Clinical trial NCT03620981
Conditions: Agitation Associated With Dementia of the Alzheimer's Type
Sponsor: Otsuka Pharmaceutical Co., Ltd.
Start date: 2018-08-20; Completion date: 2023-05-15
Enrollment: 410 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To evaluate the superiority of brexpiprazole 1 mg or 2 mg over placebo after a 10-week treatment regimen for agitation associated with dementia of the Alzheimer's type in patients who require medication, and to investigate the safety of brexpiprazole and identify the optimum dose.

Detailed description:

Arms: arm 1: Drug: 1mg/day Once daily for 10 weeks arm 2: Drug: 2mg/day Once daily for 10 weeks arm 3: Drug: Placebo (0mg/day) Once daily for 10 weeks
Interventions: intervention 1: Brexpiprazole intervention 2: Placebo
Intervention descriptions: intervention 1: Drug: 1 tablet /day Once daily for 10 weeks intervention 2: Placebo: 1 tablet /day Once daily for 10 weeks

Protocol documents:
Prot_000.pdf: 
 
 
CLINICAL STUDY PROTOCOL 
 
 
 
A multicenter, randomized, double-blind, placebo-controlled, parallel-group comparison trial to 
evaluate the efficacy and safety of brexpiprazole (OPC-34712) in the treatment of patients with 
agitation associated with dementia of the Alzheimer’s type 
 
 
 
 
NCT Number: NCT03620981 
Protocol No. 331-102-00088 
Version Date: 24 Nov 2022 (Version 6.0) 


Protocol 331-102-00088 
Confidential - Proprietary Information 
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Protocol Version 6.0, 24 Nov 2022 
Otsuka Pharmaceutical Co., Ltd. 
 
Investigational Medicinal Product 
Brexpiprazole (OPC-34712) 
 
CLINICAL PROTOCOL 
 
A multicenter, randomized, double-blind, placebo-controlled, parallel-group comparison 
trial to evaluate the efficacy and safety of brexpiprazole (OPC-34712) in the treatment of 
patients with agitation associated with dementia of the Alzheimer’s type 
 
Protocol No. 331-102-00088 
 
CONFIDENTIAL – PROPRIETARY INFORMATION 
 
Clinical Development Phase:  
2/3 
Sponsor: 
Otsuka Pharmaceutical Co., Ltd. 
Immediately Reportable Event: 
 
 
 
 
 
 
Issue Date: 
29 May 2018 
Date of Amendment 1: 
24 Aug 2018 
Date of Amendment 2: 
05 Mar 2020 
Date of Amendment 3: 
03 Feb 2021 
Date of Amendment 4: 
27 Apr 2022 
Date of Amendment 5: 
24 Nov 2022 
Version No.: 
6.0 
 
(Date of Translation: 
12 Jan 2023) 


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Protocol Synopsis 
Name of Sponsor: Otsuka Pharmaceutical 
Co., Ltd. 
Name of Investigational Medicinal Product: 
Brexpiprazole (OPC-34712) 
Protocol No.: 331-102-00088 
 
Protocol title: 
A multicenter, randomized, double-blind, placebo-controlled, 
parallel-group comparison trial to evaluate the efficacy and safety of 
brexpiprazole (OPC-34712) in the treatment of patients with 
agitation associated with dementia of the Alzheimer’s type 
Clinical phase/ 
type of trial: 
Phase 2/3 
Confirmatory study 
Treatment 
indication: 
Agitation associated with dementia of the Alzheimer’s type 
Objectives: 
To evaluate the superiority of brexpiprazole 1 or 2 mg over placebo 
after a 10-week treatment regimen for agitation associated with 
dementia of the Alzheimer’s type in patients who require medication, 
to investigate the safety of brexpiprazole, and to identify the 
optimum dose of brexpiprazole 
Trial design: 
Multicenter, randomized, double-blind, placebo-controlled, parallel-
group comparison 
Subject 
population: 
A total of 407 male or female patients aged ≥ 55 to ≤ 90 years old 
with a diagnosis of dementia of the Alzheimer’s type according to 
the Diagnostic and Statistical Manual of Mental Disorders Fifth 
Edition (DSM-5) and the National Institute of Neurological and 
Communicative Disorders and Stroke–Alzheimer’s Disease and 
Related Disorders Association (NINCDS-ADRDA) who require 
medication, who have symptoms of agitation that have persisted or 
shown frequent recurrence during each 2-week period before the 
screening examination and baseline evaluation, respectively, and 
whose condition can be observed by a caregiver in at least 4 days per 
week for 4 hours or more a day 
Inclusion/exclusi
on criteria: 
The main inclusion criteria are as follows: 
• Patients who meet both of the following diagnostic criteria: 
− Diagnosis of “Dementia due to Alzheimer’s Disease” 
according to DSM-5. 
− Diagnosis of “Probable Alzheimer’s Disease” according to 
NINCDS-ADRDA. 
• Patients who are ≥ 55 and ≤ 90 years of age at the time of 
obtaining informed consent. 
• Patients who can be followed in the same environment (as 
described below) from at least 3 weeks before baseline evaluation 
up to the completion of the examinations scheduled at the 
completion or discontinuation of investigational medicinal 
product (IMP) administration 


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− Patients who will be hospitalized in the same medical facility. 
− Patients who will be institutionalized in the same care facility. 
− Patients who will continue to receive care at home. 
For patients receiving day care or day service, those patients 
who will visit the same care facility at the same frequency 
during the above-mentioned period will be included. 
• Patients whose caregiver can properly collect the necessary 
information (the main caregiver must observe the patient’s 
condition in at least 4 days per week for 4 hours or more a day). 
Patients receiving home care must live with a specific caregiver 
and must not live alone. 
• Patients who have agitation that interferes with daily activities 
and is persistent/recurs frequently during the 2 weeks each before 
the screening examination and baseline evaluation. Agitation is 
defined according to the “Consensus provisional definition of 
agitation in cognitive disorders” from the International 
Psychogeriatric Association (IPA).a 
• Patients who have shown verbal aggression or physical 
aggression for 3 times or more during the 2 weeks before 
baseline evaluation. Examples of verbal aggression and physical 
aggression include the following symptoms in the “Consensus 
provisional definition of agitation in cognitive disorders” of IPA.a 
− Verbal aggression: yelling, speaking in an excessively loud 
voice, using profanity, screaming, shouting, etc. 
− Physical aggression: grabbing, shoving, pushing, resisting, 
hitting others, kicking objects or people, scratching, biting, 
throwing objects, self-hitting, slamming doors, tearing things, 
destroying property, etc. 
The main exclusion criteria are as follows: 
• Patients who have dementia or memory impairment other than 
dementia of the Alzheimer’s type, such as the following: 
Frontotemporal dementia, Lewy body dementia, vascular 
dementia, dementia secondary to head trauma, substance-induced 
persistent dementia, dementia due to human immunodeficiency 
virus infection, dementia due to prion disease, dementia due to 
Parkinson’s disease (including Parkinsonian diseases such as 
progressive supranuclear palsy and basal ganglion degeneration), 
dementia due to Huntington’s disease, dementia due to other 
general medical conditions (eg, subdural hematoma, normal 
pressure hydrocephalus, brain tumor, endocrine disorders, 
 
a Cummings J, Mintzer J, Brodaty H, Sano M, Banerjee S, Devanand DP, et al. Agitation in cognitive 
disorders: International Psychogeriatric Association provisional consensus clinical and research definition. 
International Psychogeriatrics. 2015;27:7–17. 


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nutritional disorders, or infections), dementia due to multiple 
diseases, and dementia not otherwise specified. 
• Patients diagnosed with delirium between 30 days before the 
screening examination and baseline evaluation according to 
DSM-5. 
• Patients diagnosed with any of the following disorders according 
to DSM-5: 
− Schizophrenia spectrum and other psychotic disorders 
− Bipolar and related disorders 
− Major depressive disorder 
However, patients who have major depressive disorder but 
whose condition is stable and asymptomatic within 30 days 
before the screening examination may be included. In regard 
to patients whose condition has been stabilized by 
medication, it should be noted that the use of antidepressants 
is prohibited from 7 days before baseline evaluation up to the 
completion of the examinations scheduled at the completion 
or discontinuation of IMP administration. 
Trial sites: 
Approximately 120 sites in Japan 
Investigational 
medicinal 
products, dose, 
dosage regimen, 
treatment period, 
formulation, 
mode of 
administration: 
The IMP will be administered orally as one tablet once a day for 10 
weeks. The doses of brexpiprazole for each group are as follows: 
Group 
Day 1–7 
Day 8–14 
Day 15–70 
Brexpiprazole 2 mg group 
0.5 mg 
1 mg 
2 mg 
Brexpiprazole 1 mg group 
0.5 mg 
1 mg 
1 mg 
Placebo group 
0 mg 
0 mg 
0 mg 
The dose will be increased to 1 mg after evaluation at Week 1 (Day 8) and to 2 
mg after evaluation at Week 2 (Day 15). 
Trial 
assessments: 
Efficacy: Cohen-Mansfield Agitation Inventory (CMAI), 
Clinical Global Impression–Severity of 
Illness (CGI-S), and CGI-Global Improvement (CGI-I) 
Safety: Adverse events, laboratory tests, 12-lead electrocardiogram, 
vital signs, body weight, physical examination, pregnancy test, Drug-
Induced Extrapyramidal Symptoms Scale, Abnormal Involuntary 
Movement Scale, Barnes Akathisia Rating Scale, and Sheehan 
Suicidality Tracking Scale 
Pharmacokinetics: Blood sampling for the measurement of the 
plasma drug concentration 
Screening and other tests: Mini-Mental State Examination, height, 
medications and therapies, blood sampling for the evaluation of 
pharmacogenomics, blood sampling for DNA storage, blood 
sampling for biomarker exploration samples storage, Alzheimer’s 
Disease Cooperative Study–Activities of Daily Living, and EuroQol 
5-dimension 5-level health questionnaire 


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Criteria for 
evaluation 
Primary endpoint:  
Change in CMAI total score from baseline to Week 10 
Secondary endpoints: 
• Changes in CMAI subscales (Aggressive Behavior, Physically 
Non-aggressive Behavior, and CMAI Verbally Agitated 
Behavior) from baseline to Week 10 
• Change in CGI-S from baseline to Week 10 
• CGI-I at Week 10 
Statistical 
methods: 
Primary endpoint: 
The primary analysis will be conducted on the full analysis set by 
using mixed models for repeated measures analysis on the basis of 
the observed cases data set. For the analysis model, the treatment 
group (brexpiprazole 1 mg group, brexpiprazole 2 mg group, or 
placebo group), time point (Weeks 2, 4, 6, 8, or 10), medical care 
category (hospitalized or outpatient), prior use of antipsychotics (yes 
or no), and interaction between treatment group and time point will 
be included as factors, the baseline and interaction between the 
baseline and time point will be included as covariates, and the error 
variance and covariance structure will be unstructured. The 
Kenward–Roger method will be used to determine the degrees of 
freedom. 
Between-group comparison will be performed by calculating the 
difference of the least squares mean between each of the 
brexpiprazole groups and the placebo group at Week 10. The fixed 
sequence procedure will be used to adjust the multiplicity of testing 
due to the performance of two comparisons (ie, the brexpiprazole 1 
mg group versus the placebo group and the brexpiprazole 2 mg group 
versus the placebo group) to control the overall type I error rate. 
Initially, the brexpiprazole 2 mg group will be compared with the 
placebo group. Only if the difference is statistically significant at a 
significance level of 5% (two sided), the brexpiprazole 1 mg group 
will be compared with the placebo group at a significance level of 
5% (two sided). 
The least squares mean for each treatment group and the difference 
of the least squares mean between each brexpiprazole group and the 
placebo group, as well as their two-sided 95% confidence intervals, 
will be calculated at each time point. 
Rationale for setting the target sample size: 
In Trial 331-12-283, which was performed outside Japan, the 2 mg 
fixed-dose group showed superiority over the placebo group in 
patients with aggressive behavior at baseline, thus suggesting that it 
may also be the optimum dose for Japanese patients. Efficacy was 
not observed in the 1 mg fixed-dose group, but in Trial 331-12-284, 
the efficacy of a dose less than 2 mg was suggested by the results 


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obtained in patients from the flexible-dose (0.5 to 2 mg) group, who 
had aggressive behavior at baseline. 
In this trial, a power of detection ≥ 80% will be achieved for 
comparison between the placebo group and the 1 mg group to allow 
evaluation of superiority over the placebo group if equivalent 
efficacy is demonstrated in the 1 and 2 mg groups. For comparison 
between the 2 mg group (possible optimum dose) and the placebo 
group, a more sufficient power of detection will be obtained by 
changing the randomization ratio. In this trial, it is assumed that the 
difference between the 2 mg group and the placebo group in the 
change in the CMAI total score from baseline to Week 10 is −5.35, 
and the standard deviation (calculated from the standard error of the 
difference between the 2 mg and placebo groups and the number of 
subjects at baseline) is 15.06 on the basis of the results of Trial 331-
12-283. By setting the number of subjects in the 2 mg group, 1 mg 
group, and placebo group as 148, 111, and 148, respectively 
(randomization ratio of 4:3:4), the power of detection is 86.1% for 
the comparison between the 2 mg group and the placebo group and is 
80.5% for the comparison between the 1 mg group and the placebo 
group in a test with a significance level of 5% (two sided). 
On the basis of the above considerations, the number of subjects will 
be set at 148 in the 2 mg group, 111 in the 1 mg group, and 148 in 
the placebo group (randomization ratio of 4:3:4). 
Trial duration: 
August 2018 to June 2023 (planned) 
The duration of participation in the trial by each subject will be up to 
20 weeks. 


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Table of Contents 
Protocol Synopsis ........................................................................................... 2 
Table of Contents ........................................................................................... 7 
List of In-text Tables ................................................................................... 13 
List of In-text Figures .................................................................................. 14 
List of Appendices........................................................................................ 15 
List of Abbreviations and Definitions of Terms ....................................... 16 
1 
Introduction .......................................................................................................18 
1.1 
Background .....................................................................................................18 
1.2 
Nonclinical Data .............................................................................................20 
1.3 
Clinical Data ...................................................................................................21 
1.3.1 
 
 .............................................................21 
1.3.1.1 
 .........................................................................................21 
1.3.1.2 
 .......................................................................................23 
1.3.1.3 
 ......................................................................................25 
1.4 
Known and Potential Risks and Benefits ........................................................26 
2 
Trial Rationale and Objectives ..........................................................................27 
2.1 
Trial Rationale ................................................................................................27 
2.2 
Rationale for CYP2D6 Genetic Testing and DNA Storage ............................28 
2.3 
Rationale of Sample Storage for Biomarker Exploration ...............................29 
2.4 
Trial Objectives ..............................................................................................30 
3 
Trial Design .......................................................................................................30 
3.1 
Type/Design of Trial .......................................................................................30 
3.2 
Trial Treatments ..............................................................................................32 
3.2.1 
Dosing and Regimen ...................................................................................32 
3.2.2 
Rationale for Dosing and Regimen .............................................................32 
3.2.3 
Rationale for Duration of Treatment ...........................................................34 
3.3 
Trial Population ..............................................................................................34 
3.3.1 
Number of Subjects and Trial Population ...................................................34 
3.3.2 
Subject Number Assignment ......................................................................34 
3.4 
Eligibility Criteria ...........................................................................................35 


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3.4.1 
Informed Consent ........................................................................................35 
3.4.2 
Inclusion Criteria .........................................................................................36 
3.4.3 
Exclusion Criteria........................................................................................38 
3.5 
Requirements for Caregivers ..........................................................................41 
3.6 
Endpoints ........................................................................................................42 
3.6.1 
Primary Endpoint ........................................................................................42 
3.6.2 
Secondary Endpoints ...................................................................................42 
3.6.3 
Exploratory Endpoints ................................................................................42 
3.6.4 
Safety Endpoints .........................................................................................42 
3.6.5 
Pharmacokinetic Endpoint ..........................................................................43 
3.6.6 
Pharmacogenomic Endpoint .......................................................................43 
3.6.7 
Other Endpoints ..........................................................................................43 
3.7 
Measures to Minimize/Avoid Bias .................................................................43 
3.8 
Trial Procedures ..............................................................................................45 
3.8.1 
Schedule of Assessments ............................................................................47 
3.8.1.1 
Screening Period ......................................................................................47 
3.8.1.2 
Day of Baseline Examination ..................................................................49 
3.8.1.3 
Randomization .........................................................................................49 
3.8.1.4 
Seven Days After Administration (Week 1, Day 8) to Seventy 
Days After Administration (Week 10, Day 71) .......................................50 
3.8.1.5 
Examination at Discontinuation ..............................................................50 
3.8.1.6 
Follow-up Observation (Twenty-eight Days After Completion or 
Discontinuation of IMP Administration) .................................................50 
3.8.2 
Efficacy Assessments ..................................................................................50 
3.8.2.1 
Cohen-Mansfield Agitation Inventory ....................................................51 
3.8.2.2 
Clinical Global Impression–Severity of Illness .......................................51 
3.8.2.3 
Clinical Global Impression–Global Improvement ..................................51 
3.8.2.4 
 ..........................................................................................51 
3.8.2.5 
 ...................................................................52 
3.8.3 
Safety Assessments .....................................................................................52 
3.8.3.1 
Adverse Events ........................................................................................52 


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3.8.3.2 
Clinical Laboratory Assessments ............................................................52 
3.8.3.3 
Physical Examination ..............................................................................54 
3.8.3.4 
Vital Signs (Blood Pressure and Pulse Rate) ..........................................54 
3.8.3.5 
Height and Body Weight .........................................................................54 
3.8.3.6 
Twelve-lead Electrocardiography ...........................................................54 
3.8.3.7 
Pregnancy Test ........................................................................................55 
3.8.3.8 
Other Safety Assessments .......................................................................56 
3.8.3.8.1 
Drug-induced Extrapyramidal Symptoms Scale ..................................56 
3.8.3.8.2 
Abnormal Involuntary Movement Scale ..............................................56 
3.8.3.8.3 
Barnes Akathisia Rating Scale .............................................................56 
3.8.3.8.4 
Sheehan Suicidality Tracking Scale .....................................................56 
3.8.4 
Pharmacokinetic Assessment, Pharmacogenomic Assessment, and 
Biomarker Exploration ................................................................................56 
3.8.4.1 
Pharmacokinetic Assessment ..................................................................57 
3.8.4.2 
Pharmacogenomic Assessment ...............................................................57 
3.8.4.2.1 
CYP2D6 Genetic Testing ....................................................................57 
3.8.4.2.2 
DNA Storage ........................................................................................58 
3.8.4.3 
Storage of Samples for Biomarker Exploration ......................................60 
3.8.5 
Other Endpoints ..........................................................................................62 
3.8.5.1 
Alzheimer's Disease Cooperative Study–Activities of Daily Living ......62 
3.8.5.2 
Mini-Mental State Examination ..............................................................62 
3.8.5.3 
EuroQol 5-Dimension 5-Level Health Questionnaire .............................63 
3.8.6 
Medications and Therapies .........................................................................63 
3.8.7 
End of Trial .................................................................................................63 
3.8.8 
Independent Data Monitoring Committee ..................................................64 
3.8.9 
Raters ..........................................................................................................64 
3.9 
Stopping Rules, Withdrawal Criteria, and Procedures ...................................65 
3.9.1 
Entire Trial ..................................................................................................65 
3.9.2 
Individual Site .............................................................................................65 
3.9.3 
Individual Subject Discontinuation .............................................................65 
3.9.3.1 
Treatment Discontinuation ......................................................................65 
3.9.3.2 
Documenting Reasons for Discontinuation .............................................66 
3.9.3.3 
Withdrawal of Consent ............................................................................67 


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3.9.3.4 
Procedures to Encourage Continued Trial Participation .........................68 
3.10 
Screen Failures ................................................................................................68 
3.11 
Definition of Completed Subjects ..................................................................69 
3.12 
Definition of Subjects Lost to Follow-up .......................................................69 
3.13 
Subject Compliance ........................................................................................69 
3.14 
Protocol Deviations ........................................................................................70 
4 
Restrictions ........................................................................................................70 
4.1 
Prohibited Medications ...................................................................................70 
4.2 
Restricted Medications ...................................................................................71 
4.3 
Restricted Therapies .......................................................................................72 
4.4 
Other Restrictions ...........................................................................................73 
5 
Reporting of Adverse Events ............................................................................73 
5.1 
Definitions ......................................................................................................73 
5.2 
Eliciting and Reporting Adverse Events .........................................................75 
5.3 
Immediately Reportable Events ......................................................................75 
5.4 
Potential Drug-induced Liver Injury ..............................................................76 
5.5 
Pregnancy .......................................................................................................76 
5.6 
Procedure for Breaking the Blind ...................................................................78 
5.7 
Follow-up of Adverse Events .........................................................................78 
5.7.1 
Follow-up of Nonserious Adverse Events ..................................................78 
5.7.2 
Follow-up of Serious Adverse Events and Immediately Reportable 
Events ..........................................................................................................78 
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) ...........................................................................................79 
6 
Statistical Analysis ............................................................................................79 
6.1 
Determination of Sample Size ........................................................................79 
6.2 
Datasets for Analysis ......................................................................................80 
6.2.1 
Pharmacokinetic Analysis Set .....................................................................80 
6.2.2 
Full Analysis Set .........................................................................................80 
6.2.3 
Safety Analysis Set .....................................................................................80 
6.3 
Handling of Missing Data ...............................................................................80 
6.4 
Primary and Secondary Endpoint Analyses ...................................................81 


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6.4.1 
Primary Endpoint Analyses.........................................................................81 
6.4.2 
Secondary Endpoint Analyses.....................................................................81 
6.4.3 
Exploratory Endpoint Analyses ..................................................................82 
6.4.4 
Interim Analysis ..........................................................................................82 
6.4.5 
Subgroup Analyses .....................................................................................82 
6.5 
Analysis of Demographic and Baseline Characteristics .................................83 
6.6 
Safety Analysis ...............................................................................................83 
6.6.1 
Adverse Events ...........................................................................................83 
6.6.2 
Clinical Laboratory Data .............................................................................84 
6.6.3 
Physical Examination and Vital Signs Data ...............................................84 
6.6.4 
Electrocardiogram Data ..............................................................................84 
6.6.5 
Other Safety Data ........................................................................................85 
6.6.5.1 
Body Weight and Body Mass Index ........................................................85 
6.6.5.2 
DIEPSS, AIMS, and BARS .....................................................................85 
6.6.5.3 
S-STS .......................................................................................................85 
6.7 
Analysis of Pharmacokinetic Endpoints .........................................................86 
6.8 
Analysis of Pharmacogenomic Endpoints ......................................................86 
6.9 
Genomic/Genetic Analysis .............................................................................86 
6.10 
Biomarker Exploration Analysis ....................................................................86 
6.11 
Analysis of Other Endpoints ...........................................................................86 
7 
Management of Investigational Medicinal Product ..........................................87 
7.1 
Packaging and Labeling ..................................................................................87 
7.2 
Storage ............................................................................................................87 
7.3 
Accountability .................................................................................................87 
7.4 
Returns and Destruction .................................................................................87 
7.5 
Reporting of Product Quality Complaints ......................................................87 
7.5.1 
Eliciting and Reporting Product Quality Complaints .................................88 
7.5.2 
Information Required for Reporting Product Quality Complaints .............88 
7.5.3 
Return Process for Product Quality Complaints .........................................88 
7.5.4 
Assessment/Evaluation ...............................................................................89 
8 
Records Management ........................................................................................89 
8.1 
Source Documents ..........................................................................................89 
8.2 
Data Collection ...............................................................................................89 


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8.3 
File Management at the Trial Site ..................................................................90 
8.4 
Record Retention at the Trial Site ..................................................................90 
9 
Quality Control and Quality Assurance ............................................................91 
9.1 
Monitoring ......................................................................................................91 
9.2 
Auditing ..........................................................................................................91 
10 
Ethics and Responsibility ..................................................................................91 
11 
Confidentiality ...................................................................................................91 
12 
Amendment Policy ............................................................................................92 
13 
Publication Authorship Requirements ...............................................................92 
14 
References .........................................................................................................93 
 


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List of In-text Tables 
Table 1.3.1.1-1 
 ........................................... 21 
Table 1.3.1.2-1 
 ............................... 23 
Table 1.3.1.2-2 
 ........................... 24 
Table 3.2.1-1 
Doses of IMPs ............................................................................... 32 
Table 3.4.2-1 
Inclusion Criteria .......................................................................... 36 
Table 3.4.3-1 
Exclusion Criteria ......................................................................... 38 
Table 3.8-1 
Schedule of Assessments .............................................................. 45 
Table 3.8-2 
Allowable Time Windows for Evaluations, Tests, and 
Observations ................................................................................. 47 
Table 3.8.3.2-1 
Clinical Laboratory Assessments .................................................. 53 
Table 3.8.9-1 
Raters of Evaluation Scales .......................................................... 65 
Table 4.1-1 
Prohibited Medications ................................................................. 70 
Table 4.1-2 
Prohibited Concomitant CYP2D6 Inhibitors, CYP3A4 
Inhibitors, and CYP3A4 Inducers (Except for External Use) ....... 71 
Table 4.2-1 
Restricted Medications.................................................................. 71 
 
 


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List of In-text Figures 
Figure 3.1-1 
Trial Design .................................................................................. 32 
 
 


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List of Appendices 
Appendix 1 
 ........................ 96 
Appendix 2 
 .......................................................... 99 
Appendix 3 
Protocol Amendments/Administrative Changes ......................... 103 
 
 


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List of Abbreviations and Definitions of Terms 
Abbreviation 
Definition 
5-HT 
5-Hydroxytryptamine 
5-HT1A 
5-Hydroxytryptamine 1A  
5-HT2A 
5-Hydroxytryptamine 2A 
ADCS-ADL 
Alzheimer’s Disease Cooperative Study–Activities of Daily Living 
AIMS 
Abnormal Involuntary Movement Scale  
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance  
APTT 
Activated partial thromboplastin time  
AST 
Aspartate aminotransferase 
BARS 
Barnes Akathisia Rating Scale  
BMI 
Body mass index  
BPSD 
Behavioral and Psychological Symptoms of Dementia  
BUN 
Blood urea nitrogen  
CGI-I 
Clinical Global Impression–Global Improvement 
CGI-S 
Clinical Global Impression–Severity of Illness 
CMAI 
Cohen-Mansfield Agitation Inventory 
CMH 
Cochran Mantel Haenszel  
CPK 
Creatine phosphokinase 
CYP 
Cytochrome P450 
D2 
Dopamine D2 
DBP 
Diastolic blood pressure 
DIEPSS 
Drug-Induced Extrapyramidal Symptoms Scale  
DNA 
Deoxyribonucleic acid 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders Fifth Edition 
EDTA 
Ethylenediaminetetraacetic acid 
EQ-5D-5L 
EuroQol 5-dimension 5-level health questionnaire 
FAS 
Full analysis set  
FT4 
Free thyroxine  
GCP 
Good Clinical Practice  
HbA1c 
Glycosylated hemoglobin 
HBsAg 
Hepatitis B surface antigen  
HCG 
Human chorionic gonadotropin  
HCV Ab 
Hepatitis C virus antibodies  
HDL 
High-density lipoprotein  
HIV 
Human immunodeficiency virus  
IB 
Investigator brochure 
ICH 
The International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
ICMJE 
International Committee of Medical Journal Editors  
IDMC 
Independent data monitoring committee 
INR 
International normalized ratio  
IPA 
International Psychogeriatric Association  
IRB 
Institutional review board  


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Abbreviation 
Definition 
IRE 
Immediately reportable event 
IUD 
Intrauterine device  
IWRS 
Interactive web response system  
LDH 
Lactate (lactic acid) dehydrogenase  
LDL 
Low-density lipoprotein 
LOCF 
Last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities  
MMRM 
Mixed models for repeated measures  
MMSE 
Mini-Mental State Examination  
NGSP 
The National Glycohemoglobin Standardization Program 
NINCDS-ADRDA 
National Institute of Neurological and Communicative Disorders and Stroke–
Alzheimer’s Disease and Related Disorders Association 
 
 
 
 
 
 
 
 
 
 
 
 
OC 
Observed cases  
PQC 
Product quality complaint 
PT 
Prothrombin time  
PV 
Pharmacovigilance  
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 
SBP 
Systolic blood pressure 
S-STS 
Sheehan Suicidality Tracking Scale 
TEAE 
Treatment-emergent adverse event 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal  
WOCBP 
Women of childbearing potential 
γ-GTP 
γ-glutamyl transpeptidase 
 


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1 
Introduction 
1.1 
Background 
Due to a recent increase in the elderly population, the number of patients with dementia is 
increasing. According to the Ministry of Health, Labour and Welfare (MHLW), Japanese 
patients with dementia account for 10% (approximately 2.42 million people) of the 
population aged ≥ 65 years, and the number is estimated to increase to 3.25 million 
people by 2020.1 A recent epidemiology study showed that dementia of the Alzheimer’s 
type is the most common form of dementia.1 
Symptoms of dementia of the Alzheimer’s type are categorized into core symptoms such 
as memory impairment and impaired cognitive function and peripheral symptoms.2 
Peripheral symptoms are referred to as the behavioral and psychological symptoms of 
dementia (BPSD) or neuropsychiatric symptoms, and agitation is included in peripheral 
symptoms.3,4 According to the definition given by the International Psychogeriatric 
Association (IPA) Working Group, agitation is a state in which the patient exhibits at 
least one of the symptoms of excessive motor activity, verbal aggression, and physical 
aggression, is not attributable solely to another psychiatric disorder or living 
environment, and causes impairment in the ability to perform or participate in daily living 
activities, other aspects of social functioning, or interpersonal relationships.5 About 40% 
to 80% of patients with dementia of the Alzheimer’s type present with agitation.6,7 
Agitation has been reported to be related to cognitive decline,8 decline in activities9 and 
function8 of daily living, progression to severe dementia of the Alzheimer’s type,10 and 
death.10 Moreover, agitation has been reported to be related to the burden imposed on 
caregivers,11,12 increases in care time and observation time,13 early admission to a care 
facility,8,14,15 and increased healthcare costs,16 this being an issue for patients, caregivers, 
and medical resources. 
The Practice Guideline for Dementia 2017 instructs as follows for agitation: “Person-
centered-care is the basis. The reason(s) and cause(s) of symptoms should be considered 
and measures to resolve them should be sought. Another effective approach is for 
caregivers to learn appropriate skills for conversing with patients with dementia and to 
exercise these skills. As nonmedication therapies, the efficacy of group activities, music 
therapy, tactile care, and massage has been demonstrated, and use of these therapies 
should also be considered” and “if the patient does not respond adequately to 
nonmedication therapies, medication should be considered.”17 This clearly implies that if 


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agitation does not respond adequately to nonmedication therapies, medication needs to be 
considered. While the guideline states that “medication should be introduced only after 
sufficient efforts have been made to reduce BPSD with nonmedication therapies,” it lists 
“aggression that endangers self or others” as one of the “exceptions to preferentially 
introduce medication.”18 According to the guideline, immediate consideration of 
medication cannot be avoided in some patients with aggressive agitation associated with 
dementia of the Alzheimer’s type. 
However, in Japan there are no drugs indicated for agitation and all drugs are 
administered as off-label use. Although it is off-label use, the Practice Guideline for 
Dementia 2017 states the following regarding medication: “The efficacy of atypical 
antipsychotics such as risperidone and aripiprazole has been demonstrated. Use of 
Yokukansan, tiapride, carbamazepine, sertraline, escitalopram and trazodone should also 
be considered.”17 The results of a meta-analysis of dementia patients in clinical trials of 
atypical antipsychotics, for which efficacy has been demonstrated according to the 
guideline, showed a mortality rate 1.54-fold higher in the atypical antipsychotic group 
compared with the rate in the placebo group,19 showing a risk of death. These findings 
show that sufficient evidence is lacking for all medications indicated for agitation and the 
use of atypical antipsychotics needs to be considered despite the reported safety risk. Due 
to these circumstances, there are unmet needs for a drug-based approach to the treatment 
of agitation. 
 


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On the basis of these background factors, Otsuka considered that the development of 
brexpiprazole could make a significant contribution to the treatment of agitation 
associated with dementia of the Alzheimer’s type and accordingly planned this clinical 
trial. 
1.2 
Nonclinical Data 
 
 
 


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1.3 
Clinical Data 
1.3.1 
 
1.3.1.1 
 
 
 
Table 1.3.1.1-1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 1.3.1.1-1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.3.1.2 
 
 
 
 
 
Table 1.3.1.2-1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 


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Table 1.3.1.2-2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.3.1.3 
 
 
 
 
 
 
 
 


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. 
1.4 
Known and Potential Risks and Benefits 
 
 


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2 
Trial Rationale and Objectives 
2.1 
Trial Rationale 
It is considered that neurotransmitters such as serotonin, dopamine and noradrenaline are 
involved in agitation. Brexpiprazole, which regulates the serotonin-dopaminergic system, 
is expected to improve agitation in patients with dementia of the Alzheimer’s type while 
suppressing expression of extrapyramidal symptoms. 
Based on the results of the 2 overseas confirmatory trials in agitation associated with 
dementia of the Alzheimer's type (Trial 331-12-283 and Trial 331-12-284), and because 


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the PK of brexpiprazole is not affected by ethnicity, it is considered that brexpiprazole 
will also show efficacy in Japanese patients with agitation associated with dementia of 
the Alzheimer's type. 
In the overall population of Trial 331-12-284, no statistically significant differences were 
noted in the flexible-dose brexpiprazole group compared with the placebo group, but the 
results of an additional analysis showed the efficacy of brexpiprazole in patients with 
aggression. 
On the basis of these findings, a multicenter, placebo-controlled, randomized, double-
blind, parallel-group comparison trial to verify the superiority of brexpiprazole over 
placebo, evaluate the safety of brexpiprazole, and confirm an optimal dose in Japanese 
patients with aggression in agitation associated with dementia of the Alzheimer’s type 
was planned. The doses of brexpiprazole were determined with reference to the data of 
the 2 overseas trials, and two doses were selected: a dose of 2 mg, which showed a 
statistically significant improvement compared with the placebo group in Trial 331-12-
283 and might be an optimal dose in Japanese patients, and a dose of 1 mg to obtain the 
dose-response relationship in Japanese patients. Duration of treatment was set to 10 
weeks. 
Furthermore, on the basis of the report19 of the risk of death associated with atypical 
antipsychotics, criteria to exclude patients at high risk of cerebrovascular disorder, 
cardiac disorder, pneumonia, and other infections, which were the causes of death 
associated with atypical antipsychotics, were established to minimize the risk to subjects 
during the trial and an Independent Data Monitoring Committee (IDMC) was established 
to monitor safety during the trial, as measures to ensure subject safety. 
Since there are no drugs indicated for “agitation associated with dementia of the 
Alzheimer’s type” in Japan, obtaining marketing approval for the indication through this 
trial would contribute to medical practice by providing another therapeutic option. 
On the basis of what has been described above, the conduct of this trial was judged to be 
scientifically and ethically justifiable. 
2.2 
Rationale for CYP2D6 Genetic Testing and DNA Storage 
The metabolism of brexpiprazole was shown to be mainly mediated by CYP3A4 and 
CYP2D6 according to in vitro metabolism studies, and CYP2D6 is known to have 
multiple genotypes with different enzyme activities. It has been clarified that CYP2D6 
genotypes affect the pharmacokinetics of brexpiprazole. Therefore, the examination of 
CYP2D6 genotypes will be performed in this trial to investigate the influence of 
CYP2D6 genotypes on the safety and efficacy of brexpiprazole, 


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2.3 
Rationale of Sample Storage for Biomarker Exploration 


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2.4 
Trial Objectives 
The objective of the trial is to evaluate the superiority of brexpiprazole 1 or 2 mg over 
placebo after a 10-week treatment regimen for agitation associated with dementia of the 
Alzheimer’s type in patients who require medication, to investigate the safety of 
brexpiprazole, and to identify the optimum dose. 
3 
Trial Design 
3.1 
Type/Design of Trial 
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group 
comparison trial to evaluate the efficacy and safety of brexpiprazole in patients with 
agitation associated with dementia of the Alzheimer’s type who require medication. The 
overview of the trial design is shown in Figure 3.1-1. 
The trial consists of a screening period, a treatment period, and a follow-up period. The 
investigator or subinvestigator will explain the details of the trial to a prospective subject 
(if the investigator or subinvestigator judges that the subject is incapable of providing 
informed consent or if the subject is hospitalized for reasons related to medical 
protection, the subject’s legally acceptable representative must provide written consent, 
and even when written consent is obtained from the legally acceptable representative, the 
subject should be given an explanation appropriate to his or her level of understanding 
and, if possible, should also provide written consent) and their caregivers using the 
explanatory materials and informed consent form (ICF) and obtain written consent for 


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participation in the trial from the patient (or their legally acceptable representatives) and 
caregivers. The subject’s clinical course will be followed in the same environment (see 
Section 3.4.2 Inclusion Criteria, 4) such as hospitalization in the same medical facility, 
institutionalization in the same care facility, and continued care at home from at least 3 
weeks before baseline evaluation up to the completion of the examinations scheduled at 
the completion or discontinuation of IMP administration. After obtaining consent from 
the patient (or their legally acceptable representatives) and caregiver, the investigator or 
subinvestigator will perform the specified observations, tests, and investigations to 
confirm the subject’s eligibility before IMP allocation. Subjects who are judged to be 
eligible in the screening examination and baseline evaluation will be randomized to the 
brexpiprazole 1 mg, brexpiprazole 2 mg, or placebo group. The IMP allocation will be 
performed using a dynamic allocation method to minimize bias in background factors 
(medical care category, prior use of antipsychotics, CMAI total score in baseline 
assessment) among the treatment groups. Duration of IMP treatment is 10 weeks. The 
subject will receive brexpiprazole or placebo for 10 weeks according to Section 3.2 Trial 
Treatments, and undergo periodic observations, tests, and investigations to assess 
efficacy and safety. The subject will return to the trial site 28 days after the completion of 
IMP administration for follow-up observation. Discontinued subjects will also undergo 
follow-up observation. 
For subjects who discontinued the trial during the treatment period, the examination at 
discontinuation will be performed. 
The trial period of each subject is from the date of informed consent to the end date of 
follow-up observation. If subjects have transitioned to the extension trial and commenced 
IMP administration, follow-up observation will not be performed. In such a case, the trial 
period is until the end date of evaluation at Week 10 (Day 71). 


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Figure 3.1-1 
Trial Design 
Follow-up observation will not be performed for subjects who have transitioned to the extension trial 
and commenced IMP administration. 
 
3.2 
Trial Treatments 
3.2.1 
Dosing and Regimen 
The IMP will be administered orally as one tablet once a day for 10 weeks. The doses of 
brexpiprazole for each group is shown in Table 3.2.1-1. Although the temporal 
relationship between IMP administration and meals will not be considered, subjects 
should take the IMP at the specified time in so far as possible. Dose reduction is not 
allowed during the trial, and if there are tolerability issues, administration of the IMP will 
be discontinued. 
Table 3.2.1-1 
Doses of IMPs 
Group 
Day 1–7 
Day 8–14 
Day 15–70 
Brexpiprazole 2 mg 
0.5 mg 
1 mg 
2 mg 
Brexpiprazole 1 mg 
0.5 mg 
1 mg 
1 mg 
Placebo 
0 mg 
0 mg 
0 mg 
The dose will be increased to 1 mg after evaluation at Week 1 (Day 8) and to 2 mg after evaluation at 
Week 2 (Day 15) 
 
3.2.2 
Rationale for Dosing and Regimen 
Doses and regimen were determined on the basis of the results of the 2 overseas trials 
(Trial 331-12-283 and Trial 331-12-284), as no significant differences due to ethnicity 
have been observed in the PK of brexpiprazole. 
Screening
period
Follow-up
period
Treatment period
1 week
2 mg
Brexpiprazole 2 mg (148 subjects)
1 week
1 mg
0.5 mg
1 mg
Brexpiprazole 1 mg (111 subjects)
0.5 mg
Placebo (148 subjects)
Day −42 to
Day −2
Day 28
Baseline Week 1 Week 2
Week 4
Week 6
Week 8
Week 10


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In Trial 331-12-283, the brexpiprazole 2 mg group showed a statistically significant 
improvement in change from baseline in CMAI total score compared with the placebo 
group. In patients with aggression in the baseline evaluation in Trial 331-12-283, 
improvement in the 2 mg group was greater than that in the placebo group. 
These findings suggested that 2 mg might be the optimal dose in Japanese patients. 
Therefore, 2 mg was selected to verify superiority over the placebo group. 
On the other hand, although the 1 mg group in Trial 331-12-283 did not demonstrate 
improvement greater than that in the placebo group among either the overall population 
or patients with aggression, in Trial 331-12-284, which was conducted using flexible 
doses, the 0.5 to 2 mg group showed greater efficacy than the placebo group among 
patients with aggression, raising the possibility that doses lower than 2 mg might be 
effective. On the basis of these findings, a 1 mg group was included so that information 
on the dose-response relationships in Japanese patients could be obtained and superiority 
over the placebo group can be confirmed if the 1 mg group demonstrates efficacy similar 
to that in the 2 mg group. 
In the 2 overseas trials, a dose titration method with a low starting dose and gradual dose 
increase was used in consideration of safety in elderly subjects, who were the target 
subjects of those trials. In the 2 overseas trials, a dose titration method in which dosing 
started from 0.25 mg and was increased to the maximum dose of 2 mg over 4 weeks was 
used, and no apparent safety problems were noted up to 2 mg. Since this trial will be 
conducted in patients with aggression who have a strong need for medication among 
patients with agitation, a dose titration method in which the dose will be started from 0.5 
mg, increased to 1 mg at Week 1 (after evaluation at Week 1 [Day 8]) and to 2 mg at 
Week 2 (after evaluation at Week 2 [Day 15]) was selected to reach 2 mg (which may 
become the optimal dose) as quickly as possible. The starting dose of 0.5 mg is 1/2 of the 
starting dose (1 mg) of brexpiprazole in schizophrenia, and conforms to the precautions 
and principles for medication in elderly patients with dementia described in the Practice 
Guideline for Dementia 201726: “depending on the type of medication, starting treatment 
at lower doses such as 1/2 to 1/4 of the doses recommended for younger patients should 
be considered.” Trial visits were set to 1 week after the start of trial treatment before a 
dose increase to 1 mg and 2 weeks after the start of trial treatment before a dose increase 
to 2 mg, and dose titration will be performed with confirmation of subject safety. 
The dosing regimen is oral administration once daily based on the PK and the 2 overseas 
trials. 


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3.2.3 
Rationale for Duration of Treatment 
Duration of treatment was determined on the basis of the clinical position of 
brexpiprazole therapy and taking the results of the 2 overseas trials into consideration. 
Brexpiprazole is positioned as symptomatic treatment for patients who require 
medication. The Practice Guideline for Dementia 201717 states that atypical 
antipsychotics including brexpiprazole “should not be continued without a compelling 
reason even if their efficacy is recognized.” Therefore, long-term administration as 
maintenance therapy after improvement of symptoms is not considered.  
However, in a repeated-dose trial in Japanese patients with schizophrenia, steady-state 
was reached from Day 10 onward, and thus a certain period is necessary to confirm if 
efficacy is sufficient after increasing the dose to 2 mg. 
In the 2 overseas trials, after the brexpiprazole dose had been increased to 2 mg 
(maximum dose), brexpiprazole was continued for 8 weeks (12 weeks in total, including 
the 4-week dose titration period) until sufficient efficacy was confirmed, and the efficacy 
of brexpiprazole 2 mg had been demonstrated. Therefore, as in the 2 overseas trials, it 
was decided that for this trial administration would be continued for 8 weeks after 
reaching the maximum dose of 2 mg. As described in Section 3.2.2 Rationale for Dosing 
and Regimen, as administration of brexpiprazole will reach the maximum dose of 2 mg at 
2 weeks, a total of 10 weeks was set as the duration of treatment. 
3.3 
Trial Population 
3.3.1 
Number of Subjects and Trial Population 
A total of 407 male and female patients (brexpiprazole 2 mg, 148 subjects; brexpiprazole 
1 mg, 111 subjects; placebo 148 subjects) with agitation associated with dementia of the 
Alzheimer’s type who require medication will be enrolled in the trial. 
3.3.2 
Subject Number Assignment 
 


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3.4 
Eligibility Criteria 
3.4.1 
Informed Consent 
Written informed consent will be obtained from all subjects (or their legally acceptable 
representatives) on their voluntary decision. If the investigator or subinvestigator judges 
that the subject is incapable of providing informed consent or is hospitalized for reasons 
related to medical protection, the subject does not have to provide informed consent, but 
the subject’s legally acceptable representative must provide written consent. Even when 
written consent is obtained from the legally acceptable representative, the subject should 
be given an explanation appropriate to his or her level of understanding and, if possible, 
should also provide written consent. 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. 
The ICF for subjects and their representatives will comply with the International Council 
for Harmonisation (ICH) Good Clinical Practice (GCP) Guideline27 and regional 
regulatory requirements. 
Investigators or subinvestigators may discuss the possibility for entry with a potential 
subject (or their legally acceptable representative) without first obtaining consent. 
However, informed consent must be obtained and documented before initiating any 
procedure that will be performed solely for the purpose of determining eligibility for this 
trial, including withdrawal from current medication(s). 
Furthermore, to facilitate management of patient compliance with the treatment regimen 
and the collection of patient information during the trial via the cooperation of their 
caregivers, the investigator or subinvestigator will explain the details of the trial to the 
caregivers of potential subjects by using explanatory materials designed for caregivers 
and obtain their written informed consent to cooperate in the trial. Potential subjects (or 
their legally acceptable representatives) and caregivers are free to refuse participation in 
the trial or withdraw from the trial at any time, without justification, and there will be no 
consequences to the further care of said patients. 
After the investigator or subinvestigator (or designee) has provided appropriate essential 
information to the subject (or their legally acceptable representative), has fully explained 
the information in plain language, has provided them with the opportunity to ask 
questions, and has made a record indicating that these procedures were followed, the 
IRB-approved written ICF will be signed and dated by the subject (or their legally 
acceptable representative), caregiver, and person obtaining the consent (investigator, 
subinvestigator, or designee). If a trial collaborator has provided supplemental 


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explanation, the IRB-approved written ICF will also be signed and dated by the trial 
collaborator. The subject (or their legally acceptable representative) and the subject’s 
caregiver will receive a copy of the signed ICF; the original shall be kept on file by the 
investigator or subinvestigator. 
Subjects (or their legally acceptable representatives) and their caregivers may be asked to 
sign additional ICFs if the protocol is amended to significantly add or change procedures. 
The investigator or subinvestigator will enter information on subjects for whom informed 
consent has been obtained into an interactive web response system (IWRS). 
For CYP2D6 genetic testing, DNA storage, and biomarker sample storage, a separate ICF 
will be used for explanation, and written informed consent will be obtained from subjects 
(or their legally acceptable representatives) on their voluntary decision in a similar 
manner. CYP2D6 genetic testing is mandatory, and if subjects (or their legally acceptable 
representatives) have not consented to CYP2D6 genetic testing, they cannot participate in 
the trial. On the other hand, DNA storage and biomarker sample storage are optional, and 
the refusal of subjects (or their legally acceptable representatives) to allow DNA storage 
and/or biomarker sample storage will not affect trial participation. 
3.4.2 
Inclusion Criteria 
Subjects must meet the inclusion criteria described in Table 3.4.2-1. 
Table 3.4.2-1 
Inclusion Criteria 
1 
Patients who have provided written informed consent (or whose legally acceptable representative has 
provided written informed consent). If the investigator or subinvestigator judges that the patient is 
incapable of providing informed consent or is hospitalized for reasons related to medical protection, 
the patient’s legally acceptable representative must provide written consent. 
2 
Patients who meet both of the following diagnostic criteria: 
• 
Diagnosis of “Dementia due to Alzheimer’s Disease” according to the Diagnostic and Statistical 
Manual of Mental Disorders Fifth Edition (DSM-5). 
• 
Diagnosis of “Probable Alzheimer’s Disease” according to the National Institute of 
Neurological and Communicative Disorders and Stroke–Alzheimer’s Disease and Related 
Disorders Association (NINCDS-ADRDA). 
3 
Patients who are ≥ 55 and ≤ 90 years of age at the time of obtaining informed consent. 
4 
Patients who can be followed in the same environment (as described below) from at least 3 weeks 
before baseline evaluation up to the completion of the examinations scheduled at the completion or 
discontinuation of investigational medicinal product (IMP) administration. 
• 
Patients who will be hospitalized in the same medical facility. 
• 
Patients who will be institutionalized in the same care facility. 
• 
Patients who will continue to receive care at home. 
For patients receiving day care or day service, those patients who will visit the same care facility 
at the same frequency during the above-mentioned period will be included. 
5 
Patients whose caregiver can properly collect the necessary information (the main caregiver must 
observe the patient’s condition in at least 4 days per week for 4 hours or more a day) Patients 
receiving home care must live with a specific caregiver and must not live alone. 


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Table 3.4.2-1 
Inclusion Criteria 
6 
Patients with a Mini-Mental State Examination (MMSE) total score of ≥ 1 to ≤ 22 at screening. 
7 
 
 
 
8 
Patients who have agitation that interferes with daily activities and is persistent/recurs frequently 
during the 2 weeks each before the screening examination and baseline evaluation. Agitation is 
defined according to the “Consensus provisional definition of agitation in cognitive disorders” from 
the International Psychogeriatric Association (IPA).a 
9 
Patients who have shown verbal aggression or physical aggression for 3 times or more during the 2 
weeks before baseline evaluation. Examples of verbal aggression and physical aggression include the 
following symptoms in the “Consensus provisional definition of agitation in cognitive disorders” of 
IPA.a 
• 
Verbal aggression: yelling, speaking in an excessively loud voice, using profanity, screaming, 
shouting, etc. 
• 
Physical aggression: grabbing, shoving, pushing, resisting, hitting others, kicking objects or 
people, scratching, biting, throwing objects, self-hitting, slamming doors, tearing things, 
destroying property, etc. 
10 
Patients who show significant improvement (of two grades or more) in CGI-S from screening to 
baseline evaluation. 
11 
Patients who show inadequate response to nonpharmacological therapy for agitation associated with 
dementia of the Alzheimer’s type or who are otherwise judged to be in need of pharmacological 
therapy. 
12 
Patients who are either capable of walking on their own or are able to move about with the use of a 
walking aid (a walker or wheelchair) and whose vision and hearing are sufficient to enable the 
required tests and observations for the trial (the use of glasses, hearing aids, etc, is acceptable).  
a Cummings J, Mintzer J, Brodaty H, Sano M, Banerjee S, Devanand DP, et al. Agitation in cognitive 
disorders: International Psychogeriatric Association provisional consensus clinical and research 
definition. International Psychogeriatrics. 2015;27:7–17. 
 
[Rationale for inclusion criteria] 
1. 
This criterion is specified for ethical considerations. 
2. 
This criterion is specified because DSM-5 is recommended in the Practice Guideline for Dementia 
2017, and NINCDS-ADRDA is widely used in clinical trials for dementia of the Alzheimer’s type. 
These standards have been established as the diagnostic standards for dementia of the Alzheimer’s 
type. 
3. 
Although it is known that most patients with dementia of the Alzheimer’s type are above the age of 
65, there is a small number of patients below the age of 65. Past trials have suggested that patients 
of ages 55 and above may be suitable for such trials. Thus, the lower age limit was set at 55. On the 
other hand, given that patients aged over 90 could interfere with the evaluations set for this trial and 
in consideration of safety, 20 the upper age limit was set at 90. 
4. 
These patients were included because the target subjects of this trial, namely, patients with agitation 
associated with dementia of the Alzheimer’s type, may not necessarily be hospitalized patients but 
may be receiving care at nursing homes or at home. This criterion was also set for the appropriate 
assessment of the safety and efficacy of brexpiprazole.  
5 to 12. These criteria are specified for the appropriate assessment of the safety and efficacy of 
brexpiprazole in the treatment of agitation associated with dementia of the Alzheimer’s type. 
 


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3.4.3 
Exclusion Criteria 
Subjects will be excluded if they fall under any of the exclusion criteria described in 
Table 3.4.3-1. 
Table 3.4.3-1 
Exclusion Criteria 
1 
Patients who have dementia or memory impairment other than dementia of the Alzheimer’s type, 
such as the following: 
• 
Frontotemporal dementia 
• 
Lewy body dementia 
• 
Vascular dementia 
• 
Dementia secondary to head trauma 
• 
Substance-induced persistent dementia 
• 
Dementia due to human immunodeficiency virus infection 
• 
Dementia due to prion disease 
• 
Dementia due to Parkinson’s disease (including Parkinsonian diseases such as progressive 
supranuclear palsy and basal ganglion degeneration) 
• 
Dementia due to Huntington’s disease 
• 
Dementia due to other general medical conditions (eg, subdural hematoma, normal pressure 
hydrocephalus, brain tumor, endocrine disorders, nutritional disorders, or infections) 
• 
Dementia due to multiple diseases 
• 
Dementia not otherwise specified 
2 
Patients diagnosed with delirium between 30 days before the screening examination and baseline 
evaluation according to DSM-5. 
3 
Patients diagnosed with any of the following disorders according to DSM-5: 
• 
Schizophrenia spectrum and other psychotic disorders 
• 
Bipolar and related disorders 
• 
Major depressive disorder 
However, patients who have major depressive disorder but whose condition is stable and 
asymptomatic within 30 days before the screening examination may be included. In regard to 
patients whose condition has been stabilized by medication, it should be noted that the use of 
antidepressants is prohibited from 7 days before baseline evaluation up to the completion of the 
examinations scheduled at the completion or discontinuation of IMP administration (see Section 4.1 
Prohibited Medications). 
4 
Patients with psychological symptoms or behavioral problems clearly due to other diseases or a drug 
substance. 
5 
• 
Patients with a complication or history of stroke or transient ischemic attack. 
• 
Patients with a complication of pulmonary embolism. 
However, patients with asymptomatic cerebral infarction or uncertain transient ischemic attack may 
be included. 
In regard to history of stroke or transient ischemic attack, a patient may be included if a medical 
monitor checks the patient’s symptoms and judges that they will have no influence on the efficacy 
and safety of the IMP. 
6 
Patients with a complication or history of convulsive disorders, such as epilepsy, not including 
patients with febrile seizures, posttraumatic seizures, alcohol withdrawal seizures, or other seizures. 
7 
Patients with clinically significant nervous, hepatic, renal, metabolic, immunological, hematological, 
cardiovascular, pulmonary, or digestive abnormality. 
8 
Patients with heart failure of New York Heart Association Class III or higher. 


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Table 3.4.3-1 
Exclusion Criteria 
9 
Patients who require pharmacological therapy for arrhythmia or ischemic heart disease, not 
including patients for whom the investigator or subinvestigator judges pharmacological therapy to be 
the primary prevention of ischemic heart disease. 
10 
Patients who test positive for hepatitis B surface antigen (HBsAg) or hepatitis C virus antibodies 
(HCV Ab). 
11 
Patients with a diagnosis of substance use disorder according to DSM-5, constituting substance 
abuse or substance dependence, including alcohol and benzodiazepines (but not including caffeine 
or nicotine), within 6 months prior to the acquisition of informed consent 
12 
Patients with a complication or history of neuroleptic malignant syndrome, tardive dyskinesia, 
paralytic ileus, or rhabdomyolysis 
13 
Patients who are unable to take oral medication due to severe dysphagia 
14 
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 
antidiabetic medication(s) or have not 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 on the basis of the results from the central laboratory) 
− 
Glycosylated hemoglobin (HbA1c) of ≥ 8.0% according to the global standard value 
(NGSP value) 
− 
Fasting blood glucose level of ≥ 126 mg/dL or nonfasting blood glucose level of 
≥ 200 mg/dL 
15 
Patients whose QTcF values based on the results from the central ECG laboratory at screening 
match the following criteria (if the criteria are matched in 2 out of 3 measurements), not including 
ventricular pacing: 
• 
Men: ≥ 450 ms; women: ≥ 470 ms 
16 
Patients whose (supine or sitting) blood pressure values at screening match the following criteria: 
• 
Poorly controlled hypertension (diastolic blood pressure [DBP] > 95 mmHg) 
17 
Patients meeting any of the following criteria at screening: 
• 
Hypotension with symptoms 
• 
Orthostatic hypotension in which blood pressure after at least 3 minutes of standing is 
≥ 30 mmHg lower for systolic blood pressure (SBP) or ≥20 mmHg lower for DBP compared 
with pressures in the supine position before standing 
18 
Patients with the following abnormal laboratory test values at screening (assessed on the basis of the 
results from the central laboratory): 
• 
Platelet count: ≤ 75,000/mm3 
• 
Hemoglobin: ≤ 9 g/dL 
• 
Neutrophil count: ≤ 1000/mm3 
• 
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT): > 2 times the upper 
limit of normal (ULN) 
• 
Creatine phosphokinase (CPK): > 3 times ULN (however, this does not apply if the medical 
monitor judges that there will be no medically significant problems) 
• 
Albumin: < 3 g/dL 
19 
Patients whose body weight at screening or baseline evaluation is < 30 kg 


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Table 3.4.3-1 
Exclusion Criteria 
20 
Patients whose Sheehan Suicidality Tracking Scale (S-STS) score at screening or baseline evaluation 
matches any of the following criteria or who are judged by the investigator or subinvestigator to be 
at high risk of suicide: 
• 
Patients with a score of 3 or 4 on any of S-STS Questions 2, 3, 4, 5, 6, or 11 
• 
Patients with a score of 2 or more on any of S-STS Questions 1a, 7, 8, 9, 10, or 12  
21 
The following patients falling under the contraindications in the package insert for REXULTI®: 
• 
Patients in a coma 
• 
Patients under the strong influence of central nervous system depressants, including barbiturate 
analogs/anesthetics 
• 
Patients receiving adrenaline 
• 
Patients with a history of hypersensitivity to the components of REXULTI® 
22 
Patients with thyroid disease (not including patients whose condition has been kept stable via drug 
therapy for at least 3 months prior to the acquisition of informed consent) or patients who show 
abnormal values for thyroid-stimulating hormone (TSH) and free thyroxine (FT4) in the screening 
examination 
23 
Patients who are likely to require any prohibited medications during the trial period  
24 
Patients who have previously taken brexpiprazole 
25 
Patients who have previously received antipsychotic medication for agitation associated with 
dementia of the Alzheimer’s type and whose condition has been judged to be treatment resistant. 
Cases in which treatment has to be stopped owing to adverse events are not counted as treatment 
resistant. 
26 
Patients who have undergone disease-modifying treatment for dementia of Alzheimer’s type (eg, 
amyloid β vaccine) within 6 months before the start of IMP administration 
27 
Patients who have taken any investigational drug within 30 days prior to informed consent 
28 
Patients who are bedridden and require assistance for excretion, eating, and changing clothes 
29 
Women who are nursing before the administration of IMP or have a positive pregnancy test result at 
screening 
30 
Sexually active men or sexually active women 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, two of the following methods must be used:  
vasectomy, tubal ligation, vaginal diaphragm, intrauterine contraceptive device (IUD), oral 
contraceptives, or condom with spermicide. 
31 
Patients who otherwise were judged by the investigator or subinvestigator to be unsuitable for 
participation in the trial 
 
Men without the ability to procreate are defined as those who have had bilateral 
orchidectomy, and women who are incapable of pregnancy are defined as those who have 
had bilateral oophorectomy or hysterectomy or who have been postmenopausal for at 
least 12 months. 
Subjects must agree to the restrictions described in Section 4 Restrictions. 


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[Rationale for the exclusion criteria] 
1 to 4 These criteria are specified to exclude patients who would be inappropriate for this trial. 
5 to 21 These criteria are specified in view of safety. 
22 to 27, 31 These criteria are specified for the appropriate assessment of safety and efficacy. 
28 This criterion is specified for the appropriate assessment of efficacy and in view of safety.20 
29, 30 These criteria are specified in consideration of safety, as the safety of brexpiprazole during 
pregnancy or while breastfeeding has not yet been established. 
 
3.5 
Requirements for Caregivers 
A caregiver who meets the following criteria will be designated as the main caregiver in 
the trial: 
• Is able to obtain the patient information required for evaluation (24-hour information 
wherever possible on the patient’s activities including toilet use, eating, bathing, 
changing, and other daily activities) during the trial period and provide this 
information during the inquiries on trial evaluation items; and 
• Provides the patient with care and can observe the patient’s condition in at least 4 
days per week for 4 hours or more a day, starting from 14 days before the day of 
baseline evaluations to the completion of the examinations scheduled at the 
completion or discontinuation of IMP administration. 
If there are multiple caregivers in charge of the patient’s care, the main caregiver will not 
only provide patient information from his or her own observations but also obtain from 
the other caregivers information on the patient’s condition during those periods when the 
patient was not under his or her observation and provide all patient information required 
for evaluations during the inquiries on the trial evaluation items.  
To the extent possible, the same main caregiver will respond to queries on the trial 
evaluation items from 14 days before the day of baseline evaluations to the completion of 
examinations scheduled at the completion or discontinuation of IMP administration. If 
the main caregiver is unable to respond to queries, a substitute caregiver is allowed to 
respond to queries on the trial evaluation items. However, to the extent possible, queries 
on the trial evaluation items at the time of baseline evaluation and at the completion or 
discontinuation of IMP administration should be answered by the person who was 
designated as the main caregiver at the start of the trial. A substitute caregiver should be 
able to obtain patient information required for evaluations from other caregivers and 
provide the same information as would have been provided by the main caregiver during 
inquiries on the trial evaluation items, and should be selected from among the caregivers 
in charge of the patient’s care. Queries at the conclusion of follow-up observation to be 
performed 28 days after the completion or discontinuation of IMP administration will 
also be answered by a caregiver who is in charge of the patient’s care and is able to 
provide patient information required for evaluations. 


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3.6 
Endpoints 
3.6.1 
Primary Endpoint 
The primary endpoint is change in CMAI total score from baseline to Week 10. 
The CMAI is a scale to assess the frequency of specific agitation symptoms. The Practice 
Guideline for Dementia 2017 recommends the NPI, Behavioral Pathology in Alzheimer’s 
Disease, and CMAI for assessment of BPSD. The CMAI evaluates the frequency of 
occurrence of specific agitation for the preceding 2 weeks and is used globally for 
assessment of agitation.22,28 Therefore, the CMAI is the most appropriate scale for 
evaluating the efficacy of brexpiprazole for agitation associated with dementia of the 
Alzheimer’s type, which is the primary objective of the trial. Furthermore, the CMAI was 
adopted as the primary endpoint in the 2 overseas trials (Trial 331-12-283 and Trial 331-
12-284). 
3.6.2 
Secondary Endpoints 
• Changes in CMAI subscales (Aggressive Behavior, Physically Non-aggressive 
Behavior, and CMAI Verbally Agitated Behavior) from baseline to Week 10 
• Change in Clinical Global Impression–Severity of Illness (CGI-S) from baseline to 
Week 10 
• Clinical Global Impression–Global Improvement (CGI-I) at Week 10 
 
3.6.3 
Exploratory Endpoints 
• 
 
• 
 
• 
 
• 
 
• 
 
 
• 
 
• 
 
• 
 
 
3.6.4 
Safety Endpoints 
• Adverse events 
• Physical examinations 


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• Laboratory tests 
• Vital signs 
• Body weight 
• Twelve-lead electrocardiogram (ECG) 
• Pregnancy test (for women of childbearing potential [WOCBP] only) 
• Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS) 
• Abnormal Involuntary Movement Scale (AIMS) 
• Barnes Akathisia Rating Scale (BARS) 
• Sheehan Suicidality Tracking Scale (S-STS) 
 
3.6.5 
Pharmacokinetic Endpoint 
Plasma concentrations of OPC-34712 at Week 10 of brexpiprazole administration  
3.6.6 
Pharmacogenomic Endpoint 
CYP2D6 genotype 
3.6.7 
Other Endpoints 
• Alzheimer's Disease Cooperative Study–Activities of Daily Living (ADCS-ADL) 
• MMSE 
• EuroQol 5-dimension 5-level health questionnaire (EQ-5D-5L) 
 
3.7 
Measures to Minimize/Avoid Bias 
Subjects who meet all the inclusion criteria and do not fall under any of the exclusion 
criteria will be randomly assigned to the brexpiprazole 1 mg/day group, the brexpiprazole 
2 mg/day group, or placebo group at a randomization ratio of 3:4:4. The IMP allocation 
will be performed using a dynamic allocation method. The details of the randomization 
method will be described in a separately produced procedural guide for dynamic 
allocation. 
This is a double-blind trial. The IMP allocation manager will prepare a “Table of 
randomization scheme and codes” (hereinafter randomization table) and conduct IMP 
coding according to the operating procedures for randomization. The IMP allocation 
manager will prepare an emergency code list for emergencies, such as when an SAE 
occurs. 
The treatment assignment code will be revealed to neither the subject (including any 
representatives or caregivers) nor the investigator. The sponsor’s staff involved in the 


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trial (except for those of the Department of Pharmacovigilance [PV department]), 
including contract research organizations (excluding the bioanalytical laboratory, genetic 
analysis laboratory, and IDMC), will also remain blind to the treatment assignment codes 
for the duration of the trial. Prior to the start of the trial, those who are involved in 
packaging the IMP and the sponsor will confirm that the IMP is not identifiable. The 
randomization table will be strictly retained until unblinding is performed after 
finalization of all the case report forms (CRFs) and database. 
The emergency code break information will be managed by the IWRS until the 
completion of the trial. In the event that a subject has a medical emergency and the 
knowledge of the treatment assignment code is necessary for treatment, the emergency 
key may be opened for the subject in question (see Section 5.6 Procedure for Breaking 
the Blind). 
The results of CYP2D6 genotyping and plasma drug concentration measurements should 
not be disclosed until unblinding at the end of the trial. The CYP2D6 genotyping and 
plasma drug concentration measurements should be performed at the designated 
laboratories and not at the clinical laboratories of the trial sites. 


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3.8 
Trial Procedures 
The schedule of assessments is shown in Table 3.8-1, and the allowable time windows for 
observations, tests, and assessments are shown in Table 3.8-2. 
Table 3.8-1 
Schedule of Assessments 
Item 
Screening 
Period 
Treatment Period 
Follow-up 
Perioda 
Day -42 to 
Day -2 
Baseline 
evaluation 
(Day 1)b 
Week 1 
(Day 8) 
Week 2 
(Day 15) 
Week 4 
(Day 29) 
Week 6 
(Day 43) 
Week 8 
(Day 57) 
Week 10 
(Day 71)  
At 
discontinu-
ation 
28 days 
after 
completion/ 
discontinu-
ation 
Same environment 
Before Day -21 ←------------------------------------------------------------------------------→ 
 
Informed consent 
• 
 
 
 
 
 
 
 
 
Subject background 
information 
• 
 
 
 
 
 
 
 
 
Subject diary 
From Day -14 ←-------------------------------------------------------------------------------→ 
 
Inclusion/exclusion 
criteria 
• 
• 
 
 
 
 
 
 
 
Compliance status 
 
 
• 
• 
• 
• 
• 
• 
 
Efficacy endpoints 
CMAI 
 
• 
 
• 
• 
• 
• 
• 
 
CGI-S 
• 
• 
 
• 
• 
• 
• 
• 
 
CGI-I 
 
 
 
• 
• 
• 
• 
• 
 
c 
•d 
• 
 
 
• 
 
 
• 
 
e 
 
• 
 
 
• 
 
 
• 
 
Safety endpoints 
Adverse events 
←-----------------------------------------------------------------------------------------------------------------→ 
Confirmation of 
medications and 
therapies 
←-----------------------------------------------------------------------------------------------------------------→ 
Height 
• 
 
 
 
 
 
 
 
 
Body weight 
• 
• 
 
 
 
 
 
• 
 
Physical 
examination 
• 
• 
• 
• 
• 
• 
• 
• 
 
Laboratory tests 
• 
•f 
 
 
• 
 
 
• 
 
Vital signs 
•g 
• 
• 
• 
• 
• 
• 
• 
 
12-lead ECG 
•h 
• 
 
• 
• 
 
 
• 
 
Pregnancy testi 
• 
 
 
 
 
 
 
• 
 
DIEPSS 
 
• 
• 
• 
• 
• 
• 
• 
• 
AIMS 
 
• 
 
 
 
 
 
• 
• 
BARS 
 
• 
 
 
 
 
 
• 
• 
S-STS 
• 
• 
 
 
• 
 
 
• 
 
Other endpoints 
ADCS-ADL 
 
• 
 
 
 
 
 
• 
• 
MMSE 
• 
 
 
 
 
 
 
• 
• 
EQ-5D-5L (subject 
and caregiver) 
 
• 
 
 
 
 
 
• 
 


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Table 3.8-1 
Schedule of Assessments 
Item 
Screening 
Period 
Treatment Period 
Follow-up 
Perioda 
Day -42 to 
Day -2 
Baseline 
evaluation 
(Day 1)b 
Week 1 
(Day 8) 
Week 2 
(Day 15) 
Week 4 
(Day 29) 
Week 6 
(Day 43) 
Week 8 
(Day 57) 
Week 10 
(Day 71)  
At 
discontinu-
ation 
28 days 
after 
completion/ 
discontinu-
ation 
Blood sampling for 
measurement of 
plasma drug 
concentration 
 
 
 
 
 
 
 
•j 
 
Blood sampling for 
CYP2D6 
genotyping 
 
•k 
 
 
 
 
 
 
 
Blood sampling for 
DNA storage 
 
 
 
 
•l, m 
 
 
 
 
Blood sampling for 
biomarker sample 
storage 
 
•l 
 
 
 
 
 
 
 
aFollow-up observation will not be performed for subjects who have transitioned to the extension trial 
and commenced IMP administration. 
bAll baseline observations, tests, and evaluations will be performed on the day before the start of IMP 
administration (Day -1) and the day of starting IMP administration (Day 1). CMAI, CGI-S, 
, and 
must be performed on the same day. 
c
. 
d
. 
e
 
 
fPerforming laboratory tests at baseline is not necessary if fasting blood sample collection was 
performed at screening and within 14 days before baseline evaluation. 
gBlood pressure and pulse rate will be measured in the order of supine, sitting, and standing positions. 
hEligibility will be assessed based on consecutive triplicate ECG measurements (central reading). The 
third measurement can be omitted if neither the first nor second measurement (central reading) meets 
the exclusion criteria. 
iPregnancy test (HCG test) will be performed for WOCBP only. If urinary test is positive, serum test 
will be performed. 
jBlood sampling will be performed before IMP administration if the IMP is administered in Week 10 but 
does not need to be performed at the time of discontinuation. 
kIf blood sampling is not performed for any other test item or for some reason cannot be performed at 
the time of baseline evaluation, or if blood resampling is necessary, blood sampling will be performed 
during the trial period. 
lOptional 
mIf for some reason it is not possible to perform blood sampling at this time or if blood resampling is 
necessary, blood sampling will be performed during the trial period. 
 


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Table 3.8-2 
Allowable Time Windows for Evaluations, Tests, and 
Observations 
Test Point 
Base Date 
Allowable Time Window From 
the Base Date 
Screening period 
At the start of screening 
Day -42 to Day -2 
Baseline evaluation date 
Day 1 
Day -1 or Day 1 
Week 1 
Day 8 
Day 6 to Day 10 
Week 2 
Day 15 
Day 13 to Day 17 
Week 4 
Day 29 
Day 27 to Day 31 
Week 6 
Day 43 
Day 40 to Day 46 
Week 8 
Day 57 
Day 54 to Day 60 
Week 10 
Day 71 
Day 68 to Day 78 
Follow-up perioda 
28 days after the final 
administration of IMP 
23 to 35 days after the final 
administration of IMP 
aFollow-up observation will not be performed for subjects who have transitioned to the extension trial 
and commenced IMP administration. 
The date of starting IMP administration is designated as Day 1. 
All baseline observations, tests, and evaluations will be performed on the day before the start of IMP 
administration (Day -1) and the day of starting IMP administration (Day 1). CMAI, CGI-S, 
, and 
must be performed on the same day. 
 
3.8.1 
Schedule of Assessments 
The investigator or subinvestigator will perform observations, tests, and assessments 
within the allowable windows shown in Table 3.8-2 according to the schedule of 
assessments shown in Table 3.8-1. Special consideration should be given to 
environmental factors (eg, physical restraint [including isolation] and transfer to a 
different ward or room, staying out overnight, and outings during 
hospitalization/institutionalization) that may affect assessments. The investigation of 
subject background information, clinical laboratory tests, and other investigation/test 
items that can be performed by the trial collaborator may be performed by the trial 
collaborator under supervision of the investigator. 
The methods employed for observations, tests, and assessments are shown in 
Section 3.8.2 Efficacy Assessments to Section 3.8.5 Other Endpoints. 
The date and time of observations, tests, and assessments and the results will be recorded 
in the source document and case report form (CRF). 
3.8.1.1 
Screening Period 
To confirm that the subject meets the inclusion criteria and does not fall under the 
exclusion criteria, observations, tests, and assessments will be performed, and the results 
will be recorded after the date of informed consent but before the baseline assessment. 


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The caregivers will be provided with the subject diary for the period up to the baseline 
evaluation and be given an explanation on how to complete the subject diary, and 
instructed to record the required information in the subject diary from 14 days before the 
baseline evaluation until the baseline evaluation. In the subject diary, occurrence of daily 
symptoms will be recorded to evaluate the frequency of occurrence of agitation 
associated with dementia of the Alzheimer’s type (CMAI). 
The investigator or subinvestigator will record subject information related to the 
enrollment criteria, which had been collected during screening, in the eligibility form 
specified by the sponsor and submit to the medical monitor for confirmation of the 
subject’s eligibility. The medical monitor will confirm the content of the eligibility form, 
and if there is any doubt regarding the subject’s eligibility, he/she will consult with the 
investigator or subinvestigator to determine the subject’s eligibility before the baseline 
examination. 
The investigator or subinvestigator will investigate subject background and other 
information as follows and record it in the source document and CRF. 
• Date of visit 
• Date of informed consent by the subject (or their legally acceptable representatives) 
and caregivers 
• Subject background information 
− Sex, date of birth, race, ethnicity, and trial country 
− Possibility of getting pregnant in women of childbearing potential (WOCBP) (see 
Section 5.5 Pregnancy) (if there is no childbearing potential, record the reason) 
− Diagnosis of dementia of the Alzheimer’s type (diagnostic criteria of DSM-5 and 
NINCDS-ADRDA) 
− Timepoint of onset of dementia of the Alzheimer’s type 
− Timepoint of diagnosis of dementia of the Alzheimer’s type 
− Timepoint of onset of agitation associated with dementia of the Alzheimer’s type 
− Complications 
− Medical history (for the 2 years preceding informed consent; however, medical 
history related to the inclusion/exclusion criteria is not limited to the preceding 2 
years.) 
− Medical care category (inpatient or outpatient; if outpatient, institutionalized or 
care at home) 
− Classification of the main caregiver specified at the start of the trial (hospital staff, 
care facility staff, family, or other), care status over the 2 weeks prior to the visit 
(amount of care time per day and days of care in a week)  
− Prior medications and therapies 


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• Confirmation of eligibility 
 
3.8.1.2 
Day of Baseline Examination 
To confirm that the subject meets the inclusion criteria and does not fall under the 
exclusion criteria before starting IMP administration, the investigator or subinvestigator 
will perform the observations, tests, and assessments shown in Table 3.8-1 and the 
investigation of the following items and record the results. 
• Date of visit 
• Confirmation of eligibility 
 
3.8.1.3 
Randomization 
The investigator or subinvestigator will select subjects who meet the inclusion criteria 
and do not fall under the exclusion criteria on the basis of the results of the screening 
examination and baseline evaluation. For the clinical laboratory test and 12-lead ECG, 
the subject’s eligibility will be judged on the basis of the results obtained by the central 
laboratory and central ECG laboratory at the time of screening. 
The investigator or subinvestigator will enter information on eligible subjects in the 
IWRS. Subjects whose registration was confirmed in the IWRS will be randomized to the 
brexpiprazole 1 mg, brexpiprazole 2 mg, or placebo group using a dynamic 
randomization method to minimize bias between the treatment groups regarding the 
following background factors. The date of randomization and randomization number will 
be recorded in the CRF. 
• Medical care category (inpatient or outpatienta) 
• Prior use of antipsychoticsb (yes or no) 
• CMAI total score (≥ 56 or < 56) in the baseline evaluation 
aSubjects who are institutionalized or receiving care at home and visit the trial site as outpatients 
bReceiving antipsychotics in the 6 months prior to the day of baseline evaluation will be considered as 
“yes.” 
The investigator or subinvestigator will provide the IMP and subject diary needed for the 
period up until the next assessment on the basis of the drug number assigned to the 
subject in the IWRS and give instructions to bring unused IMPs and the completed 
subject diary to the next assessment. 


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3.8.1.4 
Seven Days After Administration (Week 1, Day 8) to Seventy 
Days After Administration (Week 10, Day 71) 
The investigator or subinvestigator will perform the observations, tests, and assessments 
shown in Table 3.8-1 and record the results and date of visit. 
At visits where blood is collected for measurement of plasma drug concentrations, the 
date and time of last IMP administration will be recorded. 
At visits from 7 days after administration (Week 1, Day 8) until 56 days after 
administration (Week 8, Day 57), the investigator or subinvestigator will provide the IMP 
and subject diary needed up until the next assessment on the basis of the drug number 
assigned to the subject in IWRS and give instructions to bring unused IMPs and the 
completed subject diary to the next assessment. 
3.8.1.5 
Examination at Discontinuation 
At discontinuation, the investigator or subinvestigator will perform the observations, 
tests, and assessments shown in Table 3.8-1 as promptly as possible, within the same day 
if possible, after discontinuation has been decided and will record the results along with 
the date of visit. If at time of discontinuation, the subject or caregiver refuses any of the 
tests or if the investigator or subinvestigator judges that tests cannot be performed due to 
an emergency, only those observations, tests, and assessments that are feasible will be 
performed. 
3.8.1.6 
Follow-up Observation (Twenty-eight Days After Completion or 
Discontinuation of IMP Administration) 
The investigator or subinvestigator will perform the observations, tests, and assessments 
shown in Table 3.8-1 and record the results and date of visit. These observations, tests, 
and assessments will also be performed in discontinued subjects unless the subject or 
caregiver refuses any of the tests or the investigator or subinvestigator judges that tests 
cannot be performed due to an emergency. Follow-up observation will not be performed 
for subjects who have transitioned to the extension trial and commenced IMP 
administration. 
3.8.2 
Efficacy Assessments 
The rater for each of the assessment items should refer to Section 3.8.9 Raters. The 
results and the date and time of assessments should be recorded in the source documents 
and the CRF. The schedule for each of the assessment items is shown in Table 3.8-1. 


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3.8.2.1 
Cohen-Mansfield Agitation Inventory 
The rater will use CMAI to determine how often each of the 29 agitated behaviors 
associated with dementia of the Alzheimer’s type occurred with each behavior rated on a 
7-point scale of frequency through an interview with the caregiver. The evaluation will be 
made on the basis of information on the subject from 14 days before each assessment day 
and the frequency of agitation will be evaluated on the basis of the information contained 
in the subject diary. However, records in the subject diary are supplementary data for 
assessment, and the investigator or subinvestigator will perform the final assessment 
based not only on the information contained in the subject diary but also the information 
collected through an interview with the caregiver. 
[29 agitated behaviors]  
“Pace, aimless wandering,” “inappropriate dressing or disrobing,” “spitting (include at 
meal),” “cursing or verbal aggression,” “constant unwarranted request for attention or 
help,” “repetitive sentences or questions,” “hitting (including self), ” “kicking,” 
“grabbing onto people,” “pushing,” “throwing things,” “strange noises (weird laughter or 
crying),” “screaming,” “biting,” “scratching,” “trying to get to a different place (e.g., out 
of the room, building),” “intentional falling,” “complaining,” “negativism,” 
“eating/drinking inappropriate substances,” “hurt self or other (cigarette, hot water, etc.),” 
“handling things inappropriately,” “hiding things,” “hoarding things,” “tearing things or 
destroying property,” “performing repetitious mannerisms,” “making verbal sexual 
advances,” “making physical sexual advances,” and “general restlessness” 
3.8.2.2 
Clinical Global Impression–Severity of Illness 
The rater will assess (by time point evaluation) the severity of agitation associated with 
dementia of the Alzheimer’s type on an 8-point scale using the CGI-S. 
3.8.2.3 
Clinical Global Impression–Global Improvement 
The rater will assess (by time point evaluation in comparison with the date of baseline 
evaluation) improvement of agitation associated with dementia of the Alzheimer’s type 
on an 8-point scale using the CGI-I. 
3.8.2.4 
 


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3.8.2.5 
 
 
 
 
3.8.3 
Safety Assessments 
Evaluation points for each item are shown in Table 3.8-1. 
3.8.3.1 
Adverse Events 
Refer to Section 5 Reporting of Adverse Events. 
3.8.3.2 
Clinical Laboratory Assessments 
In this trial, the clinical laboratory tests shown in Table 3.8.3.2-1 will be conducted by 
central analysis. Blood and urine samples will be collected from each subject, and the 
date and time of blood sampling, the date of urine sampling, and the verification of 
whether blood sampling was performed when the subject was in a fasted state (having 
fasted for at least 8 hours) will be recorded in the source documents and the CRF. Subject 
eligibility will be verified using the clinical laboratory test values determined at the 
central laboratory. For appropriate procedures for the collection, handling, and shipment 


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of samples, the separately prepared procedures should be followed. The total amount of 
blood to be collected for clinical laboratory tests during the trial period will be described 
in the ICF and explanatory materials. 
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 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 3.8.3.2-1 
Clinical Laboratory Assessments 
Hematology: 
Red blood cell count 
White blood cell count 
Differential count of white blood cells (neutrophils, 
eosinophils, basophils, monocytes, and lymphocytes) 
Platelet count 
Hemoglobin 
Hematocrit 
Prothrombin time (PT) 
PT (international normalized ratio [INR]) 
Activated partial thromboplastin time (APTT) 
 
Urinalysis: 
pH 
Protein 
Glucose 
Occult blood 
Urobilinogen 
Specific gravity 
Ketone body 
Serum chemistry: 
ALT 
AST 
Alkaline phosphatase (ALP) 
Lactic dehydrogenase (LDH) 
Gamma-glutamyl transpeptidase (γ-GTP) 
Total protein 
Total bilirubin 
Albumin 
Cholesterol (total cholesterol, low-density 
lipoprotein [LDL] cholesterol, and high-density 
lipoprotein [HDL] cholesterol) 
Triglycerides 
Blood urea nitrogen (BUN) 
Creatinine 
Uric acid 
CPK 
Blood electrolytes (Na, K, Cl, Mg, Ca, P,) 
Blood glucose (fasting or nonfasting) 
HbA1c (NGSP value) 
Folatea 
Vitamin B12a 
  
Endocrinology: 
Serum prolactin 
Insulin 
FT4a 
TSHa 
 
Immunology 
HBsAga 
HCV Aba 
aPerformed only at screening 
 


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3.8.3.3 
Physical Examination 
The investigator or subinvestigator will conduct a physical examination for HEENT 
(head, eye, ear, nose, and throat), chest, abdomen, urogenital organs, extremities, nerves, 
and skin/mucosa. 
In the screening examination, all the physical findings obtained on the evaluation day and 
up to the observation day will be recorded in the source document and CRF. From the 
baseline evaluation, only information on whether an observation occurred or not and date 
and time of observation will be recorded in the source document and CRF. Clinically 
significant physical findings obtained in and after the baseline evaluation will be recorded 
as AEs in the source document and CRF. 
3.8.3.4 
Vital Signs (Blood Pressure and Pulse Rate) 
After the subject has been rested, the investigator or subinvestigator will measure vital 
signs in accordance with the methods specified by the trial site. In the screening 
examination, SBP, DBP, and pulse rate will be measured in the order of supine, sitting, 
and standing positions. The results, date and time of measurement will be recorded in the 
source document and CRF. Blood pressure and pulse rate will be measured in the order of 
supine, sitting, and standing positions after maintaining each position for at least 3 
minutes. From the baseline evaluation, blood pressure and pulse rate will be measured in 
a sitting position. If the subject complained of symptoms of orthostatic hypotension 
before evaluation in or after the baseline evaluation, measurement should be performed in 
the supine and sitting positions in so far as possible in the order of the supine, sitting, and 
standing positions in the same manner as the screening examination. 
3.8.3.5 
Height and Body Weight 
Height and body weight will be measured using a standard measurement method (no 
shoes, with clothes on). 
The date and results of measurements will be recorded in the source document and CRF 
(body weight in increments of 0.1 kg, height in increments of 0.1 cm). 
3.8.3.6 
Twelve-lead Electrocardiography 
After the subject has been placed in a resting position, the subject’s ECG will be recorded 
using a 12-lead electrocardiograph supplied by the central ECG laboratory. At screening, 
the subject’s eligibility will be assessed based on consecutive triplicate ECG 
measurements (central reading) obtained during screening. ECG examination will be 
performed at appropriate intervals after the subject’s resting state is confirmed. The third 


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measurement can be omitted if neither the first nor second measurement (central reading) 
meets the exclusion criteria (≥ 450 ms for men, ≥ 470 ms for women). 
The investigator or subinvestigator will check the ECG and assess whether the result is 
normal or abnormal and will 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 record or the investigator’s file. The 
central ECG laboratory will collect 12-lead ECG data and measure the 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], 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 judgment with 
reference to the analysis result report sent from the central ECG laboratory. As the results 
of analysis by the central ECG laboratory are reported directly from the central ECG 
laboratory to the sponsor as an electronic file, they do not need to be recorded in the 
source documents or the CRF. 
3.8.3.7 
Pregnancy Test 
A urine pregnancy test will be performed in WOCBP (see Section 5.5 Pregnancy), and 
the date of urine sampling and the result of the test will be recorded in the source 
documents and the CRF. The result of the pregnancy test performed at screening must be 
obtained before starting IMP administration. If the urine test is positive, 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. 


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3.8.3.8 
Other Safety Assessments 
The investigator or subinvestigator will record the results and the date and time of the 
assessments in the source documents and the CRF. The schedule for each of the 
assessment items is shown in Table 3.8-1. 
3.8.3.8.1 
Drug-induced Extrapyramidal Symptoms Scale 
By using DIEPSS, the investigator or subinvestigator will assess 9 items related to 
extrapyramidal symptoms on a 5-point scale on the basis of the subject’s information 
from the previous assessment (baseline assessment will be based on the subject’s 
information from the initial screening examination). 
Nine items related to extrapyramidal symptoms: 
Gait, bradykinesia, sialorrhea, muscle rigidity, tremor, akathisia, dystonia, dyskinesia, 
and overall severity 
3.8.3.8.2 
Abnormal Involuntary Movement Scale 
By using AIMS, the investigator or subinvestigator will assess the severity of abnormal 
involuntary movement at 7 sites and 3 global judgment items on a 5-point scale and 
assess the dental status items “current problems with teeth and/or dentures” and “Dose 
patient wear dentures” as either “yes” or “no” (assessment at specified time points). 
Seven sites: 
“Muscles of facial expression,” “lips and perioral area,” “jaw,” “tongue,” “upper (arms, 
wrists, hands, fingers),” “lower (legs, knees, ankles, toes),” and “neck, shoulders, hips” 
3.8.3.8.3 
Barnes Akathisia Rating Scale 
By using BARS, the investigator or subinvestigator will assess the “objective,” 
“subjective—awareness of restlessness,” and “subjective—distress related to 
restlessness” for akathisia on a 4-point scale and a “global clinical assessment of 
akathisia” on a 6-point scale.  
3.8.3.8.4 
Sheehan Suicidality Tracking Scale 
By using S-STS, the investigator or subinvestigator will assess suicidal attempt and 
behavior on the basis of 22 question items. At screening, assessment will cover the period 
spanning the previous 6 months, and for subsequent visits, the assessment will cover the 
period since the previous visit.  
3.8.4 
Pharmacokinetic Assessment, Pharmacogenomic Assessment, 
and Biomarker Exploration 
The schedule for each of the assessment items is shown in Table 3.8-1. 


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3.8.4.1 
Pharmacokinetic Assessment 
Plasma brexpiprazole concentrations will be measured by validated high performance 
liquid chromatography/tandem mass spectrometry method. Metabolites that are not 
presented in the protocol may be measured on the basis of newly obtained information. 
The bioanalytical laboratory will measure drug concentrations only for the samples 
collected from subjects in the brexpiprazole groups after recording the use of the 
randomization table. Access to the documents containing treatment assignment codes will 
be strictly controlled and will not be disclosed to anyone other than those who need them 
to perform trial-related activities in the opinion of the person responsible for drug 
concentration measurements. The bioanalytical laboratory will hold the results of the 
drug concentration measurements in strict confidence and submit an electronic file 
containing these results to the sponsor after unblinding. Therefore, there is no need to 
record the results of assessment in the source documents and CRF. 
1)  Timing of Blood Sampling 
Blood samples will be collected before IMP administration if the IMP is administered 
in Week 10. The date and time of blood sampling and the date and time of the most 
recent IMP administration before blood sampling will be recorded in the source 
documents and the CRF. 
2) Blood Samples for Pharmacokinetic Assessment 
Details of the sample collection, handling, and shipping methods are provided in 
Appendix 1. 
3.8.4.2 
Pharmacogenomic Assessment 
3.8.4.2.1 
CYP2D6 Genetic Testing 
CYP2D6 genotypes and phenotypes will be analyzed. CYP2D6 genetic testing is 
mandatory. 
The CYP2D6 genotype will be determined for each subject on the basis of the CYP2D6 
genotyping table (Appendix 2). In addition, on the basis of the CYP2D6 genotype, the 
phenotype will be classified into the following 4 types: extensive metabolizer (EM), 
intermediate metabolizer (IM), poor metabolizer (PM), and unknown. In principle, the 
results of CYP2D6 genetic testing will not be disclosed to subjects. 
The genetic analysis laboratory will extract DNA only from the blood samples of the 
brexpiprazole groups after recording the use of the randomization table. The blood 
samples collected from subjects in the placebo group will be discarded in accordance 
with the procedure specified by the genetic analysis laboratory. Access to the documents 
containing treatment assignment codes will be strictly controlled and will not be 


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disclosed to anyone except for those who need them to perform trial-related activities in 
the opinion of the person responsible for genetic testing. The genetic analysis laboratory 
will hold the results of CYP2D6 genetic testing in strict confidence and submit an 
electronic file containing these results to the sponsor after unblinding. Therefore, there is 
no need to record the results of the assessment in the source documents and CRF. 
1) Timing of Blood Sampling 
Blood samples will be collected before IMP administration on the day of baseline 
evaluation. If blood sampling is not performed for any other test item or for some 
reason cannot be performed at the time of baseline evaluation, or if blood resampling 
is necessary, blood sampling will be performed during the trial period. The date and 
time of blood sampling will be recorded in the source documents and the CRF. 
2) Samples for CYP2D6 Genetic Testing 
Details of the sample collection, handling, and shipping methods are provided in 
Appendix 1. 
3.8.4.2.2 
DNA Storage 
 
 
 
 
 
 
 


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3.8.4.3 
Storage of Samples for Biomarker Exploration 
 
 
 
. 


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3.8.5 
Other Endpoints 
The rater for each of the assessment items should refer to Section 3.8.9 Raters. The 
results and the date and time of assessments should be recorded in the source documents 
and the CRF. The schedule for each of the assessment items is shown in Table 3.8-1. 
3.8.5.1 
Alzheimer's Disease Cooperative Study–Activities of Daily 
Living 
The rater will review the answers to the 19 questions on the dementia patient’s activities 
of daily living through an interview with the caregiver using the ADCS-ADL severe 
dementia version and will record the results. The evaluation will be made on the basis of 
information for the period from 28 days before each evaluation day. If the caregiver 
cannot come to the trial site for a compelling reason, an interview by telephone is 
acceptable for the follow-up observation only. 
3.8.5.2 
Mini-Mental State Examination 
The rater will assess each of 11 cognitive function items for the subject at the time of 
evaluation using the MMSE and will record the results. 
[11 cognitive function items] 
“Orientation to time,” “orientation to place,” “registration,” “attention and calculation,” 
“recall,” “naming,” “repetition,” “comprehension,” “reading,” “writing,” and “drawing” 


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3.8.5.3 
EuroQol 5-Dimension 5-Level Health Questionnaire 
The caregiver will assess the health of the subject and caregiver in relation to 5 health 
domains at the time of evaluation on a 5-level scale using the EQ-5D-5L. Health will be 
assessed using a 100 mm visual analogue scale (0 = the worst health imaginable, 100 = 
the best health imaginable). 
In the subject assessment, the caregiver will evaluate the subject’s health using the EQ-
5D-5L proxy version and will record the results. In the caregiver self-evaluation, the 
caregiver will evaluate his/her own health using the EQ-5D-5L and record the results. 
The caregiver self-evaluation will be performed only when the caregiver in the baseline 
evaluation and the caregiver in subsequent evaluations are the same person. 
[5 domains] 
“Mobility,” “self-care,” “usual activities,” “pain/discomfort,” and “anxiety/depression” 
3.8.6 
Medications and Therapies 
The investigator or subinvestigator will investigate medications and therapies 
administered during the periods below. If any medication is used during the periods, the 
name of the drug, purpose of use, dose, frequency, route of administration, and start date 
and end date of treatment will be investigated. If any therapy is performed, the name of 
the therapy, purpose of therapy, and start date and end date of treatment will be 
investigated. The results of the investigation will be recorded in the source document and 
CRF. 
• Antipsychotics: from 6 months before the date of baseline evaluation through to the 
trial end date 
• Antidementia drugs: from 3 months before the date of baseline evaluation through to 
the trial end date 
• Prohibited concomitant drugs other than antipsychotics and restricted concomitant 
drugs other than antidementia drugs: from 30 days before the date of informed 
consent or date of baseline evaluation, whichever is earlier, through to the trial end 
date 
• Other medications and therapies: from the date of informed consent through to the 
trial end date 
 
3.8.7 
End of Trial 
The end of the trial date is defined as the date of completion or discontinuation of the trial 
as recorded on the trial completion page or the date of last visit or contact or date of final 


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contact attempt as recorded on the follow-up page of the CRF prepared for the last 
subject completing or withdrawing from the trial. 
3.8.8 
Independent Data Monitoring Committee 
The IDMC will be established to avoid exposing subjects to all potential risks (including 
the risk of death) during the trial period and to ensure the safe conduct of the trial. The 
IDMC will meet regularly and as needed to review the subject demographics and AEs 
and to give advice on the appropriateness of continuing the trial or the necessity of 
modifying the protocol. 
The sponsor will designate the following as IDMC members: 
. 
The IDMC members, their roles, and other details will be specified in a separate 
procedure. 
3.8.9 
Raters 
Table 3.8.9-1 shows persons who are authorized to evaluate each evaluation scale. While 
the 
, 
, ADCS-ADL, and MMSE are allowed to be 
evaluated by persons other than the investigator or subinvestigator, the investigator or 
subinvestigator will check the content and decide whether the data should be adopted. For 
EQ-5D-5L, as described in Section 3.8.5.3 EuroQol 5-Dimension 5-Level Health 
Questionnaire, the caregiver will evaluate the subject and himself/herself. 
For CMAI, the same rater will evaluate the same subject throughout the trial period. For 
CGI-S, CGI-I, DIEPSS, AIMS, BARS, S-STS, 
, 
, 
ADCS-ADL, and MMSE, the same rater will evaluate the same subject throughout the 
trial period whenever possible. 
Evaluations using the CMAI, 
, and 
will be conducted 
by a rater who has been trained and certified for the trial. Evaluations using the CGI-S, 
CGI-I, DIEPSS, AIMS, BARS, S-STS, ADCS-ADL, and MMSE will be conducted by 
the rater who has been trained for the trial. 
The investigator or subinvestigator will check how evaluations are being conducted and 
their content after receiving training for the trial. 


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Table 3.8.9-1 
Raters of Evaluation Scales 
 
Investigator or 
Subinvestigator 
Clinical 
Psychologist 
(Including Clinical 
Psychological 
Technologist) 
Occupational 
Therapist 
Speech-
language-
Hearing 
Therapist 
Nurse 
CMAI 
○ 
 
 
 
 
  
 
○ 
○ 
○ 
 
 
CGI-S 
○ 
 
 
 
 
CGI-I 
○ 
 
 
 
 
DIEPSS 
○ 
 
 
 
 
AIMS 
○ 
 
 
 
 
BARS 
○ 
 
 
 
 
S-STS 
○ 
 
 
 
 
ADCS-ADL 
○ 
○ 
○ 
 
 
MMSE 
○ 
○ 
○ 
○ 
○ 
 
3.9 
Stopping Rules, Withdrawal Criteria, and Procedures 
3.9.1 
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 the regulatory requirements. 
3.9.2 
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. 
3.9.3 
Individual Subject Discontinuation 
3.9.3.1 
Treatment Discontinuation 
After randomization, a subject may stop treatment permanently for a variety of reasons. 
Treatment discontinuations may be initiated by a subject who is not satisfied with the 
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. Regardless, 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 3.9.3.4 Procedures to Encourage Continued Trial 
Participation. 


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3.9.3.2 
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 
one main reason for discontinuation will be recorded in the CRF. 
• Adverse event 
− Death 
− 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). 
• SAE 
− The subject experiences worsening of agitation, and the investigator or 
subinvestigator judges that the subject should be withdrawn from the trial 
(worsening of agitation is to be reported as an AE). 
− The subject decides to discontinue the treatment because of annoyance or 
discomfort due to a nonserious AE that is not otherwise determined to be an 
undue hazard. 
• Subjects becoming bedridden and requiring assistance for excretion, eating, and 
changing clothes 
• Subject’s withdrawal of informed consent 
• Legally acceptable representative’s withdrawal of informed consent 
• Caregiver’s withdrawal of informed consent 
• Marked noncompliance with the IMP regimen (compliance rate of < 65% during the 
interval between the previous date of compliance verification and the current date of 
compliance verification) 
• Protocol deviation (other than marked noncompliance with the IMP regimen) 
− The subject is discovered to have not met the inclusion/exclusion criteria. 
− The subject has received any prohibited concomitant drugs or therapies or is 
judged to be in need of prohibited drugs or therapies. 
− The subject requires a change in care environmenta (for reasons other than AE 
occurrence) before the completion of the examinations at the end of IMP 
administration. 
• Lost to follow-up 
• Lack of efficacy 
• Pregnancy (see Section 5.5 Pregnancy) 
• Termination of all or part of the trial by the sponsor 
• Investigator or subinvestigator’s judgment (for reasons other than occurrence of AE) 
• Other 


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a A change in the environment under which the subject’s condition is being followed, as specified in 
Inclusion Criterion 4 (see Section 3.4.2 Inclusion Criteria). 
 
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 3.9.3.1 Treatment Discontinuation must be followed. 
3.9.3.3 
Withdrawal of Consent 
All subjects (including their legal representatives and caregivers) 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 to 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 


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not equivalent to a complete withdrawal of consent for further participation (see 
Section 3.9.3.1 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 3.9.3.2 
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. 
3.9.3.4 
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. 
3.10 
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 has not been randomized 
or has not been assigned to a treatment group. For screen failures, the following 
information will be recorded in the CRF: 
• Subject ID  
• Date of informed consent 
• Date of visit 
• Subject demographics (date of investigation, date of birth, sex, race, ethnicity, and 
country where trial is performed) 
• Results of eligibility criteria assessment 
• Date of assessment as screen failure 
• Reason for screening failure 
Subjects participating in this trial who fall under any of the exclusion criteria in the 
screening examination may undergo rescreening only if there is a change in the particular 
exclusion criterion that they met. If rescreening can be performed within the allowable 
time window for the screening period, there is no need to obtain reconsent, and only the 
tests relevant to the item that has changed need to be performed. If rescreening cannot be 
performed within the allowable time window for the screening period, written informed 


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consent must be newly obtained, and a new subject ID must be assigned prior to the 
screening examination. 
3.11 
Definition of Completed Subjects 
The treatment period is defined as the time period during which subjects are evaluated for 
the primary and/or secondary objectives of the trial (corresponding to the treatment 
period in this trial) irrespective of whether the subject has 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 10 will be defined as trial completers. 
3.12 
Definition of Subjects Lost to Follow-up 
Subjects who can no longer be contacted during 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.” 
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 that 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. When a subject is lost to follow-up, the results of the investigation (whether or not 
the subject could be contacted and the date and method of contact) will be recorded in the 
source documents and the CRF. 
3.13 
Subject Compliance 
For this trial, subjects will receive care under the same environment from at least 3 weeks 
before the date of baseline evaluations to the completion of the examinations scheduled at 
the completion or discontinuation of IMP administration. If a change in the subject’s care 
environment is unavoidable, the subject’s participation in the trial should be 
discontinued. In the case of discontinuation, the necessary measures must be followed in 
accordance with Section 3.9 Stopping Rules, Withdrawal Criteria, and Procedures. 


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3.14 
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. The process of the decision for trial continuation 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 CRF. 
4 
Restrictions 
4.1 
Prohibited Medications 
Drugs shown in Table 4.1-1 except for brexpiprazole are prohibited until completion of 
the examinations scheduled at the completion or discontinuation of IMP administration. 
Brexpiprazole is prohibited until completion of follow-up observation. 
Table 4.1-1 
Prohibited Medications 
Drug Type 
Prohibited Period 
Before Baseline 
Evaluation 
Remarks 
Antipsychotics 
 
 
• 
Clozapine 
30 days 
Brexpiprazole is prohibited until 
completion of follow-up 
observation 
• 
Sustained release injections 
1.5 cycles 
• 
Brexpiprazole 
Any past use 
 
• 
Other antipsychotics 
7 days 
 
Antidepressants 
7 days 
 
Mood stabilizers 
7 days 
 
Psychostimulants 
7 days 
 
Narcotic analgesics for agitation 
7 days 
 
Yokukansan and other herbal medicines and 
supplements for treatment of BPSD 
7 days 
 
Adrenaline 
7 days 
 
Antiepileptic drugs 
7 days 
 
Antiparkinson drugs 
7 days 
 
Varenicline 
7 days 
 
Benzodiazepines 
7 days 
 
Belsomra 
7 days 
 
Lemborexant 
7 days 
 


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Table 4.1-1 
Prohibited Medications 
Drug Type 
Prohibited Period 
Before Baseline 
Evaluation 
Remarks 
Drugs (β-blockers) for extrapyramidal 
symptoms 
7 days 
If administration is necessary due 
to AEs that occur after IMP 
administration, use will be 
permitted in accordance with the 
stipulations for restricted drugs. 
CYP2D6 inhibitors, CYP3A4 inhibitors and 
inducersa 
7 days 
 
asee Table 4.1-2 
 
Table 4.1-2 
Prohibited Concomitant CYP2D6 Inhibitors, CYP3A4 
Inhibitors, and CYP3A4 Inducers (Except for External Use) 
CYP2D6 
inhibitors 
 
CYP3A4 
inhibitors 
 
 
CYP3A4 
inducers 
 
 
 
4.2 
Restricted Medications 
Use of drugs listed in Table 4.2-1 from the baseline evaluation to the completion of the 
examinations scheduled at the completion or discontinuation of IMP administration is 
permitted under the prescribed restrictions. If the following restrictions cannot be 
complied with, restricted drugs should be discontinued before the day prior to the first 
day of IMP administration. 
Table 4.2-1 
Restricted Medications 
Drug Type 
Restriction 
Remarks 
Antidementia 
drugs 
These drugs can be continued if the dose and regimen have not been 
changed for 3 months before the baseline evaluation. The dose and 
regimen should remain the same until the completion of the 
examinations scheduled at the completion or discontinuation of IMP 
administration. 
 


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Table 4.2-1 
Restricted Medications 
Drug Type 
Restriction 
Remarks 
Narcotic 
analgesics 
If not used for agitation (eg, pain control, tooth extraction), the use of 
these drugs is permitted from the baseline evaluation to the 
completion of the examinations scheduled at the completion or 
discontinuation of IMP administration. 
 
β-Blockers 
• 
Treatment of complications (eg, cardiovascular diseases) other 
than psychiatric diseases 
These drugs can be continued if they have been used before the 
acquisition of informed consent and the dose and regimen have 
not been changed for  30 days before the baseline evaluation. 
The type, dose, and regimen should remain the same until 
completion of the examinations scheduled at the completion or 
discontinuation of IMP administration (discontinuation or dose 
reduction are permitted only when these actions are necessary due 
to AEs caused by β-blockers and for remission of symptoms). 
• 
Treatment of extrapyramidal symptoms reported as AEs after 
IMP administration 
If medication is necessary, the use at a dose up to the equivalent 
of 60 mg/day of propranolol is permitted. These drugs are 
prohibited within 12 hours prior to efficacy and safety 
assessments. 
 
Hypnotics 
• 
Ultra-short-acting nonbenzodiazepine hypnotics (zolpidem, 
zopiclone, eszopiclone), ramelteon 
These drugs can be continued if the dose and regimen have not 
been changed for  30 days before the baseline evaluation. The 
type, dose, and regimen should remain the same until completion 
of the examinations scheduled at the completion or 
discontinuation of IMP administration (discontinuation and dose 
reduction are permitted only when these actions are necessary due 
to AEs caused by hypnotics and for remission of the symptoms of 
insomnia). These drugs are prohibited within 8 hours prior to 
efficacy and safety assessments. 
• 
Treatment of insomnia reported as an AE after IMP 
administration 
If medication is necessary, one (change of the type is permitted) 
ultra-short-acting nonbenzodiazepine hypnotic (zolpidem, 
zopiclone or eszopiclone) can be used. These drugs are prohibited 
within 8 hours prior to efficacy and safety assessments. 
 
 
4.3 
Restricted Therapies 
Starting new cognitive function training, cognitive stimulation, cognitive rehabilitation, 
exercise therapy, music therapy, and reminiscence therapy, as nonmedication therapies 
for dementia, and other nonmedication therapies which are judged by the investigator or 
subinvestigator to affect the efficacy and safety assessments is prohibited from baseline 
evaluation until completion of the examinations scheduled at the completion or 
discontinuation of IMP administration. 


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4.4 
Other Restrictions 
 
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 preplanned procedures for which the underlying 
condition was known and no worsening occurred. 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. For the purpose of Investigational New Drug safety reporting, 
“reasonable possibility” means there is evidence to suggest a causal relationship between 
the IMP and the AE. Suspected adverse reaction implies a lesser degree of certainty about 
causality. 
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 


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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. 
 
Immediately Reportable Event (IRE): 
• Any SAE 
• Any AE related to occupational exposure. 
• Potential drug-induced liver injury (see Section 5.4 Potential Drug-induced Liver 
Injury). 
• 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 AE section of the CRF if there is an 
abnormality or complication. 
 
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 determine 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. 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. 
 


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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. 
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 non-leading question: 
“How have you felt since your last visit?” All AEs (serious and nonserious) reported by 
the subject must be recorded in the source documents and CRFs provided by the sponsor. 
The event name, date and time of onset, date and time of recovery, seriousness, severity, 
causal relationship to IMP, actions taken regarding IMP administration, and outcome 
thereof will be recorded in the CRF. The period for AE and SAE collection is defined as 
the period from after a subject has signed the ICF to the date of trial completion. 
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 on the basis of the course of the condition. 
Worsening of severity and seriousness of reported AEs must be reported as new AEs in 
the CRF. 
In addition, the sponsor must be notified immediately by e-mail 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, subinvestigator, or designee must report any and all IREs (see 
Section 5.1 Definitions) 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. An IRE form must be sent by e-mail to the 
sponsor. Please note that the IRE form is NOT the AE section of the CRF. Due 
consideration must be given to the subject’s privacy when an IRE form is sent by e-mail. 
For subjects experiencing SAEs or IREs, such events should be followed until the events 
are resolved or clinically stabilized, or the subject is lost to follow-up. Resolved means 


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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. 
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 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 CRF. 
5.5 
Pregnancy 
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). 
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 final administration 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, IUD, 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 


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Before trial enrollment, WOCBP must be advised of the importance of avoiding 
pregnancy during trial participation and the potential risk factors for an unintentional 
pregnancy. The subject must sign an informed consent form stating that the above-
mentioned risk factors and the consequences were discussed with her. 
All WOCBP must undergo a urine or serum pregnancy test (human chorionic 
gonadotropin [HCG] test) at screening. If a urine test is performed and is positive, the 
investigator or subinvestigator will follow up with a confirmatory serum test. 
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 the start of IMP administration, 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. (Exceptions 
to trial discontinuation may be considered for life-threatening conditions only after 
consultations with the PV department [see the cover page of this protocol for contact 
information].) 
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 final 
administration 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. The same applies to the pregnancy of a subject’s partner. 
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. 


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5.6 
Procedure for Breaking the Blind 
Only in the event that a subject has a medical emergency and knowledge of the treatment 
assignment code is necessary for treatment, the investigator or subinvestigator may obtain 
the emergency key code for the subject in question through the IWRS, in accordance with 
the separately specified procedures. When emergency key code opening is performed, the 
sponsor will receive automatic notification from the IWRS via e-mail. If the emergency 
key code is opened, the PV department must be notified immediately (see the cover page 
of this protocol for contact information).  
Documentation of emergency key code opening should be recorded in the subject’s 
medical record with the date and time of opening and the names of the personnel 
involved. Once a subject’s emergency key code is opened, IMP administration may not 
be reinitiated for that subject. 
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 AE 
section of the CRF, with the current status (ongoing or resolved/recovered) noted. All 
nonserious events (other than IREs) that are ongoing at the end of trial date (final day of 
observation) will be recorded as ongoing in the CRF. For any AE having been identified 
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 the 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 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 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 


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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 
Statistical Analysis 
The definitions of the datasets for analysis and the analysis methods for the specified 
endpoints are described below. The statistical analysis plan details are described in a 
separate Statistical Analysis Plan. The Statistical Analysis Plan will be finalized prior to 
data lock. 
6.1 
Determination of Sample Size 
In Trial 331-12-283, which was performed outside Japan, the 2 mg fixed-dose group 
showed superiority over the placebo group in patients with aggression (patients with 
aggressive behavior at baseline), thus suggesting that it may also be the optimum dose for 
Japanese patients. Efficacy was not observed in the 1 mg fixed-dose group, but in Trial 
331-12-284, the efficacy of a dose less than 2 mg was suggested by the results obtained 
in patients from the flexible-dose (0.5 to 2 mg) group, who had aggression. 
In this trial, a power of detection ≥ 80% will be achieved for comparison between the 
placebo group and the 1 mg group to allow evaluation of superiority over the placebo 
group if equivalent efficacy is demonstrated in the 1 and 2 mg groups. For comparison 
between the 2 mg group (possible optimum dose) and the placebo group, a more 
sufficient power of detection will be obtained by changing the randomization ratio. In this 
trial, it is assumed that the difference between the 2 mg group and the placebo group in 
the change in the CMAI total score from baseline to Week 10 is −5.35, and the standard 
deviation (calculated from the standard error of the difference between the 2 mg and 
placebo groups and the number of subjects at baseline) is 15.06 on the basis of the results 


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of Trial 331-12-283. By setting the number of subjects in the 2 mg group, 1 mg group, 
and placebo group as 148, 111, and 148, respectively (randomization ratio of 4:3:4), the 
power of detection is 86.1% for the comparison between the 2 mg group and the placebo 
group and is 80.5% for the comparison between the 1 mg group and the placebo group in 
a test with a significance level of 5% (two sided). 
On the basis of the above considerations, the number of subjects will be set at 148 in the 
2 mg group, 111 in the 1 mg group, and 148 in the placebo group (randomization ratio of 
4:3:4). 
6.2 
Datasets for Analysis 
6.2.1 
Pharmacokinetic Analysis Set 
The pharmacokinetic analysis set will comprise subjects who have been treated with 
brexpiprazole and for whom plasma drug concentration data have been obtained, other 
than those deemed as “not analyzed” or “not determined.” 
6.2.2 
Full Analysis Set 
The full analysis set (FAS) will comprise subjects who, after randomization, have 
received at least 1 dose of the IMP, and from whom CMAI total scores have been 
obtained at baseline and at least 1 time point after initiation of the treatment. 
6.2.3 
Safety Analysis Set 
The safety analysis set will comprise subjects who, after randomization, have received at 
least 1 dose of the IMP. 
6.3 
Handling of Missing Data 
The primary analysis of the primary endpoint will be performed in the observed cases 
(OC) dataset by mixed models for repeated measures (MMRM) without data imputation 
for missing data under the “missing at random” assumption. As a sensitivity analysis for 
the handling of missing data, placebo multiple imputation and tipping point analysis will 
be performed under the “missing not at random” assumption. Details are described in the 
statistical analysis plan. 
For efficacy and safety analyses, the last observation carried forward (LOCF) method (in 
which missing post-dose data are imputed by the last observed data after initiation of IMP 
treatment) will be used as needed. 
For pharmacokinetic analysis, no imputation will be performed for missing data. 


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6.4 
Primary and Secondary Endpoint Analyses 
6.4.1 
Primary Endpoint Analyses 
The primary endpoint will be change in CMAI total score from baseline to Week 10. 
The primary analysis will be conducted on the FAS by using MMRM analysis on the 
basis of the OC data set. For the analysis model, the treatment group (brexpiprazole 1 mg 
group, brexpiprazole 2 mg group, or placebo group), time point (Weeks 2, 4, 6, 8, or 10), 
medical care category (hospitalized or outpatient), prior use of antipsychotics (yes or no), 
and interaction between treatment group and time point will be included as factors, the 
baseline and interaction between the baseline and time point will be included as 
covariates, and the error variance and covariance structure will be unstructured. The 
Kenward–Roger method will be used to determine the degrees of freedom. 
Between-group comparison will be performed by calculating the difference of the least 
squares mean between each of the brexpiprazole groups and the placebo group at 
Week 10. The fixed sequence procedure will be used to adjust the multiplicity of testing 
due to the performance of two comparisons (ie, the brexpiprazole 1 mg group versus the 
placebo group and the brexpiprazole 2 mg group versus the placebo group) to control the 
overall type I error rate. Initially, the brexpiprazole 2 mg group will be compared with the 
placebo group. Only if the difference is statistically significant at a significance level of 
5% (two sided), the brexpiprazole 1 mg group will be compared with the placebo group 
at a significance level of 5% (two sided). 
The least squares mean for each treatment group and the difference of the least squares 
mean between each brexpiprazole group and the placebo group, as well as their two-sided 
95% CIs, will be calculated at each time point. 
If any problems in convergence status arise in the estimation of variance components of 
MMRM, heterogeneous Toeplitz, heterogeneous autoregressive of order 1, and 
heterogeneous compound symmetry, which are error variance-covariance structures, will 
be applied in this order, and the first structure that achieves convergence will be used in 
the primary analysis. If anything other than an unstructured variance-covariance structure 
is selected, a sandwich estimator for standard errors will be used. 
6.4.2 
Secondary Endpoint Analyses 
The secondary endpoint analysis will be performed on the FAS. 
• Changes in CMAI subscales (Aggressive Behavior, Physically Non-aggressive 
Behavior, and Verbally Agitated Behavior) from baseline at Week 10 
• Change in CGI-S related to agitation from baseline to Week 10 


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The same MMRM analysis as that for the primary endpoint will be performed using the 
OC dataset. 
• CGI-I at Week 10 
Each brexpiprazole group will be compared with the placebo group by the Cochran 
Mantel Haenszel (CMH) Row Mean Scores test with medical care category (inpatient or 
outpatient) and prior use of antipsychotics (yes or no) as strata using the LOCF dataset. 
Mean values in each treatment group, differences in mean values between each 
brexpiprazole group and the placebo group, and their two-sided 95% CIs will be 
calculated. 
6.4.3 
Exploratory Endpoint Analyses 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
 
 
 
• 
 
• 
 
 
 
 
6.4.4 
Interim Analysis 
Safety will be evaluated by the IDMC when approximately 25%, 50%, and 75% of the 
target number of subjects have completed or discontinued the trial. 
6.4.5 
Subgroup Analyses 
The same MMRM analysis as that for the primary endpoint will be performed on the 
change in CMAI total score from baseline to Week 10 for each of the subgroup 


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categories within each of the following items using the OC dataset (in the subgroup 
analyses of medical care category and prior use of antipsychotics, those particular factors 
will be excluded from the respective analysis models). 
• Medical care category (inpatient or outpatient) 
• Prior use of antipsychotics (yes or no) 
• Type of caregiver (hospital staff, care facility staff, family, or other)  
• Sex (male or female)  
• Age (< 80 or ≥ 80) 
• CMAI total score at baseline (< 56 or ≥ 56) 
• 
 
• Body weight (≤ median or > median) 
• Body mass index (BMI) (≤ median or > median) 
 
6.5 
Analysis of Demographic and Baseline Characteristics 
Descriptive statistics or frequency distribution of demographic and other baseline 
characteristics will be determined for each treatment group and for the overall 
brexpiprazole group in each analysis dataset. 
6.6 
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. 
6.6.1 
Adverse Events 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). The incidence of the following events will be summarized by treatment 
group and by the overall brexpiprazole group, according to system organ class and 
preferred term. 
• 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 potentially causally related to the IMP will also be summarized in the same 
manner. 


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6.6.2 
Clinical Laboratory Data 
For each quantitative laboratory parameter, descriptive statistics of actual measurements 
and changes from baseline at each time point will be calculated for each treatment group 
and for the overall brexpiprazole group. 
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 treatment group and for the overall brexpiprazole group. 
For each qualitative laboratory parameter, a shift table from baseline will be produced for 
each treatment group and for the overall brexpiprazole group. 
Numbers and proportions of subjects with potentially clinically significant laboratory test 
values will be determined for each treatment group and for the overall brexpiprazole 
group. 
6.6.3 
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 will be calculated for each treatment group and for the 
overall brexpiprazole group. 
Numbers and proportions of subjects with potentially clinically significant vital signs will 
be determined for each treatment group and for the overall brexpiprazole group. 
6.6.4 
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 will be 
calculated for each treatment group and for the overall brexpiprazole group. 
A shift table from baseline for normal/abnormal 12-lead ECG will be produced for each 
treatment group and for the overall brexpiprazole group. 
Numbers and proportions of subjects with actual measurements of corrected QT interval 
(QTcF, QTcB, and QTcN) at each time point of > 450 msec, > 480 msec, and > 500 msec 
will be determined for each treatment group and for the overall brexpiprazole group. 
Numbers and proportions of subjects with changes from baseline of > 30 msec and 
> 60 msec will be determined for each treatment group and for the overall brexpiprazole 
group. 


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Numbers and proportions of subjects with ECG results meeting the criteria for potentially 
clinically significant ECG data will be determined for each treatment group and for the 
overall brexpiprazole group. 
6.6.5 
Other Safety Data 
6.6.5.1 
Body Weight and Body Mass Index 
For body weight and BMI, descriptive statistics of actual measurements and changes 
from baseline at each time point will be calculated for each treatment group and for the 
overall brexpiprazole group. 
In addition, using the LOCF data set, analysis will be performed by the analysis of 
covariance (ANCOVA) model with treatment group, medical care category (hospitalized 
or outpatient), and prior use of antipsychotics (yes or no) as factors and baseline as a 
covariate. Least square means of each treatment group and differences in least square 
means between each brexpiprazole group and the placebo group, as well as the two-sided 
95% CIs will be determined. 
Numbers and proportions of subjects with results meeting the criteria for potentially 
clinically significant body weight gain or loss will be determined for each treatment 
group and for the overall brexpiprazole group. 
6.6.5.2 
DIEPSS, AIMS, and BARS 
For DIEPSS total score (total of scores for items 1 through 8) and score for each DIEPSS 
item, AIMS total score (total of scores for items 1 through 7) and score for each of the 3 
global judgment items (items 8 through 10), and BARS, descriptive statistics of actual 
measurements and changes from baseline at each time point will be calculated for each 
treatment group and for the overall brexpiprazole group. 
In addition, using the LOCF data set, analysis will be performed by the ANCOVA model 
with treatment group, medical care category (hospitalized or outpatient), and prior use of 
antipsychotics (yes or no) as factors and baseline as a covariate. Least square means of 
each treatment group and differences in least square means between each brexpiprazole 
group and the placebo group, as well as the two-sided 95% CIs will be determined. 
6.6.5.3 
S-STS 
For each item of S-STS, descriptive statistics of actual measurements and changes from 
baseline at each time point will be calculated for each treatment group and for the overall 
brexpiprazole group. 


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In addition, using the LOCF data set, analysis will be performed by the ANCOVA model 
with treatment group, medical care category (hospitalized or outpatient), and prior use of 
antipsychotics (yes or no) as factors and baseline as a covariate. Least square means of 
each treatment group and differences in least square means between each brexpiprazole 
group and the placebo group, as well as the two-sided 95% CIs will be determined. 
6.7 
Analysis of Pharmacokinetic Endpoints 
Descriptive statistics of plasma drug concentration at the time of blood sampling 
(Week 10) will be calculated for each dose group. 
6.8 
Analysis of Pharmacogenomic Endpoints 
A list of data obtained from CYP2D6 genetic assessment will be provided without 
summarization. 
6.9 
Genomic/Genetic Analysis 
See Section 3.8.4.2.2 5) Genomic/Genetic Analysis for genomic/genetic analysis. 
6.10 
Biomarker Exploration Analysis 
See Section 3.8.4.3 5) Biomarker Exploration for biomarker exploration analysis. 
6.11 
Analysis of Other Endpoints 
Analysis of other endpoints 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. 
• ADCS-ADL 
• MMSE 
• EQ-5D-5L 
 
For ADCS-ADL total score, MMSE total score and each item of EQ-5D-5L, descriptive 
statistics of actual measurements and changes from baseline at each time point will be 
calculated for each treatment group and for the overall brexpiprazole group. 
In addition, using the LOCF data set, analysis will be performed by the ANCOVA model 
with treatment group, medical care category (hospitalized or outpatient), and prior use of 
antipsychotics (yes or no) as factors and baseline as a covariate. Least square means of 
each treatment group and differences in least square means between each brexpiprazole 
group and the placebo group, as well as the two-sided 95% CIs will be determined. 


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7 
Management of Investigational Medicinal Product 
Refer to the investigator’s brochure on brexpiprazole and the separately-specified manual 
for details regarding IMP management. 
7.1 
Packaging and Labeling 
The IMP will be provided to the IMP manager by the sponsor or designated agent. The 
IMP will be supplied as 
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. 
7.2 
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. 
7.3 
Accountability 
The IMP manager must maintain an inventory record of IMP received, dispensed, 
administered, or returned. 
7.4 
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 
 
The assigned trial 
monitor will facilitate the return of unused and/or partially used IMP. 
7.5 
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 


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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) 
• 
 
• Product defect (eg, odor, chipped, broken, embossing illegible) 
• Loss or theft of product 
 
7.5.1 
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 7.5.2 Information Required for Reporting Product Quality 
Complaints. (
) 
Identification of a PQC by the subject should be reported to the investigator or 
subinvestigator, who should then follow the reporting mechanisms listed above. 
7.5.2 
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 
 
7.5.3 
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. 


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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. 
7.5.4 
Assessment/Evaluation 
Assessment and evaluation of PQCs will be handled by the sponsor. 
8 
Records Management 
8.1 
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 regional 
regulatory requirements. 
8.2 
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 commencement of 
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 medical records. 
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 


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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 
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 
system. Changes to the data will be captured by an automatic audit trail. 
Subject diaries collected by caregivers (original documents) will be kept by the study site. 
8.3 
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. 
8.4 
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 four 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 
• Until the date on which it is decided to end biomarker sample 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. 


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9 
Quality Control and Quality Assurance 
9.1 
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 regional 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 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. 
9.2 
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. 
10 
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 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 CRFs and IRE forms, the investigator or 
subinvestigator and their staff will take measures to ensure adequate care in protecting 
subject privacy. To this end, a subject number or 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. 
11 
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 


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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. 
Subjects will be identified only by a unique subject ID in the 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. 
12 
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. 
13 
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: 


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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. 
 
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. 
14 
References 
1 
Ministry of Health, Labour and Welfare. Let’s start with knowing—Comprehensive 
Website on Everyone's Mental Health:  Website regarding mental health, mental 
illnesses, support and service. [Internet]. Tokyo: Ministry of Health, Labour and 
Welfare; Accessed on 09 Jan 2018. Access: 
http://www.mhlw.go.jp/kokoro/speciality/detail_recog.html. 
2 
Honma A, Usui M. Basic knowledge on dementia. Monthly Shiho Shoshi. 
2011;472:11-6. 
3 
Kudo T, Takeda M. General theory on BPSD. Japanese Journal of Geriatric 
Psychiatry. 2005;16:9-15. 
4 
Cerejeira J, Lagarto L, Mukaetova-Ladinska EB. Behavioral and psychological 
symptoms of dementia. Front Neurol. 2012;3:73. 
5 
Cummings J, Mintzer J, Brodaty H, Sano M, Banerjee S, Devanand DP, et al. 
Agitation in cognitive disorders: International Psychogeriatric Association 
provisional consensus clinical and research definition. Int Psychogeriatr. 2015;27:7-
17. 
6 
Shimabukuro J, Awata S, Matsuoka H. Behavioral and psychological symptoms of 
dementia characteristic of mild Alzheimer patients. Psychiatry Clin Neurosci. 
2005;59:274-9. 
7 
Tractenberg RE, Weiner MF, Patterson MB, Teri L, Thal LJ. Comorbidity of 
psychopathological domains in Community-dwelling persons with Alzheimer’s 
disease. J Geriatr Psychiatry Neurol. 2003;16:94-9. 
8 
Scarmeas N, Brandt J, Blacker D, Albert M, Hadjigeorgiou G, Dubois B, et al. 
Disruptive Behavior as a Predictor in Alzheimer Disease. Arch Neurol. 
2007;64:1755-61. 


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9 
D’Onofrio1 G, Sancarlo D, Panza F, Copetti M, Cascavilla L, Paris F, et al. 
Neuropsychiatric Symptoms and Functional Status in Alzheimer’s Disease and 
Vascular Dementia Patients. Curr Alzheimer Res. 2012;9:759-71. 
10 Peters ME, Schwartz S, Han D, Rabins PV, Steinberg M, Tschanz JT, et al. 
Neuropsychiatric symptoms as predictors of progression to severe Alzheimer’s 
dementia and death: The Cache County Dementia Progression Study. Am J 
Psychiatry. 2015;172:460-5. 
11 Cheng ST. Dementia Caregiver Burden: a Research Update and Critical Analysis. 
Curr Psychiatry Rep. 2017;19:64. 
12 Hiyoshi-Taniguchi K, Becker CB, Kinoshita A. What Behavioral and Psychological 
Symptoms of Dementia Affect Caregiver Burnout?. Clin Gerontol. 2018;41:249-54. 
13 Okura T, Langa KM. Caregiver Burden and Neuropsychiatric Symptoms in Older 
Adults with Cognitive Impairment: The Aging, Demographics, and Memory Study 
(ADAMS). Alzheimer Dis Assoc Disord. 2011;25:116-21. 
14 Gilley DW, Bienias JL, Wilson RS, Bennett DA, Beck TL, Evans DA. Influence of 
behavioral symptoms on rates of institutionalization for persons with Alzheimer’s 
disease. Psychol Med. 2004;34:1129-35. 
15 Knapp M, Chua KC, Broadbent M, Chang CK, Fernandez JL, Milea D, et al. 
Predictors of care home and hospital admissions and their costs for older people with 
Alzheimer’s disease: findings from a large London case register. BMJ Open. 
2016;6:e013591. 
16 Morris S, Patel N, Baio G, Kelly L, Lewis-Holmes E, Omar RZ, et al. Monetary costs 
of agitation in older adults with Alzheimer's disease in the UK: prospective cohort 
study. BMJ Open. 2015;5:e007382. 
17 Committee on Practice Guideline for Dementia. Practice Guideline for Dementia 
2017. Japanese Society of Neurology. Tokyo: Igaku Shoin; 2017. CQ 3B-2, What are 
the effective non-pharmacological and pharmacological therapies for agitation?; p.74-
6. 
18 Committee on Practice Guideline for Dementia. Practice Guideline for Dementia 
2017. Japanese Society of Neurology. Tokyo: Igaku Shoin; 2017. CQ 3A-2, How to 
perform non-pharmacological therapy, pharmacological therapy and care when 
treating dementia; p.56-8. 
19 Schneider LS, Dagerman KS, Insel P. Risk of Death with Atypical Antipsychotic 
Drug Treatment for Dementia. JAMA. 2005;294:1934-43. 
20 Arai H, Nakamura Y, Taguchi M, Kobayashi H, Yamauchi K, Schneider LS, et al. 
Mortality risk in current and new antipsychotic Alzheimer's disease users: Large scale 
Japanese study. Alzheimer Dement. 2016;12:823-30. 
21 Liu KY, Stringer AE, Reeves SJ, Howard RJ. The neurochemistry of agitation in 
Alzheimer's disease: a systematic review. Ageing Res Rev. 2018;43:99-107. 
22 Rabinowitz J, Davidson M, De Deyn PP, Katz I, Brodaty H, Cohen-Mansfield J. 
Factor Analysis of the Cohen-Mansfield Agitation Inventory in Three Large Samples 
of Nursing Home Patients with Dementia and Behavioral Disturbance. Am J Geriatr 
Psychiatry. 2005;13:991-8. 


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23 Cohen-Mansfield J. INSTRUCTION MANUAL FOR THE COHEN-MANSFIELD 
AGITATION INVENTORY (CMAI). [Internet]. [cited Accessed on January 9, 
2018]. Available from: 
https://www.pdx.edu/ioa/sites/www.pdx.edu.ioa/files/CMAI_Manual%20(1).pdf 
24 Otsuka Pharmaceutical. Summary of application data for REXULTI 1 mg tablets and 
REXULTI 2 mg tablets. [Internet]. Tokyo: PMDA; Accessed on 08 May 2018. 
Access: http://www.pmda.go.jp/drugs/2018/P20180207001/index.html. 
25 Regarding Clinical Studies Utilizing Pharmacogenomics: PFSB/ELD Notification 
No. 0930007, 30 Sep 2008.  
26 Committee on Practice Guideline for Dementia. Practice Guideline for Dementia 
2017. Japanese Society of Neurology. Tokyo: Igaku Shoin; 2017. CQ 3A-3, What are 
the precautions and principles of pharmacological therapy for elderly patients with 
dementia?; p. 59-60. 
27 International Conference on Harmonisation. Guideline for Good Clinical Practice: 
E6(R1). Geneva, Switzerland: International Conference on Harmonisation; 1996. 
28 Schreiner AS, Yamamoto E, Shiotani H. Agitated Behavior in Elderly Nursing Home 
Residents With Dementia in japan. J Gerontol B Psychol Sci Soc Sci. 2000;55:P180-
6. 
 


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Appendix 1 
 
 
 
 
 
 
 
 
 


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Appendix 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2


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Appendix 3 
Protocol Amendments/Administrative Changes 
 
Amendment: Number: 1 
Issue Date: 
24 Aug 2018 
 
PURPOSE: 
 
 
BACKGROUND: 
 
 
MODIFICATIONS TO PROTOCOL: 
Sectional Revisions: 
Location 
Before Change 
After Change 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Location 
Before Change 
After Change 
 
 
 
 
 
 
 
 
 
 


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Location 
Before Change 
After Change 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Location 
Before Change 
After Change 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
ADDITIONAL RISK TO THE SUBJECT 
 
 
 


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Amendment: Number: 2 
Issue Date: 
05 Mar 2020 
 
PURPOSE: 
 
 
BACKGROUND: 
 
 
 
MODIFICATIONS TO PROTOCOL: 
Sectional Revisions: 
Location 
Before Change 
After Change 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Location 
Before Change 
After Change 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Location 
Before Change 
After Change 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Location 
Before Change 
After Change 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Location 
Before Change 
After Change 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Location 
Before Change 
After Change 
 
 
 
 
 
 
 
 
 
ADDITIONAL RISK TO THE SUBJECT 
 
 
 


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Amendment: Number: 3 
Issue Date: 
03 Feb 2021 
 
PURPOSE: 
 
 
BACKGROUND: 
 
 
MODIFICATIONS TO PROTOCOL: 
Sectional Revisions: 
Location 
Before Change 
After Change 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ADDITIONAL RISK TO THE SUBJECT 
. 


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Amendment: Number: 4 
Issue Date: 
27 Apr 2022 
 
PURPOSE: 
 
 
BACKGROUND: 
 
 
MODIFICATIONS TO PROTOCOL: 
Sectional Revisions: 
Location 
Before Change 
After Change 
 
 
 
 
 
 
 
ADDITIONAL RISK TO THE SUBJECT 
 
 
 


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Amendment: Number: 5 
Issue Date: 
24 Nov 2022 
 
PURPOSE: 
 
 
BACKGROUND: 
 
 
MODIFICATIONS TO PROTOCOL: 
Sectional Revisions: 
Location 
Before Change 
After Change 
 
 
 
 
 
 
 
ADDITIONAL RISK TO THE SUBJECT 
 


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Agreement 
I, the undersigned principal investigator, have read and understand the protocol 
(including the Investigator's Brochure) and agree that it contains all the ethical, legal and 
scientific information necessary to conduct this trial in accordance with the principles of 
Good Clinical Practices and as described herein and in the sponsor's (or designee's) 
Clinical Trial Agreement. 
I will provide copies of the protocol to all physicians, nurses, and other professional 
personnel to whom I delegate trial responsibilities. I will discuss the protocol with them 
to ensure that they are sufficiently informed regarding the investigational new drug, 
OPC-34712, the concurrent medications, the efficacy and safety parameters and the 
conduct of the trial in general. I am aware that this protocol must be approved by the 
Institutional Review Board (IRB) responsible for such matters in the clinical trial facility 
where OPC-34712 will be tested prior to commencement of this trial. I agree to adhere 
strictly to the attached protocol (unless amended in the manner set forth in the sponsor's 
Clinical Trial Agreement, at which time I agree to adhere strictly to the protocol as 
amended). 
I understand that this IRB-approved protocol will be submitted to the appropriate 
regulatory authority/ies by the sponsor. I agree that clinical data entered on case report 
forms by me and my staff will be utilized by the sponsor in various ways, such as for 
submission to governmental regulatory authorities and/or in combination with clinical 
data gathered from other trial sites, whenever applicable. I agree to allow sponsor and 
designee monitors and auditors full access to all medical records at the trial site for 
subjects screened or enrolled in the trial. 
I agree to await IRB approval before implementation of any substantial amendments to 
this protocol. If, however, there is an immediate hazard to subjects, I will implement the 
amendment immediately, and provide the information to the IRB within the required 
local applicable timelines. Administrative changes to the protocol will be transmitted to 
the IRB for informational purposes only, if required by local regulations. 
I agree to provide all subjects with informed consent forms, as required by the applicable 
regulations and by ICH guidelines. I agree to report to the sponsor any adverse events in 
accordance with the terms of the sponsor's Clinical Trial Agreement and the relevant 
regional regulation(s) and guideline(s). I further agree to provide all required information 
regarding financial certification or disclosure to the sponsor for all investigators and 
subinvestigators in accordance with the terms of the relevant regional regulation(s). I 
understand that participation in the protocol involves a commitment to publish the data 
from this trial in a cooperative publication before publication of efficacy and safety 


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results on an individual basis may occur, and I consent to be acknowledged in any such 
cooperative publications that result. 
 
 
 
 
 
 
   
 
 
 
 
 
 
Principal Investigator’s Name 
  Name of Trial Site 
 
___________________________________   
 
Signature 
 
 
 
 
Date 
 
The sponsor’s signature for this Agreement is provided as an electronic signature. The 
electronic signature page is attached to this Agreement. 
 

SAP_001.pdf: 
 
 
STATISTICAL  ANALYSIS  PLAN 
 
 
 
A multicenter, randomized, double-blind, placebo-controlled, parallel-group comparison trial to 
evaluate the efficacy and safety of brexpiprazole (OPC-34712) in the treatment of patients with 
agitation associated with dementia of the Alzheimer’s type 
 
 
 
 
 
 
 
NCT Number: NCT03620981 
Protocol No. 331-102-00088 
Version Date: 01 Jun 2023 (Version 1.0) 


Statistical Analysis Plan
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Otsuka Pharmaceutical Co., Ltd.
Investigational New Drug Brexpiprazole (OPC-34712)
Protocol No. 331-102-00088
A multicenter, randomized, double-blind, placebo-controlled, parallel-group comparison 
trial to evaluate the efficacy and safety of brexpiprazole (OPC-34712) in the treatment of 
patients with agitation associated with dementia of the Alzheimer’s type
Statistical Analysis Plan
Version: 1.0
Date: 01 Jun 2023
Protocol Version 6 Date: 24 Nov 2022
Confidential
May not be used, divulged, published, or otherwise disclosed without the prior written 
consent of Otsuka Pharmaceutical Co., Ltd
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Table of Contents
Table of Contents ..........................................................................................2
List of Appendices .........................................................................................5
List of Abbreviations and Definition of Terms...........................................6
1
Introduction .........................................................................................................8
2
Trial Objectives...................................................................................................8
3
Trial Design.........................................................................................................8
3.1
Type/Design of Trial.........................................................................................8
3.2
Trial Treatments................................................................................................9
3.3
Trial Population ..............................................................................................10
3.4
Trial Visit Window.........................................................................................10
3.5
Handling of Endpoints....................................................................................10
3.5.1
Cohen-Mansfield Agitation Inventory (CMAI)..........................................10
3.5.2
Clinical Global Impression - Severity of Illness (CGI-S)...........................11
3.5.3
Clinical Global Impression - Improvement (CGI-I) ...................................11
3.5.4
..............................................................11
3.5.5
.....................................................................11
3.5.6
Drug Induced Extra-Pyramidal Symptoms Scale (DIEPSS) ......................11
3.5.7
Abnormal Involuntary Movement Scale (AIMS) .......................................11
3.5.8
Sheehan Suicidality Tracking Scale (S-STS)..............................................11
3.5.9
Alzheimer’s Disease Cooperative Study - Activities of Daily Living 
(ADCS-ADL)..............................................................................................12
3.5.10
Mini-Mental State Examination (MMSE) ..................................................12
4
Sample Size.......................................................................................................12
5
Statistical Analysis Datasets..............................................................................13
5.1
Pharmacokinetic Analysis Set ........................................................................13
5.2
Full Analysis Set.............................................................................................13
5.3
Safety Analysis Set.........................................................................................13
5.4
Handling of Missing Data...............................................................................13
6
Primary and Secondary Outcome Variables .....................................................13
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6.1
Primary Endpoint............................................................................................13
6.2
Secondary Endpoints ......................................................................................13
7
Disposition and Demographic Analysis............................................................14
7.1
Subject Disposition.........................................................................................14
7.2
Demographic and Baseline Characteristics ....................................................14
7.3
Baseline Disease Evaluation...........................................................................14
7.4
Treatment Compliance....................................................................................14
7.5
Prior and Concomitant Medications...............................................................15
7.6
Protocol Deviations ........................................................................................15
8
Efficacy Analysis ..............................................................................................15
8.1
Primary Efficacy Endpoint .............................................................................15
8.1.1
Primary Efficacy Analysis ..........................................................................15
8.1.2
Sensitivity Analyses....................................................................................16
8.1.2.1
Sensitivity Analysis for Handling of Missing Data.................................16
8.1.2.2
Sensitivity Analysis for Normality Assumption......................................17
8.1.3
Technical Computational Details for Primary Efficacy Analysis...............17
8.2
Secondary Efficacy Analyses .........................................................................18
8.3
Subgroup Analyses.........................................................................................18
8.4
Exploratory or Other Analyses.......................................................................19
8.4.1
Exploratory Endpoint Analyses ..................................................................19
8.4.2
Other Analyses ...........................................................................................19
9
Safety Analyses.................................................................................................20
9.1
Extent of Exposure .........................................................................................20
9.2
Adverse Events...............................................................................................20
9.2.1
Adverse Events of Interest ..........................................................................21
9.2.2
Subgroup Analysis of Adverse Events........................................................21
9.3
Clinical Laboratory Data ................................................................................22
9.4
Vital Sign Data ...............................................................................................23
9.5
Physical Examination Data.............................................................................23
9.6
Electrocardiogram Data..................................................................................23
9.7
Other Safety Data ...........................................................................................24
9.7.1
Body Weight and Body Mass Index ...........................................................24
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9.7.2
DIEPSS, AIMS, and BARS ........................................................................24
9.7.3
Sheehan Suicidality Tracking Scale............................................................25
10
Pharmacokinetic Analyses ................................................................................25
11
Pharmacodynamic Analyses..............................................................................26
12
Pharmacogenomic Analyses..............................................................................26
13
Analysis of Other Endpoints .............................................................................26
14
Interim Analysis ................................................................................................26
15
Changes in the Planned Analyses......................................................................27
16
References .........................................................................................................27
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List of Appendices
Appendix 1
Criteria for Identifying Vital Signs and Weight of Potential 
Clinical Relevance.........................................................................28
Appendix 2
Criteria for Identifying Laboratory Values of Potential 
Clinical Relevance.........................................................................29
Appendix 3
Criteria for Identifying ECG Measurements of Potential 
Clinical Relevance.........................................................................30
Appendix 4
Adverse Events of Interest.............................................................31
Appendix 5
List of Summary Tables...............................................................102
Appendix 6
List of Subject Data Listings .......................................................110
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List of Abbreviations and Definition of Terms
Abbreviation
Definition
ADCS-ADL
Alzheimer’s Disease Cooperative Study - Activities of Daily Living
AIMS
Abnormal Involuntary Movement Scale
ALT
Alanine aminotransferase
ANCOVA
Analysis of covariance  
AST
Aspartate aminotransferase
BARS
Barnes Akathisia Rating Scale
BMI
Body mass index
BUN
Blood urea nitrogen
CGI-I
Clinical Global Impression - Global Improvement
CGI-S
Clinical Global Impression - Severity of Illness
CMAI
Cohen-Mansfield Agitation Inventory
CMH
Cochran Mantel Haenszel
CPK
Creatine phosphokinase
CYP
Cytochrome P450
DIEPSS
Drug Induced Extra-Pyramidal Symptoms Scale
EQ-5D-5L
EuroQol 5 dimension 5 level health questionnaire
FAS
Full analysis set
FCS
Fully Conditional Specification
HDL
High-density lipoprotein
IDMC
Independent data monitoring committee
IMP
Investigational medicinal product
LDH
Lactate (lactic acid) dehydrogenase
LDL
Low-density lipoprotein
LOCF
Last observation carried forward
MAR
Missing At Random
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed models for repeated measures 
MMSE
Mini-Mental State Examination
MNAR
Missing Not At Random
OC
Observed cases 
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
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S-STS
Sheehan Suicidality Tracking Scale
TEAE
Treatment-emergent adverse event
ULN
Upper limits of normal
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1
Introduction
This statistical analysis plan documents in detail the statistical analysis methods planned 
for the clinical study report of Trial 331-102-00088.
2
Trial Objectives
The objective of the trial is to evaluate the superiority of brexpiprazole 1 or 2 mg over 
placebo after a 10-week treatment regimen for agitation associated with dementia of the 
Alzheimer’s type in patients who require medication, to investigate the safety of 
brexpiprazole, and to identify the optimum dose.
3
Trial Design
3.1
Type/Design of Trial
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group 
comparison trial to evaluate the efficacy and safety of brexpiprazole in patients with 
agitation associated with dementia of the Alzheimer’s type who require medication. The 
overview of the trial design is shown in Figure 3.1-1.
The trial consists of a screening period, a treatment period, and a follow-up period. The 
investigator or subinvestigator will explain the details of the trial to a prospective subject 
(if the investigator or subinvestigator judges that the subject is incapable of providing 
informed consent or if the subject is hospitalized for reasons related to medical 
protection, the subject’s legally acceptable representative must provide written consent, 
and even when written consent is obtained from the legally acceptable representative, the 
subject should be given an explanation appropriate to his or her level of understanding 
and, if possible, should also provide written consent) and their caregivers using the 
explanatory materials and informed consent form (ICF) and obtain written consent for 
participation in the trial from the patient (or their legally acceptable representatives) and 
caregivers. The subject’s clinical course will be followed in the same environment (see 
Section 3.4.2 Inclusion Criteria, 4 of the protocol) such as hospitalization in the same 
medical facility, institutionalization in the same care facility, and continued care at home 
from at least 3 weeks before baseline evaluation up to the completion of the examinations 
scheduled at the completion or discontinuation of investigational medicinal product 
(IMP) administration. After obtaining consent from the patient (or their legally acceptable 
representatives) and caregiver, the investigator or subinvestigator will perform the 
specified observations, tests, and investigations to confirm the subject’s eligibility before 
IMP allocation. Subjects who are judged to be eligible in the screening examination and 
baseline evaluation will be randomized to the brexpiprazole 1 mg, brexpiprazole 2 mg, or 
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placebo group. The IMP allocation will be performed using a dynamic allocation method 
to minimize bias in background factors (medical care category, prior use of 
antipsychotics, Cohen-Mansfield Agitation Inventory (CMAI) total score in baseline 
assessment) among the treatment groups. Duration of IMP treatment is 10 weeks. The 
subject will receive brexpiprazole or placebo for 10 weeks according to Section 3.2 Trial 
Treatment, and undergo periodic observations, tests, and investigations to assess efficacy 
and safety. The subject will return to the trial site 28 days after the completion of IMP 
administration for follow-up observation. Discontinued subjects will also undergo follow-
up observation.
For subjects who discontinued the trial during the treatment period, the examination at 
discontinuation will be performed.
The trial period of each subject is from the date of informed consent to the end date of 
follow-up observation. If subjects have transitioned to the extension trial and commenced 
IMP administration, follow-up observation will not be performed. In such a case, the trial 
period is until the end date of evaluation at Week 10 (Day 71).
Figure 3.1-1
Trial Design
Follow-up observation will not be performed for subjects who have transitioned to the extension trial 
and commenced IMP administration.
3.2
Trial Treatments
The IMP will be administered orally as one tablet once a day for 10 weeks. The doses of 
brexpiprazole for each group are shown in Table 3.2-1. Although the temporal 
relationship between IMP administration and meals will not be considered, subjects 
should take the IMP at the specified time in so far as possible. Dose reduction is not 
Screening
period
Follow-up
period
Treatment period
1 week
2 mg
Brexpiprazole 2 mg (148 subjects)
1 week
1 mg
0.5 mg
1 mg
Brexpiprazole 1 mg (111 subjects)
0.5 mg
Placebo (148 subjects)
Day −42 to
Day −2
Day 28
Baseline Week 1 Week 2
Week 4
Week 6
Week 8
Week 10
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allowed during the trial, and if there are tolerability issues, administration of the IMP will 
be discontinued.
Table 3.2-1
Doses of IMPs
Group
Day 1–7
Day 8–14
Day 15–70
Brexpiprazole 2 mg
0.5 mg
1 mg
2 mg
Brexpiprazole 1 mg
0.5 mg
1 mg
1 mg
Placebo
0 mg
0 mg
0 mg
The dose will be increased to 1 mg after evaluation at Week 1 (Day 8) and to 2 mg after evaluation at 
Week 2 (Day 15).
3.3
Trial Population
A total of 407 male and female patients (brexpiprazole 2 mg, 148 subjects; brexpiprazole 
1 mg, 111 subjects; placebo 148 subjects) with agitation associated with dementia of the 
Alzheimer’s type who require medication will be enrolled in the trial.
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 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.
Table 3.4-1
Acceptable Windows for Analysis
Week
Target Day
Trial Day Interval
Baseline
1
- 1
Week 1
8
2 - 11
Week 2
15
12 - 22
Week 4
29
23 - 36
Week 6
43
37 - 50
Week 8
57
51 - 64
Week 10
71
65 - 78
3.5
Handling of Endpoints
3.5.1
Cohen-Mansfield Agitation Inventory (CMAI)
The CMAI total score will be the sum of scores for 29 CMAI items.
The CMAI Aggressive Behavior score will be the sum of scores for CMAI Items 3, 4, 7, 
8, 9, 10, 11, 13, 14, 15, 21, and 25.
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The CMAI Physically Non-aggressive Behavior score will be the sum of scores for 
CMAI Items 1, 2, 16, 22, 26, and 29.
The CMAI Verbally Agitated Behavior score will be the sum of scores for CMAI Items 
5, 6, 18, and 19.
3.5.2
Clinical Global Impression - Severity of Illness (CGI-S)
“0. Not assessed” will be handled as missing data.
3.5.3
Clinical Global Impression - Improvement (CGI-I)
“0. Not assessed” will be handled as missing data.
3.5.4
3.5.5
3.5.6
Drug Induced Extra-Pyramidal Symptoms Scale (DIEPSS)
The DIEPSS total score will be the sum of scores for DIEPSS items 1 through 8.
3.5.7
Abnormal Involuntary Movement Scale (AIMS)
The AIMS total score will be the sum of scores for AIMS items 1 through 7.
3.5.8
Sheehan Suicidality Tracking Scale (S-STS)
The S-STS total score will be the sum of scores for Item 1a, Items 2 through 11, highest 
of Item 12 or any row of Item 16, highest of Item 14 or any row of Item 15, Item 17, and 
Item 20.
The S-STS suicidal ideation subscale score will be the sum of scores for Items 2 through 
11.
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The S-STS suicidal behavior subscale score will be the sum of scores for Item 1a, highest 
of Item 12 or any row of Item 16, highest of Item 14 or any row of Item 15, Item 17, and 
Item 20.
3.5.9
Alzheimer’s Disease Cooperative Study - Activities of Daily 
Living (ADCS-ADL)
The ADCS-ADL total score will be the sum of scores for ADCS-ADL Items 1 through 
19.
3.5.10
Mini-Mental State Examination (MMSE)
The MMSE total score will be the sum of scores for MMSE Items 1 through 30.
4
Sample Size
In Trial 331-12-283, which was performed outside Japan, the 2 mg fixed-dose group 
showed superiority over the placebo group in patients with aggression (patients with 
aggressive behavior at baseline), thus suggesting that it may also be the optimum dose for 
Japanese patients. Efficacy was not observed in the 1 mg fixed-dose group, but in Trial 
331-12-284, the efficacy of a dose less than 2 mg was suggested by the results obtained 
in patients from the flexible-dose (0.5 to 2 mg) group, who had aggression.
In this trial, a power of detection ≥ 80% will be achieved for comparison between the 
placebo group and the 1 mg group to allow evaluation of superiority over the placebo 
group if equivalent efficacy is demonstrated in the 1 and 2 mg groups. For comparison 
between the 2 mg group (possible optimum dose) and the placebo group, a more 
sufficient power of detection will be obtained by changing the randomization ratio. In this 
trial, it is assumed that the difference between the 2 mg group and the placebo group in 
the change in the CMAI total score from baseline to Week 10 is −5.35, and the standard 
deviation (calculated from the standard error of the difference between the 2 mg and 
placebo groups and the number of subjects at baseline) is 15.06 on the basis of the results 
of Trial 331-12-283. By setting the number of subjects in the 2 mg group, 1 mg group, 
and placebo group as 148, 111, and 148, respectively (randomization ratio of 4:3:4), the 
power of detection is 86.1% for the comparison between the 2 mg group and the placebo 
group and is 80.5% for the comparison between the 1 mg group and the placebo group in 
a test with a significance level of 5% (two sided).
On the basis of the above considerations, the number of subjects will be set at 148 in the 
2 mg group, 111 in the 1 mg group, and 148 in the placebo group (randomization ratio of 
4:3:4).
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5
Statistical Analysis Datasets
5.1
Pharmacokinetic Analysis Set
The pharmacokinetic analysis set will comprise subjects who have been treated with 
brexpiprazole and for whom plasma drug concentration data have been obtained, other 
than those deemed as “not analyzed” or “not determined.”
5.2
Full Analysis Set
The full analysis set (FAS) will comprise subjects who, after randomization, have 
received at least 1 dose of the IMP, and from whom CMAI total scores have been 
obtained at baseline and at least 1 time point after initiation of the treatment.
5.3
Safety Analysis Set
The safety analysis set will comprise subjects who, after randomization, have received at 
least 1 dose of the IMP.
5.4
Handling of Missing Data
The primary analysis of the primary endpoint will be performed in the observed cases 
(OC) dataset by mixed models for repeated measures (MMRM) without data imputation 
for missing data under the “missing at random” (MAR) assumption. As a sensitivity 
analysis for the handling of missing data, placebo multiple imputation and tipping point 
analysis will be performed under the “missing not at random” (MNAR) assumption. 
Details are described in Section 8.1.2.
For analyses of efficacy, safety, and other endpoints, the last observation carried forward 
(LOCF) method (in which missing post-dose data are imputed by the last observed data 
after initiation of IMP treatment) will be used as needed.
For pharmacokinetic analysis, no imputation will be performed for missing data.
6
Primary and Secondary Outcome Variables
6.1
Primary Endpoint
The primary endpoint is change in CMAI total score from baseline to Week 10.
6.2
Secondary Endpoints
•
Changes in CMAI subscales (Aggressive Behavior, Physically Non-aggressive 
Behavior, and Verbally Agitated Behavior) from baseline to Week 10
•
Change in Clinical Global Impression–Severity of Illness (CGI-S) from baseline to 
Week 10
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•
Clinical Global Impression–Global Improvement (CGI-I) at Week 10
7
Disposition and Demographic Analysis
7.1
Subject Disposition
Numbers and proportions of subjects from whom informed consent was obtained, those 
who were randomized, those who received trial treatment, those who completed the trial, 
those who discontinued the trial, those who discontinued the trial by reason for 
discontinuation, and those included in each analysis set will be summarized overall, for 
each treatment group, and for the overall brexpiprazole group.
7.2
Demographic and Baseline Characteristics
Descriptive statistics (mean, standard deviation, minimum, median, and maximum; 
hereinafter the same applies) of age, height, baseline body weight, and baseline body 
mass index (BMI), and frequency distribution of age category (< 80, ≥ 80) (< 65, ≥ 65 to 
< 75, ≥ 75), sex, race, ethnicity, country where trial is conducted, complications, medical 
history, and CYP2D6 phenotype will be determined in each analysis set, overall, for each 
treatment group, and for the overall brexpiprazole group.
7.3
Baseline Disease Evaluation
Descriptive statistics of the duration of dementia of the Alzheimer’s type, duration of 
agitation associated with dementia of the Alzheimer’s type, baseline 
, CGI-S, CMAI (total score, subscale scores), 
MMSE total score, and ADCS-ADL total score, and frequency distribution of medical 
care category, type of caregiver, prior use of antipsychotics, prior medication other than 
antipsychotics (for agitation associated with dementia of the Alzheimer’s type), and 
concomitant use of antidementia drugs (yes or no) will be determined overall, for each 
treatment group, and for the overall brexpiprazole group.
The duration of dementia of the Alzheimer’s type and the duration of agitation associated 
with dementia of the Alzheimer’s type 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 
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determined overall, for each treatment group, and for the overall brexpiprazole group in 
the FAS.
7.5
Prior and Concomitant Medications
Numbers and proportions of subjects who used medications (antipsychotics, antidementia 
drugs, other) 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 overall, for each treatment group, and for the overall 
brexpiprazole group in the safety analysis set.
7.6
Protocol Deviations
In randomized subjects, numbers and proportions of subjects with major deviations from 
the protocol will be determined for each deviation category (treatment-related deviations, 
eligibility-related deviations, 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, overall, for each 
treatment group, and for the overall brexpiprazole group.
8
Efficacy Analysis
Efficacy analyses will be performed on the FAS. Baseline is defined as the last data 
obtained prior to initiation of IMP treatment.
8.1
Primary Efficacy Endpoint
8.1.1
Primary Efficacy Analysis
The primary analysis will be performed by MMRM using the OC dataset in the FAS. The 
model will include treatment group (brexpiprazole 1 mg group, brexpiprazole 2 mg 
group, or placebo group), time point (Week 2, 4, 6, 8, or 10), medical care category 
(inpatient or outpatient), prior use of antipsychotics (yes or no), and interaction between 
treatment group and time point as factors and baseline and interaction between baseline 
and time point as covariates. Unstructured error variance-covariance structure will be 
assumed. For a degree-of-freedom approximation, the Kenward-Roger method will be 
used.
Between-group comparison will be performed by calculating the difference of the least 
squares mean between each of the brexpiprazole groups and the placebo group at 
Week 10. The fixed sequence procedure will be used to adjust the multiplicity of testing 
due to the performance of two comparisons (ie, the brexpiprazole 1 mg group versus the 
placebo group and the brexpiprazole 2 mg group versus the placebo group) to control the 
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overall type I error rate. Initially, the brexpiprazole 2 mg group will be compared with the 
placebo group. Only if the difference is statistically significant at a significance level of 
5% (two sided), the brexpiprazole 1 mg group will be compared with the placebo group 
at a significance level of 5% (two sided).
For each time point, least square means of each treatment group and differences in least 
square means between each brexpiprazole group and the placebo group, as well as the 
two-sided 95% confidence intervals (CIs) will be determined.
If any problems in convergence status arise in the estimation of variance components of 
MMRM, heterogeneous Toeplitz, heterogeneous autoregressive of order 1, and 
heterogeneous compound symmetry, which are error variance-covariance structures, will 
be applied in this order, and the first structure that achieves convergence will be used in 
the primary analysis. If anything other than an unstructured variance-covariance structure 
is selected, a sandwich estimator for standard errors will be used.
8.1.2
Sensitivity Analyses
8.1.2.1
Sensitivity Analysis for Handling of Missing Data
As a sensitivity analysis for handling of missing data, placebo multiple imputation and 
tipping point analysis on MNAR assumption will be performed using a pattern-mixture 
model with multiple imputation.
Multiple imputation analysis will be performed according to the following procedure. 
The number of imputations will be 100.
1) The Fully Conditional Specification (FCS) method will be used to impute missing 
data. The imputation model for each period will include the medical care category 
(inpatient or outpatient) and prior use of antipsychotics (yes or no), as well as the 
CMAI total score for the preceding periods. 
2) The same MMRM as that of the primary efficacy analysis will be used to analyze 
the multiple-imputed datasets.
3) The MIANALYZE procedure will be used to integrate the analysis results of the 
multiple-imputed datasets, and the estimate of the difference between each 
brexpiprazole group and the placebo group at Week 10 and its 95% CI and p-
value will be determined.
In placebo multiple imputation, for discontinued subjects in each brexpiprazole group, 
MNAR will be assumed for missing data and an imputation model based on the placebo 
group will be used in imputation.
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In tipping point analysis, for subjects in each brexpiprazole group who discontinued 
treatment for any of the following reasons, MNAR will be assumed for missing data after 
discontinuation.
•
Withdrawal for any reason
•
Withdrawal due to adverse events (AEs), a lack of efficacy, or consent withdrawal 
(by subject, legally acceptable representative, or caregiver)
•
Withdrawal due to AEs or a lack of efficacy
For subjects in each brexpiprazole group who discontinued treatment for reasons 
assumed as MNAR, the MAR assumption will be used to impute missing data, add Δ 
(intergroup differences in MMRM of the primary efficacy analysis) × k% to the imputed 
value after withdrawal, and increase k (with 200 as the upper limit) until a statistically 
significant conclusion is reversed (p > 0.05). 
8.1.2.2
Sensitivity Analysis for Normality Assumption
As a sensitivity analysis for normality assumption, multiple imputation under the MAR 
assumption will be performed, and the Van Elteren test with medical care category 
(inpatient or outpatient) and prior use of antipsychotics (yes or no) as strata will be used 
to compare each brexpiprazole group and the placebo group for each time point, and the 
Hodges-Lehmann estimator of the intergroup difference will be determined. A robust 
regression analysis with treatment group, medical care category (inpatient or outpatient), 
and prior use of antipsychotics (yes or no) as factors and baseline as a covariate will also 
be performed for each time point. Similar analysis without multiple imputation will also 
be performed.
8.1.3
Technical Computational Details for Primary Efficacy Analysis
The SAS code for the MIXED procedure to perform the primary efficacy MMRM 
analysis is shown below.
proc mixed;
    class treatment visit subjid hoterm beformed;
    model change=treatment visit baseline treatment*visit baseline*visit hoterm beformed 
/ ddfm=kr;    
    repeated visit /type=un subject=subjid;
    lsmeans treament*visit / diff cl;
    ods output diffs=diffs lsmeans=lsmeans;
run;
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*hoterm: medical care category
*beformed: prior use of antipsychotics
8.2
Secondary Efficacy Analyses
•
Changes in CMAI subscales (Aggressive Behavior, Physically Non-aggressive 
Behavior, and Verbally Agitated Behavior) from baseline at Week 10
•
Change in CGI-S related to agitation from baseline to Week 10
The same MMRM analysis as that for the primary endpoint will be performed using the 
OC dataset.
•
CGI-I at Week 10
Each brexpiprazole group will be compared with the placebo group by the Cochran 
Mantel Haenszel (CMH) Row Mean Scores test with medical care category (inpatient or 
outpatient) and prior use of antipsychotics (yes or no) as strata using the LOCF dataset. 
Mean values in each treatment group, differences in mean values between each 
brexpiprazole group and the placebo group based on CMH Row Mean Scores test,1 and 
their two-sided 95% CIs will be calculated. The same analysis will be performed on the 
OC dataset.
8.3
Subgroup Analyses
The same MMRM analysis as that for the primary endpoint will be performed on the 
change in CMAI total score from baseline for each of the subgroup categories within 
each of the following items using the OC dataset (in the subgroup analyses of medical 
care category and prior use of antipsychotics, those particular factors will be excluded 
from the respective analysis models). For CYP2D6 phenotype, all subjects in the placebo 
group will be included in each subgroup.
•
Medical care category (inpatient, outpatient)
•
Prior use of antipsychotics (yes or no)
•
Type of caregiver (hospital staff, care facility staff, family)
•
Sex (male, female)
•
Age (< 80, ≥ 80) (< 65, ≥ 65 to < 75, ≥ 75)
•
CMAI total score at baseline (≤ median or > median)
•
•
Body weight (≤ median, > median)
•
BMI (≤ median, > median)
•
CYP2D6 phenotype (IM, EM)
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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)
•
Concomitant use of antidementia drugs (yes or no)
8.4
Exploratory or Other Analyses
8.4.1
Exploratory Endpoint Analyses
•
•
•
•
•
•
•
•
•
•
•
•
•
•
8.4.2
Other Analyses 
The CMAI total score, CMAI subscales (Aggressive Behavior, Physically Non-
aggressive Behavior, and Verbally Agitated Behavior), CGI-S, CGI-I, 
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at 
each time point will be analyzed in the same manner as for the primary and secondary 
efficacy endpoints and the exploratory endpoints. Descriptive statistics or frequency 
distribution of actual measurements and changes from baseline at each time point will be 
calculated by treatment group.
9
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.
9.1
Extent of Exposure
Descriptive statistics and frequency distribution (1-7, 8-14, 15-21, 22-28, 29-35, 36-42, 
43-49, 50-56, 57-63, 64-70, > 70 and ≥ 7, ≥ 14, ≥ 28, ≥ 42, ≥ 56, ≥ 70) of the duration 
(days) of treatment with the IMP will be determined for each treatment group and for the 
overall brexpiprazole group.
9.2
Adverse Events
Adverse events will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA) (Ver. 25.0). The incidences of the following events will be summarized 
according to System Organ Class (SOC) and Preferred Term (PT) for each treatment 
group and for the overall brexpiprazole group. 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 brexpiprazole group and more frequently 
than in the placebo group 
•
TEAEs by days of initial onset (1-7, 8-14, 15-21, 22-28, 29-35, 36-42, 43-49, 50-56, 
57-63, 64-70, > 70, post-trial treatment).
TEAEs potentially causally related to the IMP will also be summarized in the same 
manner.
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9.2.1
Adverse Events of Interest
Each AE of interest is defined in Appendix 4. Numbers and proportions of subjects with 
the following AEs of interest will be summarized by SOC and PT for each treatment 
group and for the overall brexpiprazole group.
•
Extrapyramidal AEs
•
Accident- and injury-related AEs
•
Cerebrovascular AEs
•
Cardiovascular AEs
•
Glucose metabolism-related AEs
•
Lipid metabolism-related AEs
•
Body weight-related AEs
•
Blood disorder-related AEs
•
Hypersensitive symptom-related AEs
•
Neuroleptic malignant syndrome-related AEs
•
Orthostatic disorder-related AEs
•
Prolactin increase-related AEs
•
QT interval prolongation-related AEs
•
Rhabdomyolysis
•
Seizure-related AEs
•
Oversedation-related AEs
•
Suicide/suicide attempt-related AEs
•
Venous thrombosis
•
Pneumonia-related AEs
9.2.2
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, for each treatment group and for the overall 
brexpiprazole group. 
•
Medical care category (inpatient, outpatient)
•
Prior use of antipsychotics (yes or no)
•
Type of caregiver (hospital staff, care facility staff, family, or other)
•
Sex (male, female)
•
Age (< 80, ≥ 80) (< 65, ≥ 65 to < 75, ≥ 75)
•
Body weight (≤ median, > median)
•
BMI (≤ median, > median)
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CYP2D6 phenotype (IM, EM, PM, Unknown)
•
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)
•
Concomitant use of antidementia drugs (yes or no)
9.3
Clinical Laboratory Data
For each quantitative laboratory parameter, descriptive statistics of actual measurements 
and changes from baseline at each time point and the last time point will be calculated for 
each treatment group and for the overall brexpiprazole group.
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 treatment 
group and for the overall brexpiprazole group.
For each qualitative laboratory parameter, a shift table from baseline will be produced for 
each treatment group and for the overall brexpiprazole group.
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 for each treatment group and for 
the overall brexpiprazole group. 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 for each treatment group and for the overall brexpiprazole group. 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 for each treatment group and for the overall brexpiprazole 
group. 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-
related parameters (Table 9.3-1) will be determined by baseline value for each treatment 
group and for the overall brexpiprazole group. A listing of these subjects will be 
provided.
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Table 9.3-1
Changes in Glucose and Lipid Metabolism-related 
Parameters
LAB PARAMETER
BASELINE
ANYTIME POST BASELINE
Cholesterol, Fasting 
(mg/dL)
Normal <200
Borderline 200-<240
Normal/Borderline <240
Normal <200
Any Value
High >=240
High >=240
High >=240
Borderline/High >=200
Increased >=40 
LDL Cholesterol, Fasting 
(mg/dL)
Normal <100
Borderline 100-<160
Normal/Borderline <160
Normal <100
Any Value
High >=160
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
Normal <150
Borderline 150-<200
Normal/Borderline <200
Normal/Borderline <200
Normal <150
Normal/Borderline/high <500
Any Value
High 200-<500
Very High >=500
High 200-<500
High 200-<500
Very High >=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
9.4
Vital Sign Data
For each vital sign parameter (in the sitting position), descriptive statistics of actual 
measurements and changes from baseline at each time point and the last assessment time 
point will be calculated for each treatment group and for the overall brexpiprazole group.
Numbers and proportions of subjects with vital signs meeting the criteria for potentially 
clinically significant vital signs (Appendix 1) will be determined for each treatment group 
and for the overall brexpiprazole group. A listing of these subjects will be provided.
9.5
Physical Examination Data
Physical examination data will be provided in a listing.
9.6
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 time point will be calculated for each treatment group and 
for the overall brexpiprazole group.
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A shift table from baseline for normal/abnormal 12-lead electrocardiogram (ECG) 
(evaluated at the trial site) will be produced for each treatment group and for the overall 
brexpiprazole group.
Numbers and proportions of subjects with actual measurements of QTc (QTcF, QTcB, 
QTcN = QT interval/[RR interval]0.37) not meeting the criteria of > 450 msec, 
> 480 msec, and > 500 msec at baseline and meeting the criteria after treatment and 
numbers and proportions of subjects with changes from baseline of > 30 msec and 
> 60 msec will be determined for each treatment group and for the overall brexpiprazole 
group. Numbers and proportions of subjects with actual measurements of > 450 msec 
with a % change from baseline of > 10% will be determined for each treatment group and 
for the overall brexpiprazole group.
Numbers and proportions of subjects with ECG results meeting the criteria for potentially 
clinically significant ECG data (Appendix 3) will be determined for each treatment group 
and for the overall brexpiprazole group. A listing of these subjects will be provided.
9.7
Other Safety Data
9.7.1
Body Weight and Body Mass Index
For body weight and BMI, descriptive statistics of actual measurements and changes 
from baseline at each time point and the last assessment time point will be calculated for 
each treatment group and for the overall brexpiprazole group.
In addition, analysis will be performed by the analysis of covariance (ANCOVA) model 
with treatment group, medical care category (inpatient or outpatient), and prior use of 
antipsychotics (yes or no) as factors and baseline as a covariate. Least square means of 
each treatment group and differences in least square means between each brexpiprazole 
group and the placebo group, as well as the two-sided 95% CIs will be determined.
Numbers and proportions of subjects with results meeting the criteria for potentially 
clinically significant body weight gain or loss (Appendix 1) will be determined for each 
treatment group and for the overall brexpiprazole group. 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.
9.7.2
DIEPSS, AIMS, and BARS
For DIEPSS total score (total of scores for items 1 through 8) and score for each DIEPSS 
item, AIMS total score (total of scores for items 1 through 7) and score for each of the 3 
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global judgment items (items 8 through 10), and BARS, descriptive statistics of actual 
measurements and changes from baseline at each time point, at the last assessment time 
point, and for the worst postdose measurement, will be calculated for each treatment 
group and for the overall brexpiprazole group.
In addition, analysis will be performed by the ANCOVA model with treatment group, 
medical care category (hospitalized or outpatient), and prior use of antipsychotics (yes or 
no) as factors and baseline as a covariate. Least square means of each treatment group 
and differences in least square means between each brexpiprazole group and the placebo 
group, as well as the two-sided 95% CIs will be determined.
9.7.3
Sheehan Suicidality Tracking Scale
For the score for each S-STS item (2 through 14), total score, suicidal ideation subscale 
score, and suicidal behavior subscale score, descriptive statistics of actual measurements 
and changes from baseline at each time point and the last assessment time point will be 
calculated for each treatment group and for the overall brexpiprazole group.
In addition, analysis will be performed by the ANCOVA model with treatment group, 
medical care category (hospitalized or outpatient), and prior use of antipsychotics (yes or 
no) as factors and baseline as a covariate. Least square means of each treatment group 
and differences in least square means between each brexpiprazole group and the placebo 
group, as well as the two-sided 95% CIs will be determined.
10
Pharmacokinetic Analyses
Pharmacokinetic analysis will be performed on the pharmacokinetic analysis set.
Descriptive statistics of plasma brexpiprazole concentrations at time points (0-6, 6-12, 
12-18, 18-24, 24-30 hours and > 30 hours) after the most recent dosing as well as trough 
brexpiprazole concentrations (20-28 hours after the most recent dosing) and plasma 
brexpiprazole concentrations at all time points will be calculated by treatment group. The 
descriptive statistics will also be calculated by CYP2D6 phenotype (EM, IM, PM, and 
Unknown) in each treatment group in the same manner.
The mean plasma brexpiprazole concentration over time will be plotted by treatment 
group. Plotted diagrams by CYP2D6 phenotype in each treatment group will also be 
provided in the same manner.
Scatter plots of plasma brexpiprazole concentrations will be provided by treatment group. 
Scatter plots by CYP2D6 phenotype in each treatment group will also be provided in the 
same manner.
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Plasma brexpiprazole concentrations below the lower limit of quantitation will be 
handled as 0 (ng/mL) when their descriptive statistics are calculated and when plotted 
diagrams and scatter plots are created.
11
Pharmacodynamic Analyses
Not applicable.
12
Pharmacogenomic Analyses
CYP2D6 genotype (phenotype) will be tabulated as specified in Section 7.2. CYP2D6 
phenotype will also be summarized in subgroup efficacy and safety analyses.
13
Analysis of Other Endpoints
Analysis of other endpoints will be performed using the safety analysis set. Baseline is 
defined as the last data obtained prior to initiation of IMP treatment.
•
ADCS-ADL
•
MMSE
•
EQ-5D-5L
For ADCS-ADL total score, MMSE total score and each item of EQ-5D-5L (subject 
evaluation [proxy version] and caregiver evaluation), descriptive statistics of actual 
measurements and changes from baseline at each time point and the last assessment time 
point will be calculated for each treatment group and for the overall brexpiprazole group.
In addition, analysis will be performed by the ANCOVA model with treatment group, 
medical care category (hospitalized or outpatient), and prior use of antipsychotics (yes or 
no) as factors and baseline as a covariate. Least square means of each treatment group 
and differences in least square means between each brexpiprazole group and the placebo 
group, as well as the two-sided 95% CIs will be determined.
14
Interim Analysis
Safety will be evaluated by the IDMC when approximately 25%, 50%, and 75% of the 
target number of subjects have completed or discontinued the trial.
A statistical analysis plan for interim analysis is described in a separate interim analysis 
plan.
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Changes in the Planned Analyses
•
•
In the subgroup efficacy analysis, “other” was excluded from the type of caregiver. 
The CMAI total score category at baseline was changed from “< 56 or ≥ 56” to 
“≤ median or > median.”
•
The following changes were made to categorical analyses of QTc:
Only subjects with postdose QTc meeting the criteria were summarized, instead of 
summarization at all time points.
Only subjects with QTc not meeting the criteria at baseline and meeting the criteria 
after baseline were summarized.
•
It was decided that CYP2D6 phenotype would be tabulated as specified in 
Section 7.2. CYP2D6 phenotype were also summarized in subgroup efficacy and 
safety analyses.
•
The original plan of using the LOCF dataset in ANCOVA of safety endpoints and 
other endpoints was changed as follows: Measurements at each time point and at the 
last assessment time point and, as necessary, the worst postdose measurement were 
included in the analysis.
•
The original plan of calculating descriptive statistics of plasma brexpiprazole 
concentrations by treatment group in pharmacokinetic analysis was changed as 
follows: Descriptive statistics of plasma brexpiprazole concentrations at each time 
point after the most recent dosing, trough concentrations, and plasma drug 
concentrations at all time points were calculated by treatment group and by CYP2D6 
phenotype in each treatment group. Additionally, the mean plasma brexpiprazole 
concentration over time and scatter plots of plasma brexpiprazole concentrations were 
provided by treatment group and by CYP2D6 phenotype in each treatment group.
16
References
1
C.S. Davis, Y. Chung. Randomization model methods for evaluating treatment 
efficacy in multicenter clinical trials. Biometrics. 1995; 51(3): 1163-1174.
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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
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)
> 470 msec
(females)
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 4
Adverse Events of Interest
Category
Preferred Term
ACCIDENTS AND INJURIES INCLUDING FALL
Abdomen crushing
Abdominal injury
Abdominal wall wound
Accident
Accident at home
Accident at work
Accidental death
Acetabulum fracture
Acoustic shock
Acquired asplenia
Acquired cerebral palsy
Acquired encephalocele
Acrotrophodynia
Adrenal gland injury
Anal injury
Animal attack
Animal bite
Ankle fracture
Anterior capsular rupture
Anterior cord syndrome
Anterior labroligamentous periosteal sleeve avulsion lesion
Aortic annulus rupture
Aortic injury
Aortic rupture
Aponeurosis contusion
Application site wound
Arterial injury
Arterial rupture
Atrial rupture
Atypical femur fracture
Atypical fracture
Avulsion fracture
Axillary nerve injury
Back injury
Bankart lesion
Battle's sign
Bile duct stenosis traumatic
Bladder injury
Bladder perforation
Blast injury
Blindness traumatic
Bone contusion
Bone fissure
Bone fragmentation
Bowman's membrane injury
Brachial plexus injury
Brain contusion
Breast injury
Burn oral cavity
Burns first degree
Burns fourth degree
Burns second degree
Burns third degree
Bursa injury
Buttock injury
Cardiac contusion
Cartilage injury
Cataract traumatic
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Central cord syndrome
Central nervous system injury
Cervical vertebral fracture
Cervix injury
Chance fracture
Chemical burn
Chemical burn of genitalia
Chemical burn of oral cavity
Chemical burn of respiratory tract
Chemical burn of skin
Chemical burns of eye
Chest crushing
Chest injury
Chillblains
Clavicle fracture
Closed globe injury
Cochlear injury
Cold burn
Cold exposure injury
Cold shock response
Colon injury
Comminuted fracture
Commotio retinae
Complicated fracture
Compression fracture
Concussion
Conjunctival abrasion
Conjunctival laceration
Contusion
Corneal abrasion
Corneal laceration
Corneal perforation
Costal cartilage fracture
Costochondral separation
Cranial nerve injury
Craniocerebral injury
Craniocervical dislocation
Craniofacial fracture
Craniofacial injury
Crush injury
Crush syndrome
Crushing injury of trunk
Cuboid syndrome
Deafness traumatic
Decapitation
Deep dissecting haematoma
Depressed fracture
Diaphragmatic injury
Diaphragmatic rupture
Diffuse axonal injury
Dislocation of sternum
Dislocation of vertebra
Drowning
Duodenal rupture
Dural tear
Ear canal abrasion
Ear canal injury
Ear canal stenosis traumatic
Ear injury
Electric injury
Electric shock
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Electrocution
Enophthalmos traumatic
Epidural haemorrhage
Epiphyseal fracture
Epiphyseal injury
Epiphysiolysis
External genitalia crushing
Extradural haematoma
Extrahepatic biliary tree injury
Eye abrasion
Eye contusion
Eye injury
Eye luxation
Eyeball avulsion
Eyelash injury
Eyelid contusion
Eyelid haematoma
Eyelid injury
Face crushing
Face injury
Facial bones fracture
Facial nerve injury due to birth trauma
Fall
Femoral neck fracture
Femoral nerve injury
Femur fracture
Fibula fracture
First degree chemical burn of skin
Flail chest
Foot fracture
Forearm fracture
Foreign body aspiration
Foreign body in eye
Foreign body in gastrointestinal tract
Foreign body in mouth
Foreign body in reproductive tract
Foreign body in respiratory tract
Foreign body in skin or subcutaneous tissue
Foreign body in throat
Foreign body in urogenital tract
Foreign body ingestion
Fourth degree chemical burn of skin
Fracture
Fracture displacement
Fracture of clavicle due to birth trauma
Fracture of penis
Fracture pain
Fractured coccyx
Fractured sacrum
Fractured skull depressed
Frostbite
Gallbladder injury
Gallbladder rupture
Gastrointestinal injury
Gastrointestinal organ contusion
Genital contusion
Genital injury
Gingival injury
Glaucoma traumatic
Greenstick fracture
Gun shot wound
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Haematuria traumatic
Haemothorax
Hand fracture
Hanging
Head crushing injury
Head injury
Heat cramps
Heat exhaustion
Heat stroke
Hepatic rupture
Hernia perforation
High-energy trauma
Hip fracture
Human bite
Humerus fracture
Hyperthermia
Hyphaema
Hypothermia
IIIrd nerve injury
IVth nerve injury
Ilium fracture
Impacted fracture
Implant site injury
Inguinal hernia perforation
Injury
Injury corneal
Injury of conjunctiva
Injury to brachial plexus due to birth trauma
Internal injury
Intervertebral disc injury
Intra-abdominal organ avulsion
Intra-abdominal vascular injury
Iris injury
Iris tear
Jaw fracture
Joint dislocation
Joint hyperextension
Joint injury
Keratorhexis
Keraunoparalysis
Kidney contusion
Kidney rupture
Laryngeal injury
Lens dislocation
Lenticular injury
Ligament injury
Ligament rupture
Ligament sprain
Limb crushing injury
Limb fracture
Limb injury
Limb reattachment surgery
Limb traumatic amputation
Lip injury
Lisfranc fracture
Liver contusion
Liver injury
Loose body removal
Lower limb fracture
Lumbar vertebral fracture
Lumbosacral plexus injury
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Lung perforation
Lymphatic duct injury
Macular detachment
Maisonneuve fracture
Median nerve injury
Meniscus cyst
Meniscus injury
Metallosis of globe
Metaphyseal corner fracture
Mouth injury
Multiple fractures
Multiple injuries
Muscle contusion
Muscle injury
Muscle reattachment
Muscle rupture
Muscle strain
Musculocutaneous nerve injury
Musculoskeletal foreign body
Musculoskeletal injury
Myocardial rupture
Nail avulsion
Nail injury
Nasal injury
Near drowning
Neck crushing
Neck injury
Nerve compression
Nerve injury
Nerve root injury
Nerve root injury cervical
Nerve root injury lumbar
Nerve root injury sacral
Nerve root injury thoracic
Oesophageal injury
Oesophageal rupture
Open fracture
Open globe injury
Optic nerve injury
Optic pathway injury
Oral contusion
Orbital compartment syndrome
Osteo-meningeal breaches
Osteochondral fracture
Osteophyte fracture
Ovarian injury
Palate injury
Pancreatic contusion
Pancreatic duct rupture
Pancreatic injury
Paranasal sinus injury
Parasympathetic nerve injury
Patella fracture
Pellegrini Stieda disease
Pelvic bone injury
Pelvic fracture
Pelvic organ injury
Penetrating abdominal trauma
Penetrating eye injury repair
Penile contusion
Penis injury
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Penis reattachment
Perforation bile duct
Perineal injury
Peripheral nerve injury
Peritoneal perforation
Pernio-like erythema
Peroneal nerve injury
Pharyngeal contusion
Pharyngeal injury
Photoelectric conjunctivitis
Phrenic nerve injury
Pleural injury
Pneumothorax traumatic
Post concussion syndrome
Post-traumatic headache
Post-traumatic neck syndrome
Post-traumatic osteoporosis
Post-traumatic pain
Posterior capsule rupture
Posterior tibial nerve injury
Prevertebral soft tissue swelling of cervical space
Product package associated injury
Pulmonary contusion
Puncture site injury
Radial head dislocation
Radial nerve injury
Radius fracture
Rectal injury
Renal injury
Repair of diaphragm injury
Retinal detachment
Retinal injury
Retinal tear
Rhegmatogenous retinal detachment
Rib fracture
Road traffic accident
Sacroiliac fracture
Scapula fracture
Scapulothoracic dissociation
Sciatic nerve injury
Scratch
Scrotal injury
Second degree chemical burn of skin
Second impact syndrome
Serous retinal detachment
Shrapnel wound
Sinus tarsi syndrome
Skeletal injury
Skin abrasion
Skin injury
Skin laceration
Skin pressure mark
Skull fracture
Skull fracture treatment
Skull fractured base
Snake bite
Soft tissue foreign body
Soft tissue injury
Spinal column injury
Spinal compression fracture
Spinal cord injury
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Spinal cord injury cauda equina
Spinal cord injury cervical
Spinal cord injury lumbar
Spinal cord injury sacral
Spinal cord injury thoracic
Spinal epidural haematoma
Spinal epidural haemorrhage
Spinal fracture
Spinal fracture treatment
Spinal fusion fracture
Spinal shock
Spinal subarachnoid haemorrhage
Spinal subdural haematoma
Spleen contusion
Splenic injury
Splenic rupture
Splenosis
Splinter
Spondylopathy traumatic
Sports injury
Stab wound
Stapes fracture
Sternal fracture
Sternal injury
Stress fracture
Struck by lightning
Subcapsular hepatic haematoma
Subchondral insufficiency fracture
Subdural haematoma
Subdural haematoma evacuation
Subdural haemorrhage
Subendocardial haemorrhage
Subretinal fluid
Sunburn
Superficial injury of eye
Sympathetic nerve injury
Synovial rupture
Tendon dislocation
Tendon injury
Tendon rupture
Testicular injury
Testicular rupture
Thermal burn
Thermal burns of eye
Third degree chemical burn of skin
Thoracic vertebral fracture
Thyroid gland injury
Tibia fracture
Tissue injury
Tissue rupture
Tongue injury
Tooth avulsion
Tooth dislocation
Tooth fracture
Tooth injury
Torus fracture
Tracheal injury
Tractional retinal detachment
Traumatic amputation
Traumatic anuria
Traumatic arthritis
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Traumatic arthropathy
Traumatic arthrosis
Traumatic coma
Traumatic ear amputation
Traumatic fracture
Traumatic haematoma
Traumatic haemorrhage
Traumatic haemothorax
Traumatic heart injury
Traumatic intracranial haematoma
Traumatic intracranial haemorrhage
Traumatic iritis
Traumatic liver injury
Traumatic lung injury
Traumatic pancreatitis
Traumatic renal injury
Traumatic shock
Traumatic spinal cord compression
Traumatic torticollis
Traumatic ulcer
Traumatic ulcerative granuloma with stromal eosinophilia
Trench foot
Trunk injury
Tympanic membrane perforation
Ulna fracture
Ulnar nerve injury
Upper limb fracture
Ureteric injury
Ureteric perforation
Ureteric rupture
Urethral injury
Urethral perforation
Urethral stricture traumatic
Urinary bladder explosion
Urinary bladder haematoma
Urinary bladder rupture
Urinary tract injury
Uveal prolapse
VIIIth nerve injury
VIIth nerve injury
VIth nerve injury
Vaginal perforation
Vascular injury
Vascular rupture
Vena cava injury
Venous injury
Ventricle rupture
Vessel puncture site injury
Vitreous detachment
Vitreous injury
Vitreous loss
Vitreous prolapse
Vth nerve injury
Vulvovaginal injury
Wound
Wrist fracture
XIIth nerve injury
XIth nerve injury
CARDIOVASCULAR EVENT
Accelerated idioventricular rhythm
Accessory cardiac pathway
Acute cardiac event
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Acute cardiac event
Acute coronary syndrome
Acute left ventricular failure
Acute myocardial infarction
Acute pulmonary oedema
Acute right ventricular failure
Adams-Stokes syndrome
Agonal rhythm
Andersen-Tawil syndrome
Angina pectoris
Angina unstable
Angina unstable
Anginal equivalent
Anomalous atrioventricular excitation
Arrhythmia
Arrhythmia neonatal
Arrhythmia supraventricular
Arrhythmic storm
Arrhythmogenic right ventricular dysplasia
Arteriosclerosis coronary artery
Arteriospasm coronary
Atrial conduction time prolongation
Atrial escape rhythm
Atrial escape rhythm
Atrial fibrillation
Atrial flutter
Atrial parasystole
Atrial standstill
Atrial tachycardia
Atrioventricular block
Atrioventricular block complete
Atrioventricular block first degree
Atrioventricular block second degree
Atrioventricular conduction time shortened
Atrioventricular dissociation
Atrioventricular node dispersion
Atrioventricular node dysfunction
BRASH syndrome
Bifascicular block
Blood creatine phosphokinase MB abnormal
Blood creatine phosphokinase MB increased
Blood creatine phosphokinase abnormal
Blood creatine phosphokinase increased
Bradyarrhythmia
Brugada syndrome
Brugada syndrome
Bundle branch block
Bundle branch block bilateral
Bundle branch block left
Bundle branch block right
Cardiac asthma
Cardiac failure
Cardiac failure acute
Cardiac failure chronic
Cardiac failure congestive
Cardiac failure high output
Cardiac fibrillation
Cardiac fibrillation
Cardiac flutter
Cardiac perfusion defect
Cardiac ventricular scarring
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Cardiogenic shock
Cardiohepatic syndrome
Cardiopulmonary failure
Cardiorenal syndrome
Chronic atrial and intestinal dysrhythmia syndrome
Chronic coronary syndrome
Chronic left ventricular failure
Chronic right ventricular failure
Chronotropic incompetence
Conduction disorder
Congenital supraventricular tachycardia
Congestive hepatopathy
Cor pulmonale
Cor pulmonale acute
Cor pulmonale chronic
Coronary angioplasty
Coronary arterial stent insertion
Coronary artery bypass
Coronary artery compression
Coronary artery disease
Coronary artery dissection
Coronary artery embolism
Coronary artery insufficiency
Coronary artery occlusion
Coronary artery reocclusion
Coronary artery restenosis
Coronary artery stenosis
Coronary artery surgery
Coronary artery thrombosis
Coronary brachytherapy
Coronary bypass stenosis
Coronary bypass thrombosis
Coronary endarterectomy
Coronary no-reflow phenomenon
Coronary ostial stenosis
Coronary revascularisation
Coronary steal syndrome
Coronary vascular graft occlusion
Coronary vascular graft stenosis
Defect conduction intraventricular
Diabetic coronary microangiopathy
ECG electrically inactive area
ECG signs of myocardial infarction
ECG signs of myocardial ischaemia
Early repolarisation syndrome
Early repolarisation syndrome
Ejection fraction decreased
Electrocardiogram PR prolongation
Electrocardiogram PR shortened
Electrocardiogram Q wave abnormal
Electrocardiogram QRS complex prolonged
Electrocardiogram QT prolonged
Electrocardiogram RR interval prolonged
Electrocardiogram ST segment abnormal
Electrocardiogram ST segment elevation
Electrocardiogram ST-T segment elevation
Electrocardiogram U wave inversion
Electrocardiogram U wave inversion
Electrocardiogram U wave present
Electrocardiogram U-wave abnormality
Electrocardiogram delta waves abnormal
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Electrocardiogram repolarisation abnormality
Electrocardiogram repolarisation abnormality
External counterpulsation
Extrasystoles
Fascicular block
Foetal arrhythmia
Foetal heart rate disorder
Foetal tachyarrhythmia
Frederick's syndrome
Haemorrhage coronary artery
Heart alternation
Heart block congenital
Heart rate irregular
Hepatojugular reflux
Holiday heart syndrome
Infarction
Ischaemic cardiomyopathy
Ischaemic mitral regurgitation
Junctional ectopic tachycardia
Junctional ectopic tachycardia
Kounis syndrome
Left ventricular failure
Lenegre's disease
Long QT syndrome
Long QT syndrome congenital
Low cardiac output syndrome
Lown-Ganong-Levine syndrome
Microvascular coronary artery disease
Myocardial hypoperfusion
Myocardial hypoxia
Myocardial infarction
Myocardial ischaemia
Myocardial necrosis
Myocardial necrosis marker increased
Myocardial reperfusion injury
Myocardial stunning
Neonatal bradyarrhythmia
Neonatal cardiac failure
Neonatal tachyarrhythmia
Nodal arrhythmia
Nodal rhythm
Obstructive shock
Pacemaker generated arrhythmia
Pacemaker syndrome
Papillary muscle infarction
Parasystole
Paroxysmal arrhythmia
Paroxysmal atrioventricular block
Percutaneous coronary intervention
Periprocedural myocardial infarction
Post procedural myocardial infarction
Postinfarction angina
Prinzmetal angina
Pulmonary oedema
Pulmonary oedema neonatal
Pulseless electrical activity
Radiation associated cardiac failure
Reperfusion arrhythmia
Rhythm idioventricular
Right ventricular ejection fraction decreased
Right ventricular failure
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Scan myocardial perfusion abnormal
Silent myocardial infarction
Sinoatrial block
Sinus arrest
Sinus arrhythmia
Sinus bradycardia
Sinus node dysfunction
Sinus tachycardia
Stress cardiomyopathy
Subclavian coronary steal syndrome
Subendocardial ischaemia
Sudden cardiac death
Supraventricular extrasystoles
Supraventricular tachyarrhythmia
Supraventricular tachycardia
Tachyarrhythmia
Torsade de pointes
Trifascicular block
Troponin I increased
Troponin T increased
Troponin increased
Vascular graft occlusion
Vascular stent occlusion
Vascular stent thrombosis
Ventricular arrhythmia
Ventricular asystole
Ventricular dyssynchrony
Ventricular extrasystoles
Ventricular failure
Ventricular fibrillation
Ventricular flutter
Ventricular parasystole
Ventricular pre-excitation
Ventricular tachyarrhythmia
Ventricular tachycardia
Wandering pacemaker
Wellens' syndrome
Withdrawal arrhythmia
Wolff-Parkinson-White syndrome
Wolff-Parkinson-White syndrome congenital
CEREBROVASCULAR EVENT
Amaurosis fugax
Balint's syndrome
Basal ganglia haematoma
Basal ganglia haemorrhage
Basal ganglia infarction
Basal ganglia stroke
Basal ganglia stroke
Basilar artery aneurysm
Basilar artery occlusion
Basilar artery perforation
Basilar artery stenosis
Basilar artery thrombosis
Benedikt's syndrome
Brachiocephalic arteriosclerosis
Brachiocephalic artery occlusion
Brachiocephalic artery stenosis
Brain hypoxia
Brain stem embolism
Brain stem haematoma
Brain stem haemorrhage
Brain stem infarction
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Brain stem ischaemia
Brain stem microhaemorrhage
Brain stem stroke
Brain stem stroke
Brain stem thrombosis
Brain stent insertion
CADASIL
CARASIL syndrome
CSF bilirubin positive
Capsular warning syndrome
Carotid aneurysm rupture
Carotid angioplasty
Carotid arterial embolus
Carotid arteriosclerosis
Carotid artery aneurysm
Carotid artery bypass
Carotid artery disease
Carotid artery dissection
Carotid artery insufficiency
Carotid artery occlusion
Carotid artery perforation
Carotid artery restenosis
Carotid artery stenosis
Carotid artery stent insertion
Carotid artery stent removal
Carotid artery thrombosis
Carotid endarterectomy
Carotid revascularisation
Central nervous system haemorrhage
Central nervous system vasculitis
Cerebellar artery occlusion
Cerebellar artery thrombosis
Cerebellar atherosclerosis
Cerebellar embolism
Cerebellar haematoma
Cerebellar haemorrhage
Cerebellar infarction
Cerebellar ischaemia
Cerebellar microhaemorrhage
Cerebellar stroke
Cerebellar stroke
Cerebral aneurysm perforation
Cerebral aneurysm ruptured syphilitic
Cerebral arteriosclerosis
Cerebral arteriovenous malformation haemorrhagic
Cerebral arteritis
Cerebral artery embolism
Cerebral artery occlusion
Cerebral artery perforation
Cerebral artery restenosis
Cerebral artery stenosis
Cerebral artery stent insertion
Cerebral artery thrombosis
Cerebral capillary telangiectasia
Cerebral cavernous malformation
Cerebral circulatory failure
Cerebral congestion
Cerebral cyst haemorrhage
Cerebral endovascular aneurysm repair
Cerebral gas embolism
Cerebral haematoma
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Cerebral haemorrhage
Cerebral haemorrhage foetal
Cerebral haemorrhage neonatal
Cerebral hypoperfusion
Cerebral infarction
Cerebral infarction foetal
Cerebral ischaemia
Cerebral microembolism
Cerebral microhaemorrhage
Cerebral microinfarction
Cerebral reperfusion injury
Cerebral revascularisation
Cerebral septic infarct
Cerebral small vessel ischaemic disease
Cerebral thrombosis
Cerebral vascular occlusion
Cerebral vasoconstriction
Cerebral venous sinus thrombosis
Cerebral venous thrombosis
Cerebral ventricular rupture
Cerebrovascular accident
Cerebrovascular accident
Cerebrovascular accident prophylaxis
Cerebrovascular disorder
Cerebrovascular disorder
Cerebrovascular insufficiency
Cerebrovascular pseudoaneurysm
Cerebrovascular stenosis
Charcot-Bouchard microaneurysms
Claude's syndrome
Congenital hemiparesis
Delayed ischaemic neurological deficit
Delayed ischaemic neurological deficit
Dural arteriovenous fistula
Embolic cerebellar infarction
Embolic cerebral infarction
Embolic stroke
Epidural haemorrhage
Extra-axial haemorrhage
Extradural haematoma
Extradural haematoma evacuation
Extraischaemic cerebral haematoma
Foville syndrome
Foville syndrome
Haemorrhage intracranial
Haemorrhagic cerebellar infarction
Haemorrhagic cerebral infarction
Haemorrhagic stroke
Haemorrhagic transformation stroke
Hemianaesthesia
Hemiasomatognosia
Hemiataxia
Hemidysaesthesia
Hemihyperaesthesia
Hemihypoaesthesia
Hemiparaesthesia
Hemiparesis
Hemiplegia
Hypoxic-ischaemic encephalopathy
Inner ear infarction
Internal capsule infarction
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Intra-cerebral aneurysm operation
Intracerebral haematoma evacuation
Intracranial aneurysm
Intracranial haematoma
Intracranial haemorrhage neonatal
Intracranial tumour haemorrhage
Intraventricular haemorrhage
Intraventricular haemorrhage neonatal
Ischaemic cerebral infarction
Ischaemic stroke
Lacunar infarction
Lacunar stroke
Lateral medullary syndrome
Lateropulsion
Malignant middle cerebral artery syndrome
Meningorrhagia
Metabolic stroke
Migrainous infarction
Millard-Gubler syndrome
Moyamoya disease
Perinatal stroke
Perinatal stroke
Periventricular haemorrhage neonatal
Pituitary apoplexy
Pituitary haemorrhage
Post cardiac arrest syndrome
Post procedural stroke
Post stroke depression
Posthaemorrhagic hydrocephalus
Precerebral arteriosclerosis
Precerebral artery aneurysm
Precerebral artery dissection
Precerebral artery embolism
Precerebral artery occlusion
Precerebral artery thrombosis
Pseudo-occlusion of internal carotid artery
Putamen haemorrhage
Reversible cerebral vasoconstriction syndrome
Reversible ischaemic neurological deficit
Ruptured cerebral aneurysm
Septic cerebral embolism
Spinal artery embolism
Spinal artery thrombosis
Spinal cord haematoma
Spinal cord haemorrhage
Spinal cord infarction
Spinal cord ischaemia
Spinal epidural haematoma
Spinal epidural haemorrhage
Spinal stroke
Spinal stroke
Spinal subarachnoid haemorrhage
Spinal subdural haematoma
Spinal subdural haemorrhage
Stroke in evolution
Stroke in evolution
Subarachnoid haematoma
Subarachnoid haemorrhage
Subarachnoid haemorrhage neonatal
Subclavian steal syndrome
Subdural haematoma
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Subdural haematoma evacuation
Subdural haemorrhage
Subdural haemorrhage neonatal
Superior sagittal sinus thrombosis
Thalamic infarction
Thalamus haemorrhage
Thrombotic cerebral infarction
Thrombotic stroke
Transient ischaemic attack
Transverse sinus thrombosis
Vascular encephalopathy
Vascular stent occlusion
Vascular stent stenosis
Vein of Galen aneurysmal malformation
Vertebral artery aneurysm
Vertebral artery arteriosclerosis
Vertebral artery dissection
Vertebral artery occlusion
Vertebral artery perforation
Vertebral artery stenosis
Vertebral artery thrombosis
Vertebrobasilar insufficiency
Vertebrobasilar stroke
Vertebrobasilar stroke
Weber's syndrome
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 generalised lipodystrophy
Acquired mixed hyperlipidaemia
Apolipoprotein
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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
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
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Familial partial lipodystrophy
Fat redistribution
Fatty acid deficiency
Fatty acid oxidation disorder
Fatty liver alcoholic
Free fatty acids
Free fatty acids abnormal
Free fatty acids decreased
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
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Lipoprotein metabolism disorder
Long-chain acyl-coenzyme A dehydrogenase deficiency
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 fatty liver
Non-alcoholic steatohepatitis
Non-high-density lipoprotein cholesterol
Non-high-density lipoprotein cholesterol decreased
Non-high-density lipoprotein cholesterol increased
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
EFFECTS ON WEIGHT
Abnormal weight gain
Body mass index abnormal
Body mass index increased
Obesity
Overweight
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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
Chronic tic disorder
Clumsiness
Cogwheel rigidity
Complex tic
Complex tic
Dopamine dysregulation syndrome
Drooling
Drooling
Drooling
Dysarthria
Dyskinesia
Dyskinesia neonatal
Dyskinesia oesophageal
Dyslalia
Dysphonia
Dystonia
Dystonic tremor
Emprosthotonus
Essential tremor
Excessive eye blinking
Extrapyramidal disorder
Extrapyramidal disorder
Extrapyramidal disorder
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
Hypokinesia
Hypokinesia neonatal
Hypokinetic dysarthria
Intention tremor
Laryngeal tremor
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Laryngospasm
Meige's syndrome
Micrographia
Mobility decreased
Motor dysfunction
Motor dysfunction
Motor dysfunction
Motor dysfunction
Movement disorder
Movement disorder
Movement disorder
Movement disorder
Muscle contractions involuntary
Muscle contracture
Muscle rigidity
Muscle spasms
Muscle spasticity
Muscle tightness
Muscle tone disorder
Muscle tone disorder
Muscle twitching
Muscle twitching
Musculoskeletal stiffness
Musculoskeletal stiffness
Myoclonus
Myotonia
Nuchal rigidity
Oculogyric crisis
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
Provisional tic disorder
Psychomotor hyperactivity
Rabbit syndrome
Reduced facial expression
Respiratory dyskinesia
Resting tremor
Restless legs syndrome
Restlessness
Risus sardonicus
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Saliva altered
Salivary hypersecretion
Secondary tic
Secondary tic
Spasmodic dysphonia
Tardive dyskinesia
Tic
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 V 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
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
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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
Agranulocytosis
Aleukaemic leukaemia
Allergic bronchopulmonary mycosis
Allergic eosinophilia
Allergic lymphangitis
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
Anaemia of malignant disease
Anaemia of pregnancy
Anaemia postoperative
Anaemia splenic
Anaemia vitamin B12 deficiency
Anaemia vitamin B6 deficiency
Anaemic hypoxia
Anaemic retinopathy
Anaphylactoid syndrome of pregnancy
Anaplastic large cell lymphoma T- and null-cell types
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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
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-platelet factor 4 antibody negative
Anti-platelet factor 4 antibody positive
Anti-platelet factor 4 antibody test
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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 lymphoma unclassifiable
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
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 abnormalities
B-lymphocyte count
B-lymphocyte count abnormal
B-lymphocyte count abnormal
B-lymphocyte count decreased
B-lymphocyte count decreased
B-lymphocyte count increased
Babesiosis
Band neutrophil count
Band neutrophil count decreased
Band neutrophil count decreased
Band neutrophil count increased
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Band neutrophil percentage
Band neutrophil percentage decreased
Band neutrophil percentage decreased
Band neutrophil percentage increased
Bandaemia
Banti's syndrome
Basophil count
Basophil count abnormal
Basophil count abnormal
Basophil count decreased
Basophil count decreased
Basophil count increased
Basophil count normal
Basophil morphology
Basophil morphology abnormal
Basophil morphology normal
Basophil percentage
Basophil percentage decreased
Basophil percentage decreased
Basophil percentage increased
Basophilia
Basophilopenia
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
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 disorder
Blood erythropoietin
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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
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
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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
CD19 lymphocyte count abnormal
CD19 lymphocytes decreased
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
CHAPLE syndrome
Capillary fragility abnormal
Capillary fragility decreased
Capillary fragility increased
Capillary fragility normal
Capillary fragility test
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
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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
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
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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
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
Cyclic neutropenia
Cystic lymphangioma
Cytomegalovirus mononucleosis
Cytopenia
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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 abnormal
Differential white blood cell count normal
Diffuse infiltrative lymphocytosis syndrome
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
Eosinopenia
Eosinophil count
Eosinophil count abnormal
Eosinophil count abnormal
Eosinophil count decreased
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 decreased
Eosinophil percentage increased
Eosinophilia
Eosinophilia myalgia syndrome
Eosinophilic angiocentric fibrosis
Eosinophilic bronchitis
Eosinophilic cellulitis
Eosinophilic colitis
Eosinophilic cystitis
Eosinophilic fasciitis
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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
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 electrophoretic index increased
Erythrocyte osmotic fragility test
Erythroid dysplasia
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
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Factor V deficiency
Factor V inhibition
Factor VII deficiency
Factor VII inhibition
Factor VIII activity test
Factor VIII deficiency
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
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 abnormal
Full blood count decreased
Full blood count increased
Full blood count normal
GATA2 deficiency
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 decreased
Granulocyte count increased
Granulocyte percentage
Granulocyte percentage decreased
Granulocyte percentage decreased
Granulocyte percentage increased
Granulocytes abnormal
Granulocytes abnormal
Granulocytes maturation arrest
Granulocytes maturation arrest
Granulocytopenia
Granulocytopenia
Granulocytopenia neonatal
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
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Haematological cyst
Haematological malignancy
Haematological neoplasm
Haematology test
Haematology test abnormal
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 J present
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
Haemophilic pseudotumour
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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 cofactor II deficiency
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 microcytic anaemia
Hereditary persistence of foetal haemoglobin
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
Histiocytosis-lymphadenopathy plus syndrome
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
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
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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
Hypergammaglobulinaemic purpura of Waldenstrom
Hyperglobulinaemia
Hyperhomocysteinaemia
Hyperleukocytosis
Hyperplasia of thymic epithelium
Hyperprothrombinaemia
Hypersensitivity vasculitis
Hypersplenism
Hypersplenism congenital
Hyperthrombinaemia
Hyperviscosity syndrome
Hypochromasia
Hypochromic anaemia
Hypocoagulable state
Hypocomplementaemia
Hypofibrinogenaemia
Hypoglobulinaemia
Hypoplastic anaemia
Hypoprothrombinaemia
Hyposplenism
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Hypothrombinaemia
Hypothromboplastinaemia
Hypotransferrinaemia
ISTH score for disseminated intravascular coagulation
Idiopathic CD4 lymphocytopenia
Idiopathic neutropenia
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
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
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Leukaemic infiltration renal
Leukaemic lymphoma
Leukaemic retinopathy
Leukaemoid reaction
Leukocyte adhesion deficiency type I
Leukocyte vacuolisation
Leukocytosis
Leukoerythroblastic anaemia
Leukoerythroblastosis
Leukopenia
Leukopenia
Leukopenia neonatal
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
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
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Lymphocele
Lymphocyte count
Lymphocyte count abnormal
Lymphocyte count abnormal
Lymphocyte count decreased
Lymphocyte count decreased
Lymphocyte count increased
Lymphocyte count normal
Lymphocyte morphology
Lymphocyte morphology abnormal
Lymphocyte morphology normal
Lymphocyte percentage
Lymphocyte percentage abnormal
Lymphocyte percentage abnormal
Lymphocyte percentage decreased
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
Lymphocyte/monocyte ratio increased
Lymphocytic infiltration
Lymphocytic leukaemia
Lymphocytic lymphoma
Lymphocytic oesophagitis
Lymphocytopenia neonatal
Lymphocytopenia neonatal
Lymphocytosis
Lymphoedema
Lymphogranuloma venereum
Lymphoid hyperplasia of intestine
Lymphoid leukaemia (in remission)
Lymphoid tissue hyperplasia
Lymphoid tissue hypoplasia
Lymphoma
Lymphoma AIDS related
Lymphoma transformation
Lymphopenia
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
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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
Malignant unclassifiable lymphoma
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
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
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Meningitis eosinophilic
Metamyelocyte count
Metamyelocyte count decreased
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 decreased
Monoblast count increased
Monoclonal B-cell lymphocytosis
Monoclonal gammopathy
Monocyte count
Monocyte count abnormal
Monocyte count abnormal
Monocyte count decreased
Monocyte count decreased
Monocyte count increased
Monocyte count normal
Monocyte morphology
Monocyte morphology abnormal
Monocyte percentage
Monocyte percentage abnormal
Monocyte percentage decreased
Monocyte percentage decreased
Monocyte percentage increased
Monocytic leukaemia in remission
Monocytopenia
Monocytopenia
Monocytosis
Mononuclear cell count
Mononuclear cell count abnormal
Mononuclear cell count decreased
Mononuclear cell count decreased
Mononuclear cell count increased
Mononuclear cell percentage
Mononucleosis syndrome
Multicentric reticulohistiocytosis
Myeloblast count
Myeloblast count decreased
Myeloblast count decreased
Myeloblast count increased
Myeloblast percentage
Myeloblast percentage decreased
Myeloblast percentage decreased
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Myeloblast percentage increased
Myeloblast present
Myeloblastoma
Myelocyte count
Myelocyte count decreased
Myelocyte count decreased
Myelocyte count increased
Myelocyte percentage
Myelocyte percentage decreased
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 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
Natural killer-cell leukaemia
Natural killer-cell lymphoblastic lymphoma
Necrotic lymphadenopathy
Neonatal alloimmune thrombocytopenia
Neonatal leukaemia
Neoplasm of thymus
Nephrogenic anaemia
Neuroacanthocytosis
Neutropenia
Neutropenia
Neutropenia neonatal
Neutropenia neonatal
Neutropenic colitis
Neutropenic infection
Neutropenic infection
Neutropenic sepsis
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 abnormal
Neutrophil count decreased
Neutrophil count decreased
Neutrophil count increased
Neutrophil count normal
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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 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
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
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PFAPA syndrome
POEMS syndrome
PSTPIP1-associated myeloid-related proteinaemia inflammatory 
syndrome
Pancytopenia
Panmyelopathy
Paraneoplastic eosinophilia
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
Pigment nephropathy
Placental transfusion syndrome
Plasma cell count
Plasma cell disorder
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 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
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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
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
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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 hypercoagulability
Postoperative lymphocele
Postsplenectomy syndrome
Precursor B-lymphoblastic lymphoma
Precursor B-lymphoblastic lymphoma recurrent
Precursor B-lymphoblastic lymphoma refractory
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 decreased
Promyelocyte count increased
Protein C
Protein C decreased
Protein C deficiency
Protein C increased
Protein S
Protein S abnormal
Protein S decreased
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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
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
Pure white cell aplasia
Purpura
Purpura fulminans
Purpura neonatal
Purpura non-thrombocytopenic
Purpura senile
Pyruvate kinase deficiency anaemia
Radiation anaemia
Radiation leukopenia
Radiation leukopenia
Radiation lymphoedema
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
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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
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 decreased
Reticulocyte haemoglobin equivalent
Reticulocyte haemoglobin increased
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
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Rhesus antibodies negative
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
Sarcoidosis of lymph node
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
Scorbutic anaemia
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
Splenic artery thrombosis
Splenic calcification
Splenic candidiasis
Splenic cyst
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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
T-cell lymphoma stage I
T-cell lymphoma stage II
T-cell lymphoma stage III
T-cell lymphoma stage IV
T-cell lymphoma unclassifiable
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
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T-lymphocyte count abnormal
T-lymphocyte count decreased
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 generation assay
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
Thrombomodulin increased
Thrombopoietin level abnormal
Thrombosis with thrombocytopenia syndrome
Thrombotic microangiopathy
Thrombotic thrombocytopenic purpura
Thromboxane decreased
Thromboxane increased
Thymic cancer metastatic
Thymic carcinoma
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
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 lymph nodes
Ultrasound spleen
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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 autoimmune haemolytic anaemia
White blood cell agglutination present
White blood cell analysis
White blood cell analysis abnormal
White blood cell analysis abnormal
White blood cell analysis normal
White blood cell count
White blood cell count abnormal
White blood cell count abnormal
White blood cell count decreased
White blood cell count decreased
White blood cell count increased
White blood cell count normal
White blood cell disorder
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
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
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Airway remodelling
Allergic bronchitis
Allergic colitis
Allergic cough
Allergic cystitis
Allergic eosinophilia
Allergic gastroenteritis
Allergic hepatitis
Allergic keratitis
Allergic lymphangitis
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
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
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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
Bone cement allergy
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
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
Dermal filler reaction
Dermatitis
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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
Eosinophil percentage increased
Eosinophilia
Eosinophilia myalgia syndrome
Eosinophilic angiocentric fibrosis
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
Foreskin oedema
Gastrointestinal oedema
Generalised bullous fixed drug eruption
Generalised oedema
Genital rash
Genital swelling
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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
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
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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
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
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Panniculitis
Pathergy reaction
Penile exfoliation
Penile oedema
Penile rash
Penile swelling
Perineal rash
Perioral dermatitis
Periorbital dermatitis
Periorbital oedema
Periorbital swelling
Pharyngeal oedema
Pharyngeal swelling
Photosensitivity reaction
Pneumonitis
Polymers allergy
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 flavouring
Reaction to food additive
Reaction to preservatives
Reaction to sweetener
Reactive airways dysfunction 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
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Serum sickness-like reaction
Shock
Shock symptom
Skin erosion
Skin exfoliation
Skin necrosis
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
Superficial inflammatory dermatosis
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
Vancomycin infusion reaction
Vascular access site dermatitis
Vascular access site eczema
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
PNEUMONIA
Acinetobacter infection
Acinetobacter test positive
Actinomycotic pulmonary infection
Acute pulmonary histoplasmosis
Adenovirus infection
Adenovirus test positive
Aspergillus infection
Aspergillus test positive
Aspiration tracheal abnormal
Atelectasis
Atypical mycobacterial infection
Atypical mycobacterial lower respiratory tract infection
Atypical mycobacterial pneumonia
Atypical pneumonia
Auscultation
Avian influenza
Bacterial test positive
Blastomycosis
Bronchopneumopathy
Bronchopulmonary aspergillosis
Burkholderia cepacia complex infection
Burkholderia pseudomallei infection
Burkholderia test positive
COVID-19
COVID-19 pneumonia
Candida pneumonia
Carbon dioxide abnormal
Carbon dioxide increased
Chest X-ray abnormal
Chlamydia test positive
Chlamydial infection
Chronic pulmonary histoplasmosis
Coccidioidomycosis
Coronavirus infection
Coronavirus pneumonia
Coronavirus test positive
Coxiella test positive
Crepitations
Cryptococcosis
Culture throat positive
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Disseminated aspergillosis
Disseminated blastomycosis
Disseminated coccidioidomycosis
Disseminated mucormycosis
Disseminated paracoccidioidomycosis
Disseminated sporotrichosis
Disseminated tuberculosis
Egobronchophony
Embolic pneumonia
Empyema
Enterobacter infection
Enterobacter pneumonia
Enterobacter test positive
Escherichia infection
Escherichia test positive
Francisella test positive
Fungal test positive
H1N1 influenza
H2N2 influenza
H3N2 influenza
Haemophilus infection
Haemophilus test positive
Haemoptysis
Haemorrhagic pneumonia
Hantavirus pulmonary infection
Hantavirus test positive
Herpes simplex pneumonia
Histoplasmosis
Human metapneumovirus test positive
Hypoventilation
Hypoxia
Increased bronchial secretion
Infectious pleural effusion
Influenza
Influenza A virus test positive
Influenza virus test positive
Klebsiella infection
Klebsiella test positive
Legionella infection
Legionella test positive
Low lung compliance
Lower respiratory tract congestion
Lower respiratory tract herpes infection
Lower respiratory tract infection
Lower respiratory tract infection bacterial
Lower respiratory tract infection fungal
Lower respiratory tract infection viral
Lung abscess
Lung consolidation
Lung infiltration
Lung opacity
MERS-CoV test positive
Metapneumovirus infection
Metapneumovirus pneumonia
Middle East respiratory syndrome
Miliary pneumonia
Moraxella infection
Moraxella test positive
Mucormycosis
Mycobacterial infection
Mycobacterium test positive
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Mycoplasma infection
Mycoplasma test positive
Nocardiosis
Organising pneumonia
Oxygen saturation abnormal
Oxygen saturation decreased
PCO2 abnormal
PCO2 decreased
PO2 abnormal
PO2 decreased
Paracancerous pneumonia
Paracoccidioides infection
Parasitic pneumonia
Percussion test abnormal
Pleural effusion
Pleural infection
Pleural infection bacterial
Pleural rub
Pleurisy bacterial
Pleurisy viral
Pleuritic pain
Pneumococcal bacteraemia
Pneumococcal infection
Pneumococcal sepsis
Pneumocystis jirovecii pneumonia
Pneumocystis test positive
Pneumonia
Pneumonia acinetobacter
Pneumonia adenoviral
Pneumonia anthrax
Pneumonia bacterial
Pneumonia bordetella
Pneumonia chlamydial
Pneumonia cryptococcal
Pneumonia cytomegaloviral
Pneumonia escherichia
Pneumonia fungal
Pneumonia haemophilus
Pneumonia helminthic
Pneumonia herpes viral
Pneumonia influenzal
Pneumonia klebsiella
Pneumonia legionella
Pneumonia measles
Pneumonia moraxella
Pneumonia mycoplasmal
Pneumonia necrotising
Pneumonia parainfluenzae viral
Pneumonia pneumococcal
Pneumonia proteus
Pneumonia pseudomonal
Pneumonia respiratory syncytial viral
Pneumonia salmonella
Pneumonia serratia
Pneumonia staphylococcal
Pneumonia streptococcal
Pneumonia toxoplasmal
Pneumonia tularaemia
Pneumonia viral
Pneumonic plague
Pneumovirus test positive
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Post procedural pneumonia
Productive cough
Proteus infection
Proteus test positive
Pseudomonas infection
Pseudomonas test positive
Psittacosis
Pulmonary blastomycosis
Pulmonary congestion
Pulmonary echinococciasis
Pulmonary histoplasmosis
Pulmonary imaging procedure abnormal
Pulmonary mucormycosis
Pulmonary nocardiosis
Pulmonary paracoccidioidomycosis
Pulmonary sepsis
Pulmonary sporotrichosis
Pulmonary syphilis
Pulmonary trichosporonosis
Pulmonary tuberculoma
Pulmonary tuberculosis
Pyopneumothorax
Q fever
Rales
Respiratory tract infection
Respiratory tract infection bacterial
Respiratory tract infection fungal
Respiratory tract infection viral
Rhonchi
SARS-CoV-1 test positive
SARS-CoV-2 antibody test positive
SARS-CoV-2 test false negative
SARS-CoV-2 test positive
Septic pulmonary embolism
Serratia infection
Serratia test positive
Severe acute respiratory syndrome
Sporotrichosis
Sputum abnormal
Sputum culture positive
Sputum discoloured
Sputum purulent
Staphylococcal infection
Staphylococcus test positive
Streptococcal infection
Streptococcus test positive
Suspected COVID-19
Tachypnoea
Tuberculosis
Tuberculous pleurisy
Tularaemia
Use of accessory respiratory muscles
Varicella zoster pneumonia
Venous oxygen saturation abnormal
Venous oxygen saturation decreased
Pneumonia aspiration
NEUROLEPTIC MALIGNANT SYNDROME
Altered state of consciousness
Autonomic nervous system imbalance
Blood creatine phosphokinase MM increased
Blood creatine phosphokinase abnormal
Blood creatine phosphokinase increased
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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
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
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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
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
Arrhythmic storm
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
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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
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 infarction
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
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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
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
Epilepsia partialis continua
Epilepsy
Epilepsy of infancy with migrating focal seizures
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
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Hypoglycaemic seizure
Hyponatraemic seizure
Idiopathic generalised epilepsy
Infantile spasms
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
PURA syndrome
Parietal lobe epilepsy
Partial seizures
Partial seizures with secondary generalisation
Petit mal epilepsy
Photosensitive seizure
Polymicrogyria
Post stroke epilepsy
Post stroke seizure
Post-traumatic epilepsy
Postictal headache
Postictal paralysis
Postictal psychosis
Postictal state
Preictal state
Progressive encephalopathy, hypsarrhythmia and optic atrophy 
syndrome
Schizencephaly
Seizure
Seizure anoxic
Seizure cluster
Seizure like phenomena
Seizure prophylaxis
Severe myoclonic epilepsy of infancy
Simple partial seizures
Sleep related hypermotor epilepsy
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
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Columbia suicide severity rating scale abnormal
Completed suicide
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 thrombosis
Peripheral vein thrombus extension
Phlebectomy
Portal vein cavernous transformation
Portal vein embolism
Portal vein occlusion
Portal vein thrombosis
Portosplenomesenteric venous thrombosis
Post procedural pulmonary embolism
Post thrombotic syndrome
Postoperative thrombosis
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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
Sigmoid sinus thrombosis
Splenic vein occlusion
Splenic vein thrombosis
Subclavian vein occlusion
Subclavian vein thrombosis
Superficial vein thrombosis
Superior sagittal sinus thrombosis
Superior vena cava occlusion
Superior vena cava syndrome
Thrombophlebitis
Thrombophlebitis migrans
Thrombophlebitis neonatal
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
Subject Disposition (Enrolled Subjects)
CT-2
Reasons for Discontinuation (Randomized Subjects )
CT-3.1.1
Demographic Characteristics (Full Analysis Set)
CT-3.1.2
Demographic Characteristics (Safety Analysis Set)
CT-3.1.3
Demographic Characteristics (Pharmacokinetic Analysis Set)
CT-3.2.1
Baseline Disease Characteristics (Full Analysis Set)
CT-3.2.2
Baseline Disease Characteristics (Safety Analysis Set)
CT-4.1.1
Concomitant Medications (Antipsychotic): Medications Taken Prior to Start of 
Study Therapy (Safety Analysis Set)
CT-4.1.2
Concomitant Medications (Antipsychotic): Medications Taken During Study 
Therapy (Safety Analysis Set)
CT-4.1.3
Concomitant Medications (Antipsychotic): Medications Taken Post Study Therapy 
(Safety Analysis Set)
CT-4.2.1
Concomitant Medications (Antidementia Drug): Medications Taken Prior to Start of 
Study Therapy (Safety Analysis Set)
CT-4.2.2
Concomitant Medications (Antidementia Drug): Medications Taken During Study 
Therapy (Safety Analysis Set)
CT-4.2.3
Concomitant Medications (Antidementia Drug): Medications Taken Post Study 
Therapy (Safety Analysis Set)
CT-4.3.1
Concomitant Medications (Other): Medications Taken Prior to Start of Study 
Therapy (Safety Analysis Set)
CT-4.3.2
Concomitant Medications (Other): Medications Taken During Study Therapy 
(Safety Analysis Set)
CT-4.3.3
Concomitant Medications (Other): Medications Taken Post Study Therapy (Safety 
Analysis Set)
CT-4.4
Summary of Major Protocol Deviations by Center and Type of Deviation 
(Randomized Subjects)
CT-5.1
Summary of Efficacy Results at Week 10 (Full Analysis Set)
CT-5.2
Summary of Mean Change From Baseline to Double Blind Treatment Period by 
Study Week in CMAI Total Score - MMRM (Full Analysis Set)
CT-5.3
Summary of Mean Change From Baseline to Double Blind Treatment Period by 
Study Week in CMAI Subscale Score - MMRM (Full Analysis Set)
CT-5.4
Summary of Mean Change From Baseline to Double Blind Treatment Period by 
Study Week in CGI-S Scale - MMRM (Full Analysis Set)
CT-5.5.1
Summary of Mean CGI-I Score by Study Week in Double Blind Treatment Period 
Relative to Baseline - LOCF (Full Analysis Set)
CT-5.5.2
Summary of Mean CGI-I Score by Study Week in Double Blind Treatment Period 
Relative to Baseline - OC (Full Analysis Set)
CT-5.6.1
CT-5.6.2
CT-5.6.3
CT-5.6.4
CT-5.7.1
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CT-5.7.2
CT-5.7.3
CT-5.7.4
CT-5.8.1
CT-5.8.2
CT-5.8.3
CT-5.8.4
CT-5.9.1
CT-5.9.2
CT-5.10.1
CT-5.10.2
CT-5.11.1
Sensitivity Analysis of MNAR using Tipping Point Analysis in CMAI Total Score 
Assume All Dropouts as MNAR (Full Analysis Set)
CT-5.11.2
Sensitivity Analysis of MNAR using Tipping Point Analysis in CMAI Total Score 
Dropout due to AE or LOE or Withdrew Consent as MNAR (Full Analysis Set)
CT-5.11.3
Sensitivity Analysis of MNAR using Tipping Point Analysis in CMAI Total Score 
Dropout due to AE or LOE as MNAR (Full Analysis Set)
CT-5.11.4
Sensitivity Analysis of MNAR using Placebo Based Imputation in CMAI Total 
Score (Full Analysis Set)
CT-5.11.5
Summary of Mean Change From Baseline to Double Blind Treatment Period by 
Study Week in CMAI Total Score - Van Elteren Test, Robust Regression - MI (Full 
Analysis Set)
CT-5.11.6
Summary of Mean Change From Baseline to Double Blind Treatment Period by 
Study Week in CMAI Total Score - Van Elteren Test, Robust Regression - OC (Full 
Analysis Set)
CT-6.1.1
Summary of Mean Change From Baseline to Double Blind Treatment Period by 
Study Week in CMAI Total Score by Medical Care Category: In-patient - MMRM 
(Full Analysis Set)
CT-6.1.2
Summary of Mean Change From Baseline to Double Blind Treatment Period by 
Study Week in CMAI Total Score by Medical Care Category: Out-patient - MMRM 
(Full Analysis Set)
CT-6.2.1
Summary of Mean Change From Baseline to Double Blind Treatment Period by 
Study Week in CMAI Total Score by Prior Antipsychotics: Present - MMRM (Full 
Analysis Set)
CT-6.2.2
Summary of Mean Change From Baseline to Double Blind Treatment Period by 
Study Week in CMAI Total Score by Prior Antipsychotics: Absent - MMRM (Full 
Analysis Set)
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CT-6.3.1
Summary of Mean Change From Baseline to Double Blind Treatment Period by 
Study Week in CMAI Total Score by Main Care Giver: Staff of Hospital - MMRM 
(Full Analysis Set)
CT-6.3.2
Summary of Mean Change From Baseline to Double Blind Treatment Period by 
Study Week in CMAI Total Score by Main Care Giver: Staff of Care Facility - 
MMRM (Full Analysis Set)
CT-6.3.3 
Summary of Mean Change From Baseline to Double Blind Treatment Period by 
Study Week in CMAI Total Score by Main Care Giver: Family - MMRM (Full 
Analysis Set)
CT-6.4.1
Summary of Mean Change From Baseline to Double Blind Treatment Period by 
Study Week in CMAI Total Score by Gender: Male - MMRM (Full Analysis Set)
CT-6.4.2
Summary of Mean Change From Baseline to Double Blind Treatment Period by 
Study Week in CMAI Total Score by Gender: Female - MMRM (Full Analysis Set)
CT-6.5.1
Summary of Mean Change From Baseline to Double Blind Treatment Period by 
Study Week in CMAI Total Score by Age: < 80 Years - MMRM (Full Analysis Set)
CT-6.5.2
Summary of Mean Change From Baseline to Double Blind Treatment Period by 
Study Week in CMAI Total Score by Age: >= 80 Years - MMRM (Full Analysis 
Set)
CT-6.5.3
Summary of Mean Change From Baseline to Double Blind Treatment Period by 
Study Week in CMAI Total Score by Age: < 65 Years - MMRM (Full Analysis Set)
CT-6.5.4
Summary of Mean Change From Baseline to Double Blind Treatment Period by 
Study Week in CMAI Total Score by Age: >= 65 - < 75 Years - MMRM (Full 
Analysis Set)
CT-6.5.5 
Summary of Mean Change From Baseline to Double Blind Treatment Period by 
Study Week in CMAI Total Score by Age: >= 75 Years - MMRM (Full Analysis 
Set) 
CT-6.6.1
Summary of Mean Change From Baseline to Double Blind Treatment Period by 
Study Week in CMAI Total Score by Baseline CMAI Total Score: <= Median - 
MMRM (Full Analysis Set)
CT-6.6.2
Summary of Mean Change From Baseline to Double Blind Treatment Period by 
Study Week in CMAI Total Score by Baseline CMAI Total Score: > Median  - 
MMRM (Full Analysis Set)
CT-6.7.1
CT-6.7.2
CT-6.8.1
Summary of Mean Change From Baseline to Double Blind Treatment Period by 
Study Week in CMAI Total Score by Baseline Weight: <= Median - MMRM (Full 
Analysis Set)
CT-6.8.2
Summary of Mean Change From Baseline to Double Blind Treatment Period by 
Study Week in CMAI Total Score by Baseline Weight: > Median - MMRM (Full 
Analysis Set)
CT-6.9.1
Summary of Mean Change From Baseline to Double Blind Treatment Period by 
Study Week in CMAI Total Score by Baseline BMI: <= Median - MMRM (Full 
Analysis Set)
CT-6.9.2
Summary of Mean Change From Baseline to Double Blind Treatment Period by 
Study Week in CMAI Total Score by Baseline BMI: > Median - MMRM (Full 
Analysis Set)
CT-6.10.1
Summary of Mean Change From Baseline to Double Blind Treatment Period by 
Study Week in CMAI Total Score by CYP2D6 Metabolism Status: IM - MMRM 
(Full Analysis Set)
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CT-6.10.2
Summary of Mean Change From Baseline to Double Blind Treatment Period by 
Study Week in CMAI Total Score by CYP2D6 Metabolism Status: EM - MMRM 
(Full Analysis Set)
CT-6.11.1
Summary of Mean Change From Baseline to Double Blind Treatment Period by 
Study Week in CMAI Total Score by Impact of COVID-19 Pandemic: Subjects 
Completed/Discontinued before 07APR2020 - MMRM (Full Analysis Set)
CT-6.11.2
Summary of Mean Change From Baseline to Double Blind Treatment Period by 
Study Week in CMAI Total Score by Impact of COVID-19 Pandemic: Subjects 
Completed/Discontinued on or after 07APR2020 - MMRM (Full Analysis Set)
CT-6.12.1
Summary of Mean Change From Baseline to Double Blind Treatment Period by 
Study Week in CMAI Total Score by Concomitant Antidementia Drugs: Present - 
MMRM (Full Analysis Set)
CT-6.12.2
Summary of Mean Change From Baseline to Double Blind Treatment Period by 
Study Week in CMAI Total Score by Concomitant Antidementia Drugs: Absent - 
MMRM (Full Analysis Set)
CF-1
LS Mean Change From Baseline to Double Blind Treatment Period in CMAI Total 
Score - MMRM (Full Analysis Set)
CT-7.1
Extent of Exposure (Safety Analysis Set)
CT-7.2
Duration of Exposure Summary (Safety Analysis Set)
CT-7.3
Summary of Treatment Compliance (Full 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 of IMP by MedDRA 
System Organ Class and Preferred Term (Safety Analysis Set)
CT-8.7.1
Incidence of TEAEs of at Least 2% in Any Brex Group and Greater Than Placebo 
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 Brex Group and Greater 
Than Placebo 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 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 Accidents and Injuries Including Fall (Safety Analysis Set)
 CT-8.9.3
Incidence of TEAEs for Cerebrovascular Events (Safety Analysis Set)
CT-8.9.4
Incidence of TEAEs for Cardiovascular Events (Safety Analysis Set)
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CT-8.9.5
Incidence of TEAEs for Effect on Glucose (Safety Analysis Set)
CT-8.9.6
Incidence of TEAEs for Effect on Lipids (Safety Analysis Set)
CT-8.9.7
Incidence of TEAEs for Effect on Weight (Safety Analysis Set)
CT-8.9.8
Incidence of TEAEs for Haematopoietic/Leukopenia (Safety Analysis Set)
CT-8.9.9
Incidence of TEAEs for Hypersensitivity (Safety Analysis Set)
CT-8.9.10
Incidence of TEAEs for Neuroleptic Malignant Syndrome (Safety Analysis Set)
CT-8.9.11
Incidence of TEAEs for Orthostatic Hypotension, Dizziness, and Syncope (Safety 
Analysis Set)
CT-8.9.12
Incidence of TEAEs for Effect on Prolactin (Safety Analysis Set)
CT-8.9.13
Incidence of TEAEs for QT Prolongation (Safety Analysis Set)
CT-8.9.14
Incidence of TEAEs for Rhabdomyolysis and CPK Elevation (Safety Analysis Set)
CT-8.9.15
Incidence of TEAEs for Seizures (Safety Analysis Set)
CT-8.9.16
Incidence of TEAEs for Somnolence (Safety Analysis Set)
CT-8.9.17
Incidence of TEAEs for Suicidality (Safety Analysis Set)
CT-8.9.18
Incidence of TEAEs for VTE (Thrombotic and Embolic Events) (Safety Analysis 
Set)
CT-8.9.19
Incidence of TEAEs for Pneumonia  (Safety Analysis Set)
CT-8.10.1
Incidence of TEAEs by MedDRA System Organ Class and Preferred Term by 
Medical Care Category (Safety Analysis Set)
CT-8.10.2
Incidence of TEAEs by MedDRA System Organ Class and Preferred Term by Prior 
Antipsychotics (Safety Analysis Set)
CT-8.10.3
Incidence of TEAEs by MedDRA System Organ Class and Preferred Term by Main 
Care Giver (Safety Analysis Set)
CT-8.10.4
Incidence of TEAEs by MedDRA System Organ Class and Preferred Term by 
Gender (Safety Analysis Set)
CT-8.10.5.1
Incidence of TEAEs by MedDRA System Organ Class and Preferred Term by 
Age  (< 80, >= 80) (Safety Analysis Set)
CT-8.10.5.2
Incidence of TEAEs by MedDRA System Organ Class and Preferred Term by Age 
(< 65, >= 65 - < 75, >= 75) (Safety Analysis Set)
CT-8.10.6
Incidence of TEAEs by MedDRA System Organ Class and Preferred Term by 
Baseline Weight (Safety Analysis Set)
CT-8.10.7
Incidence of TEAEs by MedDRA System Organ Class and Preferred Term by 
Baseline BMI (Safety Analysis Set)
CT-8.10.8
Incidence of TEAEs by MedDRA System Organ Class and Preferred Term by 
CYP2D6 Metabolism Status (Safety Analysis Set)
CT-8.10.9
Incidence of TEAEs by MedDRA System Organ Class and Preferred Term by 
Impact of COVID-19 Pandemic (Safety Analysis Set)
CT-8.10.10
Incidence of TEAEs by MedDRA System Organ Class and Preferred Term by 
Concomitant Antidementia Drugs (Safety Analysis Set)
CT-9.1
Listing of Deaths (Safety Analysis Set)
CT-9.2
Listing of Serious Adverse Events (Safety Analysis Set)
CT-9.3
Listing of Discontinuation of IMP due to Adverse Events (Safety Analysis Set)
CT-9.4.1
Listing of TEAEs for EPS (Safety Analysis Set)
CT-9.4.2
Listing of TEAEs for Accidents and Injuries Including Fall (Safety Analysis Set)
CT-9.4.3
Listing of TEAEs for Cerebrovascular Events (Safety Analysis Set)
CT-9.4.4
Listing of TEAEs for Cardiovascular Events (Safety Analysis Set)
CT-9.4.5
Listing of TEAEs for Effect on Glucose (Safety Analysis Set)
CT-9.4.6
Listing of TEAEs for Effect on Lipids (Safety Analysis Set)
CT-9.4.7
Listing of TEAEs for Effect on Weight (Safety Analysis Set)
CT-9.4.8
Listing of TEAEs for Haematopoietic/Leukopenia (Safety Analysis Set)
CT-9.4.9
Listing of TEAEs for Hypersensitivity (Safety Analysis Set)
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CT-9.4.10
Listing of TEAEs for Neuroleptic Malignant Syndrome (Safety Analysis Set)
CT-9.4.11
Listing of TEAEs for Orthostatic Hypotension, Dizziness, and Syncope (Safety 
Analysis Set)
CT-9.4.12
Listing of TEAEs for Effect on Prolactin (Safety Analysis Set)
CT-9.4.13
Listing of TEAEs for QT Prolongation (Safety Analysis Set)
CT-9.4.14
Listing of TEAEs for Rhabdomyolysis and CPK Elevation (Safety Analysis Set)
CT-9.4.15
Listing of TEAEs for Seizures (Safety Analysis Set)
CT-9.4.16
Listing of TEAEs for Somnolence (Safety Analysis Set)
CT-9.4.17
Listing of TEAEs for Suicidality (Safety Analysis Set)
CT-9.4.18
Listing of TEAEs for VTE (Thrombotic and Embolic Events) (Safety Analysis Set)
CT-9.4.19
Listing of TEAEs for Pneumonia (Safety Analysis Set)
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
Incidence of  Potential Hy's Law Cases (Safety Analysis Set)
CT-10.4.2
Listing of Potential Hy's Law Cases (Safety Analysis Set)
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-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 to Double Blind Treatment Period by 
Study Week in Body Weight (kg) (Safety Analysis Set)
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CT-11.5
Summary of Mean Change From Baseline to Double Blind Treatment Period by 
Study Week in BMI (kg/m^2) (Safety Analysis Set)
CT-11.6
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 Increases in QT Evaluations (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 to Double Blind Treatment Period by 
Study Week in DIEPSS (Safety Analysis Set)
CT-13.2
Summary of Mean Change From Baseline to Double Blind Treatment Period by 
Study Week in AIMS Total Score and Item Scores 8, 9 and 10 (Safety Analysis Set)
CT-13.3
Summary of Mean Change From Baseline to Double Blind Treatment Period by 
Study Week in BARS, Global Clinical Assessment of Akathisia    (Safety Analysis 
Set)
CT-14.1
Summary of Mean Change From Baseline to Double Blind Treatment Period by 
Study Week in Sheehan-STS Score (Safety Analysis Set)
CT-14.2
Summary of Mean Change From Baseline to Double Blind Treatment Period by 
Study Week in Sheehan-STS - Total Score (Safety Analysis Set)
CT-14.3
Summary of Mean Change From Baseline to Double Blind Treatment Period by 
Study Week in Sheehan-STS - Suicidal Ideation Subscale Score (Safety Analysis 
Set)
CT-14.4
Summary of Mean Change From Baseline to Double Blind Treatment Period by 
Study Week in Sheehan-STS - Suicidal Behavior Subscale Score (Safety Analysis 
Set)
CT-15.1
Summary of Mean Change From Baseline to Double Blind Treatment Period by 
Study Week in ADCS-ADL Total Score (Safety Analysis Set)
CT-15.2
Summary of Mean Change From Baseline to Double Blind Treatment Period by 
Study Week in MMSE Total Score (Safety Analysis Set)
CT-15.3.1
Summary of Mean Change From Baseline to Double Blind Treatment Period by 
Study Week in EQ-5D-5L - Proxy Version (Safety Analysis Set)
CT-15.3.2
Summary of Mean Change From Baseline to Double Blind Treatment Period by 
Study Week in EQ-5D-5L (Safety Analysis Set)
PKT-1
Individual Subject and Summary of Brexpiprazole Plasma Concentrations Following 
1 mg/day Doses of Brexpiprazole at Week 10 (Pharmacokinetic Analysis Set)
PKT-2
Individual Subject and Summary of Brexpiprazole Plasma Concentrations Following 
2 mg/day Doses of Brexpiprazole at Week 10 (Pharmacokinetic Analysis Set)
PKT-3
Summary of Brexpiprazole  Plasma Concentrations for Each CYP2D6 Phenotype 
Following 1 mg/day Doses of Brexpiprazole at Week 10 (Pharmacokinetic Analysis 
Set)
PKT-4
Summary of Brexpiprazole Plasma Concentrations for Each CYP2D6 Phenotype 
Following 2 mg/day Doses of Brexpiprazole at Week 10 (Pharmacokinetic Analysis 
Set)
PKF-1
Mean (SD) and Scatter Plots of Brexpiprazole Plasma Concentrations Following 1 
mg/day Doses of Brexpiprazole at Week 10 (Pharmacokinetic Analysis Set)
PKF-2
Mean (SD) and Scatter Plots of Brexpiprazole Plasma Concentrations Following 2 
mg/day Doses of Brexpiprazole at Week 10 (Pharmacokinetic Analysis Set)
PKF-3
Mean (SD) and Scatter Plots of Brexpiprazole Plasma Concentrations for Each 
CYP2D6 Phenotype Following 1 mg/day Doses of Brexpiprazole at Week 10 
(Pharmacokinetic Analysis Set)
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PKF-4
Mean (SD) and Scatter Plots of Brexpiprazole Plasma Concentrations for Each 
CYP2D6 Phenotype Following 2 mg/day Doses of Brexpiprazole at Week 10 
(Pharmacokinetic Analysis Set)
PKF-5
Scatter Plot of Brexpiprazole Plasma Concentrations Following 1 mg/day Doses of 
Brexpiprazole at Week 10 (Pharmacokinetic Analysis Set)
PKF-6
Scatter Plot of Brexpiprazole Plasma Concentrations Following 2 mg/day Doses of 
Brexpiprazole at Week 10 (Pharmacokinetic Analysis Set)
PKF-7
Scatter Plot of Brexpiprazole Plasma Concentrations for Each CYP2D6 Phenotype 
Following 1 mg/day Doses of Brexpiprazole at Week 10 (Pharmacokinetic Analysis 
Set)
PKF-8
Scatter Plot of Brexpiprazole Plasma Concentrations for Each CYP2D6 Phenotype 
Following 2 mg/day Doses of Brexpiprazole at Week 10 (Pharmacokinetic Analysis 
Set)
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Appendix 6
List of Subject Data Listings
AE-1
Adverse Events (Randomized Subjects)
DEMOG-1
Demographic Characteristics (Randomized Subjects)
DREAS-1
Discontinued Subjects and Reason for Discontinuation (Randomized Subjects)
LAB-1
Laboratory Test Results: Serum Chemistry (Randomized Subjects)
LAB-2
Laboratory Test Results: Hematology (Randomized Subjects)
LAB-3
Laboratory Test Results: Urinalysis (Randomized Subjects)
LAB-4
Laboratory Test Results: Other Laboratory Tests (Randomized Subjects)
LAB-5
Pregnancy Test (Randomized Subjects)
EFF-1
Cohen-Mansfield Agitation Inventory (CMAI) (Randomized Subjects)
EFF-2
Clinical Global Impression - Severity of Illness  (CGI-S) (Randomized Subjects)
EFF-3
Clinical Global Impression - Improvement (CGI-I) (Randomized Subjects)
EFF-4
EFF-5
PDATA-1.1
Inclusion and Exclusion Criteria (Randomized Subjects)
PDATA-1.2
Inclusion and Exclusion Criteria (Screening Failure)
PDATA-2
Subject Randomization List (Randomized Subjects)
PDATA-3
Study Completion Status and Reasons for Discontinuation (Randomized Subjects)
PDATA-4
Medical History (Randomized Subjects)
PDATA-5
Alzheimer's Disease History (Randomized Subjects)
PDATA-6
Patient Care (Randomized Subjects)
PDATA-7.1
Prior and Concomitant Medications (Antipsychotic) (Randomized Subjects)
PDATA-7.2
Prior and Concomitant Medications (Antidementia Drug) (Randomized Subjects)
PDATA-7.3
Prior and Concomitant Medications (Other) (Randomized Subjects)
PDATA-7.4
Prior and Concomitant Therapy (Randomized Subjects)
PDATA-8
Physical Examination (Randomized Subjects)
PDATA-9
Vital Signs (Randomized Subjects)
PDATA-10
Electrocardiogram Results (Randomized Subjects)
PDATA-11.1
Sheehan-Suicidality Tracking Scale (S-STS) - Other than Q15 and Q16 (Randomized 
Subjects)
PDATA-11.2
Sheehan-Suicidality Tracking Scale (S-STS) - Q15 (Randomized Subjects)
PDATA-11.3
Sheehan-Suicidality Tracking Scale (S-STS) - Q16 (Randomized Subjects)
PDATA-12
Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS) (Randomized Subjects)
PDATA-13
Barnes Akathisia Rating Scale (BARS) (Randomized Subjects)
PDATA-14
Abnormal Involuntary Movement Scale (AIMS) (Randomized Subjects)
PDATA-15
Mini-Mental State Examination (MMSE) (Randomized Subjects)
PDATA-16
Alzheimer’s Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) 
(Randomized Subjects)
PDATA-17
EuroQol 5 Dimension 5 Level Health Questionnaire   (EQ-5D-5L) - Proxy Version 
(Randomized Subjects)
PDATA-18
EuroQol 5 Dimension 5 Level Health Questionnaire (EQ-5D-5L) (Randomized 
Subjects)
PDATA-19
Pharmacokinetic Blood Draw Time (Randomized Subjects)
PDATA-20
CYP2D6 Genetic Test (Randomized Subjects)
PDATA-21
Blood Draw Time for DNA Storage and Biomar ker (Randomized Subjects)
PDATA-22
Post-treatment Follow-up (Randomized Subjects)
PDATA-23
Screening Failures
PDEV-1
Major Protocol Deviations by Type of Deviation (Randomized Subjects)
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SMED-1
Study Medication Administration (Randomized Subjects)
SMED-2
Study Medication Compliance (Randomized Subjects)
SUBEX-1
Subjects Excluded From Analysis Set (Randomized Subjects)
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