
despite it having a lower intrinsic activity for D2 receptors and higher antipsychotic 
potency than aripiprazole, the liability for catalepsy of brexpiprazole was comparable 
with that of aripiprazole, but less than that for haloperidol, olanzapine, and risperidone, 
suggesting brexpiprazole has a low potential to induce extrapyramidal symptoms. In 
other in vivo studies, it was demonstrated that brexpiprazole is a D2 receptor partial 
agonist in rats consistent with findings in the in vitro functional assays. 
Behavioral studies were also conducted to evaluate brexpiprazole as adjunct treatment to 
antidepressants in rodent models of depression-like (forced swim test and chronic mild 
stress model) and anxiety-like (marble burying) activity. In the forced swim test 
(behavioral despair), the administration of brexpiprazole either intraperitoneally (IP) at a 
very low dose (0.001 or 0.003 mg/kg) in mice or orally at a dose of (3 mg/kg) in rats, 
significantly reduced immobility time in adjunct treatment with SSRI (paroxetine: 
p < 0.05; sertraline: p < 0.001; fluoxetine: p < 0.001; escitalopram: p < 0.05; 
fluvoxamine: p < 0.01) or SNRI (duloxetine: p < 0.05; venlafaxine: p < 0.05; 
desvenlafaxine: p < 0.001; milnacipran: p < 0.05), whereas each compound alone was 
ineffective at the dose used in this test. In a chronic mild stress model in mice, adjunct 
administration of brexpiprazole (0.03 and 0.1 mg/kg, oral, twice daily) further enhanced 
the effect of fluoxetine alone (10 mg/kg, IP) on coat state score, and significantly 
improved the nest building during 5 hours while fluoxetine alone was not effective on 
this behavior. In the marble burying test, co-administration of brexpiprazole (0.1 mg/kg, 
oral) with paroxetine, sertraline, fluoxetine, or fluvoxamine (10 or 15 mg/kg, oral), 
enhanced the reduction in marble-burying (anxiolytic-like activity) seen with each SSRI 
alone. These studies strongly suggested that brexpiprazole has good potential as adjunct 
treatment for anti-depressant therapy. 
These results suggest that, in addition to schizophrenia, brexpiprazole also has excellent 
therapeutic effect against major depressive disorder. 


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1.2 
Clinical Data 
1.2.1 
Clinical Data From Japanese Trials in Subjects With 
Schizophrenia 
1.2.1.1 
Dose-finding Trial in Subjects With Schizophrenia (331-10-002) 
A double-blind, placebo-controlled trial was conducted in Japan to assess the efficacy 
and safety of fixed-dose brexpiprazole in adult subjects with an acute relapse of 
schizophrenia. This trial had a total of 4 groups consisting of a placebo group and 3 
fixed-dose groups of brexpiprazole (1, 2, and 4 mg/day). The change from baseline to 
Week 6 in the Positive and Negative Syndrome Scale (PANSS) total score, the primary 
endpoint, showed significant improvement in the 2-mg group compared with the placebo 
group (least square mean difference [LSMD]: −7.32, p = 0.0124). Although there was no 
significant difference between the 4-mg group and the placebo group, improvement in the 
PANSS total score was numerically greater in the 4-mg group than in the placebo group 
(LSMD: −3.86, p = 0.1959). There was no significant difference between the 1-mg group 
and the placebo group (LSMD = −0.63). 
The efficacy of brexpiprazole at a dose of 2 mg was demonstrated in subjects with an 
acute relapse of schizophrenia. 
The incidence of AEs was 70.4% in the 1-mg group, 69.3% in the 2-mg group, 65.5% in 
the 4-mg group, and 76.7% in the placebo group. Adverse events reported in any of the 
brexpiprazole groups at an incidence of ≥ 5% and at more than double the incidence in 
the placebo group were vomiting, blood prolactin increased, diarrhoea, nausea, and dental 
caries. There was no evident relationship between the dose of brexpiprazole and the 
incidence of AEs. Most AEs reported in brexpiprazole groups were mild or moderate in 
severity. One subject in the 4-mg group died. The AE resulting in death was asphyxia. 
This event was considered unrelated to the investigational medicinal product (IMP). The 
incidence of serious adverse events (SAEs) including death was 7.0% in the 1-mg group, 
4.4% in the 2-mg group, 4.4% in the 4-mg group, and 4.3% in the placebo group. In any 
treatment group, schizophrenia was the only SAE that occurred in more than 1 subject. 
The incidence of AEs leading to discontinuation was 16.5% in the 1-mg group, 10.5% in 
the 2-mg group, 15.0% in the 4-mg group, and 17.2% in the placebo group. The most 
frequently reported AE leading to discontinuation was schizophrenia in any treatment 
group. No marked changes were noted in laboratory test values, vital signs, body weight, 
or electrocardiogram (ECG) in brexpiprazole groups. 


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1.2.1.2 
Long-term Trial in Subjects With Schizophrenia (331-10-003) 
This long-term trial conducted in Japan was an open-label trial to evaluate the safety and 
efficacy of long-term administration of brexpiprazole in subjects with schizophrenia, 
either continuing treatment from the dose-finding trial 331-10-002 (rollover subjects) or 
newly enrolled in this trial. 
The incidence of AEs was 85.2% in newly enrolled subjects, 80.6% in rollover subjects, 
and 83.6% in all subjects. The most frequently reported AE was nasopharyngitis (25.1%) 
in newly enrolled subjects, schizophrenia (26.5%) in rollover subjects, and 
nasopharyngitis (23.1%) in all subjects. Most AEs were mild or moderate in severity. No 
deaths were reported. The incidence of SAEs was 10.4% in newly enrolled subjects, 
18.4% in rollover subjects, and 13.2% in all subjects. Serious adverse events reported in 
more than 1 subject were schizophrenia in newly enrolled and rollover subjects and 
dehydration, akathisia, and schizophrenia in all subjects. The incidence of AEs leading to 
discontinuation was 10.9% in newly enrolled subjects, 23.5% in rollover subjects, and 
15.3% in all subjects. The most frequently reported AE leading to discontinuation was 
schizophrenia in newly enrolled subjects, rollover subjects, and all subjects. No clinically 
meaningful changes were noted in laboratory test values, vital signs, or ECGs in newly 
enrolled subjects, rollover subjects, or all subjects. The mean change in body weight from 
baseline to the final assessment was 0.34 kg in newly enrolled subjects, 2.02 kg in 
rollover subjects, and 0.93 kg in all subjects. There was no marked difference in safety 
findings between newly enrolled subjects and rollover subjects, indicating that 
switchover to brexpiprazole monotherapy from prior treatment with existing 
antipsychotic drugs has no significant impact on safety. 
All efficacy endpoints, including the PANSS total score and Clinical Global Impression - 
Severity of Illness (CGI-S) scores, remained stable until Week 52. 
1.2.2 
Clinical Data From Non-Japanese Trial in Subjects With Major 
Depressive Disorder 
1.2.2.1 
Confirmatory Trial in Subjects With Major Depressive Disorder 
(331-10-227) 
A double-blind, placebo-controlled trial was conducted outside Japan to evaluate the 
efficacy, safety, and tolerability of fixed doses of brexpiprazole in subjects with major 
depressive disorder who had an insufficient response to antidepressant therapy. All 
eligible subjects who passed the screening test entered an 8-week antidepressant 
treatment period (Phase A) in which SSRI/SNRI and placebo were administered in a 
single-blind manner. Subjects who responded to SSRI/SNRI and placebo in Phase A 


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entered a 6-week antidepressant-responder treatment-continuation period (Phase A+) in 
which SSRI/SNRI and placebo continued to be concomitantly administered for another 6 
weeks. Subjects who had an insufficient response to SSRI/SNRI and placebo in Phase A 
entered a double-blind period (Phase B) in which brexpiprazole or placebo was 
administered concomitantly with SSRI/SNRI for 6 weeks in a double-blind manner. This 
trial had a total of 3 treatment groups consisting of a placebo group and 2 fixed-dose 
groups of brexpiprazole (1 and 3 mg/day). The change from baseline to Week 6 in the 
Montgomery Åsberg Depression Rating Scale (MADRS) total score, the primary 
endpoint, showed numerical improvement in the 3-mg group compared with the placebo 
group (LSMD: −1.52, p = 0.0327). Improvement in the MADRS total score was 
numerically greater in the 1-mg group than in the placebo group (LSMD: −1.19, 
p = 0.0925). In the efficacy data from a subgroup meeting the inclusion criteria revised 
during the trial, the change from baseline to Week 6 in the MADRS total score showed 
improvement in the 3-mg group compared with the placebo group (LSMD: −1.95, p = 
0.0079). Meanwhile, the change from baseline in the 1-mg group was −1.30 (p = 0.0737). 
The incidence of AEs was 54.9% in the brexpiprazole 1-mg group, 63.3% in the 3-mg 
group, and 46.8% in the placebo group. The AEs reported in the brexpiprazole 3-mg 
group at an incidence of ≥ 5% and at more than double the incidence in the placebo group 
were akathisia (13.5% in the 3-mg group and 2.3% in the placebo group; hereinafter, the 
same order shall apply), somnolence (5.7%, 0.5%), and weight increased (5.7%, 0.9%). 
The AEs reported in the brexpiprazole 1-mg group at an incidence of ≥ 5% and at more 
than double the incidence in the placebo group were weight increased (6.6% in the 1-mg 
group and 0.9% in the placebo group; hereinafter, the same order shall apply) and 
nasopharyngitis (6.6%, 1.8%). Most AEs in either of the brexpiprazole groups were mild 
or moderate in severity. The incidence of SAEs was 0.4% in the 1-mg group, 0.4% in the 
3-mg group, and 0.0% in the placebo group. The incidence of AEs leading to 
discontinuation was 1.3% in the 1-mg group, 3.5% in the 3-mg group, and 1.4% in the 
placebo group. The incidences of both SAEs and AEs leading to discontinuation were 
low in the brexpiprazole groups as in the placebo group. No marked changes were noted 
in laboratory test values, vital signs, or ECGs in either of the brexpiprazole groups. 
1.2.2.2 
Confirmatory Trial in Subjects With Major Depressive Disorder 
(331-10-228) 
A double-blind, placebo-controlled trial was conducted outside Japan to evaluate the 
efficacy, safety, and tolerability of a fixed dose of brexpiprazole in subjects with major 
depressive disorder who had an insufficient response to antidepressant therapy. The trial 
was designed similarly to Trial 331-10-227 and had 2 treatment groups consisting of a 


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placebo group and a brexpiprazole 2-mg group. The change from baseline to Week 6 in 
the MADRS total score, the primary endpoint, showed significant improvement in the 2-
mg group compared with the placebo group (LSMD: −3.12, p = 0.0001). In the efficacy 
data from a subgroup meeting the inclusion criteria revised during the trial, the change 
from baseline to Week 6 in the MADRS total score showed improvement in the 2-mg 
group compared with the placebo group (LSMD: −3.21, p = 0.0002). 
The incidence of AEs was 59.0% in the brexpiprazole 2-mg group and 46.6% in the 
placebo group. The AEs reported in the brexpiprazole 2-mg group at an incidence of 
≥ 5% and at more than double the incidence in the placebo group were weight increased 
(8.0% in the 2-mg group and 3.1% in the placebo group; hereinafter, the same order shall 
apply) and akathisia (7.4%, 1.0%). Most AEs in the brexpiprazole group or the placebo 
group were mild or moderate in severity. The incidence of SAEs was 1.1% in the 2-mg 
group and 1.0% in the placebo group. The incidence of AEs leading to discontinuation 
was 3.2% in the 2-mg group and 0.0% in the placebo group. The incidences of both SAEs 
and AEs leading to discontinuation were low in the brexpiprazole group as in the placebo 
group. No marked changes were noted in laboratory test values, vital signs, or ECGs in 
the brexpiprazole group. 
1.2.2.3 
Confirmatory Trial in Subjects With Major Depressive Disorder 
(331-13-214) 
A double-blind, placebo-controlled trial was conducted outside Japan to evaluate the 
efficacy, safety, and tolerability of a fixed dose of brexpiprazole in subjects with major 
depressive disorder who had an inadequate response to antidepressant therapy. The trial 
was designed similarly to Trials 331-10-227 and 331-10-228 and had 2 treatment groups 
consisting of a placebo group and a brexpiprazole 2-mg group. The change from baseline 
to Week 6 in the MADRS total score, the primary endpoint, showed significant 
improvement in the 2-mg group compared with the placebo group (LSMD: −2.30, 
p = 0.0074). 
The incidence of AEs was 59.9% in the brexpiprazole 2-mg group and 49.5% in the 
placebo group. The AEs reported in the brexpiprazole 2-mg group at an incidence of 
≥ 5% and at more than double the incidence in the placebo group were restlessness (8.3% 
in the 2-mg group and 2.0% in the placebo group; hereinafter, the same order shall apply) 
and weight increased (5.2%, 0.5%). The AEs reported in the 2-mg group at an incidence 
of ≥ 5% and at a higher incidence than that in the placebo group were only akathisia 
(8.3%, 5.0%) and upper respiratory tract infection (5.2%, 5.0%). Most AEs in the 
brexpiprazole group were mild or moderate in severity. The incidence of SAEs was 0.5% 
in the 2-mg group and 0.0% in the placebo group. The incidence of AEs leading to 


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discontinuation was 2.1% in the 2-mg group and 0.5% in the placebo group. The 
incidences of both SAEs and AEs leading to discontinuation were low in the 
brexpiprazole group as in the placebo group. No marked changes were noted in 
laboratory test values, vital signs, or ECGs in the brexpiprazole group. 
1.2.2.4 
Long-term Trial in Subjects With Major Depressive Disorder 
(331-10-238) 
This overseas long-term open-label trial evaluated the long-term safety, tolerability, and 
efficacy of brexpiprazole in subjects with major depressive disorder who had participated 
in one of the previous phase 3 double-blind brexpiprazole trials (331-10-227, 331-10-228, 
and 331-12-282) and who remained on medication. 
The incidence of AEs was 72.3%. 
AEs with an incidence of ≥ 5% were fatigue (6.1%), viral upper respiratory tract infection 
(5.4%), weight increased (17.7%), increased appetite (6.3%), akathisia (6.7%), headache 
(7.2%), somnolence (8.0%), anxiety (5.2%), and insomnia (6.3%). 
Most AEs were mild or moderate in severity. Four deaths (0.1%) were reported. One 
death (completed suicide) was considered potentially related to the IMP and the 3 other 
deaths (gastric ulcer perforation and peritonitis, completed suicide, pulmonary embolism) 
were considered unrelated to the IMP. The incidence of SAEs was 2.4%, with depression 
(0.3%) being the most frequently reported SAE. The incidence of AEs leading to 
discontinuation was 8.6%, with weight increased (2.0%) being the most frequently 
reported AE leading to discontinuation. No clinically relevant changes were noted in 
laboratory test values except for prolactin, vital signs, or ECG. 
Improvement in all efficacy endpoints, including CGI-S score, was sustained. 
1.2.2.5 
Long-term Trial in Elderly Subjects With Major Depressive 
Disorder (16160A) 
This overseas long-term open-label trial evaluated the long-term safety, tolerability, and 
efficacy of flexibly-dosed brexpiprazole in elderly subjects with major depressive 
disorder who had an inadequate response to antidepressant therapy. 
The incidence of AEs was 77.3%. AEs with an incidence of ≥ 5% were fatigue (15.2%), 
restlessness (12.9%), increased appetite (9.8%), akathisia (8.3%), weight increased 
(8.3%), anxiety (7.6%), dizziness (7.6%), tremor (6.8%), insomnia (6.1%), 
nasopharyngitis (6.1%), back pain (5.3%), and headache (5.3%). Most AEs were mild or 
moderate in severity. One death was reported. AEs with an outcome of death were acute 
myocardial infarction and myocardial rupture. Both events were considered unrelated to 
the IMP. The incidence of SAEs was 4.5% and all these SAEs occurred in only 1 subject 


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each. The incidence of AEs leading to discontinuation was 18.9%, with fatigue (3.0%) 
being the most frequently reported AE leading to discontinuation. No clinically relevant 
changes were noted in laboratory test values, vital signs, or ECG. 
Improvement in all efficacy endpoints, including CGI-S score, was observed. 
1.3 
Known and Potential Risks and Benefits 
Extrapyramidal symptoms, seizures, suicidality, and dyslipidemia have been assessed as 
important risks associated with the administration of brexpiprazole. The potential 
mechanism of antipsychotics causing seizures is a class effect thought to be due to a 
reduction of the seizure threshold in susceptible individuals. The occurrence of suicidal 
behavior is inherent in psychotic illnesses and mood disorders. In the schizophrenia and 
major depressive disorder populations, short-term and long-term administration of 
brexpiprazole was associated with moderate weight gain; however, weight gain did not 
contribute significantly to IMP discontinuation, and only a few subjects with marked 
weight gain demonstrated metabolic syndrome. Although not clinically significant, an 
increase in triglycerides was observed in some trials. Due to this observation and 
considerations on potential clinical consequences related to weight gain, dyslipidemia is 
considered to be an important potential risk. 
With lower intrinsic activity at the D2 receptors and more potent effects on the 
serotonergic system, which is suggested to be involved in the improvement of depressive 
symptoms, extrapyramidal symptoms, and cognitive function, compared with 
aripiprazole, evidence suggests that brexpiprazole can reduce the incidence of AEs such 
as akathisia and other extrapyramidal symptoms, nausea, vomiting, excitement, and 
irritability, and also improve symptoms of depression. In clinical trials conducted 
overseas, the incidence of AEs, such as akathisia, which are considered risk factors for 
low adherence to treatment, was confirmed to be low in patients treated with 
brexpiprazole. Therefore, brexpiprazole is likely to become a useful treatment option for 
patients with major depressive disorder who need to receive treatment over a long period 
of time. 
2 
Trial Rationale and Objectives 
2.1 
Trial Rationale 
Considering the monoamine hypothesis, one of the assumptions of the underlying 
pathophysiologic bases of depression, use of drugs that act on the serotonergic, 
noradrenergic, or dopaminergic system is regarded as the most rational approach to the 
treatment of major depressive disorder. SSRIs and SNRIs, which are commonly used to 


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treat major depressive disorder, activate the serotonergic and noradrenergic systems. 
However, these drugs poorly activate the dopaminergic system with a response rate of 
50% to 60%. Mirtazapine, another first-line drug for major depressive disorder, is an 
antagonist to alpha 2 presynaptic autoreceptors and heteroreceptors, thereby increasing 
neurotransmission of serotonin and noradrenaline in the central nervous system, but it has 
no direct pharmacological effect on the dopaminergic system. Aripiprazole is the only 
antipsychotic agent that has been approved in Japan as augmentation therapy acting 
directly on the dopaminergic system. However, the drug does have some therapeutic 
issues that need to be addressed, such as akathisia and insomnia caused by its high 
intrinsic activity at the D2 receptor. Unlike aripiprazole, brexpiprazole, even at a low 
level of < 1 nM, acts on 5-HT1A receptors and 5-HT2A receptors, and acts as an agonist at 
D2 receptors with optimal intrinsic activity. Adjunct administration of brexpiprazole with 
optimal intrinsic activity to SSRI, SNRI, or mirtazapine is likely to act on not only the 
serotonergic and noradrenergic systems but also the dopaminergic system. Therefore, this 
treatment is expected to be more effective in treating major depressive disorder patients 
with a safety profile that is superior to monotherapy with an antidepressant and thereby 
improve adherence to treatment. 
Phase 3, double-blind, placebo-controlled trials of fixed doses of brexpiprazole (331-10-
227, 331-10-228, and 331-13-214) conducted outside Japan demonstrated the efficacy of 
brexpiprazole as adjunctive therapy to SSRIs or SNRIs in patients with major depressive 
disorder and found no significant safety concerns. Furthermore, in an overseas long-term 
trial in patients with major depressive disorder, 52-week brexpiprazole treatment revealed 
no significant safety concerns, and its long-term sustained effectiveness was also 
confirmed. It is expected that the long-term use of brexpiprazole as adjunctive therapy 
will also be well tolerated in Japanese patients with major depressive disorder, and that 
the effectiveness will be sustained for a longer period. Based on the above, we have 
decided to conduct this trial to assess the safety and efficacy of long-term brexpiprazole 
treatment. 
This trial will assess the long-term safety and efficacy of brexpiprazole as adjunctive 
therapy, primarily in rollover subjects from a Japanese double-blind trial (331-102-
00058). Therefore, brexpiprazole 2 mg/day, which is the dose established for the double-
blind trial (331-102-00058) and is a dose at which efficacy has been verified in multiple 
overseas clinical trials, was selected as a maintenance dose in this trial. A starting dose 
was set at brexpiprazole 1 mg/day, the same starting dose as in the double-blind trial 
(331-102-00058). The same safety and efficacy endpoints as those employed in the 
double-blind trial (331-102-00058) will also be used. In this trial, an antidepressant (any 


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one of SSRIs or SNRIs) used in the double-blind trial (331-102-00058) will be 
administered with no changes in the final dose and regimen, and brexpiprazole will be 
used at a dose of 2 mg/day (starting dose: 1 mg/day) in combination with the 
antidepressant. Duration of the treatment was set at 52 weeks, based on "The Extent of 
Population Exposure to Assess Clinical Safety for Drugs Intended for Long-Term 
Treatment of Non-Life-Threatening Conditions" (PAB/PCD Notification No. 592 dated 
24 May 1995). 
As prevalence of major depressive disorder is also high in the elderly, it is probable that 
the drug will also be used for elderly patients aged 65 years or older after approval is 
obtained for its use as adjunctive therapy in major depressive disorder. Therefore, new 
subjects 65 years or older will also be involved, in view of the necessity to assess the 
long-term safety and efficacy of brexpiprazole as adjunctive therapy in elderly patients 
with major depressive disorder and based on the recommendations in "Studies in Support 
of Special Populations: Geriatrics" (PAB/NDD Notification No. 104 dated 02 Dec 1993). 
In newly enrolled subjects, an antidepressant will be used, which will be a drug that the 
subject is using at the time of informed consent, either an SSRI, SNRI, or mirtazapine. 
An overseas long-term clinical trial in patients with major depressive disorder aged 65 
years or older also demonstrated the excellent tolerability of brexpiprazole in elderly 
patients. 
The US package insert of brexpiprazole21 contains warnings regarding antidepressant-
related suicidal ideation or suicidal behavior, and also in the Japanese package insert of 
brexpiprazole, patients with a history of suicidal ideation or suicide attempt come under 
Careful Administration. Considering the above, criteria that require the exclusion or 
discontinuation of patients at high risk of suicide have been established as exclusion or 
discontinuation criteria to minimize the risk of suicide during the trial and thereby to 
ensure the safety of subjects. 
Based on the above, we conclude that assessment of the long-term safety and efficacy of 
brexpiprazole as adjunctive therapy in conjunction with commercially available 
antidepressants (SSRIs or SNRIs for rollover subjects and SSRIs, SNRIs, or mirtazapine 
for newly enrolled subjects) in Japanese patients with major depressive disorder is 
scientifically and ethically justified. 
2.2 
Rationale for DNA Storage 
This trial will involve the optional storage of DNA samples from newly enrolled subjects. 
Samples for DNA storage will be collected only from subjects who have provided written 
consent to DNA storage and only at trial sites which have agreed to sampling for DNA 


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storage. Concerning collecting DNA samples during the trial period and storing them, 
MHLW states as follows in Q&A 1 in "Regarding Clinical Studies Utilizing 
Pharmacogenomics (PFSB/ELD Notification No. 0930007 dated 30 Sep 2008)": It is 
permissible to obtain samples from subjects for genomic/genetic analysis in association 
with the evaluation of the IMP (eg, pharmacokinetics, efficacy, safety) if either of the 
following 2 circumstances apply: 1) The target and time of genomic/genetic analysis are 
specified at the time of implementation of a trial; or 2) Genomic/genetic analysis in 
association with the IMP evaluation is planned to be performed in the future although the 
target or time of the analysis is not specified at the time of implementation of a trial. In 
Q&A 2, MHLW also states that it is permissible to obtain samples from subjects for 
genomic/genetic analysis which is not associated with the evaluation of the IMP. 
Based on the above, we concluded that DNA storage conducted to enable future 
exploratory investigation regarding the relationships between DNA mutations (eg, gene 
polymorphism) and therapeutic responses to brexpiprazole and/or relationships between 
DNA mutations and the onset, severity, or progression of the disease is justified. 
In this trial, rollover subjects from the double-blind trial (331-102-00058) will be 
excluded from DNA storage, because they are already the target of DNA storage in the 
previous trial. 
2.3 
Rationale for Dosing and Regimen 
2.3.1 
Rationale for Regimen 
All clinical trials of brexpiprazole in patients with major depressive disorder conducted 
outside Japan have employed once daily oral administration. This trial will likewise 
employ once daily oral administration of brexpiprazole, as the drug is approved in the US 
with this regimen and because it has been confirmed that there are no major differences 
in the pharmacokinetics of brexpiprazole between Japanese and non-Japanese 
populations. 
2.3.2 
Rationale for Dose 
2.3.2.1 
Rationale for Maintenance Dose 
Based on the efficacy of brexpiprazole at 2 mg/day confirmed in overseas clinical trials in 
patients with major depressive disorder and the similarity in the pharmacokinetics of 
brexpiprazole observed in Japanese and non-Japanese populations, a dose of 2 mg/day is 
likely to be effective in Japanese patients with major depressive disorder. A maintenance 
dose of 2 mg/day was selected for this trial to evaluate the long-term safety and efficacy 
of 2 mg/day of brexpiprazole. 


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2.3.2.2 
Rationale for a Starting Dose of 1 mg/day 
Overseas clinical trials of brexpiprazole involving patients with major depressive disorder 
employed a starting dose of 0.5 or 1 mg/day, with no great differences in safety noted 
during the dose-escalation period at either of the starting doses; therefore, a starting dose 
of 1 mg/day was selected in order to attain an effective dose swiftly. 
2.4 
Trial Objectives 
The objective of the trial is to assess the safety and efficacy of the long-term use of 
brexpiprazole as adjunctive therapy in concomitant use with a commercially available 
antidepressant (SSRI or SNRI for rollover subjects and SSRI, SNRI, or mirtazapine for 
new subjects) in subjects with major depressive disorder who continue receiving the 
treatment from the double-blind trial (331-102-00058) and in newly enrolled patients 65 
years or older with major depressive disorder. 
3 
Trial Design 
3.1 
Type/Design of Trial 
The trial is a multi-center, open-label trial to assess the safety and efficacy of the long-
term use of brexpiprazole as adjunctive therapy in conjunction with a commercially 
available antidepressant (SSRI or SNRI for rollover subjects and SSRI, SNRI, or 
mirtazapine for new subjects) at a dose and regimen specified in the package insert. 
Subjects of the trial are those who have completed the double-blind period (Phase B) of 
the double-blind trial (331-102-00058), and newly enrolled patients 65 years or older 
with major depressive disorder who have received 1 to 3 adequate antidepressant drug 
treatmentsa for major depressive episodes and have shown an inadequate responseb to all 
of these treatments. 
The trial design is shown in Figure 3.1-1. The trial comprises a screening period, 
treatment period, and post-treatment observation period. 
 
a Definition of "adequate antidepressant drug treatment" is provided below. 
Treatment with an antidepressant at an approved dose for at least 6 weeks (for 
combination therapy, treatment for at least 3 weeks) 
b Definition of "inadequate response" is provided below. 
With complete recovery from depressive symptoms and not the slightest improvement 
considered as 100% and 0%, respectively, patients carry out self-evaluations for 


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improvement by antidepressant drug treatments used to date, from among 4 grades 
(< 25% Improvement, 25% to 49% Improvement, 50% to < 75% Improvement, and 
≥ 75% Improvement), with the evaluations corresponding to < 25% Improvement or 
25% to 49% Improvement classified as inadequate response. 
Patients who, among 1 to 3 adequate antidepressant drug treatments, have received 
treatment for ≥ 6 weeks at least once (receiving only combination therapies for ≥ 3 
weeks does not qualify) are eligible for selection. 
 
 
Figure 3.1-1 
Trial Design 
aAdministration of brexpiprazole will commence at 1 mg/day and the dose will be increased to 2 mg/day 
after observations, examinations, and assessments at Week 1. Subjects who cannot tolerate doses of 
2 mg/day will be withdrawn from the trial. 
 
IMP
30 days after
the final IMP
administration
Post-
treatment
observation
period
(30 days)
30 days after
the final IMP
administration
Trial period
Completers of the double-blind period (Phase B)
of the double-blind trial (331-102-00058)
Treatment period
 (52 weeks)
Post-
treatment
observation
period
(30 days)
Brexpiprazole 2 mg/day a
SSRI or SNRI
Screening period
Requisite
concomitant
medication
Informed consent
Day -28 to Day -1
Starting dose:
 1 mg/day
Starting dose:
 1 mg/day
Informed consent
After completion of the
double-blind period
(Phase B) of the double-
blind trial (331-102-
00058)
New subjects (≥ 65 years old)
Trial period
Screening period
(up to 28 days)
Treatment period
(52 weeks)
Brexpiprazole 2 mg/day a
SSRI, SNRI, or
mirtazapine
SSRI, SNRI, or mirtazapine
SSRI or SNRI
Post-
treatment
observation
period
Post-
treatment
observation
period
Rollover 
subjects
n = 30 (as IMP-
treated subjects)
Week 1
Week 1
Week 52
Week 52
New 
subjects
Week 0
Week 0


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3.2 
Trial Treatments 
(1) 
Drugs, dose, and regimen 
• Commercially available antidepressant 
For rollover subjects, an antidepressant (SSRI or SNRI) used in the double-blind trial 
(331-102-00058) will continue to be used throughout the treatment period, with no 
changes from the final dose and regimen. For new subjects, an antidepressant (SSRI, 
SNRI, or mirtazapine) being used at the time of informed consent will continue to be 
used throughout the treatment period, with no changes from the dose and regimen 
used at informed consent. 
During the treatment period, dose adjustment within the approved dose range is 
allowed according to the judgement of the investigator or subinvestigator, but the 
dose may not be altered at the time of dose escalation of brexpiprazole at Week 1. 
• Brexpiprazole 
Administration of brexpiprazole will commence at 1 mg/day and subjects will 
continue to receive a single brexpiprazole 1 mg tablet once daily by the oral route 
until the observations, examinations, and evaluations at Week 1. Following the 
observations, examinations, and evaluations at Week 1, subjects will be administered 
a single brexpiprazole 2 mg tablet once daily by the oral route. Subjects who cannot 
tolerate doses of 2 mg/day will be withdrawn from the trial. 
 
(2) 
Treatment period 
52 weeks 
 
[Rationale for treatment period] 
Treatment duration was set at 52 weeks with reference to "The Extent of Population 
Exposure to Assess Clinical Safety for Drugs Intended for Long-Term Treatment of Non-
Life-Threatening Conditions" (PAB/PCD Notification No. 592 dated 24 May 1995). 
3.3 
Trial Population 
Adult and elderly patients with "major depressive disorder, single episode" or "major 
depressive disorder, recurrent episode" according to the classification criteria of the 
Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) 
3.3.1 
Number of Subjects and Trial Population 
The trial will be conducted in patients who have major depressive disorder (major 
depressive disorder, single episode; major depressive disorder, recurrent episode) 
according to the DSM-5 classification. Concerning rollover subjects from the double-
blind trial (331-102-00058), their eligibility for proceeding to the long-term trial will be 


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assessed, after acquisition of informed consent to the long-term trial, based on the results 
of examinations and assessments at Week 6 of the double-blind period (Phase B) of the 
double-blind trial (331-102-00058) and at baseline. The eligibility of new subjects will be 
judged after acquisition of informed consent from elderly patients 65 years or older, 
based on the results of examinations and assessments at screening and baseline. As the 
sample size needed to assess the safety and efficacy of brexpiprazole in the elderly, the 
number of subjects receiving the treatment was set at 30. 
3.3.2 
Subject Number Assignment 
Following the provision of written informed consent to participate in this trial, each 
rollover subject will continue to use the subject identifier (ID) assigned in the previous 
double-blind trial (331-102-00058), and each new subject will be assigned a unique 
subject ID (site number [3 digits] + subject number [S + 5 digits]). The site number will 
be designated by the sponsor. A subject number is a serial in-site number starting with 
S20001, , which is given to each subject in the order of provision of consent. 
3.4 
Eligibility Criteria 
3.4.1 
Informed Consent 
Written informed consent will be obtained from all subjects on their voluntary decision. 
Rollover subjects will provide written informed consent after completion of observations, 
examinations, and assessments at Week 6 in the double-blind period (Phase B) of the 
previous double-blind trial (331-102-00058). Consent will be documented on a written 
informed consent form (ICF) with the subject’s signature. The ICF will be approved by 
the same institutional review board (IRB) that approves this protocol. 
Each ICF will comply with the International Council for Harmonisation (ICH) Good 
Clinical Practice (GCP) Guideline22 and regulatory requirements. 
Investigators or subinvestigators may discuss the possibility for entry with a potential 
subject without first obtaining consent. However, informed consent must be obtained and 
documented before initiation of any procedures that are performed solely for the purpose 
of determining eligibility for this trial, including withdrawal from current medication(s). 
Potential subjects are free to refuse entry into the trial, or withdraw from the trial at any 
time, without justification, and there will be no consequences to their further care. 
Once appropriate essential information has been provided and fully explained in plain 
language to the potential subject by the investigator or subinvestigator, the IRB-approved 
written ICF will be signed and dated by both the potential subject and the person 
obtaining consent (investigator or subinvestigator). If a study collaborator has provided a 


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supplemental explanation, the IRB-approved written ICF will be signed and dated by the 
study collaborator. The subject will receive a copy of the signed ICF; the original shall be 
kept on file by the investigator or subinvestigator. 
Subjects may be asked to sign additional ICFs if the protocol is amended to significantly 
add or change procedures. 
For DNA storage, a separate ICF will be used for explanation and written informed 
consent will be obtained from subjects on their voluntary decision in a similar manner. 
DNA storage is optional and refusal to allow DNA storage will not affect trial 
participation. 
3.4.2 
Inclusion Criteria 
Subjects must meet the inclusion criteria described in Table 3.4.2-1. For both rollover 
subjects from the double-blind trial (331-102-00058) and new subjects, those meeting all 
the inclusion criteria below at screening (for new subjects only) and baseline are eligible 
for selection. 
Table 3.4.2-1 
Inclusion Criteria 
Rollover Subjects 
1 
Outpatients 
2 
Subjects completing the double-blind period (Phase B) of the double-blind trial (331-102-00058) 
who are able to commence treatment within 28 days from Week 6 of the double-blind period (Phase 
B) of the double-blind trial (331-102-00058) 
3 
Subjects who have a level of comprehension sufficient to allow them to give written informed 
consent to all of the observation/examination/evaluation items specified in the protocol, and who can 
understand the contents of the trial 
4 
Subjects with a DSM-5 classification-based diagnosis of "major depressive disorder, single episode" 
or "major depressive disorder, recurrent episode" 
New Subjects 
5 
Outpatients 
6 
Male and female patients ≥ 65 years of age (at the time of informed consent) 
7 
Subjects who have a level of comprehension sufficient to allow them to give written informed 
consent to all of the observation/examination/evaluation items specified in the protocol, and who can 
understand the contents of the trial 
8 
Patients with a DSM-5 classification-based diagnosis of "major depressive disorder, single episode" 
or "major depressive disorder, recurrent episode" whose current episode has persisted for at least 8 
weeks 


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Table 3.4.2-1 
Inclusion Criteria 
9 
Patients who have received 1 to 3 adequate antidepressant drug treatments for the current major 
depressive episode and whose response to all of the treatments has been inadequate. Definitions of 
"adequate antidepressant drug treatments" and "inadequate response" are provided below. 
 
Adequate antidepressant drug treatment 
Treatment with an antidepressant at an approved dose for at least 6 weeks (for combination therapy, 
treatment for at least 3 weeks) 
 
Inadequate response 
With complete recovery from depressive symptoms and not the slightest improvement considered as 
100% and 0%, respectively, patients carry out self-evaluations for improvement by antidepressant 
drug treatments used to date, from among 4 grades (< 25% Improvement, 25% to 49% Improvement, 
50% to < 75% Improvement, and ≥ 75% Improvement), with the evaluations corresponding to 
< 25% Improvement or 25% to 49% Improvement classified as inadequate response. 
Patients who, among 1 to 3 adequate antidepressant drug treatments, have received treatment for 
≥ 6 weeks at least once (receiving only combination therapies for ≥ 3 weeks does not qualify) are 
eligible for selection. 
10 
Patients undergoing treatment with SSRI, SNRI, or mirtazapine at the time of informed consent 
 
[Rationale for inclusion criteria] 
Rollover subjects 
1.  This criterion is specified in view of subject safety, as treatment should be prioritized in subjects whose 
condition requires hospitalization. 
2.  This criterion is specified to select subjects who will adhere to the protocol and in whom the long-term 
treatment will be possible. 
3.  This criterion is specified for ethical considerations. 
4.  This criterion is specified for appropriate assessment of safety and efficacy. 
 
New subjects 
5.  This criterion is specified in view of subject safety, as treatment should be prioritized in subjects whose 
condition requires hospitalization. 
6.  Patients 65 years or older will be involved, based on the specifications in "Studies in Support of Special 
Populations: Geriatrics" (PAB/NDD Notification No. 104 in 02 Dec 1993). 
7.  This criterion is specified for ethical considerations. 
8 to 10.  These criteria are specified for appropriate assessment of efficacy. 
 
3.4.3 
Exclusion Criteria 
For both rollover subjects from the double-blind trial (331-102-00058) and new subjects, 
subjects or patients will be excluded from the trial if they meet any of the exclusion 
criteria, provided in Table 3.4.3-1 at screening (only for new subjects) and baseline. 


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Table 3.4.3-1 
Exclusion Criteria 
Rollover subjects 
1 
Female subjects who are pregnant or breastfeeding or who have positive pregnancy test (urine) 
results at baseline 
2 
Sexually active male subjects or sexually active female subjects of childbearing potential, who will 
not agree to practice 2 different methods of birth control or to remain abstinent during the trial and 
for 30 days after the final IMP administration. For birth control, 2 of the following methods must be 
used: vasectomy, tubal ligation, vaginal diaphragm, intra-uterine contraceptive device (IUD), oral 
contraceptives, or condom with spermicide. 
3 
Subjects who experience a change to the manic state in the antidepressant treatment period (Phase A) 
of the double-blind trial (331-102-00058) 
4 
Subjects who are discovered to not meet the inclusion criteria or to fall under any of the exclusion 
criteria in the double-blind trial (331-102-00058) 
5 
Subjects who showed marked noncompliance with the IMP treatment in the double-blind trial (331-
102-00058) (subjects whose IMP compliance rates are < 65% between prescribed visits) 
6 
Subjects receiving treatment with antipsychotics and psychostimulants for current major depressive 
episode (excluding the use of IMP in the double-blind trial [331-102-00058] and use of sulpiride for 
depression/depressive state or gastric/duodenal ulcer) 
7 
Subjects receiving treatment with monoamine oxidase inhibitors (MAO inhibitors) within 2 weeks 
before baseline 
8 
Subjects using benzodiazepines (excluding ultrashort-acting sleep inducers) within 1 week before 
baseline 
9 
Subjects hospitalized for the current major depressive episode after the antidepressant treatment 
period (Phase A) of the double-blind trial (331-102-00058) 
10 
Subjects with a history of electroconvulsive therapy 
11 
Subjects with a diagnosis of any of the following diseases according to DSM-5 
a) Neurocognitive disorders 
b) Schizophrenia spectrum and other psychotic disorders 
c) Bipolar and related disorders 
d) Feeding and eating disorders 
e) Obsessive-compulsive disorder 
f) 
Panic disorder 
g) Posttraumatic stress disorder 
12 
Subjects with a diagnosis of any personality disorders (borderline personality disorder, antisocial 
personality disorder, paranoid personality disorder, schizoid personality disorder, schizotypal 
personality disorder, and histrionic personality disorder) according to DSM-5 
13 
Subjects experiencing hallucinations or delusions, or showing mood-incongruent psychotic features, 
in the current depressive episode 
14 
Subjects with a MADRS score of ≥ 5 for Item 10. Suicide, a Hamilton Rating Scale for Depression 
(HAM-D) score for suicide (No. 11) of ≥ 3, those answering "Yes" to question 4 or 5 of the 
Columbia Suicide Severity Rating Scale (C-SSRS) at baseline, or those who are, based on current 
psychiatric symptoms or past medical history, at high risk of suicide during the trial in the opinion of 
the investigator or subinvestigator 
15 
Subjects with clinically significant neurological, hepatic, renal, metabolic, hematological, 
immunological, cardiovascular, pulmonary, or gastrointestinal disorders; subjects can be enrolled if 
the conditions are mild or well controlled and will not hamper assessment of safety and efficacy. 


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Table 3.4.3-1 
Exclusion Criteria 
16 
Patients meeting any of the following criteria 
• 
Patients with type 1 diabetes mellitus or patients with type 2 diabetes mellitus being treated 
with insulin 
• 
Patients with type 2 diabetes mellitus who have not been maintained on a stable regimen of 
anti-diabetic medication(s) or undergone diet/exercise therapy for at least 28 days prior to 
baseline 
• 
Patients meeting either of the following criteria for poor blood glucose control at Week 6 of 
the double-blind period (Phase B) of the double-blind trial (331-102-00058) (assessed based 
on results from the central laboratory) 
a) HbA1c of ≥ 7.0% according to the global standard value [NGSP value] 
b) Fasting blood glucose level of ≥ 126 mg/dL or non-fasting blood glucose level of 
≥ 200 mg/dL 
17 
Subjects with substance abuse or substance dependence, including alcohol and benzodiazepines, 
based on DSM-5 diagnostic criteria within 180 days prior to informed consent; caffeine and nicotine 
are not included. 
18 
Subjects with a complication of hypothyroidism or hyperthyroidism at informed consent (excluding 
those in a stable condition due to medications for the previous 90 days or longer), or abnormal 
thyroid stimulating hormone (TSH) and free thyroxine (FT4) levels at Week 6 of the double-blind 
period (Phase B) of the double-blind trial (331-102-00058) (assessed based on results from the 
central laboratory) 
19 
Subjects meeting any of the following criteria or showing symptoms at baseline 
a) Poorly controlled hypertension (diastolic blood pressure of > 95 mmHg) 
b) Hypotension with symptoms 
c) Orthostatic hypotension in which blood pressure after 3 minutes of standing is 
≥ 30 mmHg lower for systolic blood pressure or ≥ 20 mmHg lower for diastolic blood 
pressure, compared with pressures in the supine position before standing 
20 
Subjects with a complication of ischemic heart diseases, myocardial infarction, or congestive heart 
failure (irrespective of well or poorly controlled), or subjects with a history of angioplasty, stent 
placement, or coronary artery bypass 
21 
Subjects with a history of neuroleptic malignant syndrome or serotonin syndrome 
22 
Subjects with a history or complication of epilepsy or epileptic seizures, excluding pediatric febrile 
seizures, post-traumatic seizures, alcohol withdrawal seizures, and other seizures 
23 
Subjects with a history of hypersensitivity to antidepressants 
24 
Subjects with the following clinical laboratory test values or ECG parameters at Week 6 of the 
double-blind period (Phase B) of the double-blind trial (331-102-00058) (assessed based on results 
from the central laboratory and central ECG measurement facility) 
a) Platelet count: ≤ 75,000 /mm3 
b) Hemoglobin: ≤ 9 g/dL 
c) Absolute neutrophil count: ≤ 1000 /mm3 
d) Aspartate aminotransferase (AST): > 2 times the upper limit of the reference range 
e) Alanine aminotransferase (ALT): > 2 times the upper limit of the reference range 
f) 
Creatine phosphokinase (CPK): > 3 times the upper limit of the reference range 
g) Creatinine: ≥ 2 mg/dL 
h) QT interval as corrected by Fridericia’s formula (QTcF): ≥ 450 msec 
25 
Subjects with a history or complication of allergy to more than one medication 


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Table 3.4.3-1 
Exclusion Criteria 
26 
The following subjects falling under the contraindications in the package insert for brexpiprazole 
tablet 
a) Subjects in a coma 
b) Subjects under the strong influence of central nervous system depressants including 
barbiturate analogs/anesthetics 
c) Subjects receiving adrenaline 
d) Subjects with a history of hypersensitivity to components of brexpiprazole tablet 
27 
Subjects who otherwise should not participate in the trial in the opinion of the investigator or 
subinvestigator 
New Subjects 
28 
Sexually active male subjects who will not agree to practice 2 different methods of birth control or to 
remain abstinent during the trial and for 30 days after the final IMP administration. For birth control, 
2 of the following methods must be used: vasectomy, tubal ligation, vaginal diaphragm, intra-uterine 
contraceptive device (IUD), oral contraceptives, or condom with spermicide. 
29 
Patients who have received at least 4 appropriate antidepressant drug treatments for the current major 
depressive episode but whose response was inadequate to all treatments 
30 
Patients receiving treatment with antipsychotics and psychostimulants for the current major 
depressive episode (excluding the use of sulpiride for depression/depressive state or gastric/duodenal 
ulcer) 
31 
Patients receiving treatment with MAO inhibitors within 2 weeks before baseline 
32 
Patients using benzodiazepines (excluding ultrashort-acting sleep inducers) within 1 week before 
baseline 
33 
Patients with a treatment history showing that all antidepressants (also including those not used for 
the current major depressive episode) cannot be tolerated 
34 
Patients with a history of electroconvulsive therapy 
35 
Patients with a diagnosis of any of the following diseases according to DSM-5 
a) 
Neurocognitive disorders 
b) Schizophrenia spectrum and other psychotic disorders 
c) 
Bipolar and related disorders 
d) Feeding and eating disorders 
e) 
Obsessive-compulsive disorder 
f) 
Panic disorder 
g) Posttraumatic stress disorder 
36 
Patients with a diagnosis of any personality disorders (borderline personality disorder, antisocial 
personality disorder, paranoid personality disorder, schizoid personality disorder, schizotypal 
personality disorder, and histrionic personality disorder) according to DSM-5 
37 
Patients experiencing hallucinations or delusions, or showing mood-incongruent psychotic features, 
in the current major depressive episode 
38 
Patients receiving a new psychotherapy within 6 weeks prior to informed consent 
39 
Patients who have previously taken brexpiprazole 
40 
Patients who have participated in other clinical trials within 60 days prior to informed consent 
41 
Patients answering "Yes" to question 4 or 5 of C-SSRS at screening or baseline, or those who are, 
based on current psychiatric symptoms or past medical history, at high risk of suicide during the trial 
in the opinion of the investigator or subinvestigator 
42 
Patients with clinically significant neurological, hepatic, renal, metabolic, hematological, 
immunological, cardiovascular, pulmonary, or gastrointestinal disorders; patients can be enrolled if 
the conditions are mild or well controlled and will not hamper assessment of safety and efficacy. 


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Protocol Version 3.0, 23 Jan 2020 
Table 3.4.3-1 
Exclusion Criteria 
43 
Patients meeting any of the following criteria 
• 
Patients with type 1 diabetes mellitus or patients with type 2 diabetes mellitus being treated 
with insulin 
• 
Patients with type 2 diabetes mellitus who have not been maintained on a stable regimen of 
anti-diabetic medication(s) or undergone diet/exercise therapy for at least 28 days prior to 
screening 
• 
Patients meeting either of the following criteria for poor blood glucose control at screening 
(assessed based on results from the central laboratory) 
a) HbA1c of ≥ 8.0% according to the global standard value [NGSP value] 
b) Fasting blood glucose level of ≥ 126 mg/dL or non-fasting blood glucose level of 
≥ 200 mg/dL 
44 
Patients with substance abuse or substance dependence, including alcohol and benzodiazepines, 
based on DSM-5 diagnostic criteria within 180 days prior to informed consent; caffeine and nicotine 
are not included 
45 
Patients with a complication of hypothyroidism or hyperthyroidism at informed consent (excluding 
those in a stable condition due to medications for the previous 90 days or longer since acquisition of 
informed consent), or abnormal TSH and FT4 levels at screening (assessed based on results from the 
central laboratory) 
46 
Patients meeting any of the following criteria or showing symptoms at screening or baseline 
a) Poorly controlled hypertension (diastolic blood pressure of > 95 mmHg) 
b) Hypotension with symptoms 
c) Orthostatic hypotension in which blood pressure after 3 minutes of standing is 
≥ 30 mmHg lower for systolic blood pressure or ≥ 20 mmHg lower for diastolic blood 
pressure, compared with pressures in the supine position before standing 
47 
Patients with a complication of ischemic heart disease, myocardial infarction, or congestive heart 
failure (irrespective of well or poorly controlled), or patients with a history of angioplasty, stent 
placement, or coronary artery bypass 
48 
Patients with a history of neuroleptic malignant syndrome or serotonin syndrome 
49 
Patients with a history or complication of epilepsy or epileptic seizures, excluding pediatric febrile 
seizures, post-traumatic seizures, alcohol withdrawal seizures, and other seizures 
50 
Patients with the following clinical laboratory test values or ECG parameters at screening (assessed 
based on results from the central laboratory and central ECG measurement facility) 
a) Platelet count: ≤ 75,000 /mm3 
b) Hemoglobin: ≤ 9 g/dL 
c) Absolute neutrophil count: ≤ 1000 /mm3 
d) AST: > 2 times the upper limit of the reference range 
e) ALT: > 2 times the upper limit of the reference range 
f) 
CPK: > 3 times the upper limit of the reference range 
g) Creatinine: ≥ 2 mg/dL 
h) QTcF: ≥ 450 msec 
51 
Patients with a history of hypersensitivity to antidepressants 
52 
Patients with a history or complication of allergy to more than one medication 


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Table 3.4.3-1 
Exclusion Criteria 
53 
The following patients falling under the contraindications in the package insert for brexpiprazole 
tablet 
a) Patients in a coma 
b) Patients under the strong influence of central nervous system depressants including 
barbiturate analogs/anesthetics 
c) Patients receiving adrenaline 
d) Patients with a history of hypersensitivity to components of brexpiprazole tablet 
54 
Patients who otherwise should not participate in the trial in the opinion of the investigator or 
subinvestigator 
 
[Rationale for exclusion criteria] 
Rollover subjects 
1, 2.  These criteria are specified in view of safety, as safety of treatment with the drug is yet to be 
established in pregnant and breastfeeding women. 
3.  This criterion is specified for appropriate assessment of efficacy. 
4.  This criterion is specified in view of safety 
5, 6.  These criteria are specified for appropriate assessment of efficacy. 
7.  This criterion is specified in view of safety, as package inserts for antidepressants indicate that for 
subjects receiving MAO inhibitors, the antidepressants should be administered after an interval of at 
least 2 weeks from discontinuation of MAO inhibitors. 
8.  This criterion is specified for appropriate assessment of efficacy. 
9.  This criterion is specified in view of safety. 
10.  This criterion is specified in view of safety, as a combination of antidepressants and electroconvulsive 
therapy is likely to lower the convulsive threshold. 
11 to 13.  These criteria are specified for appropriate assessment of efficacy. 
14. This criterion is specified to minimize the risk of suicide during the trial. 
15 to 17.  These criteria are specified in view of safety. 
18.  This criterion is specified for appropriate assessment of efficacy, as subjects with thyroid disorders 
may have depressive symptoms. 
19 to 21.  These criteria are specified in view of safety. 
22.  This criterion is specified in view of safety, as the drug may lower the convulsive threshold. 
23 to 27.  These criteria are specified in view of safety. 
 
New subjects 
28.  This criterion is specified in view of safety. 
29,30  These criteria are specified for appropriate assessment of efficacy. 
31.  This criterion is specified in view of safety, as package inserts for antidepressants indicate that for 
patients receiving MAO inhibitors, the antidepressants should be administered after an interval of at 
least 2 weeks from discontinuation of MAO inhibitors. 
32.  This criterion is specified for appropriate assessment of efficacy. 
33.  This criterion is specified in view of safety. 
34.  This criterion is specified in view of safety, as a combination of antidepressants and electroconvulsive 
therapy is likely to lower the convulsive threshold. 
35 to 40.  These criteria are specified for appropriate assessment of efficacy. 
41.  This criterion is specified to minimize the risk of suicide during the trial. 
42 to 44.  These criteria are specified in view of safety. 
45.  This criterion is specified for appropriate assessment of efficacy, as patients with thyroid disorders may 
have depressive symptoms. 
46 to 48.  These criteria are specified in view of safety. 
49.  This criterion is specified in view of safety, as the drug may lower the convulsive threshold. 
50 to 54.  These criteria are specified in view of safety. 
 


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3.5 
Endpoints 
3.5.1 
Safety Endpoints 
• Adverse events 
• Physical examination 
• Clinical laboratory tests 
• Vital signs (body temperature, diastolic blood pressure, systolic blood pressure, and 
pulse rate [supine, sitting, and standing positions]) 
• Waist circumference 
• 12-lead ECG 
• Body weight 
• Body mass index (BMI) 
• Drug induced Extra-pyramidal Symptom Scale (DIEPSS) 
• Abnormal Involuntary Movement Scale (AIMS) 
• Barnes Akathisia Rating Scale (BARS) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
 
3.5.2 
Efficacy Endpoints 
• Mean changes from baseline in MADRS total scores 
• MADRS response rate 
The proportion of subjects in whom MADRS total scores have been reduced by at 
least 50% from baseline 
• MADRS remission rate 
The proportion of subjects in whom MADRS total scores have been reduced by at 
least 50% from baseline, with their resultant MADRS total scores being ≤ 10 
• Clinical Global Impression — Improvement (CGI-I) improvement rate 
The proportion of subjects who score 1 or 2 on the CGI-I scale 
• Mean changes from baseline in CGI-S 
• Mean changes from baseline in Hamilton Rating Scale for Depression (HAM-D) 17-
item total score 
• Mean changes from baseline in mean Sheehan Disability Scale (SDS) score 
 
[Rationale] 
MADRS is used worldwide as a depression assessment scale, was created primarily to 
assess psychiatric symptoms of depression and exclude somatic symptoms, and is 
generally used in clinical trials that involve patients with major depressive disorder; 
therefore, the same endpoint will be employed in this trial also. 


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The MADRS response rate and MADRS remission rate were selected because they are 
useful for assessing the effects of antidepressants and are used in many clinical trials 
utilizing MADRS. 
CGI-I and CGI-S were selected because they are an overall assessment that enables 
comprehensive assessment of the subject’s clinical symptoms and are used in many 
clinical trials. HAM-D was selected because it is useful for assessing a wide range of 
depressive symptoms including somatic and psychiatric symptoms and is used in many 
clinical trials. SDS was selected because it is a functional impairment assessment scale 
composed of 3 daily living function-related items (work/school, social life, and 
communication and role within in family), and enables functional assessment through 
self-assessment. 
3.5.3 
Other Endpoints 
• EuroQol-5 Dimension 5-level (EQ-5D-5L) questionnaire 
 
3.6 
Measures to Minimize/Avoid Bias 
This is an uncontrolled trial. 
3.7 
Trial Procedures 
The schedule of all examinations and assessments/observations in the screening period, 
treatment period, and post-treatment observation period is provided in Table 3.7-1. 
The investigator or subinvestigator should conduct observations, examinations, and 
evaluations in accordance with the schedules. For items that can be performed by a 
clinical trial associate, such as examination of subject demographics and clinical 
laboratory tests, a clinical trial associate can perform them under the supervision of the 
investigator. 


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Table 3.7-1 
Schedule of Assessments 
 
 
Treatment Period 
Post-treatment observation period j  
30 days after final dose  
(± 5 days) 
Test Period 
(Acceptable 
Window) 
 
 
 
Items 
At screening (new subjects)b 
At baseline (rollover subjects) 
At baseline (new subjects) 
Week 1 (± 2 days) 
Week 2 (± 2 days) 
Week 4 (± 2 days) 
Week 8 (± 7 days) 
Week 12 (± 7 days) 
Week 16 (± 7 days) 
Week 20 (± 7 days) 
Week 24 (± 7 days) 
Week 28 (± 7 days) 
Week 32 (± 7 days) 
Week 36 (± 7 days) 
Week 40 (± 7 days) 
Week 44 (± 7 days) 
Week 48 (± 7 days) 
Week 52 (± 7 days) 
At discontinuation 
Acquisition of 
informed 
consent 
● 
●d 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
judgement 
● 
● 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject 
demographics 
● 
●e 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MADRS 
 
●f 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
CGI-I 
 
 
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
CGI-S 
 
●f 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
HAM-D 
 
●f 
● 
 
 
 
 
 
 
 
● 
 
 
 
 
 
 
● 
● 
 
SDS 
 
●f 
● 
 
 
 
 
 
   
 
● 
 
 
 
 
 
 
● 
● 
 
EQ-5D-5L 
questionnaire 
 
● 
● 
 
 
 
● 
 
 
 
● 
 
 
● 
 
 
 
● 
● 
 
Laboratory 
tests 
●c 
●c, f  
 
 
 
● 
● 
 
● 
 
● 
 
● 
 
● 
 
 
●c 
● 
 
Vital signs 
● 
●f 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
Physical 
examination 
● 
●f 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Waist 
circumference 
 
●f 
● 
 
 
● 
● 
 
● 
 
● 
 
● 
 
● 
 
 
● 
● 
 
Height 
● 
●g 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight 
● 
●f 
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
12-lead ECG 
● 
●f 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Pregnancy test 
 
●f, h 
 
 
 
 
●h 
 
 
 
●h 
 
 
 
●h 
 
 
●h ●h 
 
C-SSRS 
● 
●f 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
DIEPSS 
 
●f 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
AIMS 
 
●f 
● 
 
 
 
● 
 
 
 
● 
 
 
 
 
 
 
● 
● 
 
BARS 
 
●f 
● 
 
 
 
● 
 
 
 
● 
 
 
 
 
 
 
● 
● 
 
Blood 
sampling for 
DNA storage 
 
 
 
 
 
●i 
 
 
 
 
 
 
 
 
 
 
 
 
●i 
 


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Table 3.7-1 
Schedule of Assessments 
 
 
Treatment Period 
Post-treatment observation period j  
30 days after final dose  
(± 5 days) 
Test Period 
(Acceptable 
Window) 
 
 
 
Items 
At screening (new subjects)b 
At baseline (rollover subjects) 
At baseline (new subjects) 
Week 1 (± 2 days) 
Week 2 (± 2 days) 
Week 4 (± 2 days) 
Week 8 (± 7 days) 
Week 12 (± 7 days) 
Week 16 (± 7 days) 
Week 20 (± 7 days) 
Week 24 (± 7 days) 
Week 28 (± 7 days) 
Week 32 (± 7 days) 
Week 36 (± 7 days) 
Week 40 (± 7 days) 
Week 44 (± 7 days) 
Week 48 (± 7 days) 
Week 52 (± 7 days) 
At discontinuation 
Adverse events ←-----------------------------------------------------------------------------------------------------------------------------→ 
IMP and 
requisite 
concomitant 
medicationa 
 
 
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
Concomitant 
drugs/ 
therapies 
←-----------------------------------------------------------------------------------------------------------------------------→ 
a Treatment compliance regarding IMP and requisite concomitant medication will be recorded. 
b Clinical laboratory test values and body weight values at screening will be used as baseline values. 
c For this item, subjects will be asked to visit the trial site in a fasting state (a fast for at least 8 hours 
[including drinks containing sugar, such as juice]) at screening, baseline, and Week 52, and in a 
fasting state to the extent possible at other times, including at the discontinuation examination. 
d Informed consent will be obtained after the observations, examinations, and assessments at Week 6 of 
the double-blind period (Phase B) of the double-blind trial (331-102-00058) and before the baseline 
assessments for this trial. 
e Data taken at screening for the double-blind trial (331-102-00058) will be used as the subject 
demographic data for rollover subjects (date of birth, sex, childbearing potential, race, ethnicity, 
country where trial is performed, history of major depressive disorder, medical history, 
complications). Medical history and complications will be reinvestigated. 
f For rollover subjects, if the examinations and assessments at Week 6 of the double-blind period (Phase 
B) of the double-blind trial (331-102-00058) have been performed within a period of 7 days prior to 
the day of baseline assessment (Day −7 to Day 0), the data will be used as baseline data for this trial. 
g For rollover subjects, data obtained at screening in the double-blind trial (331-102-00058) will be used. 
h Pregnancy tests will be performed only in female subjects of childbearing potential. 
i Blood sampling for DNA storage will be performed once only for new subjects who have provided 
written consent. Blood sampling will be performed at discontinuation only for subjects who 
discontinue before the Week 4 visit. 
j The starting point of the post-treatment observation period is the day of the final IMP administration. 
 


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3.7.1 
Schedule of Assessments 
3.7.1.1 
Informed Consent 
Before all examinations, written informed consent is to be obtained from subjects. 
Rollover subjects will provide written informed consent after completion of the 
observations, examinations, and assessments at Week 6 of the preceding double-blind 
trial (331-102-00058). The procedures for progressing from the double-blind trial (331-
102-00058) are separately specified in written procedures. After acquisition of informed 
consent, subjects will be registered in the interactive web response system (IWRS). For 
rollover subjects, the same subject ID will be used as in the double-blind trial (331-102-
00058) and for new subjects a new subject ID will be assigned. Management of IWRS 
after the first registration is separately specified in written procedures, as a management 
system particularly for subject enrollment status and IMP. The investigator or 
subinvestigator will record the date on which signed inform consent was obtained in the 
subject screening log. The subject ID and date on which signed inform consent was 
obtained will also be recorded in the source documents and the case report form (CRF). 
3.7.1.2 
Screening (New Subjects Only) 
After acquisition of informed consent and within 28 days before commencement of the 
treatment period, the investigator or subinvestigator will perform the examinations and 
assessments at the screening (Table 3.7-1) and record the results in the source documents 
and CRF, and will also judge subject eligibility for trial participation. The investigator or 
subinvestigator will then record enrollment status, date of enrollment, and reasons for any 
failed enrollment in the subject screening log. 
The investigator or subinvestigator will examine the following subject demographics and 
record the results in the source documents and the CRF. Regarding the treatment history 
for the current major depressive episode, all antidepressant prior medications and their 
effectiveness, as well as psychotherapies/somatic therapies up until 6 weeks before 
informed consent will be examined. To determine their effectiveness, the results of 
evaluation will be classified as < 25% Improvement, 25% to 49% Improvement, 50% to 
< 75% Improvement, and ≥ 75% Improvement (complete recovery from depressive 
symptoms and not the slightest improvement considered as 100% and 0%, respectively), 
based on the patient’s self-evaluations. 
• Date of visit 
• Subject demographics 
− Date of investigation 
− Date of birth 


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− Sex 
− Race 
− Ethnicity 
− Country where trial is performed 
− DSM-5-based diagnostic name and severity as well as specific terms (with 
anxious distress, with mixed features, with melancholic features, with atypical 
features, with mood-congruent psychotic features, with mood-incongruent 
psychotic features, with catatonia, with peripartum onset, and with seasonal 
pattern) 
− Date of first onset of major depressive disorder 
− Frequency of major depressive episodes 
− Date of onset of the current depressive episode 
− Prior medication used to treat the current major depressive episode (all 
antidepressants) 
− Prior therapy used to treat the current major depressive episode 
(psychotherapies/somatic therapies up until 6 weeks before informed consent) 
− Frequency of appropriate antidepressant drug treatments of the current major 
depressive episode (treatment for at least 6 weeks at the approved dose for the 
antidepressant, or treatment for at least 3 weeks with combination therapy) 
− All prior medications and therapies used within 30 days before acquisition of 
informed consent 
− Medical history (within 2 years before acquisition of informed consent, although 
matters pertaining to the inclusion or exclusion criteria are not limited to 2 years) 
and complications 
• Results of eligibility criteria assessment 
 
3.7.1.3 
Observations/Examinations in the Treatment Period (52 Weeks) 
The investigator or subinvestigator will judge eligibility of rollover subjects from the 
double-blind trial (331-102-00058), based on the results of examinations and assessments 
at baseline and clinical laboratory values and 12-lead ECG at Week 6 of the double-blind 
period (Phase B) of the double-blind trial (331-102-00058). The treatment period will 
commence within 28 days from Week 6 of the double-blind period (Phase B) of the 
double-blind trial (331-102-00058). If the examinations and assessments at Week 6 of the 
double-blind period (Phase B) of the double-blind trial (331-102-00058) have been 
performed within a period of 7 days prior to the day of baseline assessment (Day −7 to 
Day 0), the data will be used as baseline data for this trial. The eligibility of new subjects 
will be judged based on the results of examinations and assessments at screening and 
baseline. The result of the eligibility judgement will be registered in the IWRS and 


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recorded in the source documents and CRF. If subjects are judged to be eligible, the date 
of enrollment in the treatment period will be recorded in the source documents and CRF. 
Eligible subjects will start receiving brexpiprazole at a starting dose of 1 mg/day, in an 
open-label manner. 
The investigator or subinvestigator will perform examinations/assessments in the 
treatment period, as specified in the schedule of examinations/assessments (Table 3.7-1) 
and record the result along with the visit date in the source documents and the CRF. 
The investigator or subinvestigator will register the required items in IWRS at the time of 
each subject’s completion of IMP administration in Week 52. 
3.7.1.4 
Observations/Examinations in the Post-treatment Observation 
Period 
For all subjects receiving the IMP, the investigator or subinvestigator will perform the 
assessments scheduled for the post-treatment observation period, as specified in the 
schedule of examinations/assessments (Table 3.7-1), 30 days (± 5 days) after final IMP 
administration and record the results along with the visit date in the source documents 
and the CRF. The investigator or subinvestigator will register the required items in IWRS 
at the time of each subject’s conclusion of the post-treatment observation period. 
3.7.1.5 
Examinations at Discontinuation 
If a subject is withdrawn from the trial during the treatment period, the investigator or 
subinvestigator will perform the required examinations at discontinuation, as specified in 
the schedule of examinations/assessments (Table 3.7-1) and record the results along with 
the visit date in the source documents and the CRF. 
The investigator or subinvestigator will register the required items in IWRS at the time of 
each subject’s withdrawal. 
3.7.1.6 
Acceptable Window for Testing 
Observations/examinations and other procedures are to be performed within an 
acceptable window for testing, as specified in Table 3.7.1.6-1, with consideration of the 
availability of each subject for site visits, etc. 


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Table 3.7.1.6-1 
Acceptable Window for Examinations/Assessment Period 
Examination Point 
Reference Day 
Acceptable Window 
(From the Reference 
Day) 
At screening (new subjects only) 
Day of baseline 
assessment 
−28 to −1 days 
Day of baseline assessment 
Day 1 
− 
Week 1 of the treatment period 
Day 8 
± 2 days 
Week 2 of the treatment period 
Day 15 
± 2 days 
Week 4 of the treatment period 
Day 29 
± 2 days 
Week 8 of the treatment period 
Day 57 
± 7 days 
Week 12 of the treatment period 
Day 85 
± 7 days 
Week 16 of the treatment period 
Day 113 
± 7 days 
Week 20 of the treatment period 
Day 141 
± 7 days 
Week 24 of the treatment period 
Day 169 
± 7 days 
Week 28 of the treatment period 
Day 197 
± 7 days 
Week 32 of the treatment period 
Day 225 
± 7 days 
Week 36 of the treatment period 
Day 253 
± 7 days 
Week 40 of the treatment period 
Day 281 
± 7 days 
Week 44 of the treatment period 
Day 309 
± 7 days 
Week 48 of the treatment period 
Day 337 
± 7 days 
Week 52 of the treatment period 
Day 365 
± 7 days 
At discontinuation 
− 
− 
At discontinuation: Performed within a possible window at a feasible time point. 
 
The starting point of the post-treatment observation period is the day of the final IMP 
administration. 
Period 
Reference Day 
Acceptable Window  
(From the Reference Day) 
Day of the final IMP administration 
Day 1 
− 
The post-treatment observation period 
Day 31 
± 5 days 
 
3.7.2 
Efficacy Assessments 
3.7.2.1 
Montgomery Åsberg Depression Rating Scale 
(1) 
Time points 
At baseline and Weeks 1, 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52 (or 
discontinuation) 
(2) 
Method 
A trained and qualified investigator or subinvestigator will assess the following 10 
symptoms of depression in the subject on a 7-point scale (0 to 6) using the Structured 
Interview Guide for the MADRS (SIGMA) at specified assessment time points, and 
record the date, time, and results of assessment in the source documents and the CRF. 


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1. Apparent sadness 
2. Reported sadness 
3. Inner tension 
4. Reduced sleep 
5. Reduced appetite 
6. Concentration difficulties 
7. lassitude 
8. Inability to feel 
9. Pessimistic thoughts 
 
10. Suicidal thoughts 
 
 
 
 
 
3.7.2.2 
Clinical Global Impression - Improvement 
(1) 
Time points 
At Weeks 1, 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52 (or discontinuation) 
(2) 
Method 
The investigator or subinvestigator will assess the improvement of depressive symptoms 
in the subject on the following 8-point scale using CGI-I at specified assessment time 
points, and record the date, time, and results of assessment in the source documents and 
the CRF. 
0. Not assessed 
1. Very much improved 
2. Much improved 
3. Minimally improved 
4. No change 
5. Minimally worse 
6. Much worse 
7. Very much worse 
 
3.7.2.3 
Clinical Global Impression - Severity of Illness 
(1) 
Time points 
At baseline and Weeks 1, 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52 (or 
discontinuation) 
(2) 
Method 
The investigator or subinvestigator will assess the severity of the subject’s depressive 
symptoms on the following 8-point scale using CGI-S at the specified assessment time 
points, and record the date, time, and results of assessment in the source documents and 
the CRF. 
0. Not assessed 
1. Normal, not at all ill 
2. Borderline mentally ill 
3. Mildly ill 
4. Moderately ill 
5. Markedly ill 
6. Severely ill 
 
7. Among the most extremely ill patients 
 
 
3.7.2.4 
Hamilton Rating Scale for Depression 
(1) 
Time points 
At baseline and Weeks 24 and 52 (or discontinuation) 


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(2) 
Method 
A trained and qualified investigator or subinvestigator will assess the following 21 
symptoms of depression in the subject on a 5-point scale (0 to 4) for Items No. 1, 2, 10 to 
14, 16 to17, and 19, on a 4-point scale (0 to 3) for Items No. 5 and 20, and on a 3-point 
scale (0 to 2) for Items No. 3, 4, 6 to 9, 15, 18, and 21 using the Structured Interview 
Guide for the HAM-D (SIGH-D) at specified assessment time points, and calculate the 
total score for Items No. 1 to 17, and record the date, time, and results of the assessment 
in the source documents and the CRF. 
1. Depressed mood 
2. Work and activities 
3. Genital symptoms 
 
4. Somatic symptoms, gastrointestinal 
5. Loss of weight 
6. Early (initial) insomnia 
7. Middle insomnia 
8. Late (terminal) insomnia 
9. Somatic symptoms, general 
 
10. Feelings of guilt 
11. Suicide 
12. Anxiety psychic 
13. Anxiety somatic 
14. Hypochondriasis 
15. Insight 
16. Retardation 
17. Agitation 
18. Diurnal variation 
19. Depersonalization and derealization 
20. Paranoid symptoms 
 
 
21. Obsessional and compulsive symptoms 
 
 
 
 
3.7.2.5 
Sheehan Disability Scale 
(1) 
Time points 
At baseline and Weeks 24 and 52 (or discontinuation) 
(2) 
Method 
The investigator or subinvestigator will use the SDS at specified assessment time points 
and ask subjects to self-rate the degree of impairment for each of 3 items (“work/school,” 
“social life,” and “family life/home responsibilities”) on an 11-point scale ranging from 0 
(not at all) to 10 (extremely) and the number of "days lost" and "days unproductive" 
caused by symptoms in the past week. The investigator or subinvestigator will record the 
date, time, and results of assessment in the source documents and the CRF. 
3.7.3 
Other Assessments 
3.7.3.1 
EuroQol-5 Dimension 
(1) 
Time points 
At baseline and Weeks 8, 24, 36, and 52 (or discontinuation) 


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(2) 
Method 
The investigator will use the EQ-5D-5L questionnaire at specified assessment time points 
and allow the subject self-assess their general health on the day of assessment, and record 
the date, time, and results of assessment in the source documents and the CRF. The EQ-
5D-5L questionnaire consists of 2 parts: In Part 1, the subject will self-assess 5 domains 
(mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) on a scale 
of 1 to 5 (1 = no problems, 2 = slight problems, 3 = moderate problems, 4 = severe 
problems, 5 = extreme problems); In Part 2, the subject will self-rate their health on a 
visual analog scale (0 = the worst health you can imagine, 100 = the best health you can 
imagine).  
3.7.4 
Safety Assessments 
3.7.4.1 
Adverse Events 
Refer to Section 5, Reporting of Adverse Events. 
3.7.4.2 
Clinical Laboratory Assessments 
(1) 
Time points 
At screening (new subjects only, in the fasting state), baseline (rollover subjects only, in 
the fasting state), Weeks 4, 8, 16, 24, 32, and 40 (in the fasting state to the extent 
possible), and Week 52 (in the fasting state) or discontinuation (in the fasting state to the 
extent possible) 
(2) 
Method 
Subjects will be asked to visit the trial site in a fasting state (a fast for at least 8 hours 
[including drinks containing sugar, such as juice]) at screening (new subjects only), 
baseline (rollover subjects only), and Week 52, and in a fasting state to the extent 
possible at other time points including examination at discontinuation. 
Blood and urine samples will be collected from each subject at the time of clinical 
laboratory tests as specified in the assessment schedules shown in Table 3.7-1, and the 
date and time of blood sampling and the date of urine sampling as well as the fasting or 
fed state during blood sampling will be recorded in the source documents and the CRF. In 
this trial, the central laboratory selected by the sponsor will be used. Clinical laboratory 
test values determined at the central laboratory will be used for eligibility assessment. For 
appropriate procedures for the collection, handling, and shipment of samples, separately 
documented procedures will be prepared and provided prior to the start of the trial. The 
central laboratory will report the results of tests to the investigator or subinvestigator. The 
investigator or subinvestigator will confirm the results of tests and date and sign the 


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clinical laboratory test report to make it an official document. The results of laboratory 
tests, which will be reported directly from the central laboratory to the sponsor as an 
electronic file, do not need to be recorded in the source documents or the CRF. 
Table 3.7.4.2-1 
Clinical Laboratory Assessments 
Hematology: 
Red Blood Cell count 
White blood cell count 
Differential count of white blood cells (neutrophils, 
eosinophils, basophils, monocytes, lymphocytes) 
Platelet count 
Hemoglobin 
Hematocrit 
 
Urinalysis: 
pH 
Protein 
Glucose 
Occult blood 
Urobilinogen 
Specific gravity 
Ketone body 
Serum Chemistry: 
AST (Glutamic oxaloacetic transaminase [GOT]) 
ALT (Glutamic pyruvic transaminase [GPT]) 
Alkaline Phosphatase (ALP) 
Lactic Dehydrogenase (LDH) 
Gamma-glutamyl transpeptidase (γ-GTP) 
Total protein 
Albumin 
Total bilirubin 
Cholesterol (total cholesterol, low-density 
lipoprotein [LDL] cholesterol, and high-density 
lipoprotein [HDL] cholesterol) 
Triglycerides 
Blood urea nitrogen (BUN) 
Creatinine 
Uric acid 
Creatine kinase (CK) (CPK) 
Serum electrolytes (Na, K, Cl, Ca, Mg, P, 
bicarbonate) 
Blood glucose 
HbA1c (NGSP value) 
Prothrombin time (PT) 
Activated partial thromboplastin time (APTT) 
PT (international normalized ratio [INR]) 
 
Endocrinology: 
Serum prolactin 
Insulin 
FT4 
TSH 
 
To be performed in subjects in a fasting state (a fast for at least 8 hours [including drinks containing 
sugar, such as juice]) at screening (new subjects only), baseline (rollover subjects only), and Week 52, 
and in a fasting state to the extent possible at other time points including examination at 
discontinuation 
 
3.7.4.3 
Vital Signs and Physical Examination 
(1) 
Vital signs 
(a) Time points 
At screening (new subjects only), baseline, and Weeks 1, 2, 4, 8, 12, 16, 20, 24, 28, 32, 
36, 40, 44, 48, and 52 (or discontinuation) 
(b) Method 
After keeping the subject in a relaxed state, body temperature will be measured and 
then blood pressure (systolic and diastolic) and pulse rate will be measured in the 


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supine, sitting, and standing positions in accordance with the measurement methods 
specified by the trial site. For body temperature, the date and result of measurement 
will be recorded in the source documents and the CRF. Blood pressure and pulse rate 
will be measured in the supine, sitting, and standing positions, in this order, after 
maintaining each position for at least 3 minutes. The date, time, positions, and results 
of measurement will be recorded in the source documents and the CRF. 
(2) 
Physical examination 
(a) Time points 
At screening (new subjects only), baseline, Weeks 1, 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 
40, 44, 48, and 52 (discontinuation), and post-treatment observation 
(b) Method 
The investigator or subinvestigator will perform a physical examination that includes 
assessment items shown below through a medical interview and other relevant methods 
and record physical findings in the source documents. At screening (new subjects) and 
baseline (rollover subjects), the date and results of examination will be recorded, and at 
baseline (new subjects) and from Week 1 (rollover subjects) onward, only the date of 
examination will be recorded in the source documents and the CRF. Any clinically 
significant physical findings compared with findings at screening (new subjects) or 
baseline (rollover subjects) are to be recorded as AEs. 
Assessment items: HEENT (head, eyes, ears, nose, and throat), chest, abdomen, 
urogenital system, limbs, nerves, skin, and mucosa. 
(3) 
Waist circumference 
(a) Time points 
At baseline and Weeks 4, 8, 16, 24, 32, 40, and 52 (or discontinuation) 
(b) Method 
Measurement will be performed while the subject is minimally clothed (lightly clothed, 
removing heavy outer garments). The top of the hip bone and the upper edge of the 
right iliac crest will be located, and then a measuring tape will be placed horizontally 
all the way around the abdomen at the height of the iliac crest. Prior to measurement, 
the person engaged in measurement should ensure that the measuring tape is snug 
without indenting the subject’s skin and parallel to the floor. At the end of a normal 
expiration, waist circumference will be measured in centimeters (rounded off to the 
nearest whole number) and the date and result of measurement will be recorded on the 
source documents and the CRF. 


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(4) 
Height and body weight 
(a) Time points 
At screening (new subjects only), baseline (rollover subjects only), and Weeks 4, 8, 12, 
16, 20, 24, 28, 32, 36, 40, 44, 48, and 52 (or discontinuation) 
However, height will be measured only at screening (new subjects only). 
(b) Method 
Body weight and height will be measured at the specified time points and the date and 
results of measurement will be recorded in the source documents and the CRF (body 
weight in increments of 0.1 kg, height in increments of 0.1 cm). Body weight will be 
measured by the standard measurement method (fully clothed but without shoes) using 
a reliable, calibrated scale (the same scale should always be used to measure a 
particular subject). 
3.7.4.4 
12-Lead Electrocardiography 
(1) 
Time points 
At screening (for new subjects only), baseline, and Weeks 4, 8, 16, 24, 32, 40, and 52 (or 
discontinuation) 
(2) 
Method 
The investigator or subinvestigator will perform electrocardiography using a 12-lead 
electrocardiograph supplied by the central ECG laboratory, assess whether the ECG 
result is normal or abnormal, and record the date and time of ECG, normal/abnormal 
judgment, and abnormal findings in the source documents and the CRF. The original of 
the 12-lead ECG chart will be kept in the medical records or the investigator's file. The 
central ECG laboratory will collect 12-lead ECG data and measure heart rate, PR interval, 
RR interval, QRS interval, QT interval, and QT corrected for heart rate (QTc) [QTcB = 
QT interval/(RR interval)1/2, QTcF = QT interval/(RR interval)1/3, QTcN = QT 
interval/(RR interval)0.37], and the physician of the central ECG laboratory will assess the 
data. The central ECG laboratory will report the results of analysis to the investigator or 
subinvestigator. The investigator or subinvestigator will confirm the results of analysis 
and date and sign the analysis result report to make it an official document. The 
investigator or subinvestigator will reconfirm the normal/abnormal judgement with 
reference to the analysis result report sent from the central ECG laboratory. The results of 
analysis, which will be reported directly from the central ECG laboratory to the sponsor 
as an electronic file, do not need to be recorded in the source documents or the CRF. 


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3.7.4.5 
Pregnancy Test 
(1) 
Time points 
At baseline and Weeks 8, 24, 40, and 52 (or discontinuation) 
(2) 
Method 
A urine pregnancy test will be performed in women of childbearing potentiala and the 
date of urine sampling and the result of the test will be recorded in the source documents 
and the CRF. If the urine test is positive (except for test at baseline), another pregnancy 
test will be performed using serum and the date of blood sampling will be recorded in the 
source documents and the CRF. A serum pregnancy test will be performed by the central 
laboratory selected by the sponsor. For appropriate procedures for the collection, 
handling, and shipment of samples, separately documented procedures will be prepared 
and provided prior to the start of the trial. The central laboratory will report the results of 
tests to the investigator or subinvestigator. The investigator or subinvestigator will 
confirm the results of tests and date and sign the clinical laboratory test report to make it 
an official document. The results of serum tests, which will be reported directly from the 
central laboratory to the sponsor as an electronic file, do not need to be recorded in the 
source documents or the CRF. 
a Women of childbearing potential are defined as female subjects for whom 
menstruation has started and who are not documented as sterile (ie, have had a 
bilateral oophorectomy and/or hysterectomy or who have been postmenopausal for 
at least 12 months). 
3.7.4.6 
Columbia-Suicide Severity Rating Scale 
(1) 
Time points 
At screening (new subjects only), baseline, and Weeks 1, 2, 4, 8, 12, 16, 20, 24, 28, 32, 
36, 40, 44, 48, and 52 (or discontinuation), and post-treatment observation 
(2) 
Method 
This scale consists of the "Baseline Version," which assesses the lifetime history of 
suicide-related events and suicidal ideation, and the "Since Last Visit Version," which 
focuses on suicidality since the last assessment in the trial. The "Baseline Version" will 
be used at screening and the "Since Last Visit Version" will be used at subsequent time 
points for C-SSRS assessment. The date, time, and results of assessment will be recorded 
in the source documents and the CRF. 


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The presence of suicidal ideation 1 or 2 will be assessed with “yes” or “no,” and if the 
answer to 2 is “yes,” suicidal ideation 3 to 5 will be assessed. If the answer to suicidal 
ideation 1 or 2 is “yes,” the intensity of ideation will also be rated. Intensity of ideation 
will be rated on a 5-point scale for “frequency” and “duration” and a 6-point scale for 
“controllability,” “deterrents,” and “reasons for ideation.” The following suicidal 
behavior will also be assessed with “yes” or “no,” and the total numbers of each suicide 
attempt will be recorded. If there is an actual attempt, “actual lethality/physical damage” 
will be rated on a 6-point scale, and if actual lethality/physical damage is 0, “potential 
lethality” will be rated on a 3-point scale. 
Suicidal ideation: 
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: 
Actual attempt 
Non-suicidal self-injurious behavior 
 
Interrupted attempt 
Aborted attempt Preparatory acts or behavior 
Suicidal behavior 
Suicide (only for "Since Last Visit Version") 
 
 
3.7.4.7 
Drug-induced Extrapyramidal Symptoms Scale 
(1) 
Time points 
At baseline and Weeks 1, 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52 (or 
discontinuation) 
(2) 
Method 
The investigator or subinvestigator will assess the following 9 items related to extra-
pyramidal symptoms on a 5-point scale ranging from 0 (normal) to 4 (severe) using 
DIEPSS at specified time points. The date, time, and results of assessment will be 
recorded in the source documents and the CRF. 
1. Gait 
2. Bradykinesia 
3. Sialorrhea 
4. Muscle rigidity 
5. Tremor 
6. Akathisia 
7. Dystonia 
8. Dyskinesia 
9. Global severity 
 
 
3.7.4.8 
Abnormal Involuntary Movement Scale 
(1) 
Time points 
At baseline and Weeks 8, 24, and 52 (or discontinuation) 


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(2) 
Method 
Using AIMS, the investigator or subinvestigator will assess the severity of abnormal 
involuntary movements at 7 sites ("muscles of facial expression," "lips and perioral area," 
"jaw," "tongue," "upper extremities [arms, wrists, hands, and fingers]," "lower 
extremities (legs, knees, ankles, and toes)," and "neck, shoulders, and hips,") and 3 global 
judgment items on a 5-point scale ranging from 0 (none) to 4 (severe), and assess the 
dental status items "current problems with teeth and/or dentures" and "Dose patient 
usually wear dentures" as either “yes” or “no,” at the specified time points. The date, time, 
and results of assessment will be recorded in the source documents and the CRF. 
3.7.4.9 
Barnes Akathisia Rating Scale 
(1) 
Time points 
At baseline and Weeks 8, 24, and 52 (or discontinuation) 
(2) 
Method 
Using BARS, the investigator or subinvestigator will assess "objective," "subjective—
awareness of restlessness," and "subjective—distress related to restlessness" for akathisia 
on a 4-point scale and "global clinical assessment of akathisia" on a 6-point scale at the 
specified time points. The date, time, and results of assessment will be recorded in the 
source documents and the CRF. 
3.7.5 
Prior and Concomitant Medications and Therapies 
The investigator or subinvestigator will examine the use of the following prior and 
concomitant medications and therapies. For prior and concomitant medications, the name 
of the drug, purpose of use (excluding prior medications used to treat the current major 
depressive episode), dose, frequency, route of administration, start and end dates of 
treatment, and treatment response (prior medications used to treat the current major 
depressive episode) will be examined and recorded in the source documents and the CRF. 
For prior and concomitant therapies, the name of the therapy, purpose of use (excluding 
prior therapies used to treat the current major depressive episode), and the start and end 
dates of treatment will be examined and recorded in the source documents and CRF. 
• Prior medications and therapies (new subjects) 
− Prior medications used to treat the current major depressive episode (all 
antidepressants) 
− Prior therapies used to treat the current major depressive episode 
(psychotherapies/somatic therapies up until 6 weeks before informed consent) 


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− All prior medications and therapies used within 30 days before acquisition of 
informed consent 
• Prior medications and therapies (rollover subjects) 
− All prior medications and therapies used after Week 6 of the double-blind period 
(Phase B) in the double-blind trial (331-102-00058) 
• Concomitant medications and therapies 
− Concomitant medications and therapies used during the trial (including treatments 
for AEs) 
 
3.7.6 
Investigational Medicinal Product 
(1) 
Treatment compliance 
The investigator or subinvestigator will confirm the subject's IMP compliance during the 
interval between 2 consecutive scheduled visits after commencement of the treatment 
period and record the consumed daily dose and start and end dates of treatment in the 
source documents and the CRF. 
(2) 
Compliance rate 
Compliance rate (%) = 
Doses consumed between 2 consecutive scheduled visits 
(number of tablets) 
× 100 
"Number of prescribed days between 2 consecutive scheduled 
visits"(number of days) × 1 tablet 
 
(3) 
Compliance instruction 
The investigator, subinvestigator, or IMP manager will provide subjects with compliance 
instructions with particular attention to the following points: 
• The subject should take the IMP once daily, removing only the prescribed daily 
amount of the IMP from the sheet. 
• The subject must bring any missed/unused doses (IMP tablets) to the trial site at the 
next visit. 
• Contact information for any questions about taking the IMP 
• The subject must not discard any empty IMP sheets but should bring them to the trial 
site at the next visit. 
• The subject should be withdrawn from the trial if the subject’s IMP compliance 
during an interval between 2 consecutive scheduled visits is less than 65%. 
 


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3.7.7 
Requisite Concomitant Medication 
The investigator or subinvestigator will confirm the subject's compliance with the 
requisite concomitant medication, a commercially available antidepressant (SSRI or 
SNRI for rollover subjects and SSRI, SNRI, or mirtazapine for new subjects), during the 
interval between 2 consecutive scheduled visits after commencement of the treatment 
period and record the name of drug, prescribed daily dose, consumed daily dose, and start 
and end dates of treatment in the source documents and the CRF. 
3.7.8 
Pharmacogenomic Assessments 
3.7.8.1 
DNA Storage (for New Subjects Only) 
3.7.8.1.1 
Objective of DNA Storage 
DNA storage will be conducted to enable future exploratory investigation regarding the 
relationships between specific DNA mutations and individual differences in the efficacy, 
safety, or pharmacokinetics of brexpiprazole, and/or the relationships between specific 
DNA mutations and disease onset, severity, progression, etc. 
3.7.8.1.2 
Target Subjects of DNA Storage 
New subjects from whom written informed consent for DNA storage has been obtained 
will be included. Consent to DNA storage is voluntary. DNA storage will be conducted 
only if approved by the trial site’s IRB, etc. Informed consent for DNA storage must be 
obtained prior to blood sampling for DNA storage. 
3.7.8.1.3 
Timing of Blood Sampling 
Blood sampling will be performed at Week 4 of the treatment period (or at 
discontinuation if a subject withdraws before the Week 4 visit). If resampling of blood, if 
necessary, it will be performed during the trial period. 
3.7.8.1.4 
Handling of Samples 
All blood samples will be shipped to the DNA storage facility. The timing of blood 
sampling will be recorded in the source documents and CRF. Details regarding handling 
and shipment of samples are described in Appendix 1. DNA samples will be stored until 
the earliest of the following time points: 1) when genomic/genetic analysis is judged to be 
unnecessary, 2) when 15 years have passed since receipt of informed consent from the 
first subject, 3) when the subject withdraws consent to DNA storage. 
3.7.8.1.5 
Genomic/Genetic Analysis 
Genomic/genetic analysis will be performed only when exploratory investigation 
regarding the relationships between specific DNA mutations and individual differences in 


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the efficacy, safety, or pharmacokinetics of brexpiprazole and/or the relationships 
between specific DNA mutations and disease onset, severity, progression, etc is 
considered to be useful. 
If it is decided to perform genomic/genetic analysis, a pharmacogenomic research 
protocol will be prepared and, after approval has been obtained from the sponsor’s IRB, 
the analysis will be carried out in compliance with the regulations of each country 
regarding analysis plans. 
Genes that may be targeted in genomic/genetic analysis include genes considered to be 
possibly related to individual differences in the efficacy, safety, or pharmacokinetics of 
brexpiprazole and genes considered to be possibly related to diseases; however, at present 
those genes have not yet been identified. 
A genomewide association analysis using DNA chips, microarrays, next-generation 
sequencers, etc, may also be performed for genomic/genetic analysis; however, the 
results will still only be used for the purpose of identifying genes possibly related to 
individual differences in the efficacy, safety, or pharmacokinetics of brexpiprazole and/or 
the relationships between specific DNA mutations and disease onset, severity, 
progression, etc. The results of genomic/genetic analysis will be reported to the sponsor 
by the genomic/genetic analysis facility while the samples are still double-coded. 
3.7.8.1.6 
Informed Consent for DNA Storage 
An ICF for DNA storage and genomic/genetic analysis using stored DNA will be 
prepared separately from the ICF for the trial, and written informed consent to DNA 
storage will be obtained from each subject in person. The date of informed consent will 
be recorded in the source documents and CRF. 
If the subject withdraws consent to participate in DNA storage during the DNA storage 
period, the sponsor will instruct the DNA storage facility to dispose of the subject’s DNA. 
However, withdrawal from the trial will not be considered withdrawal of consent for 
DNA storage. Upon receipt of a notification for disposal from the sponsor, the DNA 
storage facility will dispose of the DNA sample without anyone being aware of whose 
sample it is. Any results of genomic/genetic analysis obtained prior to the withdrawal of 
consent will not be disposed of. 
3.7.8.1.7 
Disclosure of Genomic/Genetic Analysis Results to Subjects 
In this trial, genomic/genetic analysis will be performed for genes considered to be 
possibly related to individual differences in the efficacy, safety, or pharmacokinetics of 
brexpiprazole, and/or genes considered to be possibly related to diseases; however, even 
if the analysis results show some relationship, such a relationship would only be 


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exploratory or at an early stage of research, and therefore its scientific reliability and 
accuracy would not have been fully confirmed. Since disclosure of information for which 
scientific evaluation has not yet been verified would be of no benefit to the subjects, the 
sponsor will not disclose the results of genomic/genetic analysis to the subjects. 
3.7.9 
End of Trial 
The end of trial date is defined as the date of last visit or contact or date of final contact 
attempt as recorded on the post-treatment follow-up page of the CRF prepared for the last 
subject completing or withdrawing from the trial. 
3.8 
Stopping Rules, Withdrawal Criteria, and Procedures 
3.8.1 
Entire Trial 
In the event of sponsor termination or suspension of the trial for any reason, prompt 
notification will be given to the heads of the trial sites and regulatory authorities in 
accordance with regulatory requirements. 
3.8.2 
Individual Site 
Individual trial site participation may be discontinued by the sponsor, the investigator, or 
the IRB for medical, safety, regulatory, ethical, or other reasons consistent with 
applicable laws, regulations, and GCP. The head of the trial site will notify the sponsor 
promptly if the trial is terminated by the investigator or the IRB at the site. 
3.8.3 
Individual Subject Discontinuation 
3.8.3.1 
Treatment Discontinuation 
After commencement of the treatment period, a subject may stop treatment permanently 
for a variety of reasons. Treatment discontinuations may be initiated by a subject who is 
no satisfied with treatment or may become medically necessary due to AEs, required 
treatment with a disallowed medication or therapy, or other issues, as determined by the 
investigator or subinvestigator. However, each investigator or subinvestigator must 
comprehensively review the circumstances and offer the subject options for continued 
treatment to the degree possible as described in Section 3.8.3.4 Procedures to Encourage 
Continued Trial Participation. 
3.8.3.2 
Documenting Reasons for Discontinuation 
All subjects have the right to withdraw and the investigator or subinvestigator can 
discontinue a subject’s participation in the trial at any time if medically necessary. In 
addition, subjects meeting the following criteria must be withdrawn from the trial. Only 


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one reason for discontinuation (the main reason) can be recorded in the source documents 
and CRF, along with the date of discontinuation. 
1) Adverse event: 
a) Death 
b) Subjects experiences exacerbation of symptoms of the underlying disease, and 
the investigator or subinvestigator judges that continued participation in the 
trial is inappropriate 
c) Subject experiences a change to the manic state 
d) Based on clinical symptoms, subject is considered to be at high risk of suicide 
in the opinion of the investigator or subinvestigator or has an MADRS score 
for Suicidal Thought (No. 10) of ≥ 5 or HAM-D suicide score (No. 11) of ≥ 3, 
or those answering "Yes" to question 4 or 5 of C-SSRS. 
e) Subject decides to discontinue because of annoyance or discomfort due to a 
nonserious AE which is not otherwise determined to be an undue hazard 
f) Continuation of IMP would place the subject at undue risk as determined by 
the investigator or subinvestigator (eg, there is a safety concern possibly, 
probably, or likely related to IMP) 
i) SAE 
ii) Other safety concern or AE possibly, probably, or likely related to IMP 
2) Subject’s withdrawal of informed consent 
a) Reasons unrelated to medical condition (issues regarding subject’s 
convenience, such as a change of residence or other commitments: provide 
detail and review AE history with subject) 
b) Withdrawal of informed consent (complete written withdrawal of consent 
form) 
3) Marked noncompliance with the IMP regimen 
a) Compliance rate of < 65% during the interval between 2 consecutive 
scheduled visits 
4) Protocol deviation 
a) Subject is discovered to have not been in accord with inclusion/exclusion 
criteria 
b) Subject has received any prohibited concomitant drugs or therapies, or is 
judged to be in need of such 
c) Subject can no longer be administered antidepressant (SSRI or SNRI for 
rollover subjects and SSRI, SNRI, or mirtazapine for new subjects) 
5) Lost to follow-up 
6) Pregnancy (see Section 5.5 Pregnancy) 
7) Termination of all or part of the trial by the sponsor 
8) Discontinuation of the trial site by the sponsor 
9) Lack of efficacy 


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10) Impossibility of protocol compliance or judgement by the investigator or 
subinvestigator that discontinuation is necessary for any reason other than the 
above 
If the subject discontinues IMP due to an AE, the investigator, subinvestigator, or other 
trial personnel will make every effort to follow the event until the event is resolved or 
stabilized, or the subject is lost to follow up or has died. Follow-up procedures in Section 
3.8.3.1 Treatment Discontinuation must be followed. 
3.8.3.3 
Withdrawal of Consent 
All subjects have the right to withdraw their consent from further participation in the trial 
at any time without prejudice. Subjects cannot withdraw consent for use of data already 
collected as part of the trial, but only for future participation. The investigator or 
subinvestigator can also discontinue a subject’s participation in the trial at any time if 
medically necessary. Unless the subject provides their written withdrawal of consent or 
there is other written documentation by the investigator or subinvestigator confirming the 
subject’s verbal intent to completely withdraw from the trial, subjects should be followed 
for all protocol-specified evaluations and assessments, if possible. 
Complete withdrawal of consent requires refusal by a subject of ALL of the following 
methods of follow up (these methods of follow up will also be noted in the trial ICF): 
• Participation in all follow-up procedures specified in the protocol (whether in-clinic, 
by telephone, or by an in-home visit). 
• Participation in a subset of protocol specified follow-up procedures (by a frequency 
schedule and method, as agreed by subject and staff). 
• Contact of the subject by trial personnel, even if only by telephone, to assess current 
medical condition, and obtain necessary medical or laboratory reports relevant to the 
trial’s objectives. 
• Contact of alternative person(s) who have been designated in source documents as 
being available to discuss the subject’s medical condition, even if only by telephone, 
mail, or e-mail (eg, family, spouse, partner, legal representative, friend, neighbor, or 
physician). 
• Access to medical information from alternative sources (eg, hospital/clinic medical 
records, referring doctor’s notes, public records, dialysis, transplantation or vital 
registries, social media sources). 
Withdrawal of consent is a critical trial event and therefore should be approached with 
the same degree of importance and care as is used in initially obtaining informed consent. 
The reasons of a subject for an intended withdrawal need to be completely understood, 
documented, and managed to protect the rights of the subject and the integrity of the trial. 
A subject may initially express their desire to discontinue IMP administration, which is 
not equivalent to a complete withdrawal of consent for further participation (see Section 


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3.8.3.1 Treatment Discontinuation). A subject may, however, indicate that further trial 
participation is creating a burden on their work or social schedule. Therefore, the 
investigator or subinvestigator should follow the procedures outlined in Section 3.8.3.2 
Documenting Reasons for Discontinuation to determine if the subject can continue 
participation in the trial if modifications to his/her treatment and/or schedule of 
assessments can be accommodated. Only subjects who withdraw their permission for all 
of the above degrees of follow-up are considered to have completely withdrawn their 
consent to participate in the trial. 
3.8.3.4 
Procedures to Encourage Continued Trial Participation 
In all cases of impending IMP discontinuation or consent withdrawal, investigators or 
subinvestigators will be given instructions to meet and discuss with the subject their 
options of continuing in the trial, preferably on therapy. The investigator or 
subinvestigator should ensure understanding and documentation of the reasons why the 
subject wishes to withdraw consent. 
3.9 
Screen Failures 
A screen failure subject is one from whom informed consent is obtained and is 
documented in writing (ie, subject has signed an ICF), but who is not enrolled in the 
treatment period of the trial. For screen failures, the following information will be 
recorded in the source documents and the CRF. 
• Date of visit 
• Date of informed consent 
• Subject demographics 
− Date of investigation 
− Date of birth 
− Sex 
− Race 
− Ethnicity 
− Country where trial is performed 
• Results of eligibility criteria assessment 
• Date of assessment as screen failure 
• Reason for screen failure 
New subjects who participate in this trial but who are categorized as screening failures 
are permitted to be rescreened. Prior to rescreening, if performed, informed consent must 
be newly obtained and a new subject ID must be assigned. 


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3.10 
Definition of Completed Subjects 
The treatment period is defined as the time period during which subjects are evaluated for 
safety and efficacy irrespective of whether the subject actually received all doses of the 
IMP. Subjects who are evaluated at the last scheduled visit during the treatment period 
will be defined as trial completers. For the purposes of this trial, subjects who are 
evaluated at Week 52 of the treatment period will be defined as trial completers. 
3.11 
Definition of Subjects Lost to Follow-up 
Subjects who cannot be contacted on or before the examinations at Week 52 of the 
treatment period, who do not have a known reason for discontinuation (eg, withdrew 
consent or AE), and for whom a survival status at the end of the trial cannot be 
determined will be classified as “lost to follow-up.” Subjects who did not undergo post-
treatment observation will also be classified as “lost to follow-up.” Survival status can be 
determined from a variety of sources, either by obtaining acceptable documentation for 
death (ie, death certificate, medical records, public records, statement by a family 
member or primary care physician) or acceptable documentation for life (ie, direct 
contact with the subject, medical records, successful telephone contact with the subject, 
statement by a family member or primary care physician, or public records). 
The investigator, subinvestigator, or designee will make 3 documented attempts to 
contact the subject by telephone and in the event the site is unable to reach the subject by 
telephone, the site will attempt to contact the subject via certified mail or an alternative 
similar method where appropriate, before assigning a “lost to follow-up” status, and will 
make a record of the inability to contact the subject, recording the dates of the 3 attempts 
at contact and the method(s) of contact in the source documents and the date and method 
of the last attempt at contact in the CRF. 
3.12 
Subject Compliance 
The investigator or subinvestigator will give subjects the following instructions to ensure 
their compliance with the protocol. 
1) Site visits are to be made on the scheduled visit days as specified in the protocol 
(see Section 3.7.1.6). 
2) No prohibited concomitant drugs are to be taken during the period from informed 
consent to Week 52 of the treatment period (or discontinuation). 
3) No commercially available brexpiprazole is to be taken during the period from the 
assessment at Week 52 of the treatment period (or discontinuation) to the end of 
the post-treatment observation period. 


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4) The requirements regarding the method, duration, and frequency of administration 
of a commercially available antidepressant and the IMP are to be complied with 
(see Section 3.2). If the IMP compliance during the interval between 2 
consecutive scheduled visits is less than 65%, the subject will be withdrawn from 
the trial (see Section 3.8.3). 
5) Subjects must take appropriate contraceptive measures as instructed (see 
Section 5.5). 
 
3.13 
Protocol Deviations 
In the event of a significant deviation from the protocol due to an emergency, accident, or 
mistake (eg, violation of informed consent process, IMP dispensing or subject dosing 
error, treatment assignment error, subject enrolled in violation of eligibility criteria or 
concomitant therapy criteria), the investigator, subinvestigator, or designee will contact 
the sponsor at the earliest possible time by telephone. The investigator or subinvestigator 
and sponsor will come as quickly as possible to a joint decision regarding the subject’s 
continuation in the trial. This decision will be documented by the investigator or 
subinvestigator and the sponsor, and reviewed by the site monitor. For major deviations, 
the date on which the deviation occurred and the details of the deviation will be recorded 
in the source documents and the CRF. 
4 
Restrictions 
4.1 
Prohibited Concomitant Medications 
For appropriate assessment of the efficacy and safety of brexpiprazole, use of the drugs 
shown below is prohibited. However, in cases where rollover subjects have been using 
such drugs after Week 6 of the double-blind period (Phase B) of the double-blind trial 
(331-102-00058) or new subjects are using them during the screening period of this trial 
at the discretion of the investigator or subinvestigator, their dose should be gradually 
reduced and then discontinued by the following prohibition period: 
• From 1 week prior to commencement of the treatment period through the end of the 
treatment period 
− Benzodiazepines (excluding ultrashort-acting sedative-hypnotic drugs) 
*Necessary washout period: 7 days 
• From 2 weeks prior to commencement of the treatment period through the end of the 
treatment period 
− MAO inhibitors 
*Necessary washout period: 14 days 
• From24 hours before commencement of the treatment period through the end of the 
treatment period 


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− Central nervous system drugs (excluding ultrashort-acting sedative-hypnotic 
drugs, anticholinergic drugs for Parkinson's disease, antipyretic analgesic anti-
inflammatory drugs, and general cold drugs) 
Note: Caution should be exercised to avoid concomitant use of CYP2D6 
inhibitors, CYP3A4 inhibitors, and CYP3A4 inducers specified in Section 4.4 
Other Restrictions (eg, chlorpheniramine, diphenhydramine, clemastine, and 
celecoxib). 
− Chinese medicine (drugs indicated for neurosis, anxiety neurosis, neurasthenia, 
insomnia, and other disorders) 
− Over-the-counter drugs used as hypnotics 
− Supplements used for improvement of depressive symptoms (St. John's wort, S-
adenosylmethionine [SAM-e], ω-3 fatty acids, Kava extracts, and gamma-
aminobutyric acid [GABA]) 
− Varenicline 
− Adrenaline 
− Drugs not approved in Japan 
• During the post-treatment observation period 
− Commercially available brexpiprazole 
 
4.2 
Prohibited Concomitant Therapies 
For appropriate assessment of the efficacy and safety of brexpiprazole, the following 
therapies are prohibited during the treatment period. 
• Somatic therapy (electroconvulsive therapy, high-intensity phototherapy, sleep 
deprivation, transcranial magnetic stimulation) 
• Psychotherapy (excluding supportive psychotherapies used in general clinical 
practice) 
 
4.3 
Restricted Concomitant Drugs 
The use of the following drugs is restricted during the treatment period. 
• Ultrashort-acting sedative-hypnotic drugs 
Ultrashort-acting sedative-hypnotic drugs that can be used in this trial are restricted to 
zolpidem, zopiclone, eszopiclone, and triazolam. The concomitant use of only one of 
the aforementioned drugs is allowed during the treatment period; 2 or more drugs are 
not to be coadministered simultaneously. Change in the types of the aforementioned 
drugs is allowed. 
• Anticholinergic drugs for Parkinson's disease 
Anticholinergic drugs for Parkinson's disease, for which concomitant use during the 
treatment period is allowed, are biperiden, trihexyphenidyl, profenamine, piroheptine, 


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and mazaticol. In the case where extrapyramidal symptoms occur and use is 
necessary in the opinion of the investigator or subinvestigator, only one drug can be 
coadministered with no prophylactic use allowed. Change in the types of the 
aforementioned drugs is allowed. 
• Antipyretic analgesic anti-inflammatory drugs, antihistamines 
Concomitant use is allowed if subjects were already using the drugs at the time of 
informed consent to treat complications; however, no changes in dose and regimen 
are allowed unless AEs occur or the use of these drugs is considered unnecessary 
because of remission of symptoms. Furthermore, short-term concomitant use, 
including use as a medication for colds during the treatment period, is also allowed. 
The topical external use of these drugs is allowed. 
Note: Caution should be exercised to avoid concomitant use of CYP2D6 inhibitors, 
CYP3A4 inhibitors, and CYP3A4 inducers specified in Section 4.4 Other Restrictions 
(eg, chlorpheniramine, diphenhydramine, clemastine, and celecoxib). 
• β-Blockers 
During the treatment period, use is allowed only for treatment of cardiovascular 
diseases, with no changes in the dose and regimen employed at the time of informed 
consent. The topical external use of these drugs is allowed. 
 
4.4 
Other Restrictions 
CYP2D6 inhibitors, CYP3A4 inhibitors and inducers, food products containing St. John's 
wort, and grapefruit, star fruit, Seville orange, and their juice and other processed 
products are likely to affect the pharmacokinetics of brexpiprazole and potentiate or 
reduce its effects. Caution should be exercised to avoid the consumption of these drugs 
and foods. 
− CYP2D6 inhibitors (excluding topical agents in the dosage forms permitted for 
concomitant use as specified in Appendix 2): 
Drug category 
Nonproprietary name 
Antihistamines 
clemastine, chlorpheniramine, 
diphenhydramine 
Antiallergic minor tranquilizers 
hydroxyzine 
Antiinflammatory agents 
celecoxib 
Analgesics 
methadone 
Antifungal agents 
terbinafine 
Antiarrhythmic agents 
quinidine 
Acid suppressants 
cimetidine 
Overactive bladder treatments 
mirabegron 
Antidepressants 
clomipramine 
Hyperthyroidism treatments 
cinacalcet 
Erythematosus treatments 
hydroxychloroquine 


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− CYP3A4 inhibitors (excluding topical agents in the dosage forms permitted for 
concomitant use as specified in Appendix 2): 
Drug category 
Nonproprietary name 
Antibiotics 
erythromycin, quinupristin/dalfopristin 
(injection), clarithromycin, chloramphenicol, 
ciprofloxacin 
Antifungal agents 
itraconazole, clotrimazole, fluconazole, 
voriconazole 
Calcium antagonists 
diltiazem, verapamil 
Antiarrhythmic agents 
amiodarone 
Acid suppressants 
cimetidine 
Antiemetics 
aprepitant 
Antineoplastic agents 
imatinib, crizotinib 
Immunosuppressants 
ciclosporin 
Anti-HIV agents 
atazanavir, indinavir, cobicistat 
(combination), saquinavir, nelfinavir, 
fosamprenavir, ritonavir, lopinavir/ritonavir 
(combination) 
Hepatitis C treatments 
telaprevir, ombitasvir/paritaprevir/ritonavir 
(combination) 
− CYP3A4 inducers (excluding topical agents in the dosage forms permitted for 
concomitant use as specified in Appendix 2): 
Drug category 
Nonproprietary name 
Corticosteroids 
cortisone, dexamethasone, triamcinolone, 
hydrocortisone, fludrocortisone, 
prednisolone, betamethasone, 
methylprednisolone 
Antihormones 
enzalutamide, mitotane 
Cervical ripening agents 
prasterone 
Central nervous system 
stimulants 
modafinil 
Antiepileptics 
oxcarbazepine, carbamazepine, phenytoin, 
fosphenytoin, phenobarbital, primidone 
Pulmonary hypertension 
treatments 
bosentan 
Antituberculous agents 
rifampicin (rifampin) 
Anti-HIV agents 
etravirine, efavirenz, nevirapine 
− Foods and beverages: Food products containing St. John's wort, and grapefruit, 
star fruit, Seville orange, and their juice and other processed products 
 


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5 
Reporting of Adverse Events 
5.1 
Definitions 
An AE is defined as any untoward medical occurrence in a patient or clinical trial subject 
administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. Adverse events would not include information recorded 
as complications at screening (for new subjects) or baseline (for rollover subjects) for 
preplanned procedures for which the underlying condition was known and no worsening 
occurred. For rollover subjects, AEs that occurred during the double-blind trial (331-102-
00058) and persist without recovery or resolution, but have not become exacerbated, will 
not be counted as AEs occurring in this trial. An adverse drug reaction is any untoward 
and unintended response to an IMP related to any dose administered. 
A suspected adverse reaction is any AE for which there is a reasonable possibility that the 
IMP caused the AE. 
 
An SAE includes any event that results in any of the following outcomes: 
• Death 
• Life-threatening; ie, the subject was, in the opinion of the investigator, or 
subinvestigator at immediate risk of death from the event as it occurred. It does not 
include an event that, had it occurred in a more severe form, might have caused death. 
• Persistent or significant incapacity/disability or substantial disruption of the ability to 
conduct normal life functions. 
• Requires inpatient hospitalization or prolongs hospitalization 
− Hospitalization itself should not be reported as an SAE; whenever possible the 
reason for the hospitalization should be reported. 
− Hospitalizations or prolonged hospitalizations for social admissions (ie, those 
required for reasons of convenience or other nonmedical need) are not considered 
SAEs. 
• Congenital anomaly/birth defect. 
• Other medically significant events that, based upon appropriate medical judgment, 
may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed above, eg, allergic bronchospasm requiring 
intensive treatment in an emergency room or home, blood dyscrasias or convulsions 
that do not result in hospitalization, or the development of drug dependency or drug 
abuse. 
Nonserious AEs are all AEs that do not meet the criteria for a “serious” AE. 
 


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Immediately Reportable Event (IRE): 
• Any SAE 
• Any AE related to occupational exposure. 
• Potential drug-induced liver injury (DILI) (see Section 5.4). 
• Pregnancies are also defined as IREs. Although normal pregnancy is not an AE, it 
will mandate IMP discontinuation and must be reported on an IRE form to the 
sponsor. Pregnancy will only be recorded in the source documents and the AE 
Section of the CRF if there is an abnormality or complication. This applies both to 
pregnancies of subjects and pregnancies of subjects' partners. 
 
Clinical Laboratory Assessment Value Changes: It is the investigator’s or 
subinvestigator’s responsibility to review the results of all laboratory tests as they become 
available. This review will be documented by the investigator’s or subinvestigator’s dated 
signature on the laboratory report. For each abnormal laboratory test result, the 
investigator or subinvestigator needs to verify whether this is an abnormal (ie, clinically 
relevant) change from baseline for that individual subject. This determination, however, 
does not necessarily need to be made the first time an abnormal value is observed. The 
investigator or subinvestigator may repeat the laboratory test or request additional tests to 
verify the results of the original laboratory tests. If this laboratory value is considered 
medically relevant by the investigator or subinvestigator (subject is symptomatic, 
requiring corrective treatment or further evaluation), or if the laboratory value leads to 
discontinuation or meets the criteria for an SAE, this is considered an AE. 
 
Severity: Adverse events will be graded on a 3-point scale and reported. The intensity of 
an AE is defined as follows: 
1 = Mild: Discomfort noticed, but no disruption to daily activity. 
2 = Moderate: Discomfort sufficient to reduce or affect normal daily activity. 
3 = Severe: Inability to work or perform normal daily activity. 
 
IMP Causality: Assessment of causal relationship between an AE and the IMP: 
Related:  
There is a reasonable possibility of a temporal and causal relationship 
between the IMP and the AE. 
Not related: There is no temporal or reasonable relationship between the IMP and the 
AE. 


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5.2 
Eliciting and Reporting Adverse Events 
The investigator or subinvestigator will periodically assess subjects for the occurrence of 
AEs. To avoid bias in eliciting AEs, subjects should be asked the nonleading question: 
“How have you felt since your last visit?” For all AEs (serious and nonserious) reported 
by the subject, the event name, start and stop dates, severity, seriousness, relationship to 
IMP, actions taken regarding IMP administration, and outcome thereof must be recorded 
in the source documents and CRFs provided by the sponsor. Adverse event and SAE 
collection is to begin after a subject has signed the ICF. 
Use medical terminology in AE reporting. Adverse events should be reported as a single 
unifying diagnosis whenever possible or, in the absence of a unifying diagnosis, as 
individual signs or symptoms. Exacerbation or disease progression should be reported as 
an AE only if there are unusual or severe clinical features that were not present, or 
experienced earlier, or not expected based on the course of the condition. If a reported 
AE has worsened in severity or seriousness, it should be reported as a new AE on the 
CRF. 
In addition, the sponsor must be notified immediately by e-mail, in principle, of any IREs 
according to the procedure outlined below, in Section 5.3 Immediately Reportable Events. 
Special attention should be paid to recording hospitalization and concomitant medications. 
5.3 
Immediately Reportable Events 
The investigator or subinvestigator must report any SAE, potential DILI, or confirmed 
pregnancy to the sponsor by e-mail (using the contact information on the title page of this 
protocol) immediately after either the investigator, subinvestigator, or designee becomes 
aware of the event. The IRE form and so on should be completed and sent by e-mail, in 
principle, to the sponsor. Please note that the IRE form is NOT the AE Section of the 
CRF. Due consideration must be given to privacy when the IRE form and so on is sent by 
mail or other means of communication. 
For subjects experiencing SAEs or IREs, such AEs should be followed until the events 
are resolved or stabilized, or the subject is lost to follow-up or has died. Resolved means 
that the subject has returned to the baseline state of health, and stabilized means that the 
investigator or subinvestigator does not expect any further improvement or worsening of 
the subject’s condition. It is expected that the investigator or subinvestigator will provide 
or arrange appropriate supportive care for the subject and will provide prompt updates on 
the subject’s status to the sponsor. 


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5.4 
Potential Drug-induced Liver Injury 
For a subject who experiences an elevation in aspartate aminotransferase (AST) or 
alanine aminotransferase (ALT) that is ≥ 3 times the upper limit of normal (ULN), total 
bilirubin level should also be evaluated. If the total bilirubin is ≥ 2 times the ULN, 
complete the IRE form and so on with all values listed and also report as an AE in the 
source documents and CRF. 
5.5 
Pregnancy 
Women of childbearing potential (WOCBP) are defined as female subjects for whom 
menstruation has started and who are not documented as sterile (ie, have had a bilateral 
oophorectomy and/or hysterectomy or who have been postmenopausal for at least 
12 months). 
For WOCBP and for men who are sexually active, there must be a documented 
agreement that the subject and/or their partner will take effective measures 
(ie, double-barrier method) to prevent pregnancy during the course of the trial and for 
30 days after the last dose of IMP. Unless the subject or their partner is sterile (ie, women 
who have had a bilateral oophorectomy and/or hysterectomy or who have been 
postmenopausal for at least 12 consecutive months; or men who have had a bilateral 
orchidectomy) or remains abstinent, 2 of the following precautions must be used: 
vasectomy, tubal ligation, vaginal diaphragm, intrauterine device, oral contraceptives, or 
condom with spermicide. Any single method of birth control, including vasectomy and 
tubal ligation, may fail, leading to pregnancy. The contraceptive method will be 
documented at each trial visit. 
Before enrolling WOCBP in this clinical trial, investigators or subinvestigators must 
review the below guidelines about trial participation with all WOCBP. The topics should 
generally include: 
• General information 
• Informed consent form 
• Pregnancy prevention information 
• Drug interactions with hormonal contraceptives 
• Contraceptives in current use 
• Guidelines for the follow-up of a reported pregnancy 
 
Before trial enrollment, WOCBP must be advised of the importance of avoiding 
pregnancy during trial participation and the potential risk factors for an unintentional 


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pregnancy. The subject must sign an informed consent form stating that the above-
mentioned risk factors and the consequences were discussed with her. 
During the trial, all WOCBP should be instructed to contact the investigator or 
subinvestigator immediately if they suspect they might be pregnant (eg, missed or late 
menstrual cycle). 
If a subject is suspected to be pregnant before she receives IMP, the IMP administration 
must be withheld until the results of pregnancy tests are available. If the pregnancy is 
confirmed, the subject must not receive the IMP and must not be enrolled in the trial. If 
pregnancy is suspected while the subject is taking IMP, the IMP must be withheld 
immediately (if reasonable, taking into consideration any potential withdrawal risks) until 
the result of the serum pregnancy test is known. If pregnancy is confirmed, the IMP will 
be permanently discontinued in an appropriate manner (eg, dose tapering if necessary for 
subject safety) and the subject will be withdrawn from the trial. 
The investigator or subinvestigator must immediately notify the sponsor of any 
pregnancy associated with IMP exposure during the trial and for 30 days after the last 
dose of IMP, and record the event on the IRE form, and forward it to the sponsor. The 
sponsor will forward Pregnancy Surveillance Form(s) for monitoring the outcome of the 
pregnancy. 
Protocol-required procedures for trial discontinuation and follow-up must be performed 
on the subject unless contraindicated by pregnancy (eg, x-ray studies). Other appropriate 
pregnancy follow-up procedures should be considered, if indicated. In addition, the 
investigator or subinvestigator must report to the sponsor, on appropriate Pregnancy 
Surveillance Form(s), follow-up information regarding the course of the pregnancy, 
including perinatal and neonatal outcome. Infants will be followed for a minimum of 6 
months from the date of birth. 
5.6 
Procedure for Breaking the Blind 
Not applicable. 
5.7 
Follow-up of Adverse Events 
5.7.1 
Follow-up of Nonserious Adverse Events 
Nonserious AEs that are identified at any time during the trial must be recorded in the 
source documents and the AE section of the CRF, with the current status (ongoing or 
resolved/recovered) noted. All nonserious events (other than immediately reportable 
events) that are ongoing at the end of trial date (final day of observation) will be recorded 
as ongoing in the source documents and CRF. For any AE having been identified 


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throughout the trial, during data analysis, additional relevant medical history information 
may be requested by the sponsor to further ascertain causality (including, but not limited 
to, information such as risk-related behavior, family history and occupation). The follow-
up information after the end of trial date (final day of observation) will be recorded in the 
subject’s medical record. 
5.7.2 
Follow-up of Serious Adverse Events and Immediately 
Reportable Events 
This trial requires that subjects be actively monitored for SAEs and IREs up to 30 days 
(±5 days) after the final day of IMP administration (end of trial date [final day of 
observation]). 
Serious AEs and IREs that are identified or ongoing at the end of trial date must be 
recorded in the source documents and the AE section of the CRF. Between the end of 
trial date for the individual subject and the end of trial date for the last subject, if any new 
information regarding an SAE or IRE becomes available (eg, the event is resolved), this 
must be reported to the sponsor using the IRE form and so on, and the information must 
be recorded in the source documents and the AE section of the CRF. The investigator or 
subinvestigator will follow SAEs and IREs, and will continue to report any significant 
information to the sponsor until the events are resolved or stabilized, or the subject is lost 
to follow-up or has died, using the IRE form and so on. 
5.7.3 
Follow-up and Reporting of Serious Adverse Events and 
Immediately Reportable Events Occurring After the End of Trial 
Date (Final Day of Observation) 
Any new SAEs or IREs reported to the investigator or subinvestigator, which occur after 
the end of trial date (final day of observation) and are determined by the investigator or 
subinvestigator to be associated with the use of the IMP, should be reported to the 
sponsor. This includes SAEs and IREs that are captured on follow-up telephone contact 
or at any other time point after the defined trial period. The investigator or 
subinvestigator will follow SAEs and IREs identified after the defined trial period and 
continue to report any significant follow-up information to the sponsor until the events 
are resolved or stabilized, or the subject is lost to follow-up or has died, using the IRE 
form and so on. 
6 
Pharmacogenomic Analysis 
6.1 
Pharmacogenomic Methods 
Refer to Section 3.7.8.1.5 Genomic/Genetic Analysis for genomic/genetic analysis. 


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7 
Statistical Analysis 
This section defines datasets for analysis and describes the methods for analyzing 
endpoints. A detailed statistical analysis plan is provided in a separate Statistical Analysis 
Plan. The Statistical Analysis Plan will be finalized prior to data lock. 
7.1 
Sample Size 
To verify the safety of long-term administration, the target number of subjects to 
complete 52 weeks of administration was set at around 100 subjects. Due to the 
availability of data on safety in elderly subjects from foreign clinical trials, the sample 
size needed to assess the safety of brexpiprazole in the elderly was set as 30 new subjects 
(elderly subjects of age 65 and above) receiving IMP administration. 
7.2 
Datasets for Analysis 
7.2.1 
Efficacy Analysis Set 
The efficacy analysis set will comprise subjects who have received at least 1 dose of the 
IMP, and from whom MADRS total scores have been obtained at baseline and at least 1 
time point after initiation of the treatment. 
7.2.2 
Safety Analysis Set 
The safety analysis set will comprise subjects who have received at least 1 dose of the 
IMP. 
Unless otherwise specified, analysis will be performed for each of the following groups: 
• Rollover subjects from the double-blind trial (331-102-00058) who were assigned to 
the brexpiprazole groups in the double-blind period (Phase B) 
• Rollover subjects from the double-blind trial (331-102-00058) who were assigned to 
the placebo group in the double-blind period (Phase B) 
• All rollover subjects from the double-blind trial (331-102-00058) 
• New subjects (elderly subjects aged 65 years or older) 
• All subjects (rollover and new subjects combined) 
 
7.3 
Handling of Missing Data 
The analysis of last assessment time point will be performed using the last observation 
carried forward method (herein after referred to as "LOCF"), by which missing data at 
Week 52 will be imputed by the last observed data after initiation of IMP treatment. 


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7.4 
Efficacy Endpoint Analysis 
Efficacy analysis will be performed using the efficacy analysis set. Baseline is defined as 
the last data obtained prior to initiation of IMP treatment in the trial. 
• MADRS total score 
• CGI-S 
• HAM-D 17 total score 
• Mean SDS score 
Descriptive statistics of actual measurements and changes from baseline at each time 
point and the last assessment time point (Week 52 LOCF) will be determined. 
 
• MADRS response rate 
• MADRS remission rate 
• CGI-I improvement rate 
Numbers and proportions of subjects will be determined at each time point and the last 
assessment time point (Week 52 LOCF). 
7.5 
Analysis of Other Endpoints 
• EQ-5D-5L 
For each item, descriptive statistics of actual measurements and changes from 
baseline at each time point and the last assessment time point (Week 52 LOCF) will 
be determined. 
 
7.6 
Analysis of Demographic and Baseline Characteristics 
Descriptive statistics or frequency distribution of demographic and other baseline 
characteristics will be determined in each analysis set. 
7.7 
Safety Analysis 
Safety analysis will be performed using the safety analysis set. Baseline is defined as the 
last data obtained prior to initiation of IMP treatment in the trial. 
7.7.1 
Adverse Events 
All AEs will be coded by system organ class and Medical Dictionary for Regulatory 
Activities (MedDRA) preferred term. The incidence of the following events will be 
summarized: 
• Adverse events occurring after initiation of IMP administration (treatment-emergent 
adverse events [TEAEs]) 


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• TEAEs by severity 
• TEAEs with an outcome of death 
• Serious TEAEs 
• TEAEs leading to discontinuation of the IMP 
TEAEs potentially causally related to the IMP will also be summarized in the same 
manner. 
7.7.2 
Clinical Laboratory Data 
For each quantitative laboratory parameter, descriptive statistics of actual measurements 
and changes from baseline at each time point and the last assessment time point (Week 
52 LOCF) will be calculated. 
For each laboratory parameter (excluding qualitative parameters), actual measurements 
will be classified as "lower than the lower limit of the reference range," "within the 
reference range," and "higher than the upper limit of the reference range" using the 
reference range specified by the central laboratory, and a shift table from baseline will be 
produced.  
For each qualitative laboratory parameter, a shift table from baseline will be produced. 
Numbers and proportions of subjects with potentially clinically significant laboratory test 
values will be determined. 
7.7.3 
Physical Examination and Vital Signs Data 
Physical examination data will be provided in a listing. 
For each vital sign parameter, descriptive statistics of actual measurements and changes 
from baseline at each time point and the last assessment time point (Week 52 LOCF) will 
be calculated. 
Numbers and proportions of subjects with potentially clinically significant vital signs will 
be determined. 
7.7.4 
Electrocardiogram Data 
For heart rate, PR interval, RR interval, QRS interval, QT interval, and QTc, descriptive 
statistics of actual measurements and changes from baseline at each time point and the 
last assessment time point (Week 52 LOCF) will be calculated. 
A shift table from baseline for normal/abnormal 12-lead ECG will be produced. 
Numbers and proportions of subjects with actual measurements of corrected QT interval 
(QTcF, QTcB, QTcN) at each time point and the last assessment time point (Week 52 


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LOCF) of > 450 msec, > 480 msec, and > 500 msec will be determined. Numbers and 
proportions of subjects with changes from baseline of > 30 msec and > 60 msec will be 
determined. 
Numbers and proportions of subjects with ECG results meeting the criteria for potentially 
clinically significant ECG data will be determined. 
7.7.5 
Other Safety Data 
• Body weight, BMI, and waist circumference 
For body weight, BMI, and waist circumference, descriptive statistics of actual 
measurements and changes from baseline at each time point and the last assessment 
time point (Week 52 LOCF) will be calculated. 
Numbers and proportions of subjects with results meeting the criteria for potentially 
clinically significant body weight gain or loss will be determined. 
• DIEPSS, AIMS, and BARS 
For DIEPSS total score (total of scores for items 1 through 8) and the score for each 
DIEPSS item, AIMS total score (total of scores for items 1 through 7) and the score 
for each of the items 8 through 10, and BARS, descriptive statistics of actual 
measurements and changes from baseline at each time point and the last assessment 
time point (Week 52 LOCF) will be calculated. 
• C-SSRS 
Numbers and proportions of subjects for each C-SSRS item (suicidality, suicidal 
ideation, suicidal behavior, completed suicide, emergence of suicidal ideation, 
emergence of serious suicidal ideation, worsening of suicidal ideation, and emergence 
of suicidal behavior) at each time point and the last assessment time point (Week 52 
LOCF) will be determined 
 
8 
Management of Investigational Medicinal Product 
Refer to the investigator’s brochure on brexpiprazole and the separately-specified manual 
for details regarding IMP management. 
8.1 
Packaging and Labeling 
The IMP will be provided to the IMP manager by the sponsor or designated agent. The 
IMP will be supplied as blister cards. Each blister card used in the dosing period will be 
labeled to clearly indicate that the drug is for clinical trial use and to disclose the subject 
ID, compound ID, the protocol number, sponsor’s name and address, route of 
administration, manufacturing number, expiry date, storage conditions, etc. 


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8.2 
Storage 
The IMP will be stored in a securely locked cabinet or enclosure. Access will be limited 
to the IMP manager. The IMP manager may not provide IMP to any subject not 
participating in this protocol. 
The IMP is to be stored at room temperature. 
The clinical site staff will maintain a temperature log in the drug storage area recording 
the temperature at least once each working day. 
8.3 
Accountability 
The IMP manager must maintain an inventory record of IMP received, dispensed, 
administered, destroyed, or returned. 
8.4 
Returns and Destruction 
Upon completion or termination of the trial, all unused and/or partially used IMP must be 
returned to the sponsor or a designated agent. 
All IMP returned to the sponsor must be accompanied by appropriate documentation and 
be identified by protocol number and trial site number on the outermost shipping 
container. Returned supplies should be in the original blister cards. The assigned trial 
monitor will facilitate the return of unused and/or partially used IMP. 
8.5 
Reporting of Product Quality Complaints 
A Product Quality Complaint (PQC) regarding the IMP is any written, electronic, or 
verbal communication by a healthcare professional, consumer, subject, medical 
representative, Competent Authority, regulatory agency, partner, affiliate, or other third 
party that alleges deficiencies or dissatisfaction related to identity, quality, labeling, 
packaging, reliability, safety, durability, tampering, counterfeiting, theft, effectiveness, or 
performance of a drug product or medical device after it is released for distribution. 
Examples include, but are not limited to, communications involving: 
• Failure/malfunction of a product to meet any of its specifications 
• Incorrect or missing labeling 
• Packaging issues (eg, damaged, dirty, crushed, missing product) 
• Blister defects (eg, missing, empty blisters) 
• Bottle defects (eg, under/over-fill, no safety seal) 
• Vial defects 
• Product defect (eg, odor, chipped, broken, embossing illegible) 
• Loss or theft of product 


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8.5.1 
Eliciting and Reporting Product Quality Complaints 
The investigator, subinvestigator, or designee must record all PQCs identified through 
any means from the receipt of the IMP from the sponsor, or sponsor’s designee, through 
and including reconciliation and up to destruction, including subject dosing. The 
investigator, subinvestigator, or designee must notify the sponsor (or sponsor’s designee) 
via e-mail immediately after becoming aware of the PQC according to the procedure 
outlined in Section 8.5.2 Information Required for Reporting Product Quality Complaints. 
(E-mail address: PQC_331-102-00059@otsuka.jp) 
Identification of a PQC by the subject should be reported to the investigator or 
subinvestigator, who should then follow the reporting mechanisms listed above. 
8.5.2 
Information Required for Reporting Product Quality Complaints 
• Description of complaint 
• Reporter identification (eg, subject, investigator or subinvestigator, site information, 
etc) 
• Reporter contact information (eg, address, phone number, e-mail address) 
• ID of material (product/compound name, drug number) 
• Clinical protocol reference (protocol number or trial name) 
• Dosage form/strength (if known) 
• Pictures (if available) 
• Complaint sample availability for return 
 
8.5.3 
Return Process for Product Quality Complaints 
Indicate during the report of the PQC if the complaint sample is available for return. If 
the complaint sample is available for return, the sponsor will provide instructions for 
complaint sample return, when applicable. 
It must be documented in the site accountability record that a complaint sample for a 
dispensed kit has been forwarded to the sponsor for complaint investigation. 
8.5.4 
Assessment/Evaluation 
Assessment and evaluation of PQCs will be handled by the sponsor. 


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9 
Records Management 
9.1 
Source Documents 
Source documents are defined as the results of original observations and activities of a 
clinical investigation. Source documents will include, but are not limited to, medical 
records, electronic data, screening logs, and recorded data from automated instruments. 
All source documents pertaining to this trial will be maintained by the trial site and made 
available for direct inspection by authorized persons. Investigator(s)/ trial site(s) will 
permit trial-related monitoring, audits, IRB review, and regulatory inspection(s) by 
providing direct access to source data/documents by authorized persons as defined in the 
ICF. In all cases, subject confidentiality must be maintained in accordance with 
regulatory requirements. 
9.2 
Data Collection 
During each subject’s visit to the trial site, an investigator or subinvestigator will 
document all significant observations and findings in the medical records. At a minimum, 
these records will contain: 
• Documentation of the informed consent process, including any revised consents; 
• Documentation of the investigator’s or subinvestigator’s decision to enroll the subject 
into the trial, the review of all inclusion/exclusion criteria prior to IMP administration, 
and confirmation of the subject’s actual participation in the trial; 
• The date of the visit and the corresponding Visit or Day in the trial schedule; 
• General subject status remarks, including any significant medical findings. The 
severity, frequency, duration, action taken, and outcome of any AEs and the 
investigator's or subinvestigator’s assessment of relationship to IMP must also be 
recorded; 
• Any changes in concomitant medications or dosages; 
• A general reference to the procedures completed; 
• The signature (or initials) and date of each clinician (or designee) who made an entry 
in the progress notes. 
In addition, any contact with the subject via telephone or other means that provides 
significant clinical information will also be documented in the medical records as 
described above. Any changes to information in the medical records and other source 
documents will be initialed and dated on the day the change is made by a trial site staff 
member authorized to make the change. Changes will be made by striking a single line 
through erroneous data (so as not to obliterate the original data), and clearly entering the 
correct data (eg, wrong data right data). If the reason for the change is not apparent, a 
brief explanation for the change will be written in the source documentation by the 


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investigator or subinvestigator. If electronic data systems are being utilized, a full audit 
trail of changes must be maintained. 
Information from the medical records and other source documents will be entered by trial 
site personnel directly onto electronic CRFs in the sponsor’s electronic data capture 
(EDC) system. Changes to the data will be captured by an automatic audit trail. 
9.3 
File Management at the Trial Site 
The head of the trial site will ensure that the trial site file is maintained in accordance 
with Section 8 of the ICH GCP Guideline E6 and as required by applicable local 
regulations. The trial site will take measures to prevent accidental or premature 
destruction of these documents. 
9.4 
Record Retention at the Trial Site 
The trial site will retain all the trial-related documents and records for whichever is the 
longer of the three periods indicated below. However, if the sponsor requires a longer 
period of archiving, the head of the trial site will consult with the sponsor on the period 
and procedures of record retention. 
• Until the date 2 years after manufacturing and marketing approval date; however, if 
the head of the trial site receives notification from the sponsor that development has 
been terminated or that results of the trial will not be submitted with the approval 
application, until the date 3 years after receipt of such notification. 
• Until the date 3 years after termination or completion of the trial. 
• Until the date on which it is decided to end DNA storage 
 
The trial site must not dispose of any records relevant to this trial without either 
(1) written permission from the sponsor or (2) providing an opportunity for the sponsor to 
collect such records. The trial site will be responsible to maintain adequate and accurate 
electronic or hard copy source documents of all observations and data generated during 
the trial. Such documentation is subject to inspection by the sponsor and relevant 
regulatory authorities. 
10 
Quality Control and Quality Assurance 
10.1 
Monitoring 
The sponsor has ethical, legal, and scientific obligations to follow this trial in accordance 
with established research principles, ICH E6 GCP: Consolidated Guidance, and 
applicable regulatory requirements and laws. As part of a concerted effort to fulfill these 
obligations (maintain current personal knowledge of the progress of the trial), the 


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sponsor’s monitors will visit the site during the trial, as well as communicate frequently 
via telephone, e-mail, and written communications. In addition, all investigators or 
subinvestigators and trial site clinical personnel will undergo initial and ongoing training 
for this particular trial, and this training will be clearly documented. 
10.2 
Auditing 
The sponsor’s Quality Assurance Unit (or representative) may conduct trial site audits. 
Audits will include, but are not limited to, IMP supply, presence of required documents, 
the informed consent process, and comparison of CRFs with source documents. The 
investigator agrees to participate with audits. 
Regulatory authorities may inspect the trial site during or after the trial. The investigator 
will cooperate with such inspections and will contact the sponsor immediately if such an 
inspection occurs. 
11 
Ethics and Responsibility 
This trial must be conducted in compliance with the protocol, ICH GCP Guideline (E6), 
international ethical principles derived from the Declaration of Helsinki and Council for 
International Organizations of Medical Science (CIOMS) guidelines, and applicable local 
laws and regulations. Each trial site will seek approval/favorable opinion by an IRB 
according to the requirements of each region, and the trial site will provide that 
documentation to the sponsor. The IRB will evaluate the ethical, scientific, and medical 
appropriateness of the trial. Further, in preparing and handling source documents, CRFs, 
and the IRE form and so on, the investigator or subinvestigator and their staff will take 
measures to ensure adequate care in protecting subject privacy. To this end, a subject ID 
will be used to identify each subject. Financial aspects, subject insurance, and publication 
policy for the trial will be documented in the agreement between the sponsor and the trial 
site. 
12 
Confidentiality 
All information generated in this trial will be considered confidential and will not be 
disclosed to anyone not directly concerned with the trial without the sponsor’s prior 
written permission. Subject confidentiality requirements of the region where the trial is 
conducted will be met. However, authorized regulatory officials and sponsor personnel 
(or their representatives) may be allowed full access to inspect and copy the records, 
consistent with local requirements. All IMPs, subject bodily fluids, and other materials 
collected shall be used solely in accordance with this protocol, unless otherwise agreed to 
in writing by the sponsor. 


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Subjects will be identified only by a unique subject ID in the source documents and CRFs. 
If further subject identification is required, subjects’ full names may be made known to a 
regulatory agency or other authorized officials if necessary, subject to local regulations. 
13 
Amendment Policy 
The investigator will not make any changes to this protocol without the sponsor’s prior 
written consent and subsequent approval/favorable opinion by the IRB. Any permanent 
change to the protocol, whether an overall change or a change for specific trial site(s), 
must be handled as a protocol amendment. Any amendment will be written by the 
sponsor. Each amendment will be submitted to the IRB, as required by local regulations. 
Except for “administrative” or “nonsubstantial” amendments, investigators or 
subinvestigators will wait for IRB approval/favorable opinion of the amended protocol 
before implementing the change(s). Administrative amendments are defined as having no 
effect on the safety of subjects, conduct or management of the trial, trial design, or the 
quality or safety of IMP(s) used in the trial. A protocol change intended to eliminate an 
apparent immediate hazard to subjects should be implemented immediately, followed by 
IRB notification within local applicable timelines. The sponsor will submit protocol 
amendments to the applicable regulatory agency within local applicable timelines. 
When the IRB, investigators, or the sponsor concludes that the protocol amendment 
substantially alters the trial design or increases the potential risk to the subject, the 
currently approved written ICF will require similar modification. In such cases, after 
approval/favorable opinion of the new ICF by the IRB, repeat written informed consent 
will be obtained from subjects enrolled in the trial before expecting continued 
participation and before the amendment-specified changes in the trial are implemented. 
14 
Publication Authorship Requirements 
Authorship for any Otsuka-sponsored publications resulting from the conduct of this trial 
will be based on International Committee of Medical Journal Editors (ICMJE) authorship 
criteria (http://www.icmje.org/recommendations). According to ICMJE guidelines, one 
may be considered an author only if the following criteria are met: 
1) Substantial contributions to the conception or design of the work; or the 
acquisition, analysis, or interpretation of data for the work; AND 
2) Drafting the work or revising it critically for important intellectual content; AND 
3) Final approval of the version to be published; AND 
4) Agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved. 


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All authors must meet the above criteria, and all who qualify for authorship based on the 
above criteria should be listed as authors. 
Investigators or other trial participants who do not qualify for authorship may be 
acknowledged in publications resulting from the trial. By agreeing to participate in the 
trial, investigators or other trial participants consent to such acknowledgement in any 
publications resulting from its conduct. 


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15 
References 
1 
Lecrubier Y. How do you define remission? Acta Psychiatr Scand 
2002;106(Suppl.415):7-11. 
2 
Takahashi Y. Mood disorder and suicide. Japanese Journal of Clinical Psychiatry. 
2000;29:877-84. 
3 
Office for Policy of Suicide Prevention, Ministry of Health, Labour and Welfare, and 
Community Safety Planning Division, National Police Agency. 2016 Situation of 
suicide [Internet]: March 23, 2017 [accessed on 2018 Jan 9]. Available from:  
http://www.npa.go.jp/safetylife/seianki/jisatsu/H28/H28_jisatunojoukyou_01.pdf 
4 
Ministry of Health, Labour and Welfare. Economic benefits of prevention of 
suicide/depression (social loss from suicide/depression). [Internet]: September 7, 
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http://www.mhlw.go.jp/stf/houdou/2r9852000000qvsy.html 
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Committee for Treatment Guidelines of Mood Disorders of the Japanese Society of 
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Shoin Ltd.; 2017. 
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Inoue T, Kitaichi Y, Honda M, Tanaka T, Suzuki K, Nakagawa S, et al. Research on 
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Crossley NA, Bauer M. Acceleration and augmentation of antidepressants with 
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McKnight RF, Adida M, Budge K, Stockton S, Goodwin GM, Geddes JR. Lithium 
toxicity profile: a systematic review and meta-analysis. Lancet. 2012;379:721–8. 
10 Kamijima K, Higuchi T, Ishigooka J, Ohmori T, Ozaki N, Kanba S, et al. 
Aripiprazole augmentation to antidepressant therapy in Japanese patients with major 
depressive disorder: A randomized, double-blind, placebo-controlled study 
(ADMIRE study). Journal of Affective Disorders. 2013;151:899-905. 
11 Berman RM, Marcus RN, Swanink R, McQuade RD, Carson WH, Corey-Lisle PK, et 
al. The efficacy and safety of aripiprazole as adjunctive therapy in major depressive 
disorder: A multicenter, randomized, double-blind, placebo-controlled study. J Clin 
Psychiatry. 2007;68(6):843-53. 
12 Marcus RN, McQuade RD, Carson WH, Hennicken D, Fava M, Simon JS, et al. The 
efficacy and safety of aripiprazole as adjunctive therapy in major depressive disorder 
a second multicenter, randomized, double-blind, placebo-controlled study. Journal of 
Clinical Psychopharmacology. 2008;28(2):156-65. 
13 Berman RM, Fava M, Those ME, Trivedi MH, Swanink R, McQuade RD, et al. 
Aripiprazole augmentation in major depressive disorder: a double-blind, placebo-


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controlled study in patients with inadequate response to antidepressants. CNS Spectr. 
2009;14(4):197-206. 
14 Otsuka Pharmaceutical Co, Ltd. A dose-finding trial of OPC-34712 in patients with 
schizophrenia. Clinical Study Report for Protocol 331-10-002, issued 18 Dec 2015. 
15 Otsuka Pharmaceutical Co, Ltd. A long-term trial of OPC-34712 in patients with 
schizophrenia. Clinical Study Report for Protocol 331-10-003, issued 18 Dec 2015. 
16 Otsuka Pharmaceutical Co, Ltd. Package insert for Rexulti (brexpiprazole). April 
2018. 
17 Kane JM, Skuban A, Ouyang J, Hobart M, Pfister S, McQuade RD, et al. A 
multicenter, randomized, double-blind, controlled phase 3 trial of fixed-dose 
brexpiprazole for the treatment of adults with acute schizophrenia. Schizophrenia 
Research. 2015;164:127-35. 
18 Correll CU, Skuban A, Ouyang J, Hobart M, Pfister S, McQuade RD, et al. Efficacy 
and safety of brexpiprazole for the treatment of acute schizophrenia: a 6-week 
randomized, double-blind, placebo-controlled trial. Am J Psychiatry. 
2015;172(9):870-80. 
19 Thase ME, Youakim JM, Skuban A, Hobart M, Zhang P, McQuade RD, et al. 
Adjunctive brexpiprazole 1 and 3 mg for patients with major depressive disorder 
following inadequate response to antidepressants: A phase 3, randomized, double-
blind study. J Clin Psychiatry. 2015;76(9):1232-40. 
20 Thase ME, Youakim JM, Skuban A, Hobart M, Augustine C, Zhang P, et al. Efficacy 
and safety adjunctive brexpiprazole 2 mg in major depressive disorder: A phase 3, 
randomized, placebo-controlled study in patients with inadequate response to 
antidepressants. J Clin Psychiatry. 2015;76(9):1224-31.  
21 Otsuka Pharmaceutical Co, Ltd. Package insert for Rexulti (brexpiprazole). USA. 
February 2017.  
22 International Conference on Harmonization (ICH) [homepage on the Internet]. E6: 
Good Clinical Practice: Consolidated Guideline [finalized 1996 May, corrected 1996 
Jun 1996; cited 2014 Dec 5]. Available from: 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E
6/E6_R1_Guideline.pdf. 
 

SAP_001.pdf: 
 
 
STATISTICAL  ANALYSIS  PLAN 
 
 
 
A multi-center, open-label trial to assess the long-term safety and efficacy of 
brexpiprazole as adjunctive therapy in patients with major depressive disorder 
 
 
 
 
NCT Number: NCT03737474 
PRT NO.: 331-102-00059 
Version Date: 19 Jul 2022 (Version 2.0) 


Statistical Analysis Plan 
1 of 84 
Version: 2.0 Date: 19/07/2022 
 
Otsuka Pharmaceutical Co., Ltd. 
 
 
Investigational New Drug Brexpiprazole (OPC-34712) 
 
 
 
 
 
Protocol No. 331-102-00059 
 
 
 
A multi-center, open-label trial to assess the long-term safety and efficacy of 
brexpiprazole as adjunctive therapy in patients with major depressive disorder 
 
Statistical Analysis Plan 
 
Version: 2.0 
Date: 19 Jul 2022 
Protocol Version 3 Date: 23 Jan 2020 
 
 
 
 
 
 
 
 
 
 
 
Confidential 
May not be used, divulged, published, or otherwise disclosed without the prior written 
consent of Otsuka Pharmaceutical Co., Ltd. 
 


Protocol 331-102-00059 
Statistical Analysis Plan 
2 of 84 
Version: 2.0 Date: 19/07/2022 
Table of Contents 
Table of Contents ........................................................................................... 2 
List of Appendices.......................................................................................... 4 
List of Abbreviations and Definition of Terms ........................................... 5 
1 
Introduction .......................................................................................... 6 
2 
Trial Objectives ..................................................................................... 6 
3 
Trial Design ........................................................................................... 6 
3.1 
Type/Design of Trial ...........................................................................................6 
3.2 
Trial Treatments ..................................................................................................7 
3.3 
Trial Population ...................................................................................................8 
3.3.1 
Number of Subjects and Trial Population ........................................................8 
3.4 
Trial Visit Window ..............................................................................................8 
3.5 
Handling of Endpoints.........................................................................................9 
3.5.1 
Montgomery Åsberg Depression Rating Scale (MADRS) ...............................9 
3.5.2 
Clinical Global Impression – Improvement (CGI-I) ........................................9 
3.5.3 
Clinical Global Impression - Severity of Illness (CGI-S) ................................9 
3.5.4 
Hamilton Rating Scale for Depression (HAM-D) ............................................9 
3.5.5 
Sheehan Disability Scale (SDS) .......................................................................9 
3.5.6 
Drug-induced Extrapyramidal Symptoms Scale (DIEPSS) .............................9 
3.5.7 
Abnormal Involuntary Movement Scale (AIMS) ...........................................10 
4 
Sample Size .......................................................................................... 10 
5 
Statistical Analysis Datasets .............................................................. 10 
5.1 
Efficacy Analysis Set ........................................................................................10 
5.2 
Safety Analysis Set ............................................................................................10 
5.3 
Handling of Missing Data .................................................................................10 
6 
Primary and Secondary Outcome Variables ................................... 11 
7 
Disposition and Demographic Analysis ............................................ 11 
7.1 
Subject Disposition ...........................................................................................11 
7.2 
Demographic and Baseline Characteristics .......................................................11 
7.3 
Baseline Disease Evaluation .............................................................................11 
7.4 
Treatment Compliance ......................................................................................12 


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7.5 
Prior and Concomitant Medications ..................................................................12 
7.6 
Protocol Deviations ...........................................................................................12 
8 
Efficacy Analysis ................................................................................. 12 
8.1 
Subgroup Analyses ............................................................................................13 
9 
Other Analyses .................................................................................... 13 
10 
Safety Analyses ................................................................................... 13 
10.1 
Extent of Exposure ............................................................................................13 
10.2 
Adverse Events ..................................................................................................14 
10.2.1 
Adverse Events of Interest ..............................................................................14 
10.2.2 
Subgroup Analysis of Adverse Events ...........................................................15 
10.3 
Clinical Laboratory Data ...................................................................................15 
10.4 
Vital Sign Data ..................................................................................................16 
10.5 
Physical Examination Data ...............................................................................17 
10.6 
Electrocardiogram Data .....................................................................................17 
10.7 
Other Safety Data ..............................................................................................17 
10.7.1 
Body Weight, BMI, and Waist Circumference ..............................................17 
10.7.2 
DIEPSS, AIMS, and Barnes Akathisia Rating Scale (BARS) .......................17 
10.7.3 
Columbia-Suicide Severity Rating Scale (C-SSRS) .......................................18 
11 
Pharmacokinetic Analyses ................................................................. 18 
12 
Pharmacodynamic Analyses .............................................................. 18 
13 
Pharmacogenomic Analyses .............................................................. 18 
14 
Interim Analysis .................................................................................. 18 
15 
Changes in the Planned Analyses ...................................................... 19 
16 
References ............................................................................................ 19 
17 
History of Amendments ..................................................................... 19 
 


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List of Appendices 
Appendix 1 
Criteria for Identifying Vital Signs and Weight of Potential 
Clinical Relevance ........................................................................ 20 
Appendix 2 
Criteria for Identifying Laboratory Values of Potential 
Clinical Relevance ........................................................................ 21 
Appendix 3 
Criteria for Identifying ECG Measurements of Potential 
Clinical Relevance ........................................................................ 22 
Appendix 4 
Adverse Events of Interest ............................................................ 23 
Appendix 5 
List of Summary Tables ................................................................ 79 
Appendix 6 
List of Subject Data Listings ......................................................... 83 
 


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List of Abbreviations and Definition of Terms 
Abbreviation 
Definition 
AIMS 
Abnormal Involuntary Movement Scale 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BARS 
Barnes Akathisia Rating Scale  
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
CGI 
Clinical Global Impression 
CGI-I 
Clinical Global Impression - Improvement 
CGI-S 
Clinical Global Impression - Severity of Illness 
CK 
Creatine kinase 
CPK 
Creatine phosphokinase 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DIEPSS 
Drug Induced Extra-Pyramidal Symptoms Scale 
DSM-5 
Diagnostic and statistical manual of mental disorders fifth edition 
EQ-5D-5L 
EuroQol-5 Dimension, 5 response level version 
GCP 
Good Clinical Practice 
GOT 
Glutamic-oxaloacetic transaminase 
GPT 
Glutamic-pyruvic transaminase 
HAM-D 
Hamilton Rating Scale for Depression 
HDL 
High-density lipoprotein 
LDH 
Lactate (lactic acid) dehydrogenase 
LDL 
Low-density lipoprotein 
LOCF 
Last observation carried forward 
MADRS 
Montgomery Åsberg Depression Rating Scale 
MedDRA 
Medical Dictionary for Regulatory Activities 
PT 
Preferred Term 
QTc 
QT corrected for heart rate 
QTcB 
QT corrected for heart rate by Bazett’s formula 
QTcF 
QT corrected for heart rate by Fridericia’s formula 
QTcN 
QT corrected for heart rate by FDA Neuropharmacological Division 
formula 
SDS 
Sheehan Disability Scale 
SNRI 
Serotonin-noradrenaline reuptake inhibitor 
SOC 
System Organ Class 
SSRI 
Selective serotonin reuptake inhibitor 
TEAE 
Treatment-emergent adverse event 
γ-GTP 
γ-glutamyl transpeptidase 


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1 
Introduction 
This statistical analysis plan documents in detail the statistical analysis methods planned 
for Trial 331-102-00059. 
2 
Trial Objectives 
The objective of the trial is to assess the safety and efficacy of the long-term use of 
brexpiprazole as adjunctive therapy in concomitant use with a commercially available 
antidepressant (selective serotonin reuptake inhibitor [SSRI] or serotonin-noradrenaline 
reuptake inhibitor [SNRI] for rollover subjects and SSRI, SNRI, or mirtazapine for new 
subjects) in subjects with major depressive disorder who continue receiving the treatment 
from the double-blind trial (331-102-00058) and in newly enrolled patients 65 years or 
older with major depressive disorder. 
3 
Trial Design 
3.1 
Type/Design of Trial 
The trial is a multi-center, open-label trial to assess the safety and efficacy of the long-
term use of brexpiprazole as adjunctive therapy in conjunction with a commercially 
available antidepressant (SSRI or SNRI for rollover subjects and SSRI, SNRI, or 
mirtazapine for new subjects) at a dose and regimen specified in the package insert. 
Subjects of the trial are those who have completed the double-blind period (Phase B) of 
the double-blind trial (331-102-00058), and newly enrolled patients 65 years or older 
with major depressive disorder who have received 1 to 3 adequate antidepressant drug 
treatmentsa for major depressive episodes and have shown an inadequate responseb to all 
of these treatments. 
The trial design is shown in Figure 3.1-1. The trial comprises a screening period, 
treatment period, and post-treatment observation period. 
aDefinition of "adequate antidepressant drug treatment" is provided below. 
Treatment with an antidepressant at an approved dose for at least 6 weeks (for combination therapy, 
treatment for at least 3 weeks) 
bDefinition of "inadequate response" is provided below. 
With complete recovery from depressive symptoms and not the slightest improvement considered as 
100% and 0%, respectively, patients carry out self-evaluations for improvement by antidepressant 
drug treatments used to date, from among 4 grades (< 25% Improvement, 25% to 49% Improvement, 
50% to < 75% Improvement, and ≥ 75% Improvement), with the evaluations corresponding to < 25% 
Improvement or 25% to 49% Improvement classified as inadequate response. 
Patients who, among 1 to 3 adequate antidepressant drug treatments, have received treatment for 
≥ 6 weeks at least once (receiving only combination therapies for ≥ 3 weeks does not qualify) are 
eligible for selection. 
 


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Figure 3.1-1 
Trial Design 
aAdministration of brexpiprazole will commence at 1 mg/day and the dose will be increased to 2 mg/day 
after observations, examinations, and assessments at Week 1. Subjects who cannot tolerate doses of 
2 mg/day will be withdrawn from the trial. 
 
3.2 
Trial Treatments 
1) Drugs, dose, and regimen 
• Commercially available antidepressant 
For rollover subjects, an antidepressant (SSRI or SNRI) used in the double-blind 
trial (331-102-00058) will continue to be used throughout the treatment period, 
with no changes from the final dose and regimen. For new subjects, an 
antidepressant (SSRI, SNRI, or mirtazapine) being used at the time of informed 
consent will continue to be used throughout the treatment period, with no changes 
from the dose and regimen used at informed consent. 
During the treatment period, dose adjustment within the approved dose range is 
allowed according to the judgement of the investigator or subinvestigator, but the 
dose may not be altered at the time of dose escalation of brexpiprazole at Week 1. 
IMP
30 days after
the final IMP
administration
Post-
treatment
observation
period
(30 days)
30 days after
the final IMP
administration
Informed consent
Day -28 to Day -1
Starting dose:
 1 mg/day
Starting dose:
 1 mg/day
Informed consent
After completion of the
double-blind period
(Phase B) of the double-
blind trial (331-102-
00058)
New subjects ( 65 years old)
Trial period
Screening period
(up to 28 days)
Treatment period
(52 weeks)
Brexpiprazole 2 mg/day a
SSRI, SNRI, or
mirtazapine
SSRI, SNRI, or mirtazapine
SSRI or SNRI
Post-
treatment
observation
period
Post-
treatment
observation
period
Trial period
Completers of the double-blind period (Phase B)
of the double-blind trial (331-102-00058)
Treatment period
 (52 weeks)
Post-
treatment
observation
period
(30 days)
Brexpiprazole 2 mg/day a
SSRI or SNRI
Screening period
Requisite
concomitant
medication
Rollover 
subjects
n = 30 (as IMP-
treated subjects)
Week 1
Week 1
Week 52
Week 52
New 
subjects
Week 0
Week 0


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• Brexpiprazole 
Administration of brexpiprazole will commence at 1 mg/day and subjects will 
continue to receive a single brexpiprazole 1 mg tablet once daily by the oral route 
until the observations, examinations, and evaluations at Week 1. Following the 
observations, examinations, and evaluations at Week 1, subjects will be 
administered a single brexpiprazole 2 mg tablet once daily by the oral route. 
Subjects who cannot tolerate doses of 2 mg/day will be withdrawn from the trial. 
 
2) Treatment period 
52 weeks 
3.3 
Trial Population 
Adult and elderly patients with "major depressive disorder, single episode" or "major 
depressive disorder, recurrent episode" according to the classification criteria of the 
Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) 
3.3.1 
Number of Subjects and Trial Population 
The trial will be conducted in patients who have major depressive disorder (major 
depressive disorder, single episode; major depressive disorder, recurrent episode) 
according to the DSM-5 classification. Concerning rollover subjects from the double-
blind trial (331-102-00058), their eligibility for proceeding to the long-term trial will be 
assessed, after acquisition of informed consent to the long-term trial, based on the results 
of examinations and assessments at Week 6 of the double-blind period (Phase B) of the 
double-blind trial (331-102-00058) and at baseline. The eligibility of new subjects will be 
judged after acquisition of informed consent from elderly patients 65 years or older, 
based on the results of examinations and assessments at screening and baseline. As the 
sample size needed to assess the safety and efficacy of brexpiprazole in the elderly, the 
number of subjects receiving the treatment was set at 30. 
3.4 
Trial Visit Window 
For all endpoints, acceptable windows for analysis are specified, and analysis should be 
based on the analysis time points regardless of time points recorded on the case report 
form. 
Acceptable windows for analysis are shown in Table 3.4-1. Day 1 is defined as the day 
when treatment with the investigational medicinal product (IMP) begins. If multiple data 
exist within an acceptable window, the last data within the window will be used in 
analysis. Data obtained 7 days or later after the final dosing will be excluded from the 
analysis. 


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Table 3.4-1 
Acceptable Windows for Analysis 
Week 
Target Day 
Trial Day Interval 
Baseline 
1 
- 1 
Week 1 
7 
2 - 10 
Week 2 
14 
11 - 21 
Week 4 
28 
22 - 42 
Week 8 
56 
43 - 70 
Week 12 
84 
71 - 98 
Week 16 
112 
99 - 126 
Week 20 
140 
127 - 154 
Week 24 
168 
155 - 182 
Week 28 
196 
183 - 210 
Week 32 
224 
211 - 238 
Week 36 
252 
239 - 266 
Week 40 
280 
267 - 294 
Week 44 
308 
295 - 322 
Week 48 
336 
323 - 350 
Week 52 
364 
351 - 385 
 
3.5 
Handling of Endpoints 
3.5.1 
Montgomery Åsberg Depression Rating Scale (MADRS) 
The MADRS total score will be the sum of scores for MADRS Items 1 through 10. 
3.5.2 
Clinical Global Impression – Improvement (CGI-I) 
“0. Not assessed” will be handled as missing data. 
3.5.3 
Clinical Global Impression - Severity of Illness (CGI-S) 
“0. Not assessed” will be handled as missing data. 
3.5.4 
Hamilton Rating Scale for Depression (HAM-D) 
The HAM-D 17-item total score will be the sum of scores for HAM-D Items 1 through 
17. 
3.5.5 
Sheehan Disability Scale (SDS) 
The mean SDS score will be the mean of scores for 3 SDS items (work/school, social life, 
and family life/home responsibilities). In the case of a missing score for work/school, the 
mean of scores for the other 2 items will be handled as the mean SDS score. 
3.5.6 
Drug-induced Extrapyramidal Symptoms Scale (DIEPSS) 
The DIEPSS total score will be the sum of scores for DIEPSS items 1 through 8. 


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3.5.7 
Abnormal Involuntary Movement Scale (AIMS) 
The AIMS total score will be the sum of scores for AIMS items 1 through 7. 
4 
Sample Size 
To verify the safety of long-term administration, the target number of subjects to 
complete 52 weeks of administration was set at around 100 subjects. Due to the 
availability of data on safety in elderly subjects from foreign clinical trials, the sample 
size needed to assess the safety of brexpiprazole in the elderly was set as 30 new subjects 
(elderly subjects of age 65 and above) receiving IMP administration. 
5 
Statistical Analysis Datasets 
In this trial, unless otherwise specified, analysis will be performed for each of the 
following groups: 
• Rollover subjects from the double-blind trial (331-102-00058) who were assigned to 
the brexpiprazole groups in the double-blind period (Phase B) 
• Rollover subjects from the double-blind trial (331-102-00058) who were assigned to 
the placebo group in the double-blind period (Phase B) 
• All rollover subjects from the double-blind trial (331-102-00058) 
• New subjects (elderly subjects aged 65 years or older) 
• All subjects (rollover and new subjects combined) 
 
5.1 
Efficacy Analysis Set 
The efficacy analysis set will comprise subjects who have received at least 1 dose of the 
IMP, and from whom MADRS total scores have been obtained at baseline and at least 1 
time point after initiation of the treatment. Subjects who did not comply with Good 
Clinical Practice (GCP) will be excluded. 
5.2 
Safety Analysis Set 
The safety analysis set will comprise subjects who have received at least 1 dose of the 
IMP. Subjects who did not comply with GCP will be excluded. 
5.3 
Handling of Missing Data 
The analysis of last assessment time point will be performed using the last observation 
carried forward method (herein after referred to as "LOCF"), by which missing data at 
Week 52 will be imputed by the last observed data after initiation of IMP treatment. 


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6 
Primary and Secondary Outcome Variables 
Neither primary nor secondary outcome variables are planned. 
7 
Disposition and Demographic Analysis 
7.1 
Subject Disposition 
Numbers and proportions of subjects from whom informed consent was obtained, those 
who received trial treatment, those who completed the trial, those who discontinued the 
trial, those who discontinued the trial by reason, and those included in each analysis set 
will be summarized. Similar summarization will be performed for each requisite 
concomitant medication. 
Numbers and proportions of subjects who completed the trial will be summarized for 
each period (days) (1-7, 8-14, 15-28, 29-56, 57-84, 85-112, 113-140, 141-168, 169-196, 
197-224, 225-252, 253-280, 281-308, 309-336, 337-364, > 364). 
7.2 
Demographic and Baseline Characteristics 
Descriptive statistics (mean, standard deviation, minimum, median, maximum; 
hereinafter the same applies) of age, height, body weight, waist circumference, and body 
mass index (BMI) and frequency distribution of sex, race, ethnicity, country where trial is 
conducted, medical history, and complications will be determined in each analysis set. 
Similar summarization will be performed for each requisite concomitant medication. 
In rollover subjects, baseline data in the present trial will be used for body weight, waist 
circumference, and BMI. For medical history and complications, baseline data in the 
present trial as well as in the double-blind trial (331-102-00058) will be used. For the 
other demographic characteristics, baseline data in the double-blind trial (331-102-00058) 
will be used. 
7.3 
Baseline Disease Evaluation 
Descriptive statistics of the duration (months) of the current major depressive episode, 
age at initial onset, duration (months) of major depressive episode from initial onset, 
MADRS total score, HAM-D17 total score, and CGI-S and frequency distribution of 
DSM-5-based diagnosis (single, recurrent), severity (mild, moderate, severe), specific 
terms (“not applicable,” “applicable,” and disposition of each specific term), frequency of 
major depressive episodes (1, 2, 3, 4, ≥ 5), frequency of appropriate antidepressant drug 
treatments of the current major depressive episode (1, 2, 3) will be determined in each 
analysis set. Similar summarization will be performed for each requisite concomitant 
medication. 


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In rollover subjects, baseline data in the present trial will be used for MADRS total score, 
HAM-D17 total score, and CGI-S. For the other demographic characteristics, baseline 
data in the double-blind trial (331-102-00058) will be used. 
The duration of the current major depressive episode and the duration of major 
depressive episode from initial onset will be calculated using the following formula: 
duration (months) = (date of subject demographic evaluation – date of onset + 1) / 30. 
Any unknown month or day of onset will be replaced with June or 15, respectively. 
7.4 
Treatment Compliance 
Treatment compliance (number of days when the subject actually received the 
IMP/number of days for which the IMP was prescribed) will be grouped into < 70%, 
≥ 70% to < 80%, ≥ 80% to < 90%, and ≥ 90%, and its frequency distribution will be 
determined in the efficacy analysis set. 
7.5 
Prior and Concomitant Medications 
Numbers and proportions of subjects who used medications before, during, and after the 
treatment period will be determined by drug class and preferred term of the World Health 
Organization Drug Dictionary (WHODD) version Global B3 March 2018 in the safety 
analysis set. 
Similar summarization will be performed for antipsychotics. 
7.6 
Protocol Deviations 
Numbers and proportions of subjects with major deviations from the protocol will be 
determined for each category (treatment-related deviations, eligibility-related deviations, 
a failure to discontinue the trial when the subject meets the withdrawal criteria, 
procedure-related deviations that affect evaluation of the primary endpoint, use of 
prohibited medications, and overall) and each trial site, in the safety analysis set. 
8 
Efficacy Analysis 
Efficacy analysis will be performed using the efficacy analysis set. Baseline is defined as 
the last data obtained prior to initiation of IMP treatment in the trial. 
• MADRS total score 
• CGI-S 
• CGI-I 
• HAM-D 17 total score 
• Mean SDS score and score for each item 


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Descriptive statistics of actual measurements and changes from baseline at each time 
point and the last assessment time point (Week 52 LOCF) will be determined. 
• MADRS response rate (proportion of subjects in whom MADRS total scores have 
been reduced by at least 50% from baseline) 
• MADRS remission rate (proportion of subjects in whom MADRS total scores have 
been reduced by at least 50% from baseline, with their resultant MADRS total scores 
being ≤ 10) 
• CGI-I improvement rate (proportion of subjects who score 1 or 2 on the CGI-I scale) 
Numbers and proportions of subjects will be determined at each time point and the last 
assessment time point (Week 52 LOCF). 
8.1 
Subgroup Analyses 
No subgroup efficacy analyses will be performed. 
9 
Other Analyses 
Other analyses will be performed using the efficacy analysis set. Baseline is defined as 
the last data obtained prior to initiation of IMP treatment in the trial. 
• EuroQol-5 Dimension, 5 response level version (EQ-5D-5L) 
For each item, descriptive statistics of actual measurements and changes from 
baseline at each time point and the last assessment time point (Week 52 LOCF) will 
be determined. 
 
10 
Safety Analyses 
Safety analysis will be performed using the safety analysis set. Baseline is defined as the 
last data obtained prior to initiation of IMP treatment in the trial. 
10.1 
Extent of Exposure 
Frequency distribution of the duration (days) of treatment with the IMP (1-7, 8-14, 15-28, 
29-56, 57-84, 85-112, 113-140, 141-168, 169-196, 197-224, 225-252, 253-280, 281-308, 
309-336, 337-364, > 364) will be determined. Similar summarization will be performed 
for each requisite concomitant medication subgroup. 
Frequency distribution of the duration (days) of treatment with a requisite concomitant 
medication (1-7, 8-14, 15-28, 29-56, 57-84, 85-112, 113-140, 141-168, 169-196, 197-
224, 225-252, 253-280, 281-308, 309-336, 337-364, > 364) will be determined. 


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10.2 
Adverse Events 
All adverse events (AEs) will be coded by Medical Dictionary for Regulatory Activities 
(MedDRA) (Ver. 24.0) System Organ Class (SOC) and Preferred Term (PT). Numbers 
and proportions of subjects with the following AEs will be summarized by SOC and PT. 
If an AE occurs more than once in the same subject, the severest event will be used in 
summarization. 
• Adverse events occurring after initiation of IMP administration (treatment-emergent 
adverse events [TEAEs]) 
• TEAEs by severity 
• TEAEs with an outcome of death 
• Serious TEAEs 
• TEAEs leading to discontinuation of the IMP 
• TEAEs occurring in ≥ 2% of subjects in any group 
• TEAEs by date of initial onset (1-7, 8-14, 15-28, 29-56, 57-84, 85-112, 113-140, 141-
168, 169-196, 197-224, 225-252, 253-280, 281-308, 309-336, 337-364, > 364, post-
trial treatment) 
 
TEAEs potentially causally related to the IMP will also be summarized in the same 
manner. 
10.2.1 
Adverse Events of Interest 
Adverse events of interest are defined in Appendix 4. Numbers and proportions of 
subjects with the following AEs of interest will be summarized by SOC and PT. 
• Extrapyramidal AEs 
• Neuroleptic malignant syndrome-related AEs 
• Rhabdomyolysis 
• Seizure-related AEs 
• Orthostatic disorder-related AEs 
• Suicide/suicide attempt-related AEs 
• Oversedation-related AEs 
• Hypersensitive symptom-related AEs 
• Venous thrombosis 
• Blood disorder-related AEs 
• Glucose metabolism-related AEs 
• Lipid metabolism-related AEs 
• Body weight-related AEs 
• QT interval prolongation-related AEs 


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• Manic switch-related AEs 
• Prolactin increase-related AEs 
 
10.2.2 
Subgroup Analysis of Adverse Events 
Numbers and proportions of subjects with TEAEs will be summarized by SOC and PT in 
each of the following subgroups: 
• Requisite concomitant medications (duloxetine, escitalopram, fluvoxamine, 
milnacipran, paroxetine, sertraline, venlafaxine, mirtazapine) 
• Sex (male, female) 
• Impact of COVID-19 pandemic (subjects who completed/discontinued the trial before 
07 Apr 2020, subjects who completed/discontinued the trial on or after 07 Apr 2020) 
 
10.3 
Clinical Laboratory Data 
For each quantitative laboratory parameter, descriptive statistics of actual measurements 
and changes from baseline at each time point and the last assessment time point (Week 
52 LOCF) will be calculated. 
For each quantitative laboratory parameter, actual measurements will be classified as 
"lower than the lower limit of the reference range," "within the reference range," and 
"higher than the upper limit of the reference range" using the reference range specified by 
the central laboratory, and a shift table from baseline will be produced. 
For each qualitative laboratory parameter, a shift table from baseline will be produced. 
Numbers and proportions of subjects with laboratory test values not meeting the criteria 
for potentially clinically significant laboratory test values (Appendix 2) at baseline and 
meeting the criteria after treatment will be determined. A listing of these subjects will be 
provided. 
Numbers and proportions of subjects with postdose values of alanine aminotransferase 
(ALT), aspartate aminotransferase (AST), and total bilirubin (TBL) meeting Hy’s Law 
criteria (ALT or AST ≥ 3 × the upper limit of normal [ULN] and TBL ≥ 2 × ULN) will 
be determined. A listing of these subjects will be provided. 
Numbers and proportions of subjects with a prolactin value not meeting the criteria of 
> 1 × ULN, > 2 × ULN, or > 3 × ULN at baseline and meeting the criteria after treatment 
will be determined by sex. A listing of these subjects will be provided. 
Numbers and proportions of subjects with postdose values of fasting low-density 
lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglyceride, 
and blood glucose meeting the criteria for changes in glucose and lipid metabolism-


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related parameters (Table 10.3-1) will be determined by baseline value. A listing of these 
subjects will be provided. 
Table 10.3-1 
Changes in Glucose and Lipid Metabolism-related 
Parameters 
LAB PARAMETER 
BASELINE 
ANYTIME POST BASELINE 
LDL Cholesterol, Fasting  
(mg/dL) 
Borderline 100-<160 
Normal/Borderline <160 
Normal <100 
Any Value 
High >=160 
High >=160 
Borderline/High >=100 
Increased >=30  
HDL Cholesterol, Fasting 
(mg/dL) 
Normal >=40 
Any Value 
Low <40 
Decreased >=20 
Triglycerides, Fasting  
(mg/dL)    
Normal <150 
Borderline 150-<200 
Normal/Borderline <200 
Normal <150 
Normal/Borderline/high <500 
Any Value 
High 200-<500 
High 200-<500 
High 200-<500 
Borderline/High/Very High >=150 
Very High >=500 
Increased >=50 
Glucose Fasting, Serum  
(mg/dL)    
Normal <100 
Impaired 100-<126 
Normal/Impaired <126 
Any Value 
High >=126 
High >=126 
High >=126 
Increased >=10 
 
Numbers and proportions of subjects not meeting the metabolic syndrome criteria (Table 
10.3-2) at baseline and meeting the criteria after treatment will be determined. A listing 
of these subjects will be provided. 
Table 10.3-2 
Metabolic Syndrome Criteria 
Description 
Metabolic Syndrome Criteria (Health, Labour and Welfare Ministry of 
Japan) 
Central obesity 
Waist Circumference ≥85 cm (Male), ≥90 cm (Female) 
Dyslipidemia 
Triglycerides, Fasting ≥150 mg/dL and/or HDL, Fasting <40 mg/dL 
Supine blood pressure 
Systolic ≥130 mmHg and/or Diastolic ≥85 mmHg 
Glucose fasting, serum 
≥110 mg/dL 
Metabolic syndrome 
Met central obesity criteria and 2 of 3 other criteria at a visit 
 
10.4 
Vital Sign Data 
For each vital sign parameter (by position for blood pressure and pulse rate), descriptive 
statistics of actual measurements and changes from baseline at each time point and the 
last assessment time point (Week 52 LOCF) will be calculated. 
Numbers and proportions of subjects with vital signs meeting the criteria for potentially 
clinically significant vital signs (Appendix 1) will be determined. A listing of these 
subjects will be provided. 


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10.5 
Physical Examination Data 
Physical examination data will be provided in a listing. 
10.6 
Electrocardiogram Data 
For heart rate, PR interval, RR interval, QRS interval, QT interval, and QT corrected for 
heart rate (QTc), descriptive statistics of actual measurements and changes from baseline 
at each time point and the last assessment time point (Week 52 LOCF) will be calculated. 
A shift table from baseline for normal/abnormal 12-lead electrocardiogram (ECG) 
(evaluated at the trial site) will be produced. 
Numbers and proportions of subjects with actual measurements of QTc (QTcF, QTcB, 
QTcN) not meeting the criteria of > 450 msec, > 480 msec, and > 500 msec at baseline 
and meeting the criteria after treatment will be determined. Numbers and proportions of 
subjects with changes from baseline of > 30 msec and > 60 msec will be determined. 
Numbers and proportions of subjects with actual measurements of > 450 msec with a % 
change from baseline of > 10% will be determined. 
Numbers and proportions of subjects with ECG results meeting the criteria for potentially 
clinically significant ECG data (Appendix 3) will be determined. A listing of these 
subjects will be provided. 
10.7 
Other Safety Data 
10.7.1 
Body Weight, BMI, and Waist Circumference 
For body weight, BMI, and waist circumference, descriptive statistics of actual 
measurements and changes from baseline at each time point and the last assessment time 
point (Week 52 LOCF) will be calculated. 
Numbers and proportions of subjects with results meeting the criteria for potentially 
clinically significant body weight gain or loss (Appendix 1) will be determined. Body 
weight data will also be analyzed by baseline BMI category (< 18.5, ≥ 18.5 to < 25, ≥ 25 
to < 30, ≥ 30) in a similar manner. A listing of subjects with results meeting the criteria 
for potentially clinically significant body weight gain or loss (Appendix 1) will be 
provided. 
10.7.2 
DIEPSS, AIMS, and Barnes Akathisia Rating Scale (BARS) 
For DIEPSS total score (total of scores for items 1 through 8) and the score for each 
DIEPSS item, AIMS total score (total of scores for items 1 through 7) and the score for 
each of the items 8 through 10, and BARS, descriptive statistics of actual measurements 
and changes from baseline at each time point and the last assessment time point (Week 


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52 LOCF) and the worst postdose measurement and its change from baseline will be 
calculated. 
10.7.3 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Numbers and proportions of subjects for each C-SSRS item (suicidality, suicidal ideation, 
suicidal behavior, completed suicide, emergence of suicidal ideation, emergence of 
serious suicidal ideation, worsening of suicidal ideation, and emergence of suicidal 
behavior) at each time point and in the overall period after initiation of IMP treatment 
(including the post-treatment observation period, at discontinuation, and unscheduled 
visits) will be determined. A listing of subjects with emergence of suicidal ideation, 
emergence of serious suicidal ideation, worsening of suicidal ideation, and emergence of 
suicidal behavior will be provided. Items of suicidal ideation and suicidal behavior will 
also be summarized in the same manner. 
• Suicidality: “Yes” for any item of suicidal ideation or suicidal behavior 
• Suicidal ideation: “Yes” for any item of suicidal ideation 
• Suicidal behavior: “Yes” for any item of suicidal behavior 
• Emergence of suicidal ideation: Change from “No” at baseline to “Yes” after baseline 
for suicidal ideation 
• Emergence of serious suicidal ideation: Change from “No” at baseline to “Yes” with 
Grade 4 or 5 after baseline for suicidal ideation 
• Worsening of suicidal ideation: Increase in the grade of suicidal ideation from 
baseline 
• Emergence of suicidal behavior: Change from “No” at baseline to “Yes” after 
baseline for suicidal behavior 
 
11 
Pharmacokinetic Analyses 
Not applicable. 
12 
Pharmacodynamic Analyses 
Not applicable. 
13 
Pharmacogenomic Analyses 
Not applicable. 
14 
Interim Analysis 
None. 


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15 
Changes in the Planned Analyses 
• The following changes were made to categorical analyses of QTc: 
Only subjects with postdose QTc meeting the criteria will be summarized, instead of 
summarization at all time points. 
Only subjects with QTc not meeting the criteria at baseline and meeting the criteria 
after baseline will be summarized. 
• C-SSRS will be analyzed in the overall period after initiation of IMP treatment, not at 
the last assessment time point. 
 
16 
References 
Not applicable. 
17 
History of Amendments 
Table 17-1 
History of Amendments 
Version 
Date 
Major Changes 
1.0 
01 Jun 2021 
Not applicable 
2.0 
19 Jul 2022 
• Exclusion of subjects who did not comply with GCP 
was added to the definition of analysis sets in 
Section 5 Statistical Analysis Datasets. 
• The wording “Agranulocytosis, neutropenia, 
leukopenia” was replaced with the more appropriate 
term “Blood disorder-related AEs” in Section 10.2.1 
Adverse Events of Interest. 
• A typographical error in Section 15 Changes in the 
Planned Analysis was corrected (before correction: 
“after initiation of after IMP treatment”; after 
correction: “after initiation of IMP treatment”) 
(Please note that this error had been made only in 
the Japanese version and no correction was 
necessary in the English version.) 
 


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Appendix 1 
Criteria for Identifying Vital Signs and Weight of Potential 
Clinical Relevance 
 
Variable 
Criterion Valuea 
Change Relative to Baselinea 
Pulse Rate 
> 120 bpm 
< 50 bpm 
 15 bpm increase 
 15 bpm decrease 
Systolic Blood Pressure 
> 180 mmHg 
< 90 mmHg 
 20 mmHg increase 
 20 mmHg decrease 
Diastolic Blood Pressure 
> 105 mmHg 
< 50 mmHg 
 15 mmHg increase 
 15 mmHg decrease 
Orthostatic Hypotension 
≥ 20 mmHg decrease in systolic blood 
pressure and a ≥ 25 bpm increase in 
pulse rate from supine to 
sitting/standing 
Not Applicable 
Weight 
- 
 7% increase 
 7% decrease 
aIn order to be identified as potentially clinically relevant, an on-treatment value must meet the 
“Criterion Value” and also represent a change from the subject’s baseline value of at least the 
magnitude shown in the “Change Relative to Baseline” column. 


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Appendix 2 
Criteria for Identifying Laboratory Values of Potential 
Clinical Relevance 
 
Laboratory Tests 
Criteria 
Chemistry 
 
 
AST (SGOT) 
 3 x upper limit of normal (ULN) 
 
ALT (SGPT) 
 3 x ULN 
 
Alkaline phosphatase 
 3 x ULN 
 
LDH 
 3 x ULN 
 
BUN 
 30 mg/dL 
 
Creatinine 
 2.0 mg/dL 
 
Uric Acid 
 
 
 
Men 
 10.5 mg/dL 
 
 
Women 
 8.5 mg/dL 
 
Bilirubin (total) 
 2.0 mg/dL 
 
CPK 
 3 x ULN 
Endocrinology 
 
 
Prolactin 
> ULN 
Hematology 
 
 
Hematocrit 
 
 
 
Men 
 37 % and decrease of  3 percentage points from Baseline 
 
 
Women 
 32 % and decrease of  3 percentage points from Baseline 
 
Hemoglobin 
 
 
 
Men 
 11.5 g/dL 
 
 
Women 
 9.5 g/dL 
 
White blood count 
 2,800/ mm3 or  16,000/ mm3 
 
Eosinophils 
 10% 
 
Neutrophils 
 15% 
 
Absolute neutrophil count 
 1,000/ mm3 
 
Platelet count 
 75,000/ mm3 or  700,000/ mm3 
Urinalysis 
 
 
Protein 
Increase of  2 units 
 
Glucose 
Increase of  2 units 
Additional Criteria 
 
 
Chloride 
 90 mEq/L or  118 mEq/L 
 
Potassium 
 2.5 mEq/L or  6.5 mEq/L 
 
Sodium 
 126 mEq/L or  156 mEq/L 
 
Calcium 
 8.2 mg/dL or  12 mg/dL 
 
Glucose 
 
 
 
Fasting 
 100 mg/dL 
 
 
Non-Fasting 
 200 mg/dL 
 
Total Cholesterol, Fasting 
 240 mg/dL 
 
LDL Cholesterol, Fasting 
 160 mg/dL 
 
HDL Cholesterol, Fasting 
 
 
 
Men 
< 40 mg/dL 
 
 
Women 
< 50 mg/dL 
 
Triglycerides, Fasting 
 150 mg/dL 
 
 


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Appendix 3 
Criteria for Identifying ECG Measurements of Potential 
Clinical Relevance 
 
Variable 
Criterion Valuea 
Change Relative to Baselinea 
Heart Rate 
 120 bpm 
 50 bpm 
increase of   15 bpm 
decrease of  15 bpm 
PR 
 200 msec 
increase of   50 msec 
QRS 
 120 msec 
increase of  20 msec 
QTcF 
 
> 450 msec 
(males and females) 
 
 
 
 


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Appendix 4 
Adverse Events of Interest 
 
AE Category 
Preferred Term 
EFFECT ON GLUCOSE 
Blood glucose abnormal 
 
Blood glucose increased 
 
Diabetes mellitus 
 
Diabetes mellitus inadequate control 
 
Diabetes with hyperosmolarity 
 
Diabetic coma 
 
Diabetic hyperglycaemic coma 
 
Diabetic hyperosmolar coma 
 
Diabetic ketoacidosis 
 
Diabetic ketoacidotic hyperglycaemic coma 
 
Glucose tolerance decreased 
 
Glucose tolerance impaired 
 
Glucose tolerance test abnormal 
 
Glucose urine present 
 
Glycosuria 
 
Glycosylated haemoglobin increased 
 
Hyperglycaemia 
 
Hyperglycaemic hyperosmolar nonketotic syndrome 
 
Impaired fasting glucose 
 
Increased insulin requirement 
 
Indeterminate glucose tolerance 
 
Insulin resistance 
 
Insulin resistant diabetes 
 
Insulin tolerance test abnormal 
 
Insulin-requiring type 2 diabetes mellitus 
 
Ketoacidosis 
 
Ketonuria 
 
Ketosis 
 
Metabolic syndrome 
 
Type 1 diabetes mellitus 
 
Type 2 diabetes mellitus 
 
Urine ketone body present 
EFFECT ON LIPIDS 
3-hydroxyacetyl-coenzyme A dehydrogenase deficiency 
 
Acquired mixed hyperlipidaemia 
 
Apolipoprotein 
 
Apolipoprotein A-I 
 
Apolipoprotein A-I abnormal 
 
Apolipoprotein A-I decreased 
 
Apolipoprotein A-I increased 
 
Apolipoprotein A-I normal 
 
Apolipoprotein A-II 
 
Apolipoprotein A-II abnormal 
 
Apolipoprotein A-II decreased 
 
Apolipoprotein A-II increased 
 
Apolipoprotein A-II normal 
 
Apolipoprotein B 
 
Apolipoprotein B abnormal 
 
Apolipoprotein B decreased 
 
Apolipoprotein B increased 


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Apolipoprotein B normal 
 
Apolipoprotein B/Apolipoprotein A-1 ratio 
 
Apolipoprotein B/Apolipoprotein A-1 ratio increased 
 
Apolipoprotein C 
 
Apolipoprotein C abnormal 
 
Apolipoprotein E 
 
Apolipoprotein E abnormal 
 
Apolipoprotein E increased 
 
Apolipoprotein abnormal 
 
Apolipoprotein decreased 
 
Apolipoprotein increased 
 
Apolipoprotein normal 
 
Autoimmune hyperlipidaemia 
 
Barth syndrome 
 
Blood cholesterol 
 
Blood cholesterol abnormal 
 
Blood cholesterol decreased 
 
Blood cholesterol esterase increased 
 
Blood cholesterol increased 
 
Blood cholesterol normal 
 
Blood triglycerides 
 
Blood triglycerides abnormal 
 
Blood triglycerides decreased 
 
Blood triglycerides increased 
 
Blood triglycerides normal 
 
Body fat disorder 
 
CANDLE syndrome 
 
Cardiac steatosis 
 
Carnitine 
 
Carnitine abnormal 
 
Carnitine decreased 
 
Carnitine deficiency 
 
Carnitine increased 
 
Carnitine normal 
 
Carnitine palmitoyltransferase deficiency 
 
Carnitine-acylcarnitine translocase deficiency 
 
Cholesterol absorption efficiency decreased 
 
Cholesterosis 
 
Chylomicron decreased 
 
Chylomicron increased 
 
Chylomicrons 
 
Congenital carnitine deficiency 
 
Dyslipidaemia 
 
Epidural lipomatosis 
 
Facial wasting 
 
Familial high density lipoprotein deficiency 
 
Familial hypertriglyceridaemia 
 
Fat redistribution 
 
Fatty acid deficiency 
 
Fatty acid oxidation disorder 
 
Fatty liver alcoholic 
 
Free fatty acids 
 
Free fatty acids abnormal 
 
Free fatty acids decreased 


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Free fatty acids increased 
 
Gastric xanthoma 
 
HIV lipodystrophy 
 
Hepatic steato-fibrosis 
 
Hepatic steatosis 
 
High density lipoprotein 
 
High density lipoprotein abnormal 
 
High density lipoprotein decreased 
 
High density lipoprotein increased 
 
High density lipoprotein normal 
 
Hyper HDL cholesterolaemia 
 
Hypercholesterolaemia 
 
Hyperchylomicronaemia 
 
Hyperlipidaemia 
 
Hypertriglyceridaemia 
 
Hypo HDL cholesterolaemia 
 
Hypocarnitinaemia 
 
Hypocholesterolaemia 
 
Hypolipidaemia 
 
Hypotriglyceridaemia 
 
Inborn error of lipid metabolism 
 
Intermediate density lipoprotein decreased 
 
Intermediate density lipoprotein increased 
 
Intestinal lipomatosis 
 
Intestinal steatosis 
 
LDL/HDL ratio 
 
LDL/HDL ratio decreased 
 
LDL/HDL ratio increased 
 
Lecithin-cholesterol acyltransferase activity decreased 
 
Lecithin-cholesterol acyltransferase activity increased 
 
Lecithin-cholesterol acyltransferase deficiency 
 
Lipaemia retinalis 
 
Lipaemic index score 
 
Lipid metabolism disorder 
 
Lipid proteinosis 
 
Lipids 
 
Lipids abnormal 
 
Lipids decreased 
 
Lipids increased 
 
Lipids normal 
 
Lipoatrophy 
 
Lipodystrophy acquired 
 
Lipoedema 
 
Lipohypertrophy 
 
Lipomatosis 
 
Lipoprotein (a) 
 
Lipoprotein (a) abnormal 
 
Lipoprotein (a) decreased 
 
Lipoprotein (a) increased 
 
Lipoprotein (a) normal 
 
Lipoprotein abnormal 
 
Lipoprotein deficiency 
 
Lipoprotein increased 
 
Long-chain acyl-coenzyme A dehydrogenase deficiency 


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Low density lipoprotein 
 
Low density lipoprotein abnormal 
 
Low density lipoprotein decreased 
 
Low density lipoprotein increased 
 
Low density lipoprotein normal 
 
Medium-chain acyl-coenzyme A dehydrogenase deficiency 
 
Mesangiolipidosis 
 
Non-alcoholic steatohepatitis 
 
Non-high-density lipoprotein cholesterol 
 
Non-high-density lipoprotein cholesterol decreased 
 
Non-high-density lipoprotein cholesterol increased 
 
Nonalcoholic fatty liver disease 
 
Pancreatic steatosis 
 
Parotid lipomatosis 
 
Partial lipodystrophy 
 
Phospholipidosis 
 
Phytanic acid increased 
 
Phytosterol level 
 
Phytosterol level increased 
 
Phytosterolaemia 
 
Primary hypercholesterolaemia 
 
Remnant hyperlipidaemia 
 
Remnant-like lipoprotein particles 
 
Remnant-like lipoprotein particles increased 
 
Renal lipomatosis 
 
Renal phospholipidosis 
 
Serum pristanic acid increased 
 
Short-chain acyl-coenzyme A dehydrogenase deficiency 
 
Steatohepatitis 
 
Tangier disease 
 
Thyroid steatosis 
 
Total cholesterol/HDL ratio 
 
Total cholesterol/HDL ratio abnormal 
 
Total cholesterol/HDL ratio decreased 
 
Total cholesterol/HDL ratio increased 
 
Total cholesterol/HDL ratio normal 
 
Trifunctional protein deficiency 
 
Type I hyperlipidaemia 
 
Type II hyperlipidaemia 
 
Type III hyperlipidaemia 
 
Type IIa hyperlipidaemia 
 
Type IIb hyperlipidaemia 
 
Type IV hyperlipidaemia 
 
Type V hyperlipidaemia 
 
Very long-chain acyl-coenzyme A dehydrogenase deficiency 
 
Very low density lipoprotein 
 
Very low density lipoprotein abnormal 
 
Very low density lipoprotein decreased 
 
Very low density lipoprotein increased 
 
Very low density lipoprotein normal 
 
Xanthelasma 
 
Xanthoma 
 
Xanthomatosis 
 
Zieve syndrome 


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EFFECTS ON WEIGHT 
Abnormal weight gain 
 
Body mass index abnormal 
 
Body mass index increased 
 
Obesity 
 
Overweight 
 
Waist circumference increased 
 
Weight fluctuation 
 
Weight increased 
EPS 
Abnormal involuntary movement scale 
 
Action tremor 
 
Akathisia 
 
Akinesia 
 
Asterixis 
 
Athetosis 
 
Ballismus 
 
Blepharospasm 
 
Bradykinesia 
 
Bradyphrenia 
 
Buccoglossal syndrome 
 
Chorea 
 
Choreoathetosis 
 
Chronic tic disorder 
 
Clumsiness 
 
Cogwheel rigidity 
 
Complex tic 
 
Dopamine dysregulation syndrome 
 
Drooling 
 
Dysarthria 
 
Dyskinesia 
 
Dyskinesia neonatal 
 
Dyskinesia oesophageal 
 
Dyslalia 
 
Dysphonia 
 
Dystonia 
 
Dystonic tremor 
 
Emprosthotonus 
 
Essential tremor 
 
Excessive eye blinking 
 
Extrapyramidal disorder 
 
Facial spasm 
 
Fine motor skill dysfunction 
 
Freezing phenomenon 
 
Fumbling 
 
Gait disturbance 
 
Gait inability 
 
Gaze palsy 
 
Glabellar reflex abnormal 
 
Grimacing 
 
Head titubation 
 
Huntington's disease 
 
Hyperkinesia 
 
Hyperkinesia neonatal 
 
Hypertonia 
 
Hypertonia neonatal 


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Hypokinesia 
 
Hypokinesia neonatal 
 
Hypokinetic dysarthria 
 
Intention tremor 
 
Laryngeal tremor 
 
Laryngospasm 
 
Meige's syndrome 
 
Micrographia 
 
Mobility decreased 
 
Motor dysfunction 
 
Movement disorder 
 
Muscle contractions involuntary 
 
Muscle contracture 
 
Muscle rigidity 
 
Muscle spasms 
 
Muscle spasticity 
 
Muscle tightness 
 
Muscle tone disorder 
 
Muscle twitching 
 
Musculoskeletal stiffness 
 
Myoclonus 
 
Myotonia 
 
Nuchal rigidity 
 
Oculogyric crisis 
 
Oesophageal spasm 
 
On and off phenomenon 
 
Opisthotonus 
 
Oromandibular dystonia 
 
Oropharyngeal spasm 
 
Parkinson's disease 
 
Parkinson's disease psychosis 
 
Parkinsonian crisis 
 
Parkinsonian gait 
 
Parkinsonian rest tremor 
 
Parkinsonism 
 
Parkinsonism hyperpyrexia syndrome 
 
Periodic limb movement disorder 
 
Pharyngeal dyskinesia 
 
Pharyngeal dystonia 
 
Pleurothotonus 
 
Postural reflex impairment 
 
Postural tremor 
 
Posture abnormal 
 
Posturing 
 
Propulsive gait 
 
Protrusion tongue 
 
Provisional tic disorder 
 
Psychomotor hyperactivity 
 
Rabbit syndrome 
 
Reduced facial expression 
 
Respiratory dyskinesia 
 
Resting tremor 
 
Restless legs syndrome 
 
Restlessness 


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Risus sardonicus 
 
Saliva altered 
 
Salivary hypersecretion 
 
Secondary tic 
 
Spasmodic dysphonia 
 
Tardive dyskinesia 
 
Tic 
 
Tongue paralysis 
 
Tongue spasm 
 
Torticollis 
 
Torticollis psychogenic 
 
Tremor 
 
Tremor neonatal 
 
Trismus 
 
Uvular spasm 
 
Walking disability 
 
Writer's cramp 
HAEMATOPOIETIC/LEUKOPENIA 
5q minus syndrome 
 
ABO haemolytic disease of newborn 
 
ABO incompatibility 
 
ADAMTS13 activity abnormal 
 
ADAMTS13 activity assay 
 
ADAMTS13 activity decreased 
 
ADAMTS13 activity increased 
 
ADAMTS13 activity normal 
 
ADAMTS13 inhibitor screen assay 
 
Aase syndrome 
 
Abdominal lymphadenopathy 
 
Abnormal clotting factor 
 
Accessory spleen 
 
Acid haemolysin test 
 
Acid haemolysin test negative 
 
Acid haemolysin test positive 
 
Acquired Von Willebrand's disease 
 
Acquired amegakaryocytic thrombocytopenia 
 
Acquired antithrombin III deficiency 
 
Acquired asplenia 
 
Acquired complement deficiency disease 
 
Acquired dysfibrinogenaemia 
 
Acquired factor IX deficiency 
 
Acquired factor VIII deficiency 
 
Acquired factor XI deficiency 
 
Acquired haemoglobinopathy 
 
Acquired haemophilia 
 
Acquired protein S deficiency 
 
Acquired thalassaemia 
 
Acral angiokeratoma-like pseudolymphoma 
 
Activated partial thromboplastin time 
 
Activated partial thromboplastin time abnormal 
 
Activated partial thromboplastin time normal 
 
Activated partial thromboplastin time prolonged 
 
Activated partial thromboplastin time ratio 
 
Activated partial thromboplastin time ratio abnormal 
 
Activated partial thromboplastin time ratio decreased 


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Activated partial thromboplastin time ratio fluctuation 
 
Activated partial thromboplastin time ratio increased 
 
Activated partial thromboplastin time ratio normal 
 
Activated partial thromboplastin time shortened 
 
Activated protein C resistance 
 
Activated protein C resistance test 
 
Activated protein C resistance test positive 
 
Acute bilineal leukaemia 
 
Acute biphenotypic leukaemia 
 
Acute chest syndrome 
 
Acute erythroid leukaemia 
 
Acute febrile neutrophilic dermatosis 
 
Acute haemolytic transfusion reaction 
 
Acute haemorrhagic oedema of infancy 
 
Acute leukaemia 
 
Acute leukaemia in remission 
 
Acute lymphocytic leukaemia 
 
Acute lymphocytic leukaemia (in remission) 
 
Acute lymphocytic leukaemia recurrent 
 
Acute lymphocytic leukaemia refractory 
 
Acute megakaryocytic leukaemia 
 
Acute megakaryocytic leukaemia (in remission) 
 
Acute monocytic leukaemia 
 
Acute monocytic leukaemia (in remission) 
 
Acute myeloid leukaemia 
 
Acute myeloid leukaemia (in remission) 
 
Acute myeloid leukaemia recurrent 
 
Acute myeloid leukaemia refractory 
 
Acute myelomonocytic leukaemia 
 
Acute promyelocytic leukaemia 
 
Acute undifferentiated leukaemia 
 
Adenoiditis 
 
Administration site lymphadenopathy 
 
Adult T-cell lymphoma/leukaemia 
 
Adult T-cell lymphoma/leukaemia recurrent 
 
Adult T-cell lymphoma/leukaemia refractory 
 
Adult T-cell lymphoma/leukaemia stage I 
 
Adult T-cell lymphoma/leukaemia stage II 
 
Adult T-cell lymphoma/leukaemia stage III 
 
Adult T-cell lymphoma/leukaemia stage IV 
 
Agranulocytosis 
 
Aleukaemic leukaemia 
 
Allergic bronchopulmonary mycosis 
 
Allergic eosinophilia 
 
Alloimmunisation 
 
Alpha-thalassaemia-intellectual deficit syndrome 
 
Amegakaryocytic thrombocytopenia 
 
Anaemia 
 
Anaemia Heinz body 
 
Anaemia folate deficiency 
 
Anaemia macrocytic 
 
Anaemia megaloblastic 
 
Anaemia neonatal 
 
Anaemia of chronic disease 


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Anaemia of malignant disease 
 
Anaemia of pregnancy 
 
Anaemia postoperative 
 
Anaemia splenic 
 
Anaemia vitamin B12 deficiency 
 
Anaemia vitamin B6 deficiency 
 
Anaemic hypoxia 
 
Anaphylactoid syndrome of pregnancy 
 
Anaplastic large cell lymphoma T- and null-cell types 
 
Anaplastic large cell lymphoma T- and null-cell types recurrent 
 
Anaplastic large cell lymphoma T- and null-cell types refractory 
 
Anaplastic large cell lymphoma T- and null-cell types stage I 
 
Anaplastic large cell lymphoma T- and null-cell types stage II 
 
Anaplastic large cell lymphoma T- and null-cell types stage III 
 
Anaplastic large cell lymphoma T- and null-cell types stage IV 
 
Anaplastic large-cell lymphoma 
 
Angiocentric lymphoma 
 
Angiocentric lymphoma recurrent 
 
Angiocentric lymphoma refractory 
 
Angiocentric lymphoma stage I 
 
Angiocentric lymphoma stage II 
 
Angiocentric lymphoma stage III 
 
Angiocentric lymphoma stage IV 
 
Angioimmunoblastic T-cell lymphoma 
 
Angioimmunoblastic T-cell lymphoma recurrent 
 
Angioimmunoblastic T-cell lymphoma refractory 
 
Angioimmunoblastic T-cell lymphoma stage I 
 
Angioimmunoblastic T-cell lymphoma stage II 
 
Angioimmunoblastic T-cell lymphoma stage III 
 
Angioimmunoblastic T-cell lymphoma stage IV 
 
Angiolymphoid hyperplasia with eosinophilia 
 
Anisochromia 
 
Anisocytosis 
 
Anti A antibody 
 
Anti A antibody positive 
 
Anti B antibody 
 
Anti B antibody positive 
 
Anti Kell antibody test 
 
Anti Kell antibody test negative 
 
Anti Kell antibody test positive 
 
Anti factor IX antibody 
 
Anti factor IX antibody increased 
 
Anti factor IX antibody negative 
 
Anti factor IX antibody positive 
 
Anti factor V antibody 
 
Anti factor V antibody positive 
 
Anti factor VII antibody positive 
 
Anti factor VIII antibody increased 
 
Anti factor VIII antibody negative 
 
Anti factor VIII antibody positive 
 
Anti factor VIII antibody test 
 
Anti factor X activity 
 
Anti factor X activity abnormal 
 
Anti factor X activity decreased 


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Anti factor X activity increased 
 
Anti factor X activity normal 
 
Anti factor X antibody 
 
Anti factor X antibody negative 
 
Anti factor X antibody positive 
 
Anti factor XI antibody positive 
 
Anti factor XII antibody positive 
 
Anti factor Xa activity decreased 
 
Anti factor Xa assay normal 
 
Anti-complement antibody 
 
Anti-erythropoietin antibody 
 
Anti-erythropoietin antibody negative 
 
Anti-erythropoietin antibody positive 
 
Anti-prothrombin antibody positive 
 
Anti-thrombin antibody 
 
Antiphospholipid syndrome 
 
Antithrombin III 
 
Antithrombin III abnormal 
 
Antithrombin III decreased 
 
Antithrombin III deficiency 
 
Antithrombin III increased 
 
Aplasia pure red cell 
 
Aplastic anaemia 
 
Application site lymphadenopathy 
 
Aspiration bone marrow 
 
Aspiration bone marrow abnormal 
 
Aspiration bone marrow normal 
 
Asplenia 
 
Atypical haemolytic uraemic syndrome 
 
Atypical lymphocytic lobular panniculitis 
 
Atypical mycobacterial lymphadenitis 
 
Autoimmune anaemia 
 
Autoimmune aplastic anaemia 
 
Autoimmune haemolytic anaemia 
 
Autoimmune heparin-induced thrombocytopenia 
 
Autoimmune lymphoproliferative syndrome 
 
Autoimmune neutropenia 
 
Autoimmune pancytopenia 
 
Autosomal recessive megaloblastic anaemia 
 
Axillary web syndrome 
 
B precursor type acute leukaemia 
 
B-cell aplasia 
 
B-cell lymphoma 
 
B-cell lymphoma recurrent 
 
B-cell lymphoma refractory 
 
B-cell lymphoma stage I 
 
B-cell lymphoma stage II 
 
B-cell lymphoma stage III 
 
B-cell lymphoma stage IV 
 
B-cell prolymphocytic leukaemia 
 
B-cell small lymphocytic lymphoma 
 
B-cell small lymphocytic lymphoma recurrent 
 
B-cell small lymphocytic lymphoma refractory 
 
B-cell small lymphocytic lymphoma stage I 


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B-cell small lymphocytic lymphoma stage II 
 
B-cell small lymphocytic lymphoma stage III 
 
B-cell small lymphocytic lymphoma stage IV 
 
B-cell type acute leukaemia 
 
B-cell unclassifiable lymphoma high grade 
 
B-cell unclassifiable lymphoma low grade 
 
B-lymphocyte abnormalities 
 
B-lymphocyte count 
 
B-lymphocyte count abnormal 
 
B-lymphocyte count decreased 
 
B-lymphocyte count increased 
 
Babesiosis 
 
Band neutrophil count 
 
Band neutrophil count decreased 
 
Band neutrophil count increased 
 
Band neutrophil percentage 
 
Band neutrophil percentage decreased 
 
Band neutrophil percentage increased 
 
Bandaemia 
 
Banti's syndrome 
 
Basophil count 
 
Basophil count abnormal 
 
Basophil count decreased 
 
Basophil count increased 
 
Basophil count normal 
 
Basophil morphology 
 
Basophil morphology abnormal 
 
Basophil morphology normal 
 
Basophil percentage 
 
Basophil percentage decreased 
 
Basophil percentage increased 
 
Basophilia 
 
Basophilopenia 
 
Benign ethnic neutropenia 
 
Benign lymph node neoplasm 
 
Benign neoplasm of thymus 
 
Benign spleen tumour 
 
Benjamin syndrome 
 
Bernard-Soulier syndrome 
 
Beta globin abnormal 
 
Bicytopenia 
 
Bing-Neel syndrome 
 
Biopsy bone marrow 
 
Biopsy bone marrow abnormal 
 
Biopsy bone marrow normal 
 
Biopsy lymph gland 
 
Biopsy lymph gland abnormal 
 
Biopsy lymph gland normal 
 
Biopsy spleen 
 
Biopsy spleen abnormal 
 
Biopsy spleen normal 
 
Biopsy thymus gland 
 
Biopsy thymus gland abnormal 
 
Biopsy thymus gland normal 


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Blackwater fever 
 
Blast cell count decreased 
 
Blast cell count increased 
 
Blast cell crisis 
 
Blast cell proliferation 
 
Blast cells 
 
Blast cells absent 
 
Blast cells present 
 
Blast crisis in myelogenous leukaemia 
 
Blastic plasmacytoid dendritic cell neoplasia 
 
Bleeding time 
 
Bleeding time abnormal 
 
Bleeding time normal 
 
Bleeding time prolonged 
 
Bleeding time shortened 
 
Blood count 
 
Blood count abnormal 
 
Blood count normal 
 
Blood disorder 
 
Blood erythropoietin 
 
Blood erythropoietin abnormal 
 
Blood erythropoietin decreased 
 
Blood erythropoietin increased 
 
Blood erythropoietin normal 
 
Blood fibrinogen 
 
Blood fibrinogen abnormal 
 
Blood fibrinogen decreased 
 
Blood fibrinogen increased 
 
Blood fibrinogen normal 
 
Blood group A 
 
Blood group AB 
 
Blood group B 
 
Blood group O 
 
Blood grouping 
 
Blood incompatibility haemolytic anaemia of newborn 
 
Blood loss anaemia 
 
Blood loss anaemia neonatal 
 
Blood loss assessment 
 
Blood thrombin 
 
Blood thrombin abnormal 
 
Blood thrombin decreased 
 
Blood thrombin increased 
 
Blood thrombin normal 
 
Blood thromboplastin 
 
Blood thromboplastin abnormal 
 
Blood thromboplastin decreased 
 
Blood thromboplastin increased 
 
Blood thromboplastin normal 
 
Blood type incompatibility 
 
Blood viscosity abnormal 
 
Blood viscosity decreased 
 
Blood viscosity increased 
 
Bone marrow band neutrophil count increased 
 
Bone marrow basophilic leukocyte count increased 


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Bone marrow disorder 
 
Bone marrow eosinophilic leukocyte count increased 
 
Bone marrow failure 
 
Bone marrow granuloma 
 
Bone marrow haemorrhage 
 
Bone marrow infiltration 
 
Bone marrow ischaemia 
 
Bone marrow leukaemic cell infiltration 
 
Bone marrow metamyelocyte count increased 
 
Bone marrow myelogram 
 
Bone marrow myelogram abnormal 
 
Bone marrow myelogram normal 
 
Bone marrow necrosis 
 
Bone marrow oedema 
 
Bone marrow oedema syndrome 
 
Bone marrow plasmacyte count increased 
 
Bone marrow polymorphonuclear leukocyte count increased 
 
Bone marrow reticulin fibrosis 
 
Bone marrow transplant rejection 
 
Bone marrow tumour cell infiltration 
 
Breakthrough haemolysis 
 
Breast implant-associated anaplastic large cell lymphoma 
 
Broncholithiasis 
 
Bronchopulmonary aspergillosis allergic 
 
Burkitt's leukaemia 
 
Burkitt's lymphoma 
 
Burkitt's lymphoma recurrent 
 
Burkitt's lymphoma refractory 
 
Burkitt's lymphoma stage I 
 
Burkitt's lymphoma stage II 
 
Burkitt's lymphoma stage III 
 
Burkitt's lymphoma stage IV 
 
CANDLE syndrome 
 
CD4 lymphocyte percentage decreased 
 
CD4 lymphocyte percentage increased 
 
CD4 lymphocytes 
 
CD4 lymphocytes abnormal 
 
CD4 lymphocytes decreased 
 
CD4 lymphocytes increased 
 
CD4 lymphocytes normal 
 
CD4/CD8 ratio 
 
CD4/CD8 ratio decreased 
 
CD4/CD8 ratio increased 
 
CD8 lymphocyte percentage decreased 
 
CD8 lymphocyte percentage increased 
 
CD8 lymphocytes 
 
CD8 lymphocytes abnormal 
 
CD8 lymphocytes decreased 
 
CD8 lymphocytes increased 
 
Capillary fragility abnormal 
 
Capillary fragility decreased 
 
Capillary fragility increased 
 
Capillary fragility normal 
 
Capillary fragility test 


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Capillary permeability 
 
Capillary permeability increased 
 
Capillary permeability normal 
 
Carboxyhaemoglobinaemia 
 
Cardiac haemolytic anaemia 
 
Cardiac lymphangioma 
 
Castleman's disease 
 
Central nervous system leukaemia 
 
Central nervous system lymphoma 
 
Chediak-Higashi syndrome 
 
Chloroma 
 
Chloroma (in remission) 
 
Chorea-acanthocytosis 
 
Chronic eosinophilic leukaemia 
 
Chronic granulomatous disease 
 
Chronic leukaemia 
 
Chronic leukaemia in remission 
 
Chronic lymphocytic leukaemia 
 
Chronic lymphocytic leukaemia (in remission) 
 
Chronic lymphocytic leukaemia recurrent 
 
Chronic lymphocytic leukaemia refractory 
 
Chronic lymphocytic leukaemia stage 0 
 
Chronic lymphocytic leukaemia stage 1 
 
Chronic lymphocytic leukaemia stage 2 
 
Chronic lymphocytic leukaemia stage 3 
 
Chronic lymphocytic leukaemia stage 4 
 
Chronic lymphocytic leukaemia transformation 
 
Chronic myeloid leukaemia 
 
Chronic myeloid leukaemia (in remission) 
 
Chronic myeloid leukaemia recurrent 
 
Chronic myeloid leukaemia transformation 
 
Chronic myelomonocytic leukaemia 
 
Chronic myelomonocytic leukaemia (in remission) 
 
Chronic myelomonocytic leukaemia with N-ras gene mutation 
 
Chronic pigmented purpura 
 
Circulating anticoagulant 
 
Circulating anticoagulant positive 
 
Clonal haematopoiesis 
 
Clot retraction 
 
Clot retraction abnormal 
 
Clot retraction normal 
 
Clot retraction time prolonged 
 
Clot retraction time shortened 
 
Coagulation disorder neonatal 
 
Coagulation factor 
 
Coagulation factor IX level 
 
Coagulation factor IX level abnormal 
 
Coagulation factor IX level decreased 
 
Coagulation factor IX level increased 
 
Coagulation factor IX level normal 
 
Coagulation factor V level 
 
Coagulation factor V level abnormal 
 
Coagulation factor V level decreased 
 
Coagulation factor V level increased 


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Coagulation factor V level normal 
 
Coagulation factor VII level 
 
Coagulation factor VII level abnormal 
 
Coagulation factor VII level decreased 
 
Coagulation factor VII level increased 
 
Coagulation factor VII level normal 
 
Coagulation factor VIII level 
 
Coagulation factor VIII level abnormal 
 
Coagulation factor VIII level decreased 
 
Coagulation factor VIII level increased 
 
Coagulation factor VIII level normal 
 
Coagulation factor X level 
 
Coagulation factor X level abnormal 
 
Coagulation factor X level decreased 
 
Coagulation factor X level increased 
 
Coagulation factor X level normal 
 
Coagulation factor XI level 
 
Coagulation factor XI level abnormal 
 
Coagulation factor XI level decreased 
 
Coagulation factor XI level increased 
 
Coagulation factor XI level normal 
 
Coagulation factor XII level 
 
Coagulation factor XII level abnormal 
 
Coagulation factor XII level decreased 
 
Coagulation factor XII level increased 
 
Coagulation factor XII level normal 
 
Coagulation factor XIII level 
 
Coagulation factor XIII level abnormal 
 
Coagulation factor XIII level decreased 
 
Coagulation factor XIII level increased 
 
Coagulation factor XIII level normal 
 
Coagulation factor decreased 
 
Coagulation factor deficiency 
 
Coagulation factor increased 
 
Coagulation factor inhibitor assay 
 
Coagulation factor level normal 
 
Coagulation factor mutation 
 
Coagulation test 
 
Coagulation test abnormal 
 
Coagulation test normal 
 
Coagulation time 
 
Coagulation time abnormal 
 
Coagulation time normal 
 
Coagulation time prolonged 
 
Coagulation time shortened 
 
Coagulopathy 
 
Cold type haemolytic anaemia 
 
Complement deficiency disease 
 
Composite lymphoma 
 
Congenital anaemia 
 
Congenital aplastic anaemia 
 
Congenital coagulopathy 
 
Congenital dyserythropoietic anaemia 
 
Congenital dysfibrinogenaemia 


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Congenital dyskeratosis 
 
Congenital haematological disorder 
 
Congenital hypercoagulation 
 
Congenital hypotransferrinaemia 
 
Congenital lymphatic dysplasia 
 
Congenital lymphoedema 
 
Congenital malaria 
 
Congenital methaemoglobinaemia 
 
Congenital thrombocyte disorder 
 
Congenital thrombocytopenia 
 
Congenital thymus absence 
 
Congenital white blood cell disorder 
 
Conjunctival lymphangiectasia 
 
Conjunctival pallor 
 
Coombs direct test 
 
Coombs direct test negative 
 
Coombs direct test positive 
 
Coombs indirect test 
 
Coombs indirect test negative 
 
Coombs indirect test positive 
 
Coombs negative haemolytic anaemia 
 
Coombs positive haemolytic anaemia 
 
Coombs test 
 
Coombs test negative 
 
Coombs test positive 
 
Crossmatch 
 
Crossmatch compatible 
 
Crossmatch incompatible 
 
Cutaneous B-cell lymphoma 
 
Cutaneous T-cell dyscrasia 
 
Cutaneous T-cell lymphoma 
 
Cutaneous T-cell lymphoma recurrent 
 
Cutaneous T-cell lymphoma refractory 
 
Cutaneous T-cell lymphoma stage I 
 
Cutaneous T-cell lymphoma stage II 
 
Cutaneous T-cell lymphoma stage III 
 
Cutaneous T-cell lymphoma stage IV 
 
Cutaneous extramedullary haemopoiesis 
 
Cutaneous lymphoma 
 
Cutaneovisceral angiomatosis with thrombocytopenia 
 
Cyclic neutropenia 
 
Cystic lymphangioma 
 
Cytomegalovirus mononucleosis 
 
Cytopenia 
 
Cytophagic histiocytic panniculitis 
 
Deficiency anaemia 
 
Delayed haematopoietic reconstitution 
 
Delayed haemolytic transfusion reaction 
 
Delayed serologic transfusion reaction 
 
Delta-beta thalassaemia 
 
Dermatopathic lymphadenopathy 
 
Differential white blood cell count 
 
Differential white blood cell count abnormal 
 
Differential white blood cell count normal 


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Diffuse large B-cell lymphoma 
 
Diffuse large B-cell lymphoma recurrent 
 
Diffuse large B-cell lymphoma refractory 
 
Diffuse large B-cell lymphoma stage I 
 
Diffuse large B-cell lymphoma stage II 
 
Diffuse large B-cell lymphoma stage III 
 
Diffuse large B-cell lymphoma stage IV 
 
Dilutional coagulopathy 
 
Disseminated intravascular coagulation 
 
Disseminated intravascular coagulation in newborn 
 
Disseminated large cell lymphoma 
 
Double heterozygous sickling disorders 
 
Double hit lymphoma 
 
Dubowitz syndrome 
 
Dysglobulinaemia 
 
Ecchymosis 
 
Elephantiasis 
 
Elephantiasis nostras verrucosa 
 
Elliptocytosis 
 
Elliptocytosis hereditary 
 
Endothelial protein C receptor polymorphism 
 
Engraftment syndrome 
 
Enteritis leukopenic 
 
Enteropathy-associated T-cell lymphoma 
 
Eosinopenia 
 
Eosinophil count 
 
Eosinophil count abnormal 
 
Eosinophil count decreased 
 
Eosinophil count increased 
 
Eosinophil count normal 
 
Eosinophil morphology 
 
Eosinophil morphology abnormal 
 
Eosinophil morphology normal 
 
Eosinophil percentage 
 
Eosinophil percentage abnormal 
 
Eosinophil percentage decreased 
 
Eosinophil percentage increased 
 
Eosinophilia 
 
Eosinophilia myalgia syndrome 
 
Eosinophilic bronchitis 
 
Eosinophilic cellulitis 
 
Eosinophilic colitis 
 
Eosinophilic cystitis 
 
Eosinophilic fasciitis 
 
Eosinophilic gastritis 
 
Eosinophilic granulomatosis with polyangiitis 
 
Eosinophilic leukaemia 
 
Eosinophilic myocarditis 
 
Eosinophilic oesophagitis 
 
Eosinophilic otitis media 
 
Eosinophilic panniculitis 
 
Eosinophilic pleural effusion 
 
Eosinophilic pneumonia 
 
Eosinophilic pneumonia acute 


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Eosinophilic pneumonia chronic 
 
Eosinophilic pustular folliculitis 
 
Eosinophilic pustulosis 
 
Eosinophilic rhinitis 
 
Epstein Barr virus positive mucocutaneous ulcer 
 
Epstein-Barr virus associated lymphoma 
 
Epstein-Barr virus associated lymphoproliferative disorder 
 
Erdheim-Chester disease 
 
Erythraemic myelosis (in remission) 
 
Erythroblast count 
 
Erythroblast count abnormal 
 
Erythroblast count decreased 
 
Erythroblast count increased 
 
Erythroblast count normal 
 
Erythroblast morphology 
 
Erythroblast morphology abnormal 
 
Erythroblastosis 
 
Erythroblastosis foetalis 
 
Erythrocyte osmotic fragility test 
 
Erythroid maturation arrest 
 
Erythroid series abnormal 
 
Erythropenia 
 
Erythrophagocytosis 
 
Erythropoiesis abnormal 
 
Erythropoietin deficiency anaemia 
 
Erythrosis 
 
Essential thrombocythaemia 
 
Ethanol gelation test 
 
Ethanol gelation test negative 
 
Ethanol gelation test positive 
 
Evans syndrome 
 
Extramedullary haemopoiesis 
 
Extranodal marginal zone B-cell lymphoma (BALT type) 
 
Extranodal marginal zone B-cell lymphoma (MALT type) 
 
Extranodal marginal zone B-cell lymphoma (MALT type) recurrent 
 
Extranodal marginal zone B-cell lymphoma (MALT type) refractory 
 
Extranodal marginal zone B-cell lymphoma (MALT type) stage I 
 
Extranodal marginal zone B-cell lymphoma (MALT type) stage II 
 
Extranodal marginal zone B-cell lymphoma (MALT type) stage III 
 
Extranodal marginal zone B-cell lymphoma (MALT type) stage IV 
 
Extravascular haemolysis 
 
Factor I deficiency 
 
Factor II deficiency 
 
Factor II inhibition 
 
Factor II mutation 
 
Factor III deficiency 
 
Factor IX deficiency 
 
Factor IX inhibition 
 
Factor V Leiden mutation 
 
Factor V deficiency 
 
Factor V inhibition 
 
Factor VII deficiency 
 
Factor VII inhibition 
 
Factor VIII deficiency 


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Factor VIII inhibition 
 
Factor X deficiency 
 
Factor X inhibition 
 
Factor XI deficiency 
 
Factor XII deficiency 
 
Factor XIII Inhibition 
 
Factor XIII deficiency 
 
Factor Xa activity abnormal 
 
Factor Xa activity decreased 
 
Factor Xa activity increased 
 
Factor Xa activity normal 
 
Factor Xa activity test 
 
Familial haemophagocytic lymphohistiocytosis 
 
Familial polycythaemia 
 
Febrile bone marrow aplasia 
 
Febrile neutropenia 
 
Felty's syndrome 
 
Fibrin 
 
Fibrin D dimer 
 
Fibrin D dimer decreased 
 
Fibrin D dimer increased 
 
Fibrin D dimer normal 
 
Fibrin abnormal 
 
Fibrin decreased 
 
Fibrin degradation products 
 
Fibrin degradation products increased 
 
Fibrin degradation products normal 
 
Fibrin increased 
 
Fibrin normal 
 
Fibrinogen degradation products increased 
 
Fibrinolysis 
 
Fibrinolysis abnormal 
 
Fibrinolysis decreased 
 
Fibrinolysis increased 
 
Fibrinolysis normal 
 
Filariasis lymphatic 
 
Foetal anaemia 
 
Foetal haemoglobin 
 
Foetal haemoglobin decreased 
 
Foetal haemoglobin increased 
 
Foetal haemoglobin normal 
 
Follicle centre lymphoma diffuse small cell lymphoma 
 
Follicle centre lymphoma diffuse small cell lymphoma recurrent 
 
Follicle centre lymphoma diffuse small cell lymphoma refractory 
 
Follicle centre lymphoma diffuse small cell lymphoma stage I 
 
Follicle centre lymphoma diffuse small cell lymphoma stage II 
 
Follicle centre lymphoma diffuse small cell lymphoma stage III 
 
Follicle centre lymphoma diffuse small cell lymphoma stage IV 
 
Follicle centre lymphoma, follicular grade I, II, III 
 
Follicle centre lymphoma, follicular grade I, II, III recurrent 
 
Follicle centre lymphoma, follicular grade I, II, III refractory 
 
Follicle centre lymphoma, follicular grade I, II, III stage I 
 
Follicle centre lymphoma, follicular grade I, II, III stage II 
 
Follicle centre lymphoma, follicular grade I, II, III stage III 


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Follicle centre lymphoma, follicular grade I, II, III stage IV 
 
Follicular dendritic cell sarcoma 
 
Follicular lymphoma 
 
Follicular lymphoma stage I 
 
Follicular lymphoma stage II 
 
Follicular lymphoma stage III 
 
Follicular lymphoma stage IV 
 
Free haemoglobin 
 
Free haemoglobin absent 
 
Free haemoglobin present 
 
Full blood count 
 
Full blood count abnormal 
 
Full blood count decreased 
 
Full blood count increased 
 
Full blood count normal 
 
Gammopathy 
 
Gastroenteritis eosinophilic 
 
Gastrointestinal lymphoma 
 
Gastrosplenic fistula 
 
Gelatinous transformation of the bone marrow 
 
Glanzmann's disease 
 
Gleich's syndrome 
 
Glucose-6-phosphate dehydrogenase 
 
Glucose-6-phosphate dehydrogenase abnormal 
 
Glucose-6-phosphate dehydrogenase deficiency 
 
Glucose-6-phosphate dehydrogenase normal 
 
Glutathione decreased 
 
Glutathione increased 
 
Glutathione synthetase deficiency 
 
Glutathione test 
 
Good syndrome 
 
Granulocyte count 
 
Granulocyte count decreased 
 
Granulocyte count increased 
 
Granulocyte percentage 
 
Granulocytes abnormal 
 
Granulocytes maturation arrest 
 
Granulocytopenia 
 
Granulocytopenia neonatal 
 
Granulocytosis 
 
Granulomatous T-cell pseudolymphoma 
 
Granulomatous lymphadenitis 
 
Grey zone lymphoma 
 
HELLP syndrome 
 
Haemangioma of spleen 
 
Haemangioma-thrombocytopenia syndrome 
 
Haematocrit 
 
Haematocrit abnormal 
 
Haematocrit decreased 
 
Haematocrit increased 
 
Haematocrit normal 
 
Haematological malignancy 
 
Haematology test 
 
Haematology test abnormal 


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Haematology test normal 
 
Haematopoietic neoplasm 
 
Haematotoxicity 
 
Haemoconcentration 
 
Haemodilution 
 
Haemoglobin 
 
Haemoglobin A absent 
 
Haemoglobin A present 
 
Haemoglobin A2 
 
Haemoglobin Barts absent 
 
Haemoglobin Barts present 
 
Haemoglobin C 
 
Haemoglobin C disease 
 
Haemoglobin C present 
 
Haemoglobin C trait 
 
Haemoglobin D disease 
 
Haemoglobin D trait 
 
Haemoglobin E 
 
Haemoglobin E absent 
 
Haemoglobin E disease 
 
Haemoglobin E present 
 
Haemoglobin E trait 
 
Haemoglobin E-thalassaemia disease 
 
Haemoglobin Lepore trait 
 
Haemoglobin S 
 
Haemoglobin S decreased 
 
Haemoglobin S increased 
 
Haemoglobin S normal 
 
Haemoglobin abnormal 
 
Haemoglobin decreased 
 
Haemoglobin distribution width 
 
Haemoglobin distribution width decreased 
 
Haemoglobin distribution width increased 
 
Haemoglobin electrophoresis 
 
Haemoglobin electrophoresis abnormal 
 
Haemoglobin electrophoresis normal 
 
Haemoglobin increased 
 
Haemoglobin normal 
 
Haemoglobinaemia 
 
Haemoglobinopathy 
 
Haemoglobinuria 
 
Haemolysis 
 
Haemolysis neonatal 
 
Haemolytic anaemia 
 
Haemolytic anaemia enzyme specific 
 
Haemolytic icteroanaemia 
 
Haemolytic transfusion reaction 
 
Haemolytic uraemic syndrome 
 
Haemophagocytic lymphohistiocytosis 
 
Haemophilia 
 
Haemophilia A with anti factor VIII 
 
Haemophilia A without inhibitors 
 
Haemophilia B with anti factor IX 
 
Haemophilia B without inhibitors 


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Haemophilic pseudotumour 
 
Haemorrhagic diathesis 
 
Haemorrhagic disease of newborn 
 
Haemorrhagic disorder 
 
Haemorrhagic vasculitis 
 
Haemosiderinuria 
 
Hairy cell leukaemia 
 
Hairy cell leukaemia recurrent 
 
Hand and foot syndrome secondary to sickle cell anaemia 
 
Heavy chain disease 
 
Heinz bodies 
 
Henoch-Schonlein purpura 
 
Henoch-Schonlein purpura nephritis 
 
Heparin resistance 
 
Heparin-induced thrombocytopenia 
 
Heparin-induced thrombocytopenia test 
 
Heparin-induced thrombocytopenia test positive 
 
Hepatic infiltration eosinophilic 
 
Hepatic lymphocytic infiltration 
 
Hepatosplenic T-cell lymphoma 
 
Hepatosplenic abscess 
 
Hepatosplenic candidiasis 
 
Hepatosplenomegaly 
 
Hepatosplenomegaly neonatal 
 
Hereditary haemolytic anaemia 
 
Hereditary sideroblastic anaemia 
 
Hereditary spherocytosis 
 
Hereditary stomatocytosis 
 
Hermansky-Pudlak syndrome 
 
Hexokinase deficiency anaemia 
 
High grade B-cell lymphoma Burkitt-like lymphoma 
 
High grade B-cell lymphoma Burkitt-like lymphoma recurrent 
 
High grade B-cell lymphoma Burkitt-like lymphoma refractory 
 
High grade B-cell lymphoma Burkitt-like lymphoma stage I 
 
High grade B-cell lymphoma Burkitt-like lymphoma stage II 
 
High grade B-cell lymphoma Burkitt-like lymphoma stage III 
 
High grade B-cell lymphoma Burkitt-like lymphoma stage IV 
 
High-grade B-cell lymphoma 
 
Hilar lymphadenopathy 
 
Histiocytic medullary reticulosis 
 
Histiocytic necrotising lymphadenitis 
 
Histiocytic sarcoma 
 
Histiocytosis 
 
Hodgkin's disease 
 
Hodgkin's disease lymphocyte depletion stage I site unspecified 
 
Hodgkin's disease lymphocyte depletion stage I subdiaphragm 
 
Hodgkin's disease lymphocyte depletion stage I supradiaphragm 
 
Hodgkin's disease lymphocyte depletion stage II site unspecified 
 
Hodgkin's disease lymphocyte depletion stage II subdiaphragm 
 
Hodgkin's disease lymphocyte depletion stage II supradiaphragm 
 
Hodgkin's disease lymphocyte depletion type recurrent 
 
Hodgkin's disease lymphocyte depletion type refractory 
 
Hodgkin's disease lymphocyte depletion type stage III 
 
Hodgkin's disease lymphocyte depletion type stage IV 


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Hodgkin's disease lymphocyte depletion type stage unspecified 
 
Hodgkin's disease lymphocyte predominance stage I site unspec 
 
Hodgkin's disease lymphocyte predominance stage I subdiaphragm 
 
Hodgkin's disease lymphocyte predominance stage I supradiaphragm 
 
Hodgkin's disease lymphocyte predominance stage II site unspec 
 
Hodgkin's disease lymphocyte predominance stage II subdiaphragm 
 
Hodgkin's disease lymphocyte predominance stage II supradiaphragm 
 
Hodgkin's disease lymphocyte predominance type recurrent 
 
Hodgkin's disease lymphocyte predominance type refractory 
 
Hodgkin's disease lymphocyte predominance type stage III 
 
Hodgkin's disease lymphocyte predominance type stage IV 
 
Hodgkin's disease lymphocyte predominance type stage unspecified 
 
Hodgkin's disease mixed cellularity recurrent 
 
Hodgkin's disease mixed cellularity refractory 
 
Hodgkin's disease mixed cellularity stage I site unspecified 
 
Hodgkin's disease mixed cellularity stage I subdiaphragmatic 
 
Hodgkin's disease mixed cellularity stage I supradiaphragmatic 
 
Hodgkin's disease mixed cellularity stage II subdiaphragmatic 
 
Hodgkin's disease mixed cellularity stage II supradiaphragmatic 
 
Hodgkin's disease mixed cellularity stage III 
 
Hodgkin's disease mixed cellularity stage IV 
 
Hodgkin's disease mixed cellularity stage unspecified 
 
Hodgkin's disease nodular sclerosis 
 
Hodgkin's disease nodular sclerosis recurrent 
 
Hodgkin's disease nodular sclerosis refractory 
 
Hodgkin's disease nodular sclerosis stage I 
 
Hodgkin's disease nodular sclerosis stage II 
 
Hodgkin's disease nodular sclerosis stage III 
 
Hodgkin's disease nodular sclerosis stage IV 
 
Hodgkin's disease recurrent 
 
Hodgkin's disease refractory 
 
Hodgkin's disease stage I 
 
Hodgkin's disease stage II 
 
Hodgkin's disease stage III 
 
Hodgkin's disease stage IV 
 
Hodgkin's disease unclassifiable 
 
Hyperbilirubinaemia 
 
Hyperchromasia 
 
Hyperchromic anaemia 
 
Hypercoagulation 
 
Hypereosinophilic syndrome 
 
Hyperfibrinogenaemia 
 
Hyperfibrinolysis 
 
Hypergammaglobulinaemia 
 
Hypergammaglobulinaemia benign monoclonal 
 
Hyperglobulinaemia 
 
Hyperhomocysteinaemia 
 
Hyperleukocytosis 
 
Hyperplasia of thymic epithelium 
 
Hyperprothrombinaemia 
 
Hypersensitivity vasculitis 
 
Hypersplenism 
 
Hypersplenism congenital 
 
Hyperthrombinaemia 


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Hyperviscosity syndrome 
 
Hypochromasia 
 
Hypochromic anaemia 
 
Hypocoagulable state 
 
Hypocomplementaemia 
 
Hypofibrinogenaemia 
 
Hypoglobulinaemia 
 
Hypoplastic anaemia 
 
Hypoprothrombinaemia 
 
Hyposplenism 
 
Hypothrombinaemia 
 
Hypothromboplastinaemia 
 
Hypotransferrinaemia 
 
ISTH score for disseminated intravascular coagulation 
 
Idiopathic CD4 lymphocytopenia 
 
Idiopathic neutropenia 
 
Immature granulocyte count 
 
Immature granulocyte count increased 
 
Immature granulocyte percentage increased 
 
Immune thrombocytopenia 
 
Immune-mediated cytopenia 
 
Immunoblastic lymphoma 
 
Increased tendency to bruise 
 
Indeterminable ABO blood type 
 
Infantile genetic agranulocytosis 
 
Infantile scurvy 
 
Infected lymphocele 
 
Infectious mononucleosis 
 
Infusion site lymphadenopathy 
 
Injection site lymphadenopathy 
 
International normalised ratio 
 
International normalised ratio abnormal 
 
International normalised ratio decreased 
 
International normalised ratio fluctuation 
 
International normalised ratio increased 
 
International normalised ratio normal 
 
Intestinal T-cell lymphoma recurrent 
 
Intestinal T-cell lymphoma refractory 
 
Intestinal T-cell lymphoma stage I 
 
Intestinal T-cell lymphoma stage II 
 
Intestinal T-cell lymphoma stage III 
 
Intestinal T-cell lymphoma stage IV 
 
Intravascular haemolysis 
 
Iron deficiency anaemia 
 
Isoimmune haemolytic disease 
 
Jaundice 
 
Jaundice acholuric 
 
Jaundice neonatal 
 
Jessner's lymphocytic infiltration 
 
Juvenile chronic myelomonocytic leukaemia 
 
Kell blood group positive 
 
Lactescent serum 
 
Langerhans cell sarcoma 
 
Langerhans' cell histiocytosis 


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Large granular lymphocytosis 
 
Leptomeningeal myelomatosis 
 
Leukaemia 
 
Leukaemia basophilic 
 
Leukaemia cutis 
 
Leukaemia granulocytic 
 
Leukaemia in remission 
 
Leukaemia monocytic 
 
Leukaemia recurrent 
 
Leukaemic cardiac infiltration 
 
Leukaemic infiltration 
 
Leukaemic infiltration extramedullary 
 
Leukaemic infiltration gingiva 
 
Leukaemic infiltration hepatic 
 
Leukaemic infiltration ovary 
 
Leukaemic infiltration pulmonary 
 
Leukaemic infiltration renal 
 
Leukaemic lymphoma 
 
Leukaemic retinopathy 
 
Leukaemoid reaction 
 
Leukocyte adhesion deficiency type I 
 
Leukocyte vacuolisation 
 
Leukocytosis 
 
Leukoerythroblastic anaemia 
 
Leukoerythroblastosis 
 
Leukopenia 
 
Leukopenia neonatal 
 
Leukostasis syndrome 
 
Light chain disease 
 
Lineage switch leukaemia 
 
Loeffler's syndrome 
 
Loefgren syndrome 
 
Loss of CAR T-cell persistence 
 
Lupus anticoagulant hypoprothrombinaemia syndrome 
 
Lymph gland infection 
 
Lymph node abscess 
 
Lymph node calcification 
 
Lymph node fibrosis 
 
Lymph node haemorrhage 
 
Lymph node pain 
 
Lymph node rupture 
 
Lymph node tuberculosis 
 
Lymph node ulcer 
 
Lymph nodes scan abnormal 
 
Lymph nodes scan normal 
 
Lymphadenitis 
 
Lymphadenitis bacterial 
 
Lymphadenitis fungal 
 
Lymphadenitis helminthic 
 
Lymphadenitis viral 
 
Lymphadenocyst 
 
Lymphadenopathy 
 
Lymphadenopathy mediastinal 
 
Lymphangiectasia 


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Lymphangiectasia intestinal 
 
Lymphangiectasia intestinal congenital 
 
Lymphangioleiomyomatosis 
 
Lymphangioma 
 
Lymphangiopathy 
 
Lymphangiosarcoma 
 
Lymphangiosis carcinomatosa 
 
Lymphangitis 
 
Lymphatic disorder 
 
Lymphatic duct injury 
 
Lymphatic fistula 
 
Lymphatic insufficiency 
 
Lymphatic obstruction 
 
Lymphatic sinus catarrh 
 
Lymphatic system neoplasm 
 
Lymphoblast count 
 
Lymphoblast count increased 
 
Lymphoblast morphology 
 
Lymphoblast morphology abnormal 
 
Lymphoblast morphology normal 
 
Lymphoblastosis 
 
Lymphocele 
 
Lymphocyte count 
 
Lymphocyte count abnormal 
 
Lymphocyte count decreased 
 
Lymphocyte count increased 
 
Lymphocyte count normal 
 
Lymphocyte morphology 
 
Lymphocyte morphology abnormal 
 
Lymphocyte morphology normal 
 
Lymphocyte percentage 
 
Lymphocyte percentage abnormal 
 
Lymphocyte percentage decreased 
 
Lymphocyte percentage increased 
 
Lymphocyte stimulation test 
 
Lymphocyte stimulation test negative 
 
Lymphocyte stimulation test positive 
 
Lymphocyte transformation test 
 
Lymphocyte transformation test negative 
 
Lymphocyte transformation test positive 
 
Lymphocyte/monocyte ratio decreased 
 
Lymphocytic infiltration 
 
Lymphocytic leukaemia 
 
Lymphocytic lymphoma 
 
Lymphocytic oesophagitis 
 
Lymphocytopenia neonatal 
 
Lymphocytosis 
 
Lymphoedema 
 
Lymphogranuloma venereum 
 
Lymphoid hyperplasia of intestine 
 
Lymphoid leukaemia (in remission) 
 
Lymphoid tissue hyperplasia 
 
Lymphoid tissue hypoplasia 
 
Lymphoma 


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Lymphoma AIDS related 
 
Lymphoma transformation 
 
Lymphopenia 
 
Lymphoplasia 
 
Lymphoplasmacytoid lymphoma/immunocytoma 
 
Lymphoplasmacytoid lymphoma/immunocytoma recurrent 
 
Lymphoplasmacytoid lymphoma/immunocytoma refractory 
 
Lymphoplasmacytoid lymphoma/immunocytoma stage I 
 
Lymphoplasmacytoid lymphoma/immunocytoma stage II 
 
Lymphoplasmacytoid lymphoma/immunocytoma stage III 
 
Lymphoplasmacytoid lymphoma/immunocytoma stage IV 
 
Lymphoproliferative disorder 
 
Lymphoproliferative disorder in remission 
 
Lymphorrhoea 
 
Lymphostasis 
 
MLASA syndrome 
 
MNS system antibodies positive 
 
MYH9-related disease 
 
Macrocytosis 
 
Macrophage count 
 
Macrophages decreased 
 
Macrophages increased 
 
Malaria 
 
Malaria recrudescence 
 
Malaria relapse 
 
Malignant histiocytosis 
 
Malignant lymphoid neoplasm 
 
Malignant lymphoma unclassifiable high grade 
 
Malignant lymphoma unclassifiable low grade 
 
Malignant mast cell neoplasm 
 
Malignant neoplasm of thymus 
 
Malignant splenic neoplasm 
 
Mantle cell lymphoma 
 
Mantle cell lymphoma recurrent 
 
Mantle cell lymphoma refractory 
 
Mantle cell lymphoma stage I 
 
Mantle cell lymphoma stage II 
 
Mantle cell lymphoma stage III 
 
Mantle cell lymphoma stage IV 
 
March haemoglobinuria 
 
Marginal zone lymphoma 
 
Marginal zone lymphoma recurrent 
 
Marginal zone lymphoma refractory 
 
Marginal zone lymphoma stage I 
 
Marginal zone lymphoma stage II 
 
Marginal zone lymphoma stage III 
 
Marginal zone lymphoma stage IV 
 
Marrow hyperplasia 
 
Mast cell activation syndrome 
 
Mastocytic leukaemia 
 
Mastocytosis 
 
Mature B-cell type acute leukaemia 
 
McLeod neuroacanthocytosis syndrome 
 
Mean cell haemoglobin 


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Mean cell haemoglobin concentration 
 
Mean cell haemoglobin concentration abnormal 
 
Mean cell haemoglobin concentration decreased 
 
Mean cell haemoglobin concentration increased 
 
Mean cell haemoglobin concentration normal 
 
Mean cell haemoglobin decreased 
 
Mean cell haemoglobin increased 
 
Mean cell haemoglobin normal 
 
Mean cell volume 
 
Mean cell volume abnormal 
 
Mean cell volume decreased 
 
Mean cell volume increased 
 
Mean cell volume normal 
 
Mean platelet volume 
 
Mean platelet volume abnormal 
 
Mean platelet volume decreased 
 
Mean platelet volume increased 
 
Mean platelet volume normal 
 
Medical device site lymphadenopathy 
 
Megakaryocyte destruction increased 
 
Megakaryocytes 
 
Megakaryocytes abnormal 
 
Megakaryocytes decreased 
 
Megakaryocytes increased 
 
Megakaryocytes normal 
 
Megaloblasts increased 
 
Melanaemia 
 
Meningitis eosinophilic 
 
Metamyelocyte count 
 
Metamyelocyte count decreased 
 
Metamyelocyte count increased 
 
Metamyelocyte percentage 
 
Metamyelocyte percentage increased 
 
Metastases to bone marrow 
 
Metastases to lymph nodes 
 
Metastases to spleen 
 
Metastatic lymphoma 
 
Methaemoglobinaemia 
 
Methaemoglobinuria 
 
Methylenetetrahydrofolate reductase deficiency 
 
Methylenetetrahydrofolate reductase polymorphism 
 
Microangiopathic haemolytic anaemia 
 
Microcytic anaemia 
 
Microcytosis 
 
Minimal residual disease 
 
Mitogen stimulation test 
 
Mitogen stimulation test abnormal 
 
Mitogen stimulation test normal 
 
Monoblast count 
 
Monoblast count decreased 
 
Monoblast count increased 
 
Monoclonal B-cell lymphocytosis 
 
Monoclonal gammopathy 
 
Monocyte count 


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Monocyte count abnormal 
 
Monocyte count decreased 
 
Monocyte count increased 
 
Monocyte count normal 
 
Monocyte morphology 
 
Monocyte morphology abnormal 
 
Monocyte percentage 
 
Monocyte percentage abnormal 
 
Monocyte percentage decreased 
 
Monocyte percentage increased 
 
Monocytic leukaemia in remission 
 
Monocytopenia 
 
Monocytosis 
 
Mononuclear cell count 
 
Mononuclear cell count abnormal 
 
Mononuclear cell count decreased 
 
Mononuclear cell count increased 
 
Mononuclear cell percentage 
 
Mononucleosis syndrome 
 
Multicentric reticulohistiocytosis 
 
Myeloblast count 
 
Myeloblast count decreased 
 
Myeloblast count increased 
 
Myeloblast percentage 
 
Myeloblast percentage decreased 
 
Myeloblast percentage increased 
 
Myeloblast present 
 
Myeloblastoma 
 
Myelocyte count 
 
Myelocyte count decreased 
 
Myelocyte count increased 
 
Myelocyte percentage 
 
Myelocyte percentage decreased 
 
Myelocyte percentage increased 
 
Myelocyte present 
 
Myelocytosis 
 
Myelodysplastic syndrome 
 
Myelodysplastic syndrome transformation 
 
Myelodysplastic syndrome unclassifiable 
 
Myelofibrosis 
 
Myeloid leukaemia 
 
Myeloid leukaemia in remission 
 
Myeloid maturation arrest 
 
Myeloid metaplasia 
 
Myelolipoma 
 
Myeloperoxidase deficiency 
 
Myeloproliferative neoplasm 
 
Myelosuppression 
 
Natural killer T cell count 
 
Natural killer T cell count decreased 
 
Natural killer T cell count increased 
 
Natural killer cell count 
 
Natural killer cell count decreased 
 
Natural killer cell count increased 


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Natural killer-cell leukaemia 
 
Natural killer-cell lymphoblastic lymphoma 
 
Necrotic lymphadenopathy 
 
Neonatal alloimmune thrombocytopenia 
 
Neonatal leukaemia 
 
Neoplasm of thymus 
 
Nephrogenic anaemia 
 
Neuroacanthocytosis 
 
Neutropenia 
 
Neutropenia neonatal 
 
Neutropenic colitis 
 
Neutropenic infection 
 
Neutropenic sepsis 
 
Neutrophil Fc gamma RIIIb deficiency 
 
Neutrophil Pelger-Huet anomaly present 
 
Neutrophil chemotaxis 
 
Neutrophil chemotaxis abnormal 
 
Neutrophil chemotaxis normal 
 
Neutrophil count 
 
Neutrophil count abnormal 
 
Neutrophil count decreased 
 
Neutrophil count increased 
 
Neutrophil count normal 
 
Neutrophil function disorder 
 
Neutrophil function test 
 
Neutrophil function test abnormal 
 
Neutrophil function test normal 
 
Neutrophil hypersegmented morphology present 
 
Neutrophil morphology 
 
Neutrophil morphology abnormal 
 
Neutrophil morphology normal 
 
Neutrophil percentage 
 
Neutrophil percentage abnormal 
 
Neutrophil percentage decreased 
 
Neutrophil percentage increased 
 
Neutrophil toxic granulation present 
 
Neutrophil/lymphocyte ratio 
 
Neutrophil/lymphocyte ratio decreased 
 
Neutrophil/lymphocyte ratio increased 
 
Neutrophilia 
 
Neutrophilic dermatosis 
 
Nodal marginal zone B-cell lymphoma 
 
Nodal marginal zone B-cell lymphoma recurrent 
 
Nodal marginal zone B-cell lymphoma refractory 
 
Nodal marginal zone B-cell lymphoma stage I 
 
Nodal marginal zone B-cell lymphoma stage II 
 
Nodal marginal zone B-cell lymphoma stage III 
 
Nodal marginal zone B-cell lymphoma stage IV 
 
Nodular lymphocyte predominant Hodgkin lymphoma 
 
Non-Hodgkin's lymphoma 
 
Non-Hodgkin's lymphoma metastatic 
 
Non-Hodgkin's lymphoma recurrent 
 
Non-Hodgkin's lymphoma refractory 
 
Non-Hodgkin's lymphoma stage I 


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Non-Hodgkin's lymphoma stage II 
 
Non-Hodgkin's lymphoma stage III 
 
Non-Hodgkin's lymphoma stage IV 
 
Non-Hodgkin's lymphoma transformed recurrent 
 
Non-Hodgkin's lymphoma unspecified histology aggressive 
 
Non-Hodgkin's lymphoma unspecified histology aggressive recurrent 
 
Non-Hodgkin's lymphoma unspecified histology aggressive refractory 
 
Non-Hodgkin's lymphoma unspecified histology aggressive stage I 
 
Non-Hodgkin's lymphoma unspecified histology aggressive stage II 
 
Non-Hodgkin's lymphoma unspecified histology aggressive stage III 
 
Non-Hodgkin's lymphoma unspecified histology aggressive stage IV 
 
Non-Hodgkin's lymphoma unspecified histology indolent 
 
Non-Hodgkin's lymphoma unspecified histology indolent stage I 
 
Non-Hodgkin's lymphoma unspecified histology indolent stage II 
 
Non-Hodgkin's lymphoma unspecified histology indolent stage III 
 
Non-Hodgkin's lymphoma unspecified histology indolent stage IV 
 
Non-immune heparin associated thrombocytopenia 
 
Nontherapeutic agent blood negative 
 
Nontherapeutic agent blood positive 
 
Normochromic anaemia 
 
Normochromic normocytic anaemia 
 
Normocytic anaemia 
 
Nucleated red cells 
 
Ocular icterus 
 
Ocular lymphoma 
 
Oculoglandular syndrome 
 
Omenn syndrome 
 
Oral purpura 
 
Oropharyngeal lymphoid hyperplasia 
 
PFAPA syndrome 
 
POEMS syndrome 
 
PSTPIP1-associated myeloid-related proteinaemia inflammatory 
syndrome 
 
Pancytopenia 
 
Panmyelopathy 
 
Paraproteinaemia 
 
Paratracheal lymphadenopathy 
 
Paroxysmal nocturnal haemoglobinuria 
 
Passenger lymphocyte syndrome 
 
Pearson's syndrome 
 
Peripheral T-cell lymphoma unspecified 
 
Peripheral T-cell lymphoma unspecified recurrent 
 
Peripheral T-cell lymphoma unspecified refractory 
 
Peripheral T-cell lymphoma unspecified stage I 
 
Peripheral T-cell lymphoma unspecified stage II 
 
Peripheral T-cell lymphoma unspecified stage III 
 
Peripheral T-cell lymphoma unspecified stage IV 
 
Perisplenitis 
 
Pernicious anaemia 
 
Persistent generalised lymphadenopathy 
 
Petechiae 
 
Philadelphia positive acute lymphocytic leukaemia 
 
Philadelphia positive chronic myeloid leukaemia 
 
Pickwickian syndrome 


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Pigment nephropathy 
 
Placental transfusion syndrome 
 
Plasma cell count 
 
Plasma cell disorder 
 
Plasma cell leukaemia 
 
Plasma cell leukaemia in remission 
 
Plasma cell myeloma 
 
Plasma cell myeloma in remission 
 
Plasma cell myeloma recurrent 
 
Plasma cell myeloma refractory 
 
Plasma cells absent 
 
Plasma cells decreased 
 
Plasma cells increased 
 
Plasma cells present 
 
Plasma viscosity 
 
Plasma viscosity abnormal 
 
Plasma viscosity decreased 
 
Plasma viscosity normal 
 
Plasmablast count 
 
Plasmablast count decreased 
 
Plasmablast count increased 
 
Plasmablastic lymphoma 
 
Plasmacytoma 
 
Plasmacytosis 
 
Plasmin decreased 
 
Plasmin increased 
 
Plasmin inhibitor 
 
Plasmin inhibitor decreased 
 
Plasmin inhibitor increased 
 
Plasminogen 
 
Plasminogen activator inhibitor 
 
Plasminogen activator inhibitor decreased 
 
Plasminogen activator inhibitor increased 
 
Plasminogen activator inhibitor polymorphism 
 
Plasminogen activator inhibitor type 1 deficiency 
 
Plasminogen decreased 
 
Plasminogen increased 
 
Plasminogen normal 
 
Plasmodium falciparum infection 
 
Plasmodium knowlesi infection 
 
Plasmodium malariae infection 
 
Plasmodium ovale infection 
 
Plasmodium vivax infection 
 
Platelet adhesiveness 
 
Platelet adhesiveness abnormal 
 
Platelet adhesiveness decreased 
 
Platelet adhesiveness increased 
 
Platelet adhesiveness normal 
 
Platelet aggregation abnormal 
 
Platelet aggregation decreased 
 
Platelet aggregation increased 
 
Platelet aggregation inhibition 
 
Platelet aggregation normal 
 
Platelet aggregation test 


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Platelet anisocytosis 
 
Platelet count 
 
Platelet count abnormal 
 
Platelet count decreased 
 
Platelet count increased 
 
Platelet count normal 
 
Platelet destruction increased 
 
Platelet disorder 
 
Platelet distribution width 
 
Platelet distribution width abnormal 
 
Platelet distribution width decreased 
 
Platelet distribution width increased 
 
Platelet dysfunction 
 
Platelet factor 4 
 
Platelet factor 4 decreased 
 
Platelet factor 4 increased 
 
Platelet function test 
 
Platelet function test abnormal 
 
Platelet function test normal 
 
Platelet glycoprotein gene mutation 
 
Platelet maturation arrest 
 
Platelet morphology 
 
Platelet morphology abnormal 
 
Platelet morphology normal 
 
Platelet production decreased 
 
Platelet storage pool deficiency 
 
Platelet toxicity 
 
Platelet-large cell ratio 
 
Platelet-large cell ratio decreased 
 
Platelet-large cell ratio increased 
 
Plateletcrit 
 
Plateletcrit abnormal 
 
Plateletcrit decreased 
 
Plateletcrit increased 
 
Plateletcrit normal 
 
Poikilocytosis 
 
Polychromasia 
 
Polychromic red blood cells present 
 
Polyclonal B-cell lymphocytosis 
 
Polycythaemia 
 
Polycythaemia neonatorum 
 
Polycythaemia vera 
 
Polymorphonuclear chromatin clumping 
 
Post transfusion purpura 
 
Post transplant distal limb syndrome 
 
Post transplant lymphoproliferative disorder 
 
Post-anaphylaxis mast cell anergy 
 
Post-depletion B-cell recovery 
 
Postmastectomy lymphoedema syndrome 
 
Postoperative lymphocele 
 
Postsplenectomy syndrome 
 
Precursor B-lymphoblastic lymphoma 
 
Precursor B-lymphoblastic lymphoma recurrent 
 
Precursor B-lymphoblastic lymphoma refractory 


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Precursor B-lymphoblastic lymphoma stage I 
 
Precursor B-lymphoblastic lymphoma stage II 
 
Precursor B-lymphoblastic lymphoma stage III 
 
Precursor B-lymphoblastic lymphoma stage IV 
 
Precursor T-lymphoblastic leukaemia acute 
 
Precursor T-lymphoblastic lymphoma/leukaemia 
 
Precursor T-lymphoblastic lymphoma/leukaemia recurrent 
 
Precursor T-lymphoblastic lymphoma/leukaemia refractory 
 
Precursor T-lymphoblastic lymphoma/leukaemia stage I 
 
Precursor T-lymphoblastic lymphoma/leukaemia stage II 
 
Precursor T-lymphoblastic lymphoma/leukaemia stage III 
 
Precursor T-lymphoblastic lymphoma/leukaemia stage IV 
 
Prekallikrein decreased 
 
Prekallikrein increased 
 
Prekallikrein test 
 
Prekallikrein test abnormal 
 
Prekallikrein test normal 
 
Primary breast lymphoma 
 
Primary cardiac lymphoma 
 
Primary effusion lymphoma 
 
Primary gastrointestinal follicular lymphoma 
 
Primary mediastinal large B-cell lymphoma 
 
Primary mediastinal large B-cell lymphoma recurrent 
 
Primary mediastinal large B-cell lymphoma refractory 
 
Primary mediastinal large B-cell lymphoma stage I 
 
Primary mediastinal large B-cell lymphoma stage II 
 
Primary mediastinal large B-cell lymphoma stage III 
 
Primary mediastinal large B-cell lymphoma stage IV 
 
Primary myelofibrosis 
 
Proerythroblast count 
 
Proerythroblast count abnormal 
 
Proerythroblast count decreased 
 
Proerythroblast count increased 
 
Proerythroblast count normal 
 
Prolymphocytic leukaemia 
 
Promyelocyte count 
 
Promyelocyte count decreased 
 
Promyelocyte count increased 
 
Protein C 
 
Protein C decreased 
 
Protein C deficiency 
 
Protein C increased 
 
Protein S 
 
Protein S abnormal 
 
Protein S decreased 
 
Protein S deficiency 
 
Protein S increased 
 
Protein S normal 
 
Protein deficiency anaemia 
 
Prothrombin consumption time prolonged 
 
Prothrombin consumption time shortened 
 
Prothrombin fragment 1.2 
 
Prothrombin fragment 1.2 increased 
 
Prothrombin index 


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Prothrombin level 
 
Prothrombin level abnormal 
 
Prothrombin level decreased 
 
Prothrombin level increased 
 
Prothrombin level normal 
 
Prothrombin time 
 
Prothrombin time abnormal 
 
Prothrombin time normal 
 
Prothrombin time prolonged 
 
Prothrombin time ratio 
 
Prothrombin time ratio abnormal 
 
Prothrombin time ratio decreased 
 
Prothrombin time ratio increased 
 
Prothrombin time shortened 
 
Pseudolymphoma 
 
Pseudomononucleosis 
 
Pulmonary eosinophilia 
 
Pulmonary lymphangiectasia 
 
Pulmonary nodular lymphoid hyperplasia 
 
Punctate basophilia 
 
Pure white cell aplasia 
 
Purpura 
 
Purpura fulminans 
 
Purpura neonatal 
 
Purpura non-thrombocytopenic 
 
Purpura senile 
 
Pyruvate kinase deficiency anaemia 
 
Radiation leukopenia 
 
Radiation-induced lymphocyte apoptosis 
 
Red blood cell Heinz bodies present 
 
Red blood cell abnormality 
 
Red blood cell acanthocytes present 
 
Red blood cell agglutination 
 
Red blood cell agglutination present 
 
Red blood cell analysis 
 
Red blood cell analysis abnormal 
 
Red blood cell analysis normal 
 
Red blood cell anisocytes 
 
Red blood cell anisocytes present 
 
Red blood cell burr cells present 
 
Red blood cell count 
 
Red blood cell count abnormal 
 
Red blood cell count decreased 
 
Red blood cell count increased 
 
Red blood cell count normal 
 
Red blood cell elliptocytes present 
 
Red blood cell enzymes abnormal 
 
Red blood cell hyperchromic morphology 
 
Red blood cell hyperchromic morphology present 
 
Red blood cell hypochromic morphology present 
 
Red blood cell macrocytes present 
 
Red blood cell microcytes 
 
Red blood cell microcytes absent 
 
Red blood cell microcytes present 


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Red blood cell morphology 
 
Red blood cell morphology abnormal 
 
Red blood cell morphology normal 
 
Red blood cell nucleated morphology 
 
Red blood cell nucleated morphology present 
 
Red blood cell poikilocytes 
 
Red blood cell poikilocytes present 
 
Red blood cell punctate basophilia present 
 
Red blood cell rouleaux formation present 
 
Red blood cell schistocytes 
 
Red blood cell schistocytes present 
 
Red blood cell sedimentation rate 
 
Red blood cell sedimentation rate abnormal 
 
Red blood cell sedimentation rate decreased 
 
Red blood cell sedimentation rate increased 
 
Red blood cell sedimentation rate normal 
 
Red blood cell sickled cells present 
 
Red blood cell siderocytes present 
 
Red blood cell spherocytes 
 
Red blood cell spherocytes present 
 
Red blood cell target cells present 
 
Red blood cell vacuolisation 
 
Red cell distribution width 
 
Red cell distribution width abnormal 
 
Red cell distribution width decreased 
 
Red cell distribution width increased 
 
Red cell distribution width normal 
 
Red cell fragmentation syndrome 
 
Refractory anaemia with an excess of blasts 
 
Refractory anaemia with ringed sideroblasts 
 
Refractory cytopenia with multilineage dysplasia 
 
Refractory cytopenia with unilineage dysplasia 
 
Renal lymphocele 
 
Renal-limited thrombotic microangiopathy 
 
Reticular cell count 
 
Reticulocyte count 
 
Reticulocyte count abnormal 
 
Reticulocyte count decreased 
 
Reticulocyte count increased 
 
Reticulocyte count normal 
 
Reticulocyte haemoglobin equivalent 
 
Reticulocyte percentage 
 
Reticulocyte percentage abnormal 
 
Reticulocyte percentage decreased 
 
Reticulocyte percentage increased 
 
Reticulocyte percentage normal 
 
Reticulocytopenia 
 
Reticulocytosis 
 
Reticuloendothelial dysfunction 
 
Reticuloendothelial system stimulated 
 
Retinopathy sickle cell 
 
Retroperitoneal lymphadenopathy 
 
Rhesus antibodies 
 
Rhesus antibodies negative 


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Rhesus antibodies positive 
 
Rhesus antigen 
 
Rhesus antigen negative 
 
Rhesus antigen positive 
 
Rhesus haemolytic disease of newborn 
 
Rhesus incompatibility 
 
Richter's syndrome 
 
Rosai-Dorfman syndrome 
 
Rouleaux formation 
 
Russell's viper venom time 
 
Russell's viper venom time abnormal 
 
Russell's viper venom time normal 
 
Scan bone marrow 
 
Scan bone marrow abnormal 
 
Scan bone marrow normal 
 
Scan lymph nodes 
 
Scan spleen 
 
Schistocytosis 
 
Schumm's test 
 
Schumm's test negative 
 
Schumm's test positive 
 
Secondary thrombocytosis 
 
Septic coagulopathy 
 
Serum colour abnormal 
 
Severe fever with thrombocytopenia syndrome 
 
Sezary cell count 
 
Sezary cells increased 
 
Shift to the left 
 
Shift to the right 
 
Shwachman-Diamond syndrome 
 
Sickle cell anaemia 
 
Sickle cell anaemia with crisis 
 
Sickle cell disease 
 
Sickle cell nephropathy 
 
Sickle cell trait 
 
Sideroblastic anaemia 
 
Solitary epithelioid histiocytoma 
 
Soluble fibrin monomer complex 
 
Soluble fibrin monomer complex increased 
 
Spherocytic anaemia 
 
Spleen atrophy 
 
Spleen congestion 
 
Spleen contusion 
 
Spleen disorder 
 
Spleen follicular hyperplasia 
 
Spleen ischaemia 
 
Spleen malformation 
 
Spleen procedural complication 
 
Spleen scan abnormal 
 
Spleen scan normal 
 
Spleen tuberculosis 
 
Splenic abscess 
 
Splenic artery perforation 
 
Splenic artery stenosis 


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Splenic artery thrombosis 
 
Splenic calcification 
 
Splenic candidiasis 
 
Splenic cyst 
 
Splenic embolism 
 
Splenic fibrosis 
 
Splenic granuloma 
 
Splenic haematoma 
 
Splenic haemorrhage 
 
Splenic hamartoma 
 
Splenic induration 
 
Splenic infarction 
 
Splenic infection 
 
Splenic infection bacterial 
 
Splenic infection fungal 
 
Splenic infection helminthic 
 
Splenic infection viral 
 
Splenic injury 
 
Splenic lesion 
 
Splenic marginal zone lymphoma 
 
Splenic marginal zone lymphoma recurrent 
 
Splenic marginal zone lymphoma refractory 
 
Splenic marginal zone lymphoma stage I 
 
Splenic marginal zone lymphoma stage II 
 
Splenic marginal zone lymphoma stage III 
 
Splenic marginal zone lymphoma stage IV 
 
Splenic necrosis 
 
Splenic neoplasm malignancy unspecified 
 
Splenic peliosis 
 
Splenic rupture 
 
Splenic thrombosis 
 
Splenic varices 
 
Splenic varices haemorrhage 
 
Splenic vein occlusion 
 
Splenic vein thrombosis 
 
Splenitis 
 
Splenomegaly 
 
Splenorenal shunt 
 
Splenosis 
 
Spontaneous haematoma 
 
Spontaneous haemorrhage 
 
Spontaneous heparin-induced thrombocytopenia syndrome 
 
Spur cell anaemia 
 
Sticky platelet syndrome 
 
Stomatocytes present 
 
Stress polycythaemia 
 
Subacute combined cord degeneration 
 
Subcapsular splenic haematoma 
 
Sulphaemoglobinaemia 
 
Systemic mastocytosis 
 
T-cell chronic lymphocytic leukaemia 
 
T-cell lymphoma 
 
T-cell lymphoma recurrent 
 
T-cell lymphoma refractory 


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T-cell lymphoma stage I 
 
T-cell lymphoma stage II 
 
T-cell lymphoma stage III 
 
T-cell lymphoma stage IV 
 
T-cell prolymphocytic leukaemia 
 
T-cell type acute leukaemia 
 
T-cell unclassifiable lymphoma high grade 
 
T-cell unclassifiable lymphoma low grade 
 
T-lymphocyte count 
 
T-lymphocyte count abnormal 
 
T-lymphocyte count decreased 
 
T-lymphocyte count increased 
 
T-lymphocyte count normal 
 
TEMPI syndrome 
 
Thalassaemia 
 
Thalassaemia alpha 
 
Thalassaemia beta 
 
Thalassaemia minor 
 
Thalassaemia sickle cell 
 
Thrombasthenia 
 
Thrombin time 
 
Thrombin time abnormal 
 
Thrombin time normal 
 
Thrombin time prolonged 
 
Thrombin time shortened 
 
Thrombin-antithrombin III complex 
 
Thrombin-antithrombin III complex abnormal 
 
Thrombin-antithrombin III complex decreased 
 
Thrombin-antithrombin III complex increased 
 
Thrombin-antithrombin III complex normal 
 
Thrombocytopenia 
 
Thrombocytopenia neonatal 
 
Thrombocytopenia-absent radius syndrome 
 
Thrombocytopenic purpura 
 
Thrombocytosis 
 
Thromboelastogram 
 
Thrombopoietin level abnormal 
 
Thrombotic microangiopathy 
 
Thrombotic thrombocytopenic purpura 
 
Thromboxane decreased 
 
Thromboxane increased 
 
Thymic cancer metastatic 
 
Thymic cyst 
 
Thymoma 
 
Thymoma benign 
 
Thymoma malignant 
 
Thymoma malignant recurrent 
 
Thymus abscess 
 
Thymus disorder 
 
Thymus enlargement 
 
Thymus hypoplasia 
 
Thyroid B-cell lymphoma 
 
Transcobalamin deficiency 
 
Transformation to acute myeloid leukaemia 


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Transfusion reaction 
 
Transfusion-related alloimmune neutropenia 
 
Traumatic ulcerative granuloma with stromal eosinophilia 
 
Triple hit lymphoma 
 
Trisomy 12 
 
Tropical eosinophilia 
 
Tropical sprue 
 
Tuberculosis of intrathoracic lymph nodes 
 
Tuberculosis of peripheral lymph nodes 
 
Ultrasound spleen 
 
Vaccination site lymphadenopathy 
 
Vascular purpura 
 
Venolymphatic malformation 
 
Vitamin C deficiency 
 
Von Willebrand's disease 
 
Von Willebrand's factor activity abnormal 
 
Von Willebrand's factor activity decreased 
 
Von Willebrand's factor activity increased 
 
Von Willebrand's factor activity normal 
 
Von Willebrand's factor activity test 
 
Von Willebrand's factor antibody 
 
Von Willebrand's factor antibody positive 
 
Von Willebrand's factor antigen abnormal 
 
Von Willebrand's factor antigen decreased 
 
Von Willebrand's factor antigen increased 
 
Von Willebrand's factor antigen normal 
 
Von Willebrand's factor antigen test 
 
Von Willebrand's factor inhibition 
 
Von Willebrand's factor multimers abnormal 
 
Von Willebrand's factor multimers normal 
 
Von Willebrand's factor multimers test 
 
Waldenstrom's macroglobulinaemia 
 
Waldenstrom's macroglobulinaemia recurrent 
 
Waldenstrom's macroglobulinaemia refractory 
 
Waldenstrom's macroglobulinaemia stage I 
 
Waldenstrom's macroglobulinaemia stage II 
 
Waldenstrom's macroglobulinaemia stage III 
 
Waldenstrom's macroglobulinaemia stage IV 
 
Warm type haemolytic anaemia 
 
White blood cell agglutination present 
 
White blood cell analysis 
 
White blood cell analysis abnormal 
 
White blood cell analysis normal 
 
White blood cell count 
 
White blood cell count abnormal 
 
White blood cell count decreased 
 
White blood cell count increased 
 
White blood cell count normal 
 
White blood cell disorder 
 
White blood cell morphology 
 
White blood cell morphology abnormal 
 
White blood cell morphology normal 
 
White clot in blood present 
 
Wiskott-Aldrich syndrome 


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X-linked lymphoproliferative syndrome 
HYPERSENSITIVITY 
Acquired C1 inhibitor deficiency 
 
Acute generalised exanthematous pustulosis 
 
Acute respiratory failure 
 
Administration related reaction 
 
Administration site dermatitis 
 
Administration site eczema 
 
Administration site hypersensitivity 
 
Administration site photosensitivity reaction 
 
Administration site rash 
 
Administration site recall reaction 
 
Administration site urticaria 
 
Administration site vasculitis 
 
Airway remodelling 
 
Allergic bronchitis 
 
Allergic colitis 
 
Allergic cough 
 
Allergic cystitis 
 
Allergic eosinophilia 
 
Allergic gastroenteritis 
 
Allergic hepatitis 
 
Allergic keratitis 
 
Allergic oedema 
 
Allergic otitis externa 
 
Allergic otitis media 
 
Allergic pharyngitis 
 
Allergic reaction to excipient 
 
Allergic respiratory disease 
 
Allergic respiratory symptom 
 
Allergic sinusitis 
 
Allergic stomatitis 
 
Allergic transfusion reaction 
 
Allergy alert test positive 
 
Allergy test positive 
 
Allergy to chemicals 
 
Allergy to fermented products 
 
Allergy to immunoglobulin therapy 
 
Allergy to surgical sutures 
 
Allergy to vaccine 
 
Alpha tumour necrosis factor increased 
 
Alveolitis 
 
Anal eczema 
 
Anaphylactic reaction 
 
Anaphylactic shock 
 
Anaphylactic transfusion reaction 
 
Anaphylactoid reaction 
 
Anaphylactoid shock 
 
Anaphylaxis treatment 
 
Angioedema 
 
Anti-insulin antibody increased 
 
Anti-insulin antibody positive 
 
Anti-insulin receptor antibody increased 
 
Anti-insulin receptor antibody positive 
 
Anti-neutrophil cytoplasmic antibody positive vasculitis 


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Antiallergic therapy 
 
Antibody test abnormal 
 
Antibody test positive 
 
Antiendomysial antibody positive 
 
Application site dermatitis 
 
Application site eczema 
 
Application site hypersensitivity 
 
Application site photosensitivity reaction 
 
Application site rash 
 
Application site recall reaction 
 
Application site urticaria 
 
Application site vasculitis 
 
Arthritis allergic 
 
Aspirin-exacerbated respiratory disease 
 
Asthma 
 
Asthma late onset 
 
Asthma-chronic obstructive pulmonary disease overlap syndrome 
 
Asthmatic crisis 
 
Atopic cough 
 
Atopy 
 
Auricular swelling 
 
Blepharitis allergic 
 
Blister 
 
Blister rupture 
 
Blood immunoglobulin A abnormal 
 
Blood immunoglobulin A increased 
 
Blood immunoglobulin D increased 
 
Blood immunoglobulin E abnormal 
 
Blood immunoglobulin E increased 
 
Blood immunoglobulin G abnormal 
 
Blood immunoglobulin G increased 
 
Blood immunoglobulin M abnormal 
 
Blood immunoglobulin M increased 
 
Bromoderma 
 
Bronchial hyperreactivity 
 
Bronchial oedema 
 
Bronchospasm 
 
Bullous haemorrhagic dermatosis 
 
Bullous impetigo 
 
Caffeine allergy 
 
Capillaritis 
 
Catheter site dermatitis 
 
Catheter site eczema 
 
Catheter site hypersensitivity 
 
Catheter site rash 
 
Catheter site urticaria 
 
Catheter site vasculitis 
 
Charcot-Leyden crystals 
 
Cheilitis 
 
Childhood asthma 
 
Choking 
 
Choking sensation 
 
Chronic eosinophilic rhinosinusitis 
 
Chronic hyperplastic eosinophilic sinusitis 


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Circulatory collapse 
 
Circumoral oedema 
 
Circumoral swelling 
 
Complement factor C1 decreased 
 
Complement factor C2 decreased 
 
Complement factor C3 decreased 
 
Complement factor C4 decreased 
 
Complement factor decreased 
 
Conjunctival oedema 
 
Conjunctivitis 
 
Conjunctivitis allergic 
 
Contact stomatitis 
 
Contrast media allergy 
 
Contrast media reaction 
 
Corneal exfoliation 
 
Corneal oedema 
 
Cough variant asthma 
 
Cross sensitivity reaction 
 
Cutaneous vasculitis 
 
Cytokine increased 
 
Cytokine release syndrome 
 
Cytokine storm 
 
Dennie-Morgan fold 
 
Dermatitis 
 
Dermatitis acneiform 
 
Dermatitis allergic 
 
Dermatitis atopic 
 
Dermatitis bullous 
 
Dermatitis contact 
 
Dermatitis exfoliative 
 
Dermatitis exfoliative generalised 
 
Dermatitis herpetiformis 
 
Dermatitis infected 
 
Dermatitis psoriasiform 
 
Device allergy 
 
Dialysis membrane reaction 
 
Distributive shock 
 
Documented hypersensitivity to administered product 
 
Drug eruption 
 
Drug hypersensitivity 
 
Drug provocation test 
 
Drug reaction with eosinophilia and systemic symptoms 
 
Ear swelling 
 
Eczema 
 
Eczema infantile 
 
Eczema nummular 
 
Eczema vaccinatum 
 
Eczema vesicular 
 
Eczema weeping 
 
Encephalitis allergic 
 
Encephalopathy allergic 
 
Eosinophil count abnormal 
 
Eosinophil count increased 
 
Eosinophil percentage abnormal 


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Eosinophil percentage increased 
 
Eosinophilia 
 
Eosinophilia myalgia syndrome 
 
Eosinophilic bronchitis 
 
Eosinophilic granulomatosis with polyangiitis 
 
Eosinophilic oesophagitis 
 
Eosinophilic pneumonia 
 
Eosinophilic pneumonia acute 
 
Eosinophilic pneumonia chronic 
 
Epidermal necrosis 
 
Epidermolysis 
 
Epidermolysis bullosa 
 
Epiglottic oedema 
 
Erythema 
 
Erythema multiforme 
 
Erythema nodosum 
 
Exfoliative rash 
 
Eye allergy 
 
Eye oedema 
 
Eye swelling 
 
Eyelid oedema 
 
Face oedema 
 
Fixed eruption 
 
Flushing 
 
Gastrointestinal oedema 
 
Generalised bullous fixed drug eruption 
 
Generalised oedema 
 
Genital rash 
 
Genital swelling 
 
Giant papillary conjunctivitis 
 
Gingival oedema 
 
Gingival swelling 
 
Gleich's syndrome 
 
HLA marker study positive 
 
Haemolytic transfusion reaction 
 
Haemorrhagic urticaria 
 
Hand dermatitis 
 
Henoch-Schonlein purpura 
 
Henoch-Schonlein purpura nephritis 
 
Heparin-induced thrombocytopenia 
 
Human anti-hamster antibody increased 
 
Human anti-hamster antibody positive 
 
Hypersensitivity 
 
Hypersensitivity myocarditis 
 
Hypersensitivity pneumonitis 
 
Hypersensitivity vasculitis 
 
Idiopathic urticaria 
 
Immediate post-injection reaction 
 
Immune complex level increased 
 
Immune thrombocytopenia 
 
Immune tolerance induction 
 
Immunoglobulins abnormal 
 
Immunoglobulins increased 
 
Immunology test abnormal 


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Implant site dermatitis 
 
Implant site hypersensitivity 
 
Implant site photosensitivity 
 
Implant site rash 
 
Implant site urticaria 
 
Incision site dermatitis 
 
Incision site rash 
 
Infusion related hypersensitivity reaction 
 
Infusion related reaction 
 
Infusion site dermatitis 
 
Infusion site eczema 
 
Infusion site hypersensitivity 
 
Infusion site photosensitivity reaction 
 
Infusion site rash 
 
Infusion site recall reaction 
 
Infusion site urticaria 
 
Infusion site vasculitis 
 
Injection related reaction 
 
Injection site dermatitis 
 
Injection site eczema 
 
Injection site hypersensitivity 
 
Injection site panniculitis 
 
Injection site photosensitivity reaction 
 
Injection site rash 
 
Injection site recall reaction 
 
Injection site urticaria 
 
Injection site vasculitis 
 
Instillation site hypersensitivity 
 
Instillation site rash 
 
Instillation site urticaria 
 
Interstitial granulomatous dermatitis 
 
Interstitial lung disease 
 
Intestinal angioedema 
 
Iodine allergy 
 
Kounis syndrome 
 
Laryngeal dyspnoea 
 
Laryngeal obstruction 
 
Laryngeal oedema 
 
Laryngitis allergic 
 
Laryngospasm 
 
Laryngotracheal oedema 
 
Leukotriene increased 
 
Limbal swelling 
 
Lip exfoliation 
 
Lip oedema 
 
Lip swelling 
 
Localised oedema 
 
Macrophage inflammatory protein-1 alpha increased 
 
Mast cell activation syndrome 
 
Mast cell degranulation present 
 
Mechanical urticaria 
 
Medical device site dermatitis 
 
Medical device site eczema 
 
Medical device site hypersensitivity 


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Medical device site photosensitivity reaction 
 
Medical device site rash 
 
Medical device site recall reaction 
 
Medical device site urticaria 
 
Mesenteric panniculitis 
 
Monocyte chemotactic protein-2 increased 
 
Mouth swelling 
 
Mouth ulceration 
 
Mucocutaneous rash 
 
Mucocutaneous ulceration 
 
Mucosa vesicle 
 
Mucosal erosion 
 
Mucosal exfoliation 
 
Mucosal necrosis 
 
Mucosal ulceration 
 
Multiple allergies 
 
Nasal crease 
 
Necrotising panniculitis 
 
Nephritis allergic 
 
Neurodermatitis 
 
Neutralising antibodies positive 
 
Nikolsky's sign 
 
Nodular rash 
 
Non-neutralising antibodies positive 
 
Noninfective conjunctivitis 
 
Nutritional supplement allergy 
 
Occupational asthma 
 
Occupational dermatitis 
 
Oculomucocutaneous syndrome 
 
Oculorespiratory syndrome 
 
Oedema mouth 
 
Oedema mucosal 
 
Oral allergy syndrome 
 
Oral mucosal exfoliation 
 
Orbital oedema 
 
Oropharyngeal blistering 
 
Oropharyngeal oedema 
 
Oropharyngeal spasm 
 
Oropharyngeal swelling 
 
Palatal oedema 
 
Palatal swelling 
 
Palisaded neutrophilic granulomatous dermatitis 
 
Palpable purpura 
 
Panniculitis 
 
Pathergy reaction 
 
Penile exfoliation 
 
Penile oedema 
 
Penile rash 
 
Penile swelling 
 
Perineal rash 
 
Perioral dermatitis 
 
Periorbital oedema 
 
Periorbital swelling 
 
Perivascular dermatitis 


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Pharyngeal oedema 
 
Pharyngeal swelling 
 
Photosensitivity reaction 
 
Pneumonitis 
 
Procedural shock 
 
Prurigo 
 
Pruritus 
 
Pruritus allergic 
 
Pulmonary eosinophilia 
 
Radioallergosorbent test positive 
 
Rash 
 
Rash erythematous 
 
Rash follicular 
 
Rash macular 
 
Rash maculo-papular 
 
Rash maculovesicular 
 
Rash morbilliform 
 
Rash neonatal 
 
Rash papulosquamous 
 
Rash pruritic 
 
Rash pustular 
 
Rash rubelliform 
 
Rash scarlatiniform 
 
Rash vesicular 
 
Reaction to azo-dyes 
 
Reaction to colouring 
 
Reaction to excipient 
 
Reaction to food additive 
 
Reaction to preservatives 
 
Reactive airways dysfunction syndrome 
 
Red man syndrome 
 
Respiratory arrest 
 
Respiratory distress 
 
Respiratory failure 
 
Respiratory tract oedema 
 
Reversible airways obstruction 
 
Rhinitis allergic 
 
Rhinitis perennial 
 
SJS-TEN overlap 
 
Scleral oedema 
 
Scleritis allergic 
 
Scrotal dermatitis 
 
Scrotal exfoliation 
 
Scrotal oedema 
 
Scrotal swelling 
 
Seasonal allergy 
 
Septal panniculitis 
 
Serum sickness 
 
Serum sickness-like reaction 
 
Shock 
 
Shock symptom 
 
Skin erosion 
 
Skin exfoliation 
 
Skin necrosis 


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Skin oedema 
 
Skin reaction 
 
Skin swelling 
 
Skin test positive 
 
Sneezing 
 
Solar urticaria 
 
Solvent sensitivity 
 
Status asthmaticus 
 
Stevens-Johnson syndrome 
 
Stoma site hypersensitivity 
 
Stoma site rash 
 
Stomatitis 
 
Streptokinase antibody increased 
 
Stridor 
 
Suffocation feeling 
 
Sunscreen sensitivity 
 
Swelling face 
 
Swelling of eyelid 
 
Swollen tongue 
 
Symmetrical drug-related intertriginous and flexural exanthema 
 
Throat tightness 
 
Tongue exfoliation 
 
Tongue oedema 
 
Toxic epidermal necrolysis 
 
Toxic skin eruption 
 
Tracheal obstruction 
 
Tracheal oedema 
 
Tracheostomy 
 
Transplantation associated food allergy 
 
Type I hypersensitivity 
 
Type II hypersensitivity 
 
Type III immune complex mediated reaction 
 
Type IV hypersensitivity reaction 
 
Upper airway obstruction 
 
Urticaria 
 
Urticaria cholinergic 
 
Urticaria chronic 
 
Urticaria contact 
 
Urticaria papular 
 
Urticaria physical 
 
Urticaria pigmentosa 
 
Urticaria vesiculosa 
 
Urticarial dermatitis 
 
Urticarial vasculitis 
 
Vaccination site dermatitis 
 
Vaccination site eczema 
 
Vaccination site exfoliation 
 
Vaccination site hypersensitivity 
 
Vaccination site photosensitivity reaction 
 
Vaccination site rash 
 
Vaccination site recall reaction 
 
Vaccination site urticaria 
 
Vaccination site vasculitis 
 
Vaccination site vesicles 


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Vaccine associated enhanced disease 
 
Vaccine associated enhanced respiratory disease 
 
Vaginal oedema 
 
Vaginal ulceration 
 
Vasculitic rash 
 
Vernal keratoconjunctivitis 
 
Vessel puncture site rash 
 
Vessel puncture site vesicles 
 
Visceral oedema 
 
Vulval eczema 
 
Vulval oedema 
 
Vulval ulceration 
 
Vulvovaginal exfoliation 
 
Vulvovaginal rash 
 
Vulvovaginal swelling 
 
Vulvovaginal ulceration 
 
Vulvovaginitis allergic 
 
Wheezing 
MANIC SWITCH 
Hypomania 
 
Mania 
 
Manic symptom 
NEUROLEPTIC MALIGNANT SYNDROME 
Altered state of consciousness 
 
Autonomic nervous system imbalance 
 
Blood creatine phosphokinase MM increased 
 
Blood creatine phosphokinase abnormal 
 
Blood creatine phosphokinase increased 
 
Blood pressure abnormal 
 
Blood pressure decreased 
 
Blood pressure fluctuation 
 
Blood pressure increased 
 
Body temperature increased 
 
Cardiovascular insufficiency 
 
Catatonia 
 
Coma 
 
Confusional state 
 
Consciousness fluctuating 
 
Delirium 
 
Depressed level of consciousness 
 
Disorientation 
 
Dyskinesia 
 
Dyslalia 
 
Dysphagia 
 
Dystonia 
 
Dystonic tremor 
 
Extrapyramidal disorder 
 
Fatigue 
 
Freezing phenomenon 
 
Heart rate abnormal 
 
Heart rate increased 
 
Hyperhidrosis 
 
Hyperkinesia 
 
Hyperpyrexia 
 
Hypertension 
 
Hyperthermia malignant 


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Hypertonia 
 
Hyporesponsive to stimuli 
 
Hypotension 
 
Labile blood pressure 
 
Labile hypertension 
 
Leukocytosis 
 
Loss of consciousness 
 
Malignant catatonia 
 
Muscle enzyme increased 
 
Muscle necrosis 
 
Muscle rigidity 
 
Muscular weakness 
 
Myalgia 
 
Myoclonus 
 
Myoglobin blood increased 
 
Myoglobin blood present 
 
Myoglobin urine present 
 
Myoglobinaemia 
 
Myoglobinuria 
 
Necrotising myositis 
 
Neuroleptic malignant syndrome 
 
Oculogyric crisis 
 
Opisthotonus 
 
Palpitations 
 
Parkinson's disease 
 
Parkinsonian crisis 
 
Parkinsonian rest tremor 
 
Parkinsonism 
 
Pyrexia 
 
Respiratory failure 
 
Resting tremor 
 
Rhabdomyolysis 
 
Salivary hypersecretion 
 
Serotonin syndrome 
 
Slow response to stimuli 
 
Stupor 
 
Tachycardia 
 
Tremor 
 
Unresponsive to stimuli 
 
Urinary retention 
 
White blood cell count abnormal 
 
White blood cell count increased 
 
Withdrawal catatonia 
ORTHOSTATIC HYPOTENSION, DIZZINESS, AND 
SYNCOPE 
Dizziness 
 
Dizziness postural 
 
Hypotension 
 
Orthostatic hypotension 
 
Presyncope 
 
Syncope 
PROLACTIN 
Amenorrhoea 
 
Amenorrhoea-galactorrhoea syndrome 
 
Anorgasmia 
 
Blood prolactin 


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Blood prolactin abnormal 
 
Blood prolactin increased 
 
Breast discharge 
 
Breast enlargement 
 
Breast swelling 
 
Ejaculation disorder 
 
Erectile dysfunction 
 
Female orgasmic disorder 
 
Female sexual dysfunction 
 
Galactorrhoea 
 
Gynaecomastia 
 
Hirsutism 
 
Hyperprolactinaemia 
 
Hypomenorrhoea 
 
Lactation disorder 
 
Libido decreased 
 
Loss of libido 
 
Male sexual dysfunction 
 
Menstrual disorder 
 
Menstruation delayed 
 
Menstruation irregular 
 
Oligomenorrhoea 
 
Orgasm abnormal 
 
Orgasmic sensation decreased 
 
Prolactin-producing pituitary tumour 
 
Sexual dysfunction 
QT PROLONGATION 
Cardiac arrest 
 
Cardiac death 
 
Cardiac fibrillation 
 
Cardio-respiratory arrest 
 
Electrocardiogram QT interval abnormal 
 
Electrocardiogram QT prolonged 
 
Electrocardiogram U wave inversion 
 
Electrocardiogram U wave present 
 
Electrocardiogram U-wave abnormality 
 
Electrocardiogram repolarisation abnormality 
 
Long QT syndrome 
 
Long QT syndrome congenital 
 
Loss of consciousness 
 
Sudden cardiac death 
 
Sudden death 
 
Syncope 
 
Torsade de pointes 
 
Ventricular arrhythmia 
 
Ventricular fibrillation 
 
Ventricular flutter 
 
Ventricular tachyarrhythmia 
 
Ventricular tachycardia 
RHABDOMYOLYSIS AND CPK ELEVATION 
Acute kidney injury 
 
Anuria 
 
Biopsy muscle abnormal 
 
Blood calcium decreased 
 
Blood creatine phosphokinase MM increased 
 
Blood creatine phosphokinase abnormal 


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Blood creatine phosphokinase increased 
 
Blood creatinine abnormal 
 
Blood creatinine increased 
 
Chromaturia 
 
Chronic kidney disease 
 
Compartment syndrome 
 
Creatinine renal clearance abnormal 
 
Creatinine renal clearance decreased 
 
Diaphragm muscle weakness 
 
Electromyogram abnormal 
 
End stage renal disease 
 
Glomerular filtration rate abnormal 
 
Glomerular filtration rate decreased 
 
Haematoma muscle 
 
Hypercreatininaemia 
 
Hypocalcaemia 
 
Muscle discomfort 
 
Muscle disorder 
 
Muscle enzyme increased 
 
Muscle fatigue 
 
Muscle haemorrhage 
 
Muscle necrosis 
 
Muscle rupture 
 
Muscle strength abnormal 
 
Muscular weakness 
 
Musculoskeletal discomfort 
 
Musculoskeletal disorder 
 
Musculoskeletal pain 
 
Musculoskeletal toxicity 
 
Myalgia 
 
Myalgia intercostal 
 
Myoglobin blood increased 
 
Myoglobin blood present 
 
Myoglobin urine present 
 
Myoglobinaemia 
 
Myoglobinuria 
 
Myopathy 
 
Myopathy toxic 
 
Myositis 
 
Necrotising myositis 
 
Oliguria 
 
Renal failure 
 
Renal impairment 
 
Renal tubular necrosis 
 
Rhabdomyolysis 
 
Subacute kidney injury 
 
Tendon discomfort 
 
Thyrotoxic myopathy 
SEIZURES 
1p36 deletion syndrome 
 
2-Hydroxyglutaric aciduria 
 
Acquired epileptic aphasia 
 
Acute encephalitis with refractory, repetitive partial seizures 
 
Alcoholic seizure 
 
Alpers disease 


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Amygdalohippocampectomy 
 
Aspartate-glutamate-transporter deficiency 
 
Atonic seizures 
 
Atypical benign partial epilepsy 
 
Aura 
 
Automatism epileptic 
 
Autonomic seizure 
 
Baltic myoclonic epilepsy 
 
Benign familial neonatal convulsions 
 
Benign rolandic epilepsy 
 
Biotinidase deficiency 
 
CDKL5 deficiency disorder 
 
CEC syndrome 
 
CSWS syndrome 
 
Change in seizure presentation 
 
Clonic convulsion 
 
Congenital bilateral perisylvian syndrome 
 
Convulsion in childhood 
 
Convulsions local 
 
Convulsive threshold lowered 
 
Corpus callosotomy 
 
Deja vu 
 
Double cortex syndrome 
 
Dreamy state 
 
Drop attacks 
 
Drug withdrawal convulsions 
 
Early infantile epileptic encephalopathy with burst-suppression 
 
Eclampsia 
 
Epilepsy 
 
Epilepsy surgery 
 
Epilepsy with myoclonic-atonic seizures 
 
Epileptic aura 
 
Epileptic psychosis 
 
Faciobrachial dystonic seizure 
 
Febrile convulsion 
 
Febrile infection-related epilepsy syndrome 
 
Foaming at mouth 
 
Focal cortical resection 
 
Focal dyscognitive seizures 
 
Frontal lobe epilepsy 
 
GM2 gangliosidosis 
 
Gelastic seizure 
 
Generalised onset non-motor seizure 
 
Generalised tonic-clonic seizure 
 
Glucose transporter type 1 deficiency syndrome 
 
Grey matter heterotopia 
 
Hemiconvulsion-hemiplegia-epilepsy syndrome 
 
Hemimegalencephaly 
 
Hyperglycaemic seizure 
 
Hypocalcaemic seizure 
 
Hypoglycaemic seizure 
 
Hyponatraemic seizure 
 
Idiopathic generalised epilepsy 
 
Infantile spasms 


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Jeavons syndrome 
 
Juvenile absence epilepsy 
 
Juvenile myoclonic epilepsy 
 
Lafora's myoclonic epilepsy 
 
Lennox-Gastaut syndrome 
 
Migraine-triggered seizure 
 
Molybdenum cofactor deficiency 
 
Multiple subpial transection 
 
Myoclonic epilepsy 
 
Myoclonic epilepsy and ragged-red fibres 
 
Narcolepsy 
 
Neonatal epileptic seizure 
 
Neonatal seizure 
 
Parietal lobe epilepsy 
 
Partial seizures 
 
Partial seizures with secondary generalisation 
 
Petit mal epilepsy 
 
Polymicrogyria 
 
Post stroke epilepsy 
 
Post stroke seizure 
 
Post-traumatic epilepsy 
 
Postictal headache 
 
Postictal paralysis 
 
Postictal psychosis 
 
Postictal state 
 
Preictal state 
 
Schizencephaly 
 
Seizure 
 
Seizure anoxic 
 
Seizure cluster 
 
Seizure like phenomena 
 
Seizure prophylaxis 
 
Severe myoclonic epilepsy of infancy 
 
Simple partial seizures 
 
Status epilepticus 
 
Sudden unexplained death in epilepsy 
 
Temporal lobe epilepsy 
 
Tongue biting 
 
Tonic clonic movements 
 
Tonic convulsion 
 
Tonic posturing 
 
Topectomy 
 
Transient epileptic amnesia 
 
Tuberous sclerosis complex 
 
Uncinate fits 
SOMNOLENCE 
Fatigue 
 
Hypersomnia 
 
Malaise 
 
Sedation 
 
Sedation complication 
 
Somnolence 
SUICIDALITY 
Assisted suicide 
 
Columbia suicide severity rating scale abnormal 
 
Completed suicide 


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Depression suicidal 
 
Intentional overdose 
 
Intentional self-injury 
 
Poisoning deliberate 
 
Self-injurious ideation 
 
Suicidal behaviour 
 
Suicidal ideation 
 
Suicide attempt 
 
Suicide threat 
 
Suspected suicide 
 
Suspected suicide attempt 
VTE (THROMBOTIC AND EMBOLIC EVENTS) 
Aseptic cavernous sinus thrombosis 
 
Axillary vein thrombosis 
 
Brachiocephalic vein occlusion 
 
Brachiocephalic vein thrombosis 
 
Budd-Chiari syndrome 
 
Catheter management 
 
Catheterisation venous 
 
Cavernous sinus thrombosis 
 
Central venous catheterisation 
 
Cerebral venous sinus thrombosis 
 
Cerebral venous thrombosis 
 
Compression garment application 
 
Deep vein thrombosis 
 
Deep vein thrombosis postoperative 
 
Embolism venous 
 
Hepatic vein embolism 
 
Hepatic vein occlusion 
 
Hepatic vein thrombosis 
 
Homans' sign positive 
 
Iliac vein occlusion 
 
Inferior vena cava syndrome 
 
Inferior vena caval occlusion 
 
Jugular vein embolism 
 
Jugular vein occlusion 
 
Jugular vein thrombosis 
 
Mahler sign 
 
May-Thurner syndrome 
 
Mesenteric vein thrombosis 
 
Mesenteric venous occlusion 
 
Obstetrical pulmonary embolism 
 
Obstructive shock 
 
Ophthalmic vein thrombosis 
 
Ovarian vein thrombosis 
 
Paget-Schroetter syndrome 
 
Pelvic venous thrombosis 
 
Penile vein thrombosis 
 
Peripheral vein occlusion 
 
Peripheral vein thrombus extension 
 
Phlebectomy 
 
Portal vein cavernous transformation 
 
Portal vein embolism 
 
Portal vein occlusion 
 
Portal vein thrombosis 


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Portosplenomesenteric venous thrombosis 
 
Post procedural pulmonary embolism 
 
Post thrombotic syndrome 
 
Postoperative thrombosis 
 
Postpartum venous thrombosis 
 
Pulmonary embolism 
 
Pulmonary infarction 
 
Pulmonary microemboli 
 
Pulmonary oil microembolism 
 
Pulmonary thrombosis 
 
Pulmonary vein occlusion 
 
Pulmonary veno-occlusive disease 
 
Pulmonary venous thrombosis 
 
Renal vein embolism 
 
Renal vein occlusion 
 
Renal vein thrombosis 
 
Retinal vein occlusion 
 
Retinal vein thrombosis 
 
SI QIII TIII pattern 
 
Septic pulmonary embolism 
 
Splenic vein occlusion 
 
Splenic vein thrombosis 
 
Subclavian vein occlusion 
 
Subclavian vein thrombosis 
 
Superior sagittal sinus thrombosis 
 
Superior vena cava occlusion 
 
Superior vena cava syndrome 
 
Thrombophlebitis 
 
Thrombophlebitis migrans 
 
Thrombophlebitis neonatal 
 
Thrombophlebitis superficial 
 
Thrombosed varicose vein 
 
Thrombosis corpora cavernosa 
 
Transverse sinus thrombosis 
 
Vascular graft 
 
Vena cava embolism 
 
Vena cava filter insertion 
 
Vena cava filter removal 
 
Vena cava thrombosis 
 
Venogram abnormal 
 
Venoocclusive disease 
 
Venoocclusive liver disease 
 
Venous angioplasty 
 
Venous occlusion 
 
Venous operation 
 
Venous recanalisation 
 
Venous repair 
 
Venous stent insertion 
 
Venous thrombosis 
 
Venous thrombosis in pregnancy 
 
Venous thrombosis limb 
 
Venous thrombosis neonatal 
 
Visceral venous thrombosis 
 


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Appendix 5 
List of Summary Tables 
 
CT-1.1 
Subject Disposition (Enrolled Subjects) 
CT-1.2 
Subject Disposition by ADT (Enrolled Subjects) 
CT-2.1 
Reasons for Discontinuation (Safety Analysis Set) 
CT-2.2 
Reasons for Discontinuation by ADT (Safety Analysis Set) 
CT-2.3 
Subject Completion Rates by Time (Safety Analysis Set) 
CT-3.1.1.1 
Demographic Characteristics (Efficacy Analysis Set) 
CT-3.1.1.2 
Demographic Characteristics by ADT: Duloxetine (Efficacy Analysis Set) 
CT-3.1.1.3 
Demographic Characteristics by ADT: Escitalopram (Efficacy Analysis Set) 
CT-3.1.1.4 
CT-3.1.1.5 
Demographic Characteristics by ADT: Fluvoxamine (Efficacy Analysis Set) 
Demographic Characteristics by ADT: Milnacipran (Efficacy Analysis Set) 
CT-3.1.1.6 
Demographic Characteristics by ADT: Paroxetine (Efficacy Analysis Set) 
CT-3.1.1.7 
Demographic Characteristics by ADT: Sertraline (Efficacy Analysis Set) 
CT-3.1.1.8 
Demographic Characteristics by ADT: Venlafaxine (Efficacy Analysis Set) 
CT-3.1.1.9 
Demographic Characteristics by ADT: Mirtazapine (Efficacy Analysis Set) 
CT-3.1.2.1 
Demographic Characteristics (Safety Analysis Set) 
CT-3.1.2.2 
Demographic Characteristics by ADT: Duloxetine (Safety Analysis Set) 
CT-3.1.2.3 
Demographic Characteristics by ADT: Escitalopram (Safety Analysis Set) 
CT-3.1.2.4 
Demographic Characteristics by ADT: Fluvoxamine (Safety Analysis Set) 
CT-3.1.2.5 
Demographic Characteristics by ADT: Milnacipran (Safety Analysis Set) 
CT-3.1.2.6 
Demographic Characteristics by ADT: Paroxetine (Safety Analysis Set) 
CT-3.1.2.7 
Demographic Characteristics by ADT: Sertraline (Safety Analysis Set) 
CT-3.1.2.8 
Demographic Characteristics by ADT: Venlafaxine (Safety Analysis Set) 
CT-3.1.2.9 
Demographic Characteristics by ADT: Mirtazapine (Safety Analysis Set) 
CT-3.2.1.1 
Baseline Disease Characteristics (Efficacy Analysis Set) 
CT-3.2.1.2 
Baseline Disease Characteristics by ADT: Duloxetine (Efficacy Analysis Set) 
CT-3.2.1.3 
Baseline Disease Characteristics by ADT: Escitalopram (Efficacy Analysis Set) 
CT-3.2.1.4 
Baseline Disease Characteristics by ADT: Fluvoxamine (Efficacy Analysis Set) 
CT-3.2.1.5 
Baseline Disease Characteristics by ADT: Milnacipran (Efficacy Analysis Set) 
CT-3.2.1.6 
Baseline Disease Characteristics by ADT: Paroxetine (Efficacy Analysis Set) 
CT-3.2.1.7 
Baseline Disease Characteristics by ADT: Sertraline (Efficacy Analysis Set) 
CT-3.2.1.8 
Baseline Disease Characteristics by ADT: Venlafaxine (Efficacy Analysis Set) 
CT-3.2.1.9 
Baseline Disease Characteristics by ADT: Mirtazapine (Efficacy Analysis Set) 
CT-3.2.2.1 
Baseline Disease Characteristics (Safety Analysis Set) 
CT-3.2.2.2 
Baseline Disease Characteristics by ADT: Duloxetine (Safety Analysis Set) 
CT-3.2.2.3 
Baseline Disease Characteristics by ADT: Escitalopram (Safety Analysis Set) 
CT-3.2.2.4 
Baseline Disease Characteristics by ADT: Fluvoxamine (Safety Analysis Set) 
CT-3.2.2.5 
Baseline Disease Characteristics by ADT: Milnacipran (Safety Analysis Set) 
CT-3.2.2.6 
Baseline Disease Characteristics by ADT: Paroxetine (Safety Analysis Set) 
CT-3.2.2.7 
Baseline Disease Characteristics by ADT: Sertraline (Safety Analysis Set) 
CT-3.2.2.8 
Baseline Disease Characteristics by ADT: Venlafaxine (Safety Analysis Set) 
CT-3.2.2.9 
Baseline Disease Characteristics by ADT: Mirtazapine (Safety Analysis Set) 
CT-4.1.1 
Concomitant Medications: Medications Taken Prior to Start of Study Therapy (Safety 
Analysis Set) 
CT-4.1.2  
Concomitant Medications: Medications Taken During Study Therapy (Safety Analysis 
Set) 


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CT-4.1.3 
Concomitant Medications: Medications Taken Post Study Period (Safety Analysis Set) 
CT-4.1.4 
Psychiatric Concomitant Medications: Medications Taken Prior to Start of Study 
Therapy (Safety Analysis Set) 
CT-4.1.5 
Psychiatric Concomitant Medications: Medications Taken During Study Therapy (Safety 
Analysis Set) 
CT-4.1.6 
Psychiatric Concomitant Medications: Medications Taken Post Study Period (Safety 
Analysis Set) 
CT-4.2 
Summary of Major Protocol Deviations by Center and Type of Deviation (Safety 
Analysis Set) 
CT-5.1 
Summary of Mean Change From Baseline in MADRS Total Score (Efficacy Analysis 
Set) 
CT-5.2 
Summary of Proportion of Subjects With a MADRS Response Relative to the Baseline 
(Efficacy Analysis Set) 
CT-5.3 
Summary of Proportion of Subjects With a MADRS Remission Relative to the Baseline 
(Efficacy Analysis Set) 
CT-5.4 
Summary of Proportion of Subjects With a CGI-I Improvement Relative to the Baseline 
(Efficacy Analysis Set) 
CT-5.5 
Summary of Mean Change From Baseline in CGI-S (Efficacy Analysis Set) 
CT-5.6 
Summary of Mean Change From Baseline in HAM-D 17 Total Score (Efficacy Analysis 
Set) 
CT-5.7 
Summary of Mean Change From Baseline in SDS Scores (Efficacy Analysis Set) 
CT-5.8 
Summary of Mean in CGI-I Score (Efficacy Analysis Set) 
CT-5.9 
Summary of Mean Change From Baseline in EQ-5D-5L (Efficacy Analysis Set) 
CT-7.1 
Extent of Exposure to Study Medication (Safety Analysis Set) 
CT-7.2 
Extent of Exposure to ADT (Safety Analysis Set) 
CT-7.3 
Summary of Treatment Compliance (Efficacy Analysis Set) 
CT-8.1 
Adverse Events (All Causalities) (Safety Analysis Set) 
CT-8.2.1 
Incidence of TEAEs by MedDRA System Organ Class and Preferred Term (Safety 
Analysis Set) 
CT-8.2.2 
Incidence of Drug-related TEAEs by MedDRA System Organ Class and Preferred Term 
(Safety Analysis Set) 
CT-8.3.1 
Incidence of TEAEs by MedDRA System Organ Class, Preferred Term and Severity 
(Safety Analysis Set) 
CT-8.3.2 
Incidence of Drug-related TEAEs by MedDRA System Organ Class, Preferred Term and 
Severity (Safety Analysis Set) 
CT-8.4.1 
Incidence of Deaths due to TEAEs by MedDRA System Organ Class and Preferred 
Term (Safety Analysis Set) 
CT-8.4.2 
Incidence of Deaths due to Drug-related TEAEs by MedDRA System Organ Class and 
Preferred Term (Safety Analysis Set) 
CT-8.5.1 
Incidence of Serious TEAEs by MedDRA System Organ Class and Preferred Term 
(Safety Analysis Set) 
CT-8.5.2 
Incidence of Serious Drug-related TEAEs by MedDRA System Organ Class and 
Preferred Term (Safety Analysis Set) 
CT-8.6.1 
Incidence of TEAEs Resulting in Discontinuation of IMP by MedDRA System Organ 
Class and Preferred Term (Safety Analysis Set) 
CT-8.6.2 
Incidence of Drug-related TEAEs Resulting in Discontinuation From Study by 
MedDRA System Organ Class and Preferred Term (Safety Analysis Set) 
CT-8.7.1   
Incidence of TEAEs of at Least 2% in Any Group by MedDRA System Organ Class and 
Preferred Term (Safety Analysis Set) 
CT-8.7.2 
Incidence of Drug-related TEAEs of at Least 2% in Any Group by MedDRA System 
Organ Class and Preferred Term (Safety Analysis Set) 
CT-8.8.1   
Incidence of TEAEs by MedDRA System Organ Class, Preferred Term and Time to 
First Onset (Safety Analysis Set) 
CT-8.8.2 
Incidence of Drug-related TEAEs by MedDRA System Organ Class, Preferred Term and 


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Time to First Onset (Safety Analysis Set) 
CT-8.9.1 
Incidence of TEAEs for EPS (Safety Analysis Set) 
CT-8.9.2 
Incidence of TEAEs for Neuroleptic Malignant Syndrome (Safety Analysis Set) 
CT-8.9.3 
Incidence of TEAEs for Rhabdomyolysis and CPK Elevation (Safety Analysis Set) 
CT-8.9.4 
Incidence of TEAEs for Seizures (Safety Analysis Set) 
CT-8.9.5 
Incidence of TEAEs for Orthostatic Hypotension, Dizziness, and Syncope (Safety 
Analysis Set) 
CT-8.9.6 
Incidence of TEAEs for Suicidality (Safety Analysis Set) 
CT-8.9.7 
Incidence of TEAEs for Somnolence (Safety Analysis Set) 
CT-8.9.8 
Incidence of TEAEs for Hypersensitivity (Safety Analysis Set) 
CT-8.9.9 
Incidence of TEAEs for VTE (Thrombotic and Embolic Events) (Safety Analysis Set) 
CT-8.9.10 
Incidence of TEAEs for Haematopoietic/Leukopenia (Safety Analysis Set) 
CT-8.9.11 
Incidence of TEAEs for Effect on Glucose (Safety Analysis Set) 
CT-8.9.12 
Incidence of TEAEs for Effect on Lipids (Safety Analysis Set) 
CT-8.9.13 
Incidence of TEAEs for Effect on Weight (Safety Analysis Set) 
CT-8.9.14 
Incidence of TEAEs for QT Prolongation (Safety Analysis Set) 
CT-8.9.15 
Incidence of TEAEs for Manic Switch (Safety Analysis Set) 
CT-8.9.16 
Incidence of TEAEs for Effect on Prolactin (Safety Analysis Set) 
CT-8.10.1 
Incidence of TEAEs by MedDRA System Organ Class and Preferred Term, by ADT 
(Safety Analysis Set) 
CT-8.10.2 
Incidence of TEAEs by MedDRA System Organ Class and Preferred Term, by Gender 
(Safety Analysis Set) 
CT-8.10.3 
Incidence of TEAEs by MedDRA System Organ Class and Preferred Term, by Impact of 
COVID-19 Pandemic (Safety Analysis Set) 
CT-9.1 
Listing of Deaths 
CT-9.2 
Listing of Serious Adverse Events 
CT-9.3 
Listing of Discontinuation of IMP due to Adverse Events 
CT-10.1.1 
Mean Change From Baseline in Clinical Laboratory Test Results - Serum Chemistry 
(Safety Analysis Set) 
CT-10.1.2 
Mean Change From Baseline in Clinical Laboratory Test Results - Hematology (Safety 
Analysis Set) 
CT-10.1.3 
Mean Change From Baseline in Clinical Laboratory Test Results - Urinalysis (Safety 
Analysis Set) 
CT-10.1.4 
Mean Change From Baseline in Clinical Laboratory Test Results - Prolactin, by Gender 
(Safety Analysis Set) 
CT-10.1.5 
Mean Change From Baseline in Clinical Laboratory Test Results - Other Tests (Safety 
Analysis Set) 
CT-10.2.1 
Shift Tables of Clinical Laboratory Test Results - Serum Chemistry (Safety Analysis 
Set) 
CT-10.2.2 
Shift Tables of Clinical Laboratory Test Results - Hematology (Safety Analysis Set) 
CT-10.2.3 
Shift Tables of Clinical Laboratory Test Results - Urinalysis1 (Safety Analysis Set) 
CT-10.2.4 
Shift Tables of Clinical Laboratory Test Results - Urinalysis2 (Safety Analysis Set) 
CT-10.2.5 
Shift Tables of Clinical Laboratory Test Results - Prolactin, by Gender (Safety Analysis 
Set) 
CT-10.2.6 
Shift Tables of Clinical Laboratory Test Results - Other Tests (Safety Analysis Set) 
CT-10.3.1 
Incidence of Laboratory Test Values With Potential Clinical Relevance (Safety Analysis 
Set) 
CT-10.3.2 
Listing of Laboratory Test Values With Potential Clinical Relevance by Subject (Safety 
Analysis Set) 
CT-10.4.1 
Potential Hy's Law Cases (Safety Analysis Set) 
CT-10.4.2 
Listing of Potential Hy's Law Cases (Safety Analysis Set) 


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CT-10.5.1 
Incidence of Laboratory Test Values With Potential Clinical Relevance - Prolactin 
(Safety Analysis Set) 
CT-10.5.2 
Listing of Laboratory Test Values With Potential Clinical Relevance - Prolactin (Safety 
Analysis Set) 
CT-10.6.1 
Incidence of Treatment-emergent Significant Change in Lipids (Safety Analysis Set) 
CT-10.6.2 
Listing of Treatment-emergent Significant Change in Lipids (Safety Analysis Set) 
CT-10.7.1 
Incidence of Treatment-emergent Significant Change in Glucose (Safety Analysis Set) 
CT-10.7.2 
Listing of Treatment-emergent Significant Change in Glucose (Safety Analysis Set) 
CT-10.8.1 
Incidence of Treatment-emergent Metabolic Syndrome (Safety Analysis Set) 
CT-10.8.2 
Listing of Treatment-emergent Metabolic Syndrome (Safety Analysis Set) 
CT-11.1 
Mean Change From Baseline in Vital Signs (Safety Analysis Set) 
CT-11.2 
Incidence of Potentially Clinically Relevant Abnormalities in Vital Signs (Safety 
Analysis Set) 
CT-11.3 
Listing of Potentially Clinically Relevant Abnormalities in Vital Signs (Safety Analysis 
Set) 
CT-11.4 
Summary of Mean Change From Baseline in Body Weight (kg) (Safety Analysis Set) 
CT-11.5 
Summary of Mean Change From Baseline in Waist Circumference (cm) (Safety 
Analysis Set) 
CT-11.6 
Summary of Mean Change From Baseline in BMI (kg/m^2) (Safety Analysis Set) 
CT-11.7 
Incidence of Potentially Clinically Relevant Weight Gain or Loss by Baseline BMI 
(Safety Analysis Set) 
CT-12.1 
Mean Change From Baseline in ECG Results (Safety Analysis Set) 
CT-12.2 
Shift Tables of ECG (Safety Analysis Set) 
CT-12.3 
Incidence of Categorical Changes in QT/QTc (Safety Analysis Set) 
CT-12.4 
Incidence of Potentially Clinically Relevant Abnormalities in ECG Evaluations (Safety 
Analysis Set) 
CT-12.5 
Listing of Potentially Clinically Relevant Abnormalities in ECG Evaluations (Safety 
Analysis Set) 
CT-13.1 
Summary of Mean Change From Baseline in DIEPSS (Safety Analysis Set) 
CT-13.2 
Summary of Mean Change From Baseline in AIMS Total Score and Item Scores 8, 9 
and 10 (Safety Analysis Set) 
CT-13.3 
Summary of Mean Change From Baseline in BARS, Global Clinical Assessment of 
Akathisia (Safety Analysis Set) 
CT-14.1 
C-SSRS, Suicidality (Safety Analysis Set) 
CT-14.2 
C-SSRS, Suicidal Behavior by Type (Safety Analysis Set) 
CT-14.3 
C-SSRS, Suicidal Ideation by Type (Safety Analysis Set) 
CT-14.4 
C-SSRS, Treatment Emergent Suicidal Behavior and Ideation (Safety Analysis Set) 
CT-14.5 
C-SSRS - Listing of Treatment-emergent Suicidal Ideation (Safety Analysis Set) 
CT-14.6 
C-SSRS - Listing of Treatment-emergent Suicidal Behavior (Safety Analysis Set) 
CT-14.7 
C-SSRS - Listing of Treatment-emergent Serious Ideation (Safety Analysis Set) 
CT-14.8 
C-SSRS - Listing of Worsening Suicidal Ideation (Safety Analysis Set) 
 
 
 


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Appendix 6 
List of Subject Data Listings 
 
AE-1 
Adverse Events (Subjects Assigned to Treatment) 
DEMOG-1  
Demographic Characteristics (Subjects Assigned to Treatment) 
DREAS-1 
Discontinued Subjects and Reason for Discontinuation (Subjects Assigned to 
Treatment) 
LAB-1 
Laboratory Test Results: Serum Chemistry (Subjects Assigned to Treatment) 
LAB-2 
Laboratory Test Results: Hematology (Subjects Assigned to Treatment) 
LAB-3  
Laboratory Test Results: Urinalysis (Subjects Assigned to Treatment) 
LAB-4 
Laboratory Test Results: Other Laboratory Tests (Subjects Assigned to Treatment) 
LAB-5  
Pregnancy Test (Subjects Assigned to Treatment) 
EFF-1 
Montgomery Åsberg Depression Rating Scale (MADRS) (Subjects Assigned to 
Treatment) 
EFF-2 
Clinical Global Impression - Severity of Illness (CGI-S) (Subjects Assigned to 
Treatment) 
EFF-3 
Clinical Global Impression - Improvement (CGI-I) (Subjects Assigned to Treatment) 
EFF-4 
Hamilton Depression Rating Scale (HAM-D) (Subjects Assigned to Treatment) 
EFF-5 
Sheehan Disability Scale (SDS) (Subjects Assigned to Treatment) 
EFF-6 
EuroQol-5 Dimension, 5 Response Level Version (Subjects Assigned to Treatment) 
PDATA-1.1 
Inclusion and Exclusion Criteria (Subjects Assigned to Treatment) 
PDATA-1.2 
Inclusion and Exclusion Criteria (Screening Failures) 
PDATA-2 
Treatment Assignment List (Subjects Assigned to Treatment) 
PDATA-3 
Study Completion Status and Reasons for Discontinuation (Subjects Assigned to 
Treatment) 
PDATA-4.1 
Prior and Concomitant Medications (Subjects Assigned to Treatment) 
PDATA-4.2 
Prior Medication for Current Major Depressive Episode (Antidepressant) (Subjects 
Assigned to Treatment) 
PDATA-4.3 
Prior and Concomitant Therapy (Subjects Assigned to Treatment) 
PDATA-4.4 
Prior Therapy for Current Major Depressive Episode (Psychotherapy/Somatic Therapy) 
(Subjects Assigned to Treatment) 
PDATA-5 
Medical History (Subjects Assigned to Treatment) 
PDATA-6 
Psychiatric Evaluation of Depression (Subjects Assigned to Treatment) 
PDATA-7 
Physical Examination (Subjects Assigned to Treatment) 
PDATA-8 
Vital Signs (Subjects Assigned to Treatment) 
PDATA-9 
Electrocardiogram Results (Subjects Assigned to Treatment) 
PDATA-10.1 
Columbia-Suicide Severity Rating Scale (C-SSRS) - Suicidal Ideation and Intensity 
(Subjects Assigned to Treatment)  
PDATA-10.2 
Columbia-Suicide Severity Rating Scale (C-SSRS) - Suicidal Behavior (Subjects 
Assigned to Treatment) 
PDATA-10.3 
Columbia-Suicide Severity Rating Scale (C-SSRS) - Actual Attempts (Subjects 
Assigned to Treatment) 
PDATA-11 
Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS) (Subjects Assigned to 
Treatment) 
PDATA-12 
Barnes Akathisia Rating Scale (BARS) (Subjects Assigned to Treatment) 
PDATA-13 
Abnormal Involuntary Movement Scale (AIMS) (Subjects Assigned to Treatment) 
PDATA-16 
Blood Draw Time for DNA Storage (Subjects Assigned to Treatment) 
PDATA-17 
Post-treatment Follow-up (Subjects Assigned to Treatment) 
PDATA-18 
Screening Failures 


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PDEV-1 
Major Protocol Deviations by Type of Deviation (Subjects Assigned to Treatment)  
SMED-1.1 
Study Medication Administration (Subjects Assigned to Treatment) 
SMED-1.2 
Study Medication Administration - Antidepressant (Subjects Assigned to Treatment) 
SMED-2 
Study Medication Compliance (Subjects Assigned to Treatment) 
SUBEX-1 
Subjects Excluded From Analysis Set (Subjects Assigned to Treatment)