A Phase 2, Multicenter, Randomized, Double-blind, Active- and Placebo-controlled Trial of the Safety and Efficacy of OPC-64005 in the Treatment of Adult Attention-deficit/Hyperactivity Disorder
Phase: PHASE2
Conditions: Adult Attention Deficit Hyperactivity Disorder
Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.

Official Title: 
A Phase 2, Multicenter, Randomized, Double-blind, Active- and 
Placebo-controlled Trial of the Safety and Efficacy of OPC-64005 in 
the Treatment of Adult Attention-deficit/Hyperactivity Disorder 
NCT Number: 
NCT03324581 
Document Date: 
Protocol Version 4.0: 28-August-2017 

Protocol 277-201-00001
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Protocol Synopsis 
Name of Sponsor:  Otsuka Pharmaceutical 
Development & Commercialization, Inc.
Name of Investigational Medicinal Product:  
OPC-64005
Protocol No.:  277-201-00001
IND No.:  133026
Protocol Title:
A Phase 2, Multicenter, Randomized, Double-blind, 
Active- and Placebo-controlled Trial of the Safety and 
Efficacy of OPC-64005 in the Treatment of Adult 
Attention-deficit/Hyperactivity Disorder
Clinical Phase:
2
Treatment Indication: Adult Attention-deficit/Hyperactivity Disorder
Objective(s): 
Primary: To assess the efficacy of OPC-64005 
(20 - 30 mg/day) relative to atomoxetine (40 - 80 mg/day) in 
adult subjects with attention-deficit/hyperactivity disorder 
(ADHD)
Other: 
To estimate the difference in effect between OPC-64005 
(20 - 30 mg/day) and placebo and its variability in adult 
subjects with ADHD in order to plan for the next trial.
To assess the safety and tolerability of OPC-64005 
(20 - 30 mg/day) in adult subjects with ADHD compared with 
both control arms.
Trial Design:
This is a multicenter, randomized, double-blind, active- and 
placebo-controlled, parallel-design trial.  The trial includes a 
Screening Period (≤28 days), a 4-day titration period, a 52-day 
treatment period, a follow-up telephone contact to occur at 
3 (± 1) days after the last dose, and a follow-up telephone 
contact to occur 30 (+ 2) days after the last dose.
Subject Population:
Approximately 201 adult male and female subjects with 
ADHD will be randomized (1:1:1) to be administered 
OPC-64005, atomoxetine, or placebo.
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Inclusion Criteria: 
Key inclusion criteria include the following:

Subjects with a primary Diagnostic and Statistical Manual 
of Mental Disorders, Fifth Edition (DSM-5) diagnosis of 
ADHD (including predominantly inattentive presentation, 
hyperactive presentation, and combined presentations) as 
confirmed by the Adult ADHD Clinical Diagnostic Scale, 
version 1.2 (ACDS v1.2). Subjects may be currently 
receiving treatment for adult ADHD at screening, but it is 
not necessary that they are currently receiving treatment.  
The rationale to discontinue current ADHD treatment must 
include either or both suboptimal efficacy response and/or 
treatment limiting safety/tolerability.

Male and female outpatients 18 to 55 years of age, 
inclusive, at the time of informed consent.

Subjects who are not currently receiving an approved 
pharmacological treatment for ADHD who have an Adult 
ADHD Investigator Symptom Rating Scale (AISRS) with 
Adult Prompts score of ≥ 26 and subjects who are 
receiving any pharmacological treatment for ADHD at 
screening who have an AISRS with Adult Prompts score of 
≥22.

Subjects who have a score of ≥ 4 on the Global Clinical 
Impression-Severity (CGI-S) scale.
Trial Site(s):
Approximately 25 trial sites in the United States
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Investigational 
Medicinal Product(s), 
Dose, Dosage 
regimen, Treatment 
period, Formulation, 
Mode of 
Administration:
Double-blind investigational medicinal product (IMP) will be 
provided to the investigator(s) by the sponsor (or contractor) 
and will consist of active OPC-64005 10-mg tablets and 
matching placebo tablets as well as atomoxetine 40-mg 
capsules (the active comparator) and matching placebo 
capsules.  The IMP will consist of tablets and capsules in 
weekly child-resistant blister cards, each containing sufficient 
tablets and capsules for 7 (+ 2) days.  When accessed by the 
site, the interactive voice response system (IVRS) or 
interactive web response system (IWRS) will assign specific 
blister cards to be dispensed to a subject. 
During the Titration Period (Days 1 - 4), subjects randomized 
to the OPC-64005 arm will receive 20 mg OPC-64005 (ie, 
two 10 mg OPC-64005 tablets) and atomoxetine placebo daily,
subjects randomized to the atomoxetine arm will receive 
40 mg of atomoxetine and OPC-64005 placebo daily, and 
subjects randomized to the placebo arm will receive both 
OPC-64005 placebo and atomoxetine placebo daily.
During the Treatment Period (Days 5 - 56), subjects 
randomized to the OPC-64005 arm will receive 30 mg 
OPC-64005 and atomoxetine placebo daily, subjects 
randomized to the atomoxetine arm will receive 80 mg of 
atomoxetine and OPC-64005 placebo daily, and subjects 
randomized to the placebo arm will receive both OPC-64005 
placebo and atomoxetine placebo daily.  If a subject is not able 
to tolerate the 30-mg dose of OPC-64005, the dose may be 
reduced to 20 mg for the duration of the Treatment Period.  If a 
subject is not able to tolerate the 80-mg dose of atomoxetine, 
the dose may be reduced to 40 mg of atomoxetine for the 
duration of the Treatment Period.  Subjects are permitted to 
have one dose reduction and one titration back up to their 
previous dose (ie, 30 mg for OPC-64005 and 80 mg for 
atomoxetine) during the trial.  When a subject is titrated down 
to a lower dose, they should be maintained on that low dose 
for a minimum of 4 days before being titrated back up to the 
higher dose.  On scheduled visit days (Days 7, 14, 21, 28, 42, 
and 56), dosing should be held until the subject is in the clinic; 
subjects will be dosed from a newly dispensed blister card.
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Trial Assessments:
Efficacy:  18-item, investigator-administered Conners' Adult 
ADHD Rating Scales–Observer: Screening Version 
(CAARS-O:SV), 18-item Conners' Adult ADHD Rating 
Scales–Self-Report: Screening Version (CAARS-S:SV), 
AISRS with Adult Prompts, CGI-S, Global Clinical 
Impression-Improvement (CGI-I), Adult ADHD Quality of 
Life Scale (AAQoL), and Profile of Mood States-Brief Form™ 
(POMS).
Pharmacokinetics:  Blood sampling for IMP plasma 
concentrations.
Safety:  Adverse events, physical examination, vital signs, 
12-lead electrocardiogram (ECG), clinical laboratory tests, 
C-SSRS, and Drug Effects Questionnaire (DEQ). 
Screening/Other:  Demographic information; medical, 
medication, and psychiatric history; identification of 
comorbidities (in part, using the Mini International 
Neuropsychiatric Interview); HIV, hepatitis B surface antigen 
(HBsAg), and anti hepatitis C virus (HCV) status; urine 
alcohol and drug screen; urine pregnancy test. 
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Criteria for 
Evaluation:
Primary Endpoint:  The primary efficacy endpoint is the 
change from baseline to the Day 56 Visit on the 
investigator-administered CAARS-O:SV 18-item ADHD 
symptoms total score in the OPC-64005 group relative to the 
atomoxetine group. 
Other Endpoint(s):   

Change from baseline to each scheduled visit (Days 7, 14, 
21, 28, 42, and 56/early termination [ET]; all visits have a 
± 1-day window) in the 18-item, investigator-administered
CAARS-O:SV score in the OPC-64005 group relative to 
the atomoxetine and placebo groups

Change from baseline to the Day 28 (± 1 day) and Day 56
(± 1 day) Visits for the AISRS with Adult Prompts score in 
the OPC-64005 group relative to the atomoxetine and 
placebo groups

Change from baseline to each scheduled visit (Days 7, 14, 
21, 28, 42, and 56/ET; all visits have a ± 1-day window) in 
the CGI-S score in the OPC-64005 group relative to the
atomoxetine and placebo groups

CGI-I score at each scheduled visit (Days 7, 14, 21, 28, 42, 
and 56/ET; all visits have a ± 1-day window) in the 
OPC-64005 group relative to the atomoxetine and placebo 
groups

Change from baseline to each scheduled visit (Days 7, 14, 
21, 28, 42, and 56/ET; all visits have a ± 1-day window) in 
the 18-item CAARS–S:SV score in the OPC-64005 group 
relative to the atomoxetine and placebo groups

Change from baseline to the Day 28 (± 1 day) and Day 56
(± 1 day) Visits in the AAQoL score in the OPC-64005, 
atomoxetine, and placebo groups

OPC-64005 potential for abuse liability and dependence as 
assessed by the DEQ at baseline and each scheduled visit 
(Days 7, 14, 21, 28, 42, and 56/ET; all visits have a 
± 1-day window)
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Statistical Methods:
Details of the planned statistical analysis will be presented in 
the statistical analysis plan (SAP).
Descriptive statistics will be provided for all efficacy and 
safety variables in general.  Continuous variables will be 
summarized by tabulations of mean, median, range, and 
standard deviation (SD).  Tabulations of frequency 
distributions will be provided for categorical variables.
Primary:  The primary efficacy endpoint is the change from 
baseline to the Day 56 Visit on the investigator-administered 
CAARS-O:SV 18-item ADHD symptoms total score in the 
OPC-64005 group relative to the atomoxetine group.  Bayesian 
posterior probability of true baseline corrected difference at 
Day 56 (± 1 day) between treatment arms (OPC-64005 and 
atomoxetine) being larger than 4 points on the 18-item, 
investigator-administered CAARS-O:SV given estimates of 
means and SD in the treatment arms will be calculated.  
Uninformative prior will be used in calculations.  Estimates for 
means and SD will be derived from mixed-effect model as 
described below.  
The change from baseline in the 18-item, 
investigator-administered CAARS-O:SV will be analyzed 
using a mixed-effect model repeated measures (MMRM) 
methodology with the unstructured variance covariance 
matrix.  The model will include fixed class-effect terms for 
treatment, trial site, visit week, an interaction term of treatment 
by visit week, and baseline 18-item, investigator-administered
CAARS-O:SV as covariate.  The need of additional fixed 
effects and its interactions in the model will be explored.
Other continuous efficacy endpoints will also be analyzed 
using MMRM methodology.  Complete model details will be 
specified in the SAP.
Trial Duration:
The duration of this trial from first subject enrolled to last 
subject completed is estimated to be approximately 9 months.   
The duration of the trial for each subject is estimated to be up 
to 16 weeks (Screening Period of up to 28 days, 56 days of 
dosing, a 3 [± 1]-day safety follow-up phone call, and a 
30 [+ 2]-day safety follow-up phone call).  
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Table of Contents 
Protocol Synopsis...........................................................................................2
Table of Contents...........................................................................................8
List of In-text Tables ...................................................................................14
List of In-text Figures..................................................................................15
List of Appendices........................................................................................16
List of Abbreviations and Definitions of Terms .......................................17
1
Introduction ........................................................................................20
1.1
Nonclinical Data................................................................................................20
1.1.1
Efficacy Pharmacology...................................................................................20
1.1.2
Safety Pharmacology......................................................................................21
1.1.3
Nonclinical Absorption, Distribution, Metabolism, and Excretion................21
1.1.3.1
Absorption...................................................................................................21
1.1.3.2
Distribution .................................................................................................22
1.1.3.3
Metabolism..................................................................................................22
1.1.3.4
Excretion .....................................................................................................22
1.1.4
Toxicology......................................................................................................23
1.1.4.1
Single-dose Toxicity ...................................................................................23
1.1.4.2
Repeated-dose Toxicity...............................................................................23
1.1.4.3
Genotoxicity................................................................................................25
1.1.4.4
Reproductive and Developmental Toxicity ................................................25
1.2
Clinical Data......................................................................................................26
1.2.1
Phase 1 Single-Dose Trial in Healthy Adult Subjects (United States, 
Trial 277-09-201)............................................................................................26
1.2.2
Phase 1 Single-Dose Trial in Healthy Adult Male Subjects (Japan, Trial 
277-10-001) ....................................................................................................27
1.2.3
Phase 1 Multiple-Dose Trial to Evaluate Pharmacokinetics, Safety, and 
Pharmacodynamics in Healthy Adult Male and Female Subjects 
(United States, 277-10-206)............................................................................28
1.2.4
Phase 1, Multiple Ascending Dose Trial in Healthy Adult Male 
Subjects (Japan, Trial 277-12-001).................................................................28
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1.2.5
Phase 1 Trial to Evaluate Serotonin, Norepinephrine, and Dopamine 
Transporter Occupancy in Healthy Adult Male Subjects (United States, 
277-10-205) ....................................................................................................29
1.2.6
Phase 1 Trial to Evaluate Dopamine Transporter Occupancy in Healthy 
Adult Male Subjects (Japan, Trial 277-13-001) .............................................30
1.2.7
Phase 1 Trial to Evaluate Dopamine Transporter Occupancy in Healthy 
Adult Male Subjects (Japan, 277-14-001)......................................................31
1.3
Known and Potential Risks and Benefits ..........................................................31
2
Trial Rationale and Objectives..........................................................32
2.1
Trial Rationale...................................................................................................32
2.2
Dosing Rationale...............................................................................................32
2.3
Trial Objectives.................................................................................................34
3
Trial Design.........................................................................................34
3.1
Type/Design of Trial .........................................................................................34
3.2
Trial Treatments ................................................................................................37
3.3
Trial Population.................................................................................................38
3.3.1
Number of Subjects and Description of Population .......................................38
3.3.2
Subject Selection and Numbering ..................................................................39
3.4
Eligibility Criteria..............................................................................................39
3.4.1
Informed Consent ...........................................................................................39
3.4.2
Inclusion Criteria ............................................................................................41
3.4.3
Exclusion Criteria...........................................................................................42
3.5
Endpoints...........................................................................................................45
3.5.1
Primary Endpoint............................................................................................45
3.5.2
Other Endpoint(s) ...........................................................................................45
3.6
Measures to Minimize/Avoid Bias....................................................................45
3.7
Trial Procedures ................................................................................................46
3.7.1
Schedule of Assessments................................................................................50
3.7.1.1
Screening.....................................................................................................50
3.7.1.2
Baseline (Day 1)..........................................................................................51
3.7.1.3
Treatment Period Visits (Day 7 through Day 56 Visits).............................52
3.7.1.4
Safety Follow-up Period .............................................................................53
3.7.2
Efficacy Assessments .....................................................................................54
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3.7.2.1
Conners’ Adult ADHD Rating Scale-Observer: Screening Version 
(CAARS-O:SV; Investigator-Administered)..............................................54
3.7.2.2
Conners’ Adult ADHD Rating Scale-Self-Report: Screening Version 
(CAARS-S:SV)...........................................................................................54
3.7.2.3
Adult ADHD Investigator Symptom Rating Scale (AISRS With 
Adult Prompts)............................................................................................54
3.7.2.4
Clinical Global Impression - Severity of Illness Scale (CGI-S) .................55
3.7.2.5
Clinical Global Impression - Improvement Scale (CGI-I)..........................55
3.7.2.6
Adult ADHD Quality of Life Scale (AAQoL)............................................55
3.7.2.7
Profile of Mood States-Brief Form (POMS)...............................................55
3.7.3
Safety Assessments.........................................................................................56
3.7.3.1
Adverse Events............................................................................................56
3.7.3.2
Clinical Laboratory Assessments................................................................56
3.7.3.3
Physical Examination and Vital Signs........................................................57
3.7.3.4
Electrocardiogram Assessments..................................................................58
3.7.3.5
Columbia-Suicide Severity Rating Scale (C-SSRS)...................................58
3.7.3.6
Drug Effects Questionnaire (DEQ).............................................................58
3.7.4
Pharmacokinetic and Pharmacogenomic Assessments ..................................58
3.7.4.1
Pharmacokinetic Assessments ....................................................................58
3.7.4.1.1
Pharmacokinetic Blood Samples.............................................................58
3.7.4.2
DNA Blood Samples for Pharmacogenomic Testing .................................59
3.7.4.3
Future Biospecimen Research.....................................................................59
3.7.5
End of Trial.....................................................................................................59
3.8
Stopping Rules, Withdrawal Criteria, and Procedures......................................60
3.8.1
Entire Trial......................................................................................................60
3.8.2
Individual Site.................................................................................................60
3.8.3
Individual Subject Discontinuation ................................................................60
3.8.3.1
Down Titration of Treatment ......................................................................60
3.8.3.2
Treatment Discontinuation..........................................................................60
3.8.3.3
Documenting Reasons for Treatment Discontinuation...............................61
3.8.3.4
Withdrawal of Consent ...............................................................................61
3.8.3.5
Procedures to Encourage Continued Trial Participation.............................63
3.9
Screen Failures ..................................................................................................63
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3.10
Definition of Completed Subjects.....................................................................63
3.11
Definition of Subjects Lost to Follow-up..........................................................63
3.12
Subject Compliance...........................................................................................64
3.12.1
IMP Adherence and Reminder System...........................................................64
3.12.2
Subject Risk....................................................................................................65
3.12.3
Subject Confidentiality...................................................................................66
3.13
Protocol Deviations...........................................................................................66
4
Restrictions..........................................................................................67
4.1
Prohibited Medications......................................................................................67
4.2
Other Restrictions..............................................................................................68
4.2.1
Restricted Therapies and Precautions.............................................................68
4.2.2
Non-therapy Precautions and Restrictions......................................................69
4.2.2.1
Precautions..................................................................................................69
4.2.2.2
Restrictions..................................................................................................69
5
Reporting of Adverse Events.............................................................69
5.1
Definitions.........................................................................................................69
5.2
Eliciting and Reporting Adverse Events ...........................................................71
5.3
Immediately Reportable Events ........................................................................72
5.4
Adverse Events of Special Interest....................................................................72
5.5
Potential Serious Hepatotoxicity.......................................................................72
5.6
Pregnancy..........................................................................................................73
5.7
Procedure for Breaking the Blind......................................................................74
5.8
Follow-up of Adverse Events............................................................................75
5.8.1
Follow-up of Nonserious Adverse Events......................................................75
5.8.2
Follow-up of Serious Adverse Events and Immediately Reportable 
Events .............................................................................................................75
5.8.3
Follow-up and Reporting of Serious Adverse Events and Immediately 
Reportable Events Occurring after Last Scheduled Contact ..........................75
6
Pharmacokinetic/Pharmacogenomic Analysis ................................76
7
Statistical Analysis..............................................................................76
7.1
Sample Size.......................................................................................................76
7.2
Datasets for Analysis.........................................................................................76
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7.3
Handling of Missing Data .................................................................................77
7.4
Endpoint Analyses.............................................................................................77
7.4.1
Primary Endpoint Analysis.............................................................................77
7.4.2
Other Endpoint Analysis.................................................................................78
7.4.3
Interim Analysis..............................................................................................78
7.5
Analysis of Demographic and Baseline Characteristics....................................78
7.6
Safety Analysis..................................................................................................79
7.6.1
Adverse Events ...............................................................................................79
7.6.2
Clinical Laboratory Data ................................................................................79
7.6.3
Physical Examination and Vital Signs Data ...................................................79
7.6.4
Electrocardiogram Data..................................................................................79
7.6.5
Other Safety Data ...........................................................................................80
8
Management of Investigational Medicinal Product........................80
8.1
Packaging and Labeling ....................................................................................80
8.2
Storage...............................................................................................................80
8.3
Accountability ...................................................................................................81
8.4
Returns and Destruction....................................................................................81
8.5
Reporting of Product Quality Complaints.........................................................81
8.5.1
Eliciting and Reporting Product Quality Complaints.....................................82
8.5.2
Information Required for Reporting Purposes ...............................................82
8.5.3
Return Process ................................................................................................82
8.5.4
Assessment/Evaluation...................................................................................82
9
Records Management.........................................................................83
9.1
Source Documents.............................................................................................83
9.2
Data Collection..................................................................................................83
9.3
File Management at the Trial Site.....................................................................85
9.4
Records Retention at the Trial Site....................................................................85
10
Quality Control and Quality Assurance...........................................85
10.1
Monitoring.........................................................................................................85
10.2
Auditing.............................................................................................................86
11
Ethics and Responsibility...................................................................86
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Confidentiality ....................................................................................86
13
Amendment Policy..............................................................................87
14
Publication Authorship Requirements.............................................87
15
References............................................................................................88
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List of In-text Tables
Table 3.2-1
Dosing Schedule ............................................................................38
Table 3.4.2-1
Inclusion Criteria ...........................................................................41
Table 3.4.3-1
Exclusion Criteria ..........................................................................42
Table 3.7-1
Schedule of Assessments...............................................................47
Table 3.7.3.2-1
Clinical Laboratory Assessments...................................................56
Table 4.1-1
List of Medications Prohibited Before the Trial............................67
Table 4.1-2
List of Medications Prohibited During the Trial............................68
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List of In-text Figures
Figure 3.1-1
Trial Design Schematic..................................................................36
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List of Appendices
Appendix 1
Names of OPDC Personnel............................................................93
Appendix 2
Institutions Concerned With the Trial............................................94
Appendix 3
Handling and Shipment of Bioanalytical Samples ........................95
Appendix 4
18-Item, Investigator-Administered Conners’ Adult ADHD 
Rating Scale-Observer:  Screening Version (CAARS-O:SV).......97
Appendix 5
18-Item Conners’ Adult ADHD Rating Scale-Self Report:  
Screening Version (CAARS-S:SV).............................................103
Appendix 6
Adult ADHD Investigator Symptom Rating Scale (AISRS 
With Adult Prompts)....................................................................105
Appendix 7
Clinical Global Impression - Severity of 
Illness Scale (CGI-S) ...................................................................108
Appendix 8
Clinical Global Impression - Improvement Scale (CGI-I) ..........109
Appendix 9
Adult ADHD Quality of Life Scale (AAQoL) ............................110
Appendix 10
Profile of Mood States-Brief Form (POMS) ...............................115
Appendix 11
OPC-64005 Skin AESI Workup Instructions ..............................118
Appendix 12
OPC-64005 Skin AESI Worksheet for Trial Site ........................120
Appendix 13
OPC-64005 Skin AESI Worksheet for Local Dermatologist ......124
Appendix 14
OPC-64005 Skin AESI Worksheet for Central Dermatologist....129
Appendix 15
Protocol Amendment(s)/Administrative Change(s) ....................130
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List of Abbreviations and Definitions of Terms
Abbreviation
Definition
5-HT
Serotonin
AAQoL
Adult ADHD Quality of Life Scale
ACDS v1.2
Adult ADHD Clinical Diagnostic Scale, version 1.2
ADHD
Attention-deficit/hyperactivity disorder
AE
Adverse event
AESI
Adverse event of special interest
AISRS
Adult ADHD Investigator Symptom Rating Scale
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC0-24
Area under the concentration-time curve from time zero to 24 hours
AUC0-∞
Area under the concentration-time curve from time zero to infinity
BMI
Body mass index
BUN
Blood urea nitrogen
CAARS-O:SV
Conners' Adult ADHD Rating Scales–Observer: Screening Version
CAARS-S:SV
Conners' Adult ADHD Rating Scales–Self-Report: Screening Version
CGI-I
Global Clinical Impression-Improvement
CGI-S
Global Clinical Impression-Severity
CIOMS
Council for International Organizations of Medical Science
Cmax
Maximum (peak) plasma concentration
CRO
Clinical Research Organization
CSF
Cerebrospinal fluid
C-SSRS
Columbia-Suicide Severity Rating Scale
CYP
Cytochrome P450
DA
Dopamine
DAT
Dopamine transporter
DBP
Diastolic blood pressure
DEQ
Drug Effects Questionnaire
DNA
Deoxyribonucleic acid
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
DSM-IV
Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition
ECG
Electrocardiogram
EC50
Concentration of plasma to obtain 50% of the maximum effect in vivo
eICF
Electronic informed consent form
ET
Early termination
FBR
Future biospecimen research
FDA
(United States) Food and Drug Administration
FSH
Follicle-stimulating hormone 
GABA
Gamma-aminobutyric acid
GCP
Good Clinical Practice
GGT
Gamma glutamyl transferase
HbA1c
Glycated hemoglobin
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HBsAg
Hepatitis B surface antigen
HCV
Hepatitis C virus
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human immunodeficiency virus
IB
Investigator’s brochure
ICF
Informed consent form
ICH
International Council for Harmonisation
ICMJE
International Committee of Medical Journal Editors
IDDM
Insulin-dependent diabetes mellitus
IMP
Investigational medicinal product
IND
Investigative new drug
IQ
Intelligence quotient
IRB
Institutional review board
IRE
Immediately reportable event
IVRS
Interactive voice response system
IWRS
Interactive web response system
LDH
Lactic dehydrogenase
LLT
Lowest level term
MCHC
Mean corpuscular hemoglobin concentration
MedDRA
Medical Dictionary for Regulatory Activities
MGH-ATRQ-
ADHD
Massachusetts General Hospital Treatment Response Questionnaire
(ATRQ) - ADHD
M.I.N.I.
Mini International Neuropsychiatric Interview
MMRM
Mixed-effect model repeated measures
MTD
Maximum tolerated dose
NE
Norepinephrine
NET
Norepinephrine transporter
NOAEL
No observed adverse effect level
OC
Observed case
OPC
Otsuka Pharmaceutical Co.
OPDC
Otsuka Pharmaceutical Development and Commercialization, Inc.
OTC
Over the counter
PET
Positron emission tomography
PK
Pharmacokinetic
POMS
Profile of Mood States-Brief Form™
PQC
Product quality complaint
QD
Once daily
QTcB
Q-T interval corrected using Bazett's formula
QTcF
Q-T interval corrected using Fridericia's formula
RBC
Red blood cell
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SD
Standard deviation
SERT
Serotonin transporter
TEAE
Treatment-emergent adverse event
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TSH
Thyroid-stimulating hormone
ULN
Upper limit of normal
WBC
White blood cell
WOCBP
Women of childbearing potential
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1
Introduction
OPC-64005 is a novel monoamine system modulator that is synthesized by Otsuka 
Pharmaceutical Co., Ltd and is being developed for the treatment of attention-deficit/ 
hyperactivity disorder (ADHD).  
1.1
Nonclinical Data
OPC-64005 doses (mg/kg) are indicated as the free base form for all in vivo nonclinical 
studies.  
1.1.1
Efficacy Pharmacology
OPC-64005 exhibits inhibitory activities on serotonin (5-HT), norepinephrine (NE), and 
dopamine (DA) reuptake into rat brain synaptosomes.1 OPC-64005 shows selective 
affinities for human 5-HT, NE, and DA transporters (inhibition constant values = 1.62, 
6.57, and 123.06 nmol/L, respectively).2,3  In addition, OPC-64005 has demonstrated the 
potential to modulate monoamine systems.  In vivo microdialysis demonstrated that 
extracellular 5-HT, NE, and DA levels in the rat medial prefrontal cortex were dose 
dependent and simultaneously increased by OPC-64005 with greater potency relative to
paroxetine, sertraline, duloxetine, and bupropion.4,5  In addition, OPC-64005, orally 
administered at doses of 0.2 mg/kg and greater, produced statistically significant 
increases in extracellular 5-HT, NE, and DA (area under the curve as an integrated 
measurement of percent of basal values during 0 to 360 minutes after administration) to
206.7%, 176.5%, and 164.8%, respectively, compared to the vehicle group.  In the medial 
prefrontal cortex, where there is a low density of dopamine transporter (DAT), 
extracellular DA levels are thought to be regulated by norepinephrine transporter (NET).6  
The effects of DAT inhibition on the extracellular DA level were therefore evaluated in 
the striatum, where there is a high density of DAT.  OPC-64005 significantly increased 
extracellular DA levels in the rat striatum at 2.5 mg/kg and higher doses.7
OPC-64005 also showed significant antidepressant-like effects in the rat forced 
swimming test following oral administration once daily for 2 days at 5 and 10 mg/kg8,9
and for 14 days at 2.5, 5, and 10 mg/kg.10,11  Furthermore, OPC-64005 demonstrated 
significant anxiolytic-like effects in the rat elevated plus maze test following single oral 
administration at 2.5, 5, and 7.5 mg/kg.12
From the results of these nonclinical pharmacology studies, OPC-64005 may have the 
potential to improve depressive symptoms related to monoamine imbalance.
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1.1.2
Safety Pharmacology
OPC-64005 showed no effect on general signs and behavior at single oral doses of 3 and 
10 mg/kg in male rats.  At 30 mg/kg, vocalization and increased body tone were noted 
only during handling.13  OPC-64005 at a single oral dose of 3 mg/kg showed no effect on 
the respiratory system in male rats.14  OPC-64005 increased respiratory rate and minute 
volume at 10 mg/kg and higher and decreased tidal volume at 30 mg/kg.  OPC-64005 
showed no effect on the cardiovascular system in conscious male monkeys at a single 
oral dose of 0.3 mg/kg.15  OPC-64005 increased mean blood pressure at 1 mg/kg and 
higher, increased heart rate, and shortened QT interval at 3 mg/kg and higher.
OPC-64005 at 1 µmol/L and higher inhibited human ether-a-go-go related gene current 
(hERG) with a half maximal inhibitory concentration of 3.34 µmol/L.16  In isolated 
guinea pig right ventricular papillary muscles, OPC-64005 at 1 µmol/L showed no effect 
on any action potential parameters.17  However, OPC-64005 at 10 µmol/L and 
100 µmol/L shortened action potential duration at 30% and 60% of repolarization.  At 
100 µmol/L, OPC-64005 shortened the action potential amplitude and action potential 
duration at 90% repolarization and decreased the maximum upstroke velocity of action 
potential.  In isolated guinea pig right atrial preparations, OPC-64005 at up to 30 µmol/L 
showed no effects on heart rate and contraction force.18  However, OPC-64005 at 
100 µmol/L showed negative chronotropic and inotropic effects and induced sinus arrest 
in 3 of 5 preparations within 30 minutes after application.
1.1.3
Nonclinical Absorption, Distribution, Metabolism, and Excretion
1.1.3.1
Absorption
Following single oral administration of OPC-64005 at 1 mg/kg as the free base form to 
fed male rats19 and at 1 mg/kg to fed male monkeys20 maximum (peak) plasma 
concentration (Cmax), area under the concentration-time curve (AUC) from time zero to 
infinity (AUC0-∞), and terminal-phase elimination half-life were respectively 38.26 and 
39.23 ng/mL, 283.2 and 972.9 ng·h/mL, and 2.915 and 8.435 hours.  Although 
dose-dependent increases in plasma Cmax and AUC0-∞were observed in both rats and 
monkeys at doses ranging from 0.1 to 3 mg/kg, the increases in systemic exposure were 
not dose proportional.  Orally administered [phenyl-14C (U)]-OPC-277 (14C-OPC-64005) 
was highly absorbed in both rats (>91%) and monkeys (> 77%).21,22  The absolute 
bioavailability of OPC-64005 (free base form) was 49.9% in rats and 57.1% in monkeys.  
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A slight food effect was observed in rats and monkeys and a slight sex difference was 
observed in rats.
1.1.3.2
Distribution
Following single oral administration of 14C-OPC-64005 in rats, the radioactivity was 
distributed throughout the entire body.21  The concentrations of radioactivity in many 
tissues were higher than the plasma concentration.  The concentrations of radioactivity in 
most tissues peaked at 2 or 4 hours postdose and then decreased slowly, which was 
similar to the plasma concentration. The pattern of distribution was similar between 
males and females.  The tissue-to-plasma partition ratios in males were lower than those 
in females in many tissues.
In vitro protein binding of 14C-OPC-64005 was 95.59% to 96.79% in human serum, 
indicating high protein binding of OPC-64005 in human serum.23  In mouse, rat, rabbit, 
dog, and monkey serum, protein binding was 85.35% to 96.92%.
1.1.3.3
Metabolism
Following oral administration of OPC-64005 in rats and monkeys, the metabolites 
OPC-124789, OPC-124975, OPC-124990, OPC-124996, OPC-144013 (OPC-64005 
glucuronide), DM-6401, DM-6402, and a sulfate of MOP-184703 were identified in the 
plasma in both species.24  In an investigation of the in vitro metabolism of OPC-64005, 
OPC-144013, OPC-124975, and DM-6401 were the main metabolites produced using 
human liver S9 and human hepatocytes, and OPC-124789, OPC-124990, and 
OPC-124996 were also observed; no unique human metabolites were observed.25  In an 
in vitro metabolism study of 14C-OPC-64005 using recombinant human cytochrome 
P450 (CYP) enzymes, 14C-OPC-64005 was slightly metabolized by CYP1A2, CYP2B6, 
CYP2D6, and CYP3A4.26
1.1.3.4
Excretion
Following single oral administration of 14C-OPC-64005 to rats, the urinary and fecal 
excretions of radioactivity within 168 hours postdose respectively accounted for 62.11% 
to 64.98% and 31.23% to 33.62% of the administered dose, and the biliary and urinary 
excretions of radioactivity within 48 hours postdose respectively accounted for 63.52% to 
72.18% and 19.64% to 29.37% of the administered dose.21,27  A high rate of 
enterohepatic circulation was seen in male rats.  Following oral administration of 
14C-OPC-64005 in monkeys, the urinary and fecal excretions of radioactivity within 
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168 hours postdose respectively accounted for 77.58% and 20.40% of the administered 
dose.22
1.1.4
Toxicology
The toxic potential of OPC-64005 was investigated in single- and repeated-dose oral 
toxicity studies in rats and monkeys, in vitro and in vivo genotoxicity studies, and 
reproductive and developmental toxicity studies in rats and rabbits.  OPC-64005 doses 
(mg/kg) are indicated as the free base form in all in vivo toxicity studies.
1.1.4.1
Single-dose Toxicity
In single-dose oral toxicity studies, the approximate lethal dose was between 30 and 
100 mg/kg in male rats, between 100 and 300 mg/kg in female rats, and between 30 and 
100 mg/kg in male and female monkeys.  In a single-dose oral toxicity study in monkeys, 
clonic convulsion was observed in 1 female at 100 mg/kg (lethal dose).28,29
1.1.4.2
Repeated-dose Toxicity
In a 4-week repeated-dose oral toxicity study in rats, deaths occurred in females at 
30 mg/kg/day, and clonic convulsion was observed in females at this dose.30  Tremor, 
accelerated touch response, increased spontaneous motor activity, decreased body weight 
or suppressed body weight gain, and decreased food consumption were observed in males 
at 30 mg/kg/day and in females at 10 mg/kg/day and higher.  In blood biochemistry, 
decreased glucose in males and decreased cholesterol and increased phosphorus and 
γ- and β-globulin in females were observed at 30 mg/kg/day.  Creatine phosphokinase 
and aspartate aminotransferase (AST) were increased in males and females at 
30 mg/kg/day.  Increased γ-globulin was also observed in females at 10 mg/kg/day.  
Almost all changes observed during the treatment period showed reversibility.  The no 
observed adverse effect level (NOAEL) was therefore estimated to be 10 mg/kg/day for 
males and 3 mg/kg/day for females.  For OPC-64005 on Day 28, the Cmax was 954 and 
415 ng/mL and the AUC from time zero to 24 hours (AUC0-24h) was 16160 and 
5120 ng·h/mL in males and females, respectively.
In a 4-week repeated-dose oral toxicity study in monkeys, since death occurred in 1 male 
and 2 females on Days 1 to 3 at the highest dose of 30 mg/kg/day, administration at that 
dose was discontinued.31  After a withdrawal period (5 days for males and 6 days for 
females), the highest dose was reduced to 20 mg/kg/day for administration to the 
surviving 4 males and 3 females for 4 weeks.  However, 1 male and 2 females at 
20 mg/kg/day died or were sacrificed in a moribund condition, and whole body tremor 
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and decreased body weight or suppressed body weight gain during the dosing period in 
both sexes and prolonged corrected QT interval (QTc) for heart rate at Week 4 in males 
were observed at this dose.  Limb tremor (males and females), decreased body weight, or 
suppressed body weight gain in females were observed at 10 mg/kg/day.  The NOAEL 
was therefore estimated to be 3 mg/kg/day for both males and females.  At the NOAEL 
on Day 28, the Cmax was 595.5 and 367 ng/mL and the AUC0-24h was 4771 and 
3207 ng·h/mL in males and females, respectively.
In a 13-week repeated-dose oral toxicity study in rats, tremor in males at 30 mg/kg/day 
and accelerated touch response, decreased body weight or suppressed body weight gain, 
and decreased food consumption in males at 10 mg/kg/day and/or 30 mg/kg/day and in 
females at 10 mg/kg/day were observed.32  In hematology, blood biochemistry, and 
urinalysis, decreases in eosinophils, glucose, and triglycerides were observed in males at 
30 mg/kg/day.  In the females, increased reticulocytes, total cholesterol, phospholipids, 
total protein, calcium, phosphorus, β-globulin, and γ-globulin, decreased water 
consumption and urine volume, and increased urine osmolarity were observed at 
10 mg/kg/day.  In histopathology, hypertrophy of centrilobular hepatocytes with 
increased smooth endoplasmic reticulum in the liver and apoptosis of acinar cells in the 
pancreas were observed in males at 10 mg/kg/day and higher.  In addition, fatty change 
of the hepatocytes with increased lipid droplets in the mid zone of the lobules in the liver 
and ventral-lobe-specific atrophy of the prostate at 10 mg/kg/day and higher and focal 
accumulation of foamy cells in the lung and bronchus at 30 mg/kg/day were observed in 
males, and none of these changes were observed in the 4-week repeated-dose oral toxicity 
study.  All changes observed during the treatment period showed reversibility after 
withdrawal of administration.  The NOAEL was therefore estimated to be 3 mg/kg/day 
for both males and females and at that dose the plasma Cmax and AUC0-24h of OPC-64005 
at Week 13 were, respectively, 257.7 ng/mL and 4053 ng∙h/mL in males and 
429.7 ng/mL and 6457 ng∙h/mL in females.
In a 13-week repeated-dose oral toxicity study in monkeys, limb tremor and decreased 
body weight or suppressed body weight gain were observed in males and females at 
10 mg/kg/day.33  The NOAEL was therefore estimated to be 3 mg/kg/day for both males 
and females and at that dose the plasma Cmax and AUC0-24h of OPC-64005 at Week 13 
were, respectively, 375.9 ng/mL and 4649 ng∙h/mL in males and 414.1 ng/mL and 
4665 ng∙h/mL in females.
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1.1.4.3
Genotoxicity
The genotoxic potential of OPC-64005 was investigated in vitro by means of the bacterial 
reverse mutation test.34  No mutagenicity was observed at up to the highest noncytotoxic 
dose of 124 μg/plate with rat liver S9 and 62 μg/plate without rat liver S9.  The potential 
genotoxicity of OPC-64005 was investigated in vitro by means of the forward mutation 
test in cultured mammalian cells.35  No mutagenicity was observed at up to 20 μmol/L 
without S9 by 3-hour exposure, at up to 50 μmol/L with S9 by 3-hour exposure or at up 
to 10 μmol/L without S9 by 24-hour exposure. 
The potential genotoxicity of OPC-64005 was investigated in vivo by means of the bone 
marrow micronucleus test in male Sprague Dawley rats.36  No increase in the incidence 
of micronuclei in bone marrow erythrocytes was observed in male rats at the highest 
evaluated dose of 10 mg/kg/day administered orally for 2 days.  The potential
genotoxicity of OPC-64005 was investigated in vivo by means of an unscheduled 
deoxyribonucleic acid (DNA) synthesis test in male Sprague Dawley rats.37  No DNA 
damage in hepatocytes was observed at up to the highest dose of 30 mg/kg.
1.1.4.4
Reproductive and Developmental Toxicity
In a fertility and early embryonic development study in male rats, decreased body weight 
or suppressed body weight gain and decreased food consumption at 3 and 10 mg/kg/day 
and accelerated touch or sound response at 10 mg/kg/day were observed in parental 
males.38  However, OPC-64005 did not affect either male reproductive function or early 
embryonic development.  In a fertility and early embryonic development study in female 
rats, decreased body weight gain and food consumption at 1 mg/kg/day and higher, 
decreased body weight at 3 and 10 mg/kg/day, and accelerated touch or sound response at 
10 mg/kg/day were observed.39  A slight prolongation of mean estrous cycle was 
observed at 10 mg/kg/day, but no treatment-related changes were observed in early 
embryonic development.  The NOAEL was therefore estimated to be lower than 
1 mg/kg/day for general toxicity in parental females, 3 mg/kg/day for female 
reproductive function, and 10 mg/kg/day for early embryonic development.
In an embryo-fetal development toxicity study with rats, maternal toxicity at 
10 mg/kg/day, the highest dose tested, was characterized by accelerated touch or sound 
response and decreased body weight and food consumption.40  Placental weights were 
increased, fetal body weights were decreased, and lower numbers of ossified cervical 
vertebral bodies at 10 mg/kg/day indicated an effect on fetal growth.  Embryo-fetal 
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survival was unaffected by maternal administration of OPC-64005, and there were no 
fetal external, visceral, or skeletal anomalies or variations in the OPC-64005-treated 
groups.  The NOAEL in rats was 1 mg/kg/day for maternal toxicity, 10 mg/kg/day for 
maternal reproductive function, and 1 mg/kg/day for embryo-fetal development.
In an embryo-fetal development toxicity study with rabbits, oral administration of 
30 mg/kg/day, the highest dose tested, resulted in abortion of 3 dams on gestation 
Days 21, 25, or 27, and maternal toxicity exemplified by decreased body weight and food 
consumption were observed in dams given 10 or 30 mg/kg/day.41  No OPC-64005 related 
changes occurred on fetal growth or survival.  No fetal external, visceral, or skeletal 
malformation or variations, including ossification, were attributed to OPC-64005.  The 
NOAEL was 3 mg/kg/day for maternal toxicity, 10 mg/kg/day for maternal reproductive 
function, and 30 mg/kg/day for embryo-fetal development in rabbits.
Please refer to the Investigator’s Brochure (IB) for more detailed information. 
1.2
Clinical Data
OPC-64005 doses (mg) are indicated as the free base form for all clinical trials.
1.2.1
Phase 1 Single-Dose Trial in Healthy Adult Subjects (United 
States, Trial 277-09-201)
This phase 1 trial was a multicenter, randomized, double-blind, placebo-controlled, 
ascending single-dose trial in healthy adult male and female subjects to administer 
OPC-64005 at doses of 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, 12 mg, 15 mg, 20 mg, 
25 mg, 30 mg, 40 mg, 50 mg, and 60 mg.  Consequently, the mean Cmax and AUC0-∞
increased dose-dependently.
Adverse events (AEs) occurred in 39 of 88 subjects and 12 of 30 subjects in all 
OPC-64005 groups and placebo group, respectively.  No serious adverse events (SAEs) 
were reported.  Adverse events reported in 2 or more subjects were: application site 
erythema (6/30 subjects; all related to electrocardiogram [ECG] patches) and dizziness 
(2/30 subjects) in the placebo group; dizziness and headache (2/6 subjects each) in the 
25 mg group; nausea and vomiting (2/6 subjects each) in the 50 mg group; and nausea 
and dizziness postural (3/6 subjects each) in the 60 mg group.
Based on the results of this trial, OPC-64005 was well tolerated at doses up to 60 mg.
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1.2.2
Phase 1 Single-Dose Trial in Healthy Adult Male Subjects (Japan, 
Trial 277-10-001)
This phase 1, placebo-controlled, ascending single-dose trial in healthy Japanese adult 
male subjects was conducted (Trial 277-10-001).  This trial was designed to assess the 
pharmacokinetics (PK), safety, and tolerability of a single dose of OPC-64005 at doses of 
1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 
60 mg, 70 mg, or placebo to healthy adult males, and to randomize 8 subjects each 
(6 subjects for OPC-64005 and 2 subject for placebo) and 9 subjects each (6 subjects for 
OPC-64005 and 3 subjects for placebo) to the 1 to 20 mg groups and the 25 to 70 mg 
groups, respectively.  However, 60 mg was the highest dose assessed in this trial.
Adverse events occurred in 22 of 84 subjects and 4 of 34 subjects in all OPC-64005 
groups and the placebo group, respectively.  Adverse events observed in 2 or more 
subjects were:  presyncope(3/34 subjects) and orthostatic hypotension (2/34 subjects) 
in the placebo group; presyncope* (3/6 subjects) in the 40 mg group; presyncope*
(4/6 subjects) in the 50 mg group; and presyncope* (6/12 subjects), tachycardia 
(3/12 subjects), nausea (4/12 subjects), vomiting (2/12 subjects), blood pressure increased 
(2/12 subjects), and heart rate increased (2/12 subjects) in the 60 mg group.  All AEs 
observed during this trial were assessed as mild or moderate in severity.  In addition, 
supraventricular tachycardia observed in the 60 mg group was assessed as a SAE at the 
Sponsor’s discretion, although the investigator and subinvestigator assessed this event as 
nonserious.  This subject was suspected to have underlying sinus node dysfunction.  The 
MTD was not determined in this trial for the following reasons: this cohort did not meet
the definition of MTD as defined in the protocol; supraventricular tachycardia observed 
in this subject was difficult to assess; and the investigator and subinvestigator did not 
change the assessment of ‘nonserious’ for supraventricular tachycardia even after the 
Sponsor had assessed the event as ‘serious’.  Although the result suggested the possibility 
to proceed to the next dose step of 70 mg, dose escalation in this trial was terminated at a 
dose of 60 mg.
                                                
The reported verbatim term was “
.”
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1.2.3
Phase 1 Multiple-Dose Trial to Evaluate Pharmacokinetics, 
Safety, and Pharmacodynamics in Healthy Adult Male and 
Female Subjects (United States, 277-10-206)
This was a phase 1, double-blind, multiple-dose, parallel-group trial to assess the 
pharmacokinetics, tolerability, safety, and plasma and cerebrospinal fluid biomarkers of 
multiple ascending oral doses of OPC-64005 in healthy subjects.
Subjects were administered daily 10, 20, or 30-mg doses of OPC-64005 (n= 6 per dose 
cohort) or placebo (n = 2 per dose cohort) for 14 days in Part 1 of the trial.  In Part 2, 
subjects were administered a daily 30-mg dose of OPC-64005 (n = 10), placebo (n = 4) or 
bupropion (n = 8) for 14 days.
In Part 1, 33 TEAEs were reported for 16 of 24 subjects (66.7%) and the most frequently 
reported TEAE was constipation.  In Part 2, 77 TEAEs were reported for 21 of 
22 subjects (95.5%) and the most frequently reported TEAE was headache.
OPC-64005 and metabolite Cmax and AUC0-24h increased more than proportionally after 
single and multiple once daily doses of 10- to 30-mg OPC-64005.  Steady state for 
OPC-64005 was reached after 10 to 12 days of dosing.  Assays to detect the presence of 
neurotransmitter metabolites in cerebrospinal fluid (CSF) suggested that the 30 mg dose 
of OPC-64005 had a significant impact on reuptake inhibition for NE and 5-HT.  
However, there was no clear evidence of DA related metabolites in CSF in either 
OPC-64005 samples or in those collected from subjects who received bupropion 
(positive control).
1.2.4
Phase 1, Multiple Ascending Dose Trial in Healthy Adult Male 
Subjects (Japan, Trial 277-12-001)
This phase 1 trial was a single-center, placebo-controlled, randomized, double-blind, 
multiple ascending oral dose trial of OPC-64005 in healthy Japanese adult male subjects 
(Trial 277-12-001).  
The trial was planned for 3 dose-cohorts (20 mg for Cohort 1, 40 mg for Cohort 2, and 
60 mg for Cohort 3).  Each cohort consisted of 8 subjects, 6 subjects randomized to 
receive OPC-64005 and 2 subjects to receive placebo.  Subjects were administered 
OPC-64005 for 14 days.
Subsequently the 40 mg dose in Cohort 2 was decreased to 30 mg due to the mean Cmax
on Day 14 following the repeated-dose administration of 20 mg OPC-64005 in Cohort 1 
being higher than expected (178 ng/mL).  Based on this result, it was assumed that the 
Day 14 exposure in Cohort 2 would be 2-times that of 20 mg with an estimated mean 
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Cmax of 356 ng/mL, if the Cohort 2 dose was 40 mg which would greatly exceed the mean 
Cmax at the maximum 60 mg dose in the single-dose trial (Trial 277-10-001) of 
249.5 ng/mL.  After the completion of Cohort 2 (30 mg), the decision was made not to 
proceed with Cohort 3 (60 mg) because sufficient data for PK and safety were obtained
from Cohorts 1 and 2.  The mean Cmax for the 30 mg group following 14 days of multiple 
administrations was 292 ng/mL.
Treatment-emergent adverse events (TEAEs) occurred in 1 subject (1/6) in the 20 mg 
OPC-64005 group and 3 subjects (3/6) in the 30 mg OPC-64005 group.  All of the 
TEAEs reported in the OPC-64005 groups were considered potentially drug-related.  
No TEAEs were reported in the placebo group.
The TEAEs observed during the trial were nausea, somnolence, and pruritic rash and all 
were reported in the OPC-64005 group:  pruritic rash, 1 subject (1/6) in the 20 mg 
OPC-64005 group:  nausea, 2 subjects (2/6) in the 30 mg OPC-64005 group:  
somnolence, 1 subject (1/6) in the 30 mg OPC-64005 group.  Of the 4 TEAEs reported in 
this trial, 1 was moderate and 3 were mild in severity.  The only TEAE leading to 
discontinuation of the investigational medicinal product (IMP) occurred while on a dose 
of 20 mg and was the rash pruritic which was moderate in severity and potentially 
drug-related.  
Based on the results of this trial, multiple administration of 20 mg and 30 mg of 
OPC-64005 once daily for 14 days was well tolerated and no significant safety concerns 
were observed in healthy Japanese adult male subjects.
1.2.5
Phase 1 Trial to Evaluate Serotonin, Norepinephrine, and 
Dopamine Transporter Occupancy in Healthy Adult Male 
Subjects (United States, 277-10-205)
This phase 1 open-label trial was designed to evaluate serotonin transporter (SERT), 
NET, and DAT occupancy in human brain after oral administration of OPC-64005 in 
healthy male subjects.
Eighteen subjects were enrolled into the trial, 17 subjects were administered IMP, and 
15 subjects completed the trial.
OPC-64005 was administered to each subject once or twice at a dose of 8, 20, or 60 mg.  
Each subject was to undergo 1 baseline PET scan prior to dosing and 2 PET scans after 
each subsequent dose of OPC-64005.  The times of postdose scans occurred at 
approximately 3 hours and at 16 to 24 hours postdose, as feasible.  Prior to the PET scan, 
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one of the following radioligands was administered:  11C-DASB, a SERT ligand; 
11C-MRB, a NET ligand; and 11C-PE2I, a DAT ligand.
Receptor occupancy increased with increasing OPC-64005 plasma concentration for 
SERT and NET, while no clear trend was visible for DAT.  The estimated overall Emax
for SERT occupancy ranged from 73.3% to 84.8% and the overall EC50 ranged from 
5.5 to 8.84 ng/mL.  The estimated overall Emax for NET occupancy was 117% and the 
EC50 was 18.8 ng/mL.  At 24 hours postdose, % receptor occupancy for SERT and NET 
receptors were greater than 74% and 71%, respectively.  At the 60 mg OPC-64005 dose, 
DAT receptor occupancy ranged from 1% to 16% at plasma concentrations of 18.1 to 
205 ng/mL.
Twelve of 17 subjects (70.6%) had 43 TEAEs across all doses of OPC-64005, with most 
TEAEs reported after dosing with 60-mg of OPC-64005.  The most frequently occurring 
TEAEs (reported by more than 2 subjects overall) were nausea (8 subjects), dizziness 
(4 subjects), and headache (3 subjects).  All of these TEAEs were considered by the 
investigator to be potentially related to the IMP except for one incidence of headache.
1.2.6
Phase 1 Trial to Evaluate Dopamine Transporter Occupancy in 
Healthy Adult Male Subjects (Japan, Trial 277-13-001)
This phase 1 open-label, single-dose, positron emission tomography (PET) trial was 
designed to evaluate DAT occupancy in the human brain following oral administration of 
OPC-64005 in 6 healthy adult male subjects.  
An established DAT ligand, 18F-FE-PE2I, was used in this trial.  
Six subjects were divided into 2 groups of 3 subjects each, receiving either a single oral 
dose of 30 mg or 60 mg of OPC-64005. The PET scans were performed 3 times (predose, 
2 hours postdose, and 24 hours postdose) for each subject.
During the trial, 5 of the 6 subjects had 14 TEAEs reported.  In the 30 mg group, all 
3 subjects had 6 TEAEs while in the 60 mg group 2 subjects had 8 TEAEs.  
Treatment-emergent AEs considered potentially drug-related were reported by 2 subjects 
(4 TEAEs) in the 30 mg group and by 2 subjects (8 TEAEs) in the 60 mg group.
The most frequently occurring TEAE (reported by more than 2 subjects overall) was 
nausea (3/6 subjects).  Other frequently reported TEAEs (reported by 2/6 subjects 
overall) were vomiting, chills, body temperature decreased, and headache.  All of the 
TEAEs reported were considered mild in severity and no moderate or severe TEAEs 
were reported.
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The DAT occupancy following a single 30 or 60 mg dose was below 20% at 2 and 
24 hours postdose (plasma concentration range was 4.68 - 154 ng/mL)
1.2.7
Phase 1 Trial to Evaluate Dopamine Transporter Occupancy in 
Healthy Adult Male Subjects (Japan, 277-14-001)
This phase 1 open-label PET trial was designed to evaluate DAT occupancy in the human 
brain after repeated oral administration of OPC-64005 for 14 days in healthy adult male 
subjects. 
Eight subjects were enrolled and were administered the IMP.  Five of these subjects 
completed the trial.  
A 30-mg dose of OPC-64005 was administered once daily for 14 days.  Sixty-minute 
PET scans were performed 3 times for each of the 5 subjects (predose, at 2 hours 
postdose on Day 14, and at 24 hours postdose after the last OPC-64005 administration on 
Day 14).  The DAT ligand, 18F-FE-PE2I, was administered intravenously before each 
PET scan.  
Two of the 8 enrolled subjects experienced the TEAE of mild rash, which was considered 
related to the IMP.  These subjects were discontinued due to the TEAE.  No other TEAEs 
were reported, and there were no safety concerns in this trial.
The mean DAT occupancy was 27.8% at 2 hours postdose and 24.4% at 24 hours 
postdose (OPC-64005 plasma concentration range was 138 - 257 ng/mL and 
60.8 - 127 ng/mL, respectively).  Mean DAT occupancy remained within the targeted 
DAT occupancy range of 10% to 30% up to 24 hours postdose, although individual 
variability was noted.
Please refer to the IB for more detailed information.
1.3
Known and Potential Risks and Benefits
Risks associated with the administration of OPC-64005 will be minimized through 
appropriate screening of healthy subjects according to the protocol selection criteria and 
carefully monitored dosing.  Safety assessments will include vital signs, ECGs, physical 
examinations, clinical laboratory assessments, and monitoring for AEs.  In clinical trials 
of OPC-64005, investigators and subinvestigators must pay very close attention to any 
subjective or objective adverse signs and symptoms that subjects may report or that the 
investigator or subinvestigator may observe by means of physical examination or 
laboratory assessment.  The subjects may or may not derive any benefit from this trial.  
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The dose of OPC-64005 to be tested in this trial (20 mg up-titrated to 30 mg) will be 
within the range of doses demonstrated to be safe and well tolerated.
Known risks associated with the administration of atomoxetine are as described in the 
prescribing information (http://www.strattera.com).  The dose of atomoxetine to be 
administered in this trial (40 mg up-titrated to 80 mg) is in accordance with this 
prescribing information.
2
Trial Rationale and Objectives
2.1
Trial Rationale
Dopamine hypoactivity has been implicated in attention-deficit/hyperactivity disorder 
(ADHD), as evidenced by stimulant-mediated improvement of inattentive and 
hyperactive/impulsive behavior in the majority of presenting and treated children, 
adolescents, and adults diagnosed with ADHD.42,43,44,45,46  In addition to DAT inhibition, 
norepinephrine transport inhibition is also a pharmaceutical target for effective treatment 
of ADHD symptomatology.  Since NET inhibitors can also inhibit DA transport in the 
prefrontal cortex, NET inhibition leads to enhanced dopaminergic signaling that may, in 
part, underlie the clinical utility of NET inhibitors in ADHD.  
Data from single- and multiple-dose positron emission tomography studies confirm the in 
vitro neuropharmacology and microdialysis-based characterization of OPC-64005 as a 
triple-reuptake-inhibitor with a unique balance of monaminergic transporter inhibition for 
5-HT, NE, and DA (data on file).  Based on this pharmacology, including potent NET 
inhibition and modest DAT inhibition at the proposed clinical doses, it is a reasonable 
hypothesis that OPC-64005 will be effective for the treatment of the core symptoms
(inattention, impulsivity, and hyperactivity) of ADHD.  In addition, OPC-64005 
inhibition of SERT is comparable to that of marketed antidepressants, at clinical doses. 
Since there is high comorbidity of mood symptoms in the general ADHD population, 
SERT inhibition may yield clinical benefit in non-core symptoms of ADHD as well.
2.2
Dosing Rationale
Dose selection for this trial is based on safety, tolerability, and PK data from single and 
multiple-dose PK studies.  In addition, pharmacodynamic outcomes from 3 separate PET 
studies were used as guidance to support dose selection.  In particular, we targeted a high 
dose with approximately 90% NET occupancy to address symptoms of inattention; and 
we targeted approximately 25 to 30% DAT occupancy in efforts to provide greater 
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magnitude of efficacy, and faster onset of action compared with other members of the 
nonstimulant class, including atomoxetine (no DAT inhibition).
OPC-64005 has been administered to healthy subjects at daily oral doses ranging from 
1 to 60 mg and at treatment durations ranging from single dose to 14 daily doses.  
In Trial 277-10-206 (conducted in the United States [US]), mean peak concentration 
(Cmax) values on Day 14 after multiple daily doses of 20 or 30 mg of OPC-64005 were 
195 ng/mL and 274 ng/mL, respectively.  Steady state of OPC-64005 was reached after 
10 to 12 days of dosing in this trial.  In Trial 277-12-001 (conducted in Japan), Cmax
values after once daily dosing for 14 days were 178 ng/mL and 292 ng/mL at OPC-64005 
doses of 20 and 30 mg, respectively. Steady state was reached by Day 7 in both the 
20-mg and 30-mg groups in this trial.
In Trial 277-10-205 the overall concentration of plasma to obtain 50% of the maximum 
effect in vivo (EC50) for SERT occupancy ranged from 5.5 to 8.84 ng/mL, and the EC50
for NET occupancy was 18.8 ng/mL.  Dopamine transporter occupancy was relatively 
low (< 20%) in 2 single-dose-trials (277-10-205 and 277-13-001) at plasma concentration 
ranges of 18.1 to 205 ng/mL and 4.68 to 154 ng/mL, respectively.  In a multiple-dose trial 
(277-14-001), mean DAT occupancy was 27.8% at 2 hours postdose (plasma 
concentration range 138 - 257 ng/mL) and 24.4% at 24 hours postdose (plasma 
concentration range 60.8 - 127 ng/mL) after repeated administration of OPC-64005 at 
30 mg once daily for 14 days.
Doses of OPC-64005 up to 30 mg were used in Trial 277-10-206. In Trial 277-12-001, 
administration of 20 and 30 mg of OPC-64005 once daily for 14 days was well tolerated, 
and no significant safety concerns were observed in healthy Japanese adult male subjects.
Considering the pharmacodynamics, pharmacokinetics, and safety results obtained from 
completed multiple-dose trials, a daily dose of 30 mg was selected as the target dose for 
administration in the current trial.
The dosage of atomoxetine (40 mg daily starting dose to a target dose of 80 mg daily) is 
the dose and regimen recommended in the Food and Drug Administration (FDA)
approved prescribing information.  Extrapolation from the available animal PET data47
suggests that a dose of atomoxetine in the clinically relevant range corresponding to 
1.0 to 1.8 mg/kg would result in > 90% NET occupancy, which is comparable with the 
observed NET receptor occupancy observed with OPC-64005 at 30 mg at steady state
(study on file).
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The trial duration of 8 weeks was selected for this exploratory phase 2 trial on the basis 
that the majority of approved and marketed drugs for treatment of ADHD have 
demonstrated maximal effectiveness in 8 weeks or less.
The 4-day Titration Period and up-titration design is being employed in this trial in 
consideration of the dosage and administration instructions for atomoxetine48 in adults, 
which states that atomoxetine should be initiated at a total daily dose of 40 mg and 
increased after a minimum of 3 days to a target total daily dose of 80 mg.
2.3
Trial Objectives
The primary objective of this trial is to assess the efficacy of OPC-64005 
(20 - 30 mg/day) relative to atomoxetine (40 - 80 mg/day) in adult subjects with 
attention-deficit/hyperactivity disorder (ADHD).
Other objectives are:

To estimate the difference in effect between OPC-64005 (20 - 30 mg/day) and 
placebo and its variability in adult subjects with ADHD in order to plan for the next 
trial.

To assess the safety and tolerability of OPC-64005 (20 - 30 mg/day) in adult subjects 
with ADHD compared with both control arms.
3
Trial Design
3.1
Type/Design of Trial
This is a multicenter, randomized, double-blind, active- and placebo-controlled trial 
designed to evaluate the efficacy and safety of OPC-64005 in the treatment of adult 
subjects with attention-deficit/hyperactivity disorder.
Approximately 201 adult subjects with ADHD will be randomized (1:1:1) to be 
administered OPC-64005, atomoxetine, or placebo to provide for 150 subjects who 
complete the trial (50 per arm).
The trial includes a Screening Period (≤ 28 days), a 4-day titration period, a 52-day 
treatment period, a follow-up telephone contact to occur 3 (± 1) days after the last dose, 
and a follow-up telephone contact to occur 30 (+ 2) days after the last dose.  A schematic 
of the trial design is provided in Figure 3.1-1.  
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Screening Period:  The Screening Period will last up to 28 days and will begin when 
informed consent is signed.  The purpose of the Screening Period is to assess eligibility 
criteria at 1 or more visits (as necessary to complete screening assessments) and to wash 
out prohibited concomitant pharmacotherapy, including current ADHD therapies, if 
applicable.  
Titration Period:  At the end of the Screening Period, the subjects will be randomized 
(1:1:1) to receive OPC-64005, atomoxetine, or placebo during the Titration Period 
(Days 1 - 4).  
Treatment Period:  During the Treatment Period (Days 5 - 56), subjects who are
randomized to the OPC-64005 arm for Titration will continue in the OPC-64005 arm for 
Treatment.  Subjects randomized to the atomoxetine arm for Titration will continue in the 
atomoxetine arm for Treatment. Subjects randomized to the placebo arm for Titration 
will continue in the placebo arm for Treatment. During the 8-week Titration/Treatment 
Period, subjects will have weekly or biweekly visits to the clinical site.  On scheduled 
visit days (Days 7, 14, 21, 28, 42, and 56), dosing should be held until the subject is in 
the clinic; subjects will be dosed from a newly dispensed blister card.  Assessments to be 
performed during the trial are listed in Table 3.7-1.
If any subject discontinues the trial early, every effort should be made to complete the 
Day 56 (± 1 day)/early termination (ET) evaluations.  All subjects (completers and early 
withdrawals) will be contacted to monitor for safety events via telephone at 3 (± 1) days
and 30 (+ 2) days after the last dose of OPC-64005, atomoxetine, or placebo.
The total duration of this trial for each subject is estimated to be up to 16 weeks 
(Screening Period of up to 28 days, 56 days of dosing, a 3 [± 1]-day safety follow-up 
phone call, and a 30 [+ 2]-day safety follow-up phone call).
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3.2
Trial Treatments
OPC-64005 will be provided as 10-mg tablets, atomoxetine will be provided as 40-mg 
capsules, and placebo will be provided as both tablets (matching the OPC-64005 tablets) 
and as capsules (matching the atomoxetine capsules).  Details of the dosing schedule and 
formulations to be administered are shown in Table 3.2-1.
During the Titration Period, subjects in the OPC-64005 group will receive daily 20-mg 
oral doses of OPC-64005 along with oral doses of atomoxetine placebo.  Subjects in the 
atomoxetine group will receive daily 40-mg oral doses of atomoxetine along with oral 
doses of OPC-64005 placebo.  Subjects in the placebo group will receive daily oral doses 
of both OPC-64005 placebo and atomoxetine placebo.  
During the Treatment Period, subjects in the OPC-64005 group will receive daily 30-mg 
oral doses of OPC-64005 and atomoxetine placebo.  During the Treatment Period, if a 
subject is not able to tolerate the 30-mg dose of OPC-64005, the dose may be reduced to 
20 mg for the duration of the Treatment Period.  Subjects in the atomoxetine group will 
receive daily 80-mg oral doses of atomoxetine and OPC-64005 placebo.  During the 
Treatment Period, if a subject is not able to tolerate the 80-mg dose of atomoxetine, the 
dose may be reduced to 40 mg of atomoxetine for the duration of the Treatment Period.  
Subjects are permitted to have one dose reduction and one titration back up to their 
previous dose (ie, 30 mg for OPC-64005 and 80 mg for atomoxetine) during the trial.  
When a subject is titrated down to a lower dose, they should be maintained on that low 
dose for a minimum of 4 days before being titrated back up to the higher dose.  Subjects 
in the placebo group will receive daily oral doses of both OPC-64005 placebo and 
atomoxetine placebo.  On scheduled visit days (Days 7, 14, 21, 28, 42, and 56), dosing 
should be held until the subject is in the clinic; subjects will be dosed from a newly 
dispensed blister card.  
All tablets/capsules are to be taken together orally once daily and can be taken without 
regard to meals. Every effort should be made to take the IMP at the same time every 
morning, every day.
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Table 3.2-1
Dosing Schedule
Trial Days
Time
Dose
1 - 4a
(Titration Period)
AM dosing
20 mg OPC-64005:  two 10-mg tablets and one placebo tablet of
OPC-64005 and two atomoxetine placebo capsules QD
or
40 mg atomoxetine:  one 40-mg capsule and one placebo capsule
of atomoxetine and three OPC-64005 placebo tablets QD
or 
Placebo:  three OPC-64005 placebo tablets and two atomoxetine
placebo capsules QD
5 - 56a
(Treatment Period)
AM dosing
30 mg OPC-64005b:  three 10-mg tablets of OPC-64005 and 
two atomoxetine placebo capsules QD
or
80 mg atomoxetinec:  two 40-mg capsules of atomoxetine and 
three OPC-64005 placebo tablets QD
or
Placebo:  three OPC-64005 placebo tablets and two atomoxetine
placebo capsules QD
QD = daily.
aBlood samples for PK analyses will be collected predose and at 1 and 3 hours postdose at the Baseline 
(Day 1) Visit, predose and at 2 hours postdose at the Day 7 (± 1 day) Visit, predose and at 3 hours 
postdose at the Day 14 (± 1 day) Visit, and predose at the Day 21 (± 1 day) Visit.
bMay be reduced to 20 mg if the 30 mg dose is not tolerable. Subjects are permitted to have one dose 
reduction and one titration back up to their previous dose (ie, 30 mg for OPC-64005) during the trial.  
When a subject is titrated down to a lower dose, they should be maintained on that low dose for a 
minimum of 4 days before being titrated back up to the higher dose.  
cMay be reduced to 40 mg if the 80 mg dose is not tolerable.  Subjects are permitted to have one dose 
reduction and one titration back up to their previous dose (ie, 80 mg for atomoxetine) during the trial.  
When a subject is titrated down to a lower dose, they should be maintained on that low dose for a 
minimum of 4 days before being titrated back up to the higher dose.  
3.3
Trial Population
3.3.1
Number of Subjects and Description of Population
Approximately 252 adult (18 - 55 years) subjects with a diagnosis of ADHD will be 
screened to randomize approximately 201 subjects to yield approximately 
150 completers.  
Subjects must meet the Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition (DSM-5) criteria for ADHD (any presentation) as confirmed by the Adult ADHD 
Clinical Diagnostic Scale, version 1.2 (ACDS v1.2).49  To confirm that ADHD is the 
primary diagnosis, the Mini International Neuropsychiatric Interview (M.I.N.I.) will be 
used to identify and exclude other psychiatric conditions.50 Subjects identified with a 
current or lifetime history of bipolar disorder, schizophrenia, other psychotic disorder, or 
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personality disorder will not be eligible for enrollment.  Medication history, specifically 
for the treatment of ADHD, will be assessed using the Massachusetts General Hospital 
Treatment Response Questionnaire (ATRQ) - ADHD (MGH-ATRQ-ADHD).51  At 
screening, subjects not currently receiving an approved pharmacological treatment for 
ADHD must have an Adult ADHD Investigator Symptom Rating Scale (AISRS) with 
Adult Prompts score of ≥ 26.  Subjects receiving any pharmacological treatment for 
ADHD at screening must have an AISRS with Adult Prompts score of ≥ 22 and will wash 
out from their current ADHD therapy prior to the baseline (ie, Day 1) evaluations for a 
period equivalent to 5 half-lives.  At baseline, all subjects must have an AISRS with 
Adult Prompts score of ≥26 to be enrolled.
3.3.2
Subject Selection and Numbering
At screening, subjects will be assigned a unique subject identification number upon 
signing the electronic informed consent form (eICF) based on sequential enrollment in 
the trial.  Subjects will be assigned a unique subject number upon randomization, prior to 
dosing on Day 1.  The clinical site will maintain a list identifying all subjects by their 
subject identification number and initials.
3.4
Eligibility Criteria
3.4.1
Informed Consent
Informed consent will be freely obtained from all subjects (or their guardian or legally 
acceptable representative, as applicable for local laws) and documented using an 
electronic informed consent system.  The eICF will be approved by the same institutional 
review board (IRB) that approves this protocol.  
Each eICF will comply with the International Council for Harmonisation (ICH) Good 
Clinical Practice (GCP) Guideline52 and local regulatory requirements.  The investigator 
will ensure that the sponsor reviews and authorizes any site-specific eICF used in the trial 
before submission to the IRB. 
Investigators may discuss trial availability and the possibility for entry with a potential 
subject without first obtaining consent.  However, informed consent must be obtained and 
documented before initiation of any procedures that are performed solely for the purpose 
of determining eligibility for this trial, including withdrawal from current medication(s).  
Potential subjects are free to refuse entry into the trial, or withdraw from the trial at any 
time, without justification, and there will be no consequences to their further care.
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Prospective trial participants will be provided with controlled access to the eICF
application by trial site staff.  When the trial site staff and the participant agree that the 
participant has enough information to make an informed decision to participate, the 
participant will electronically sign in the eICF application and an electronic date and 
timestamp will be applied to the signature.  The participant will be given a printed, signed
copy of the eICF.  Any other parties required by the IRB (trial site staff, witnesses, or 
legally authorized representative) are also required to sign electronically and these 
signatures will be stored with the eICF in accordance with the ICH GCP Guideline and 
local regulatory requirements/guidelines.  These signatures cannot be altered, removed, 
or copied.
Subjects may be asked to sign additional eICFs if the protocol is amended and the 
changes to the protocol results in additional information that needs to be provided to the 
subjects, so that they can make a knowledgeable and voluntary decision on trial 
participation.
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3.4.2
Inclusion Criteria
Subjects are required to meet the inclusion criteria presented in Table 3.4.2-1.
Table 3.4.2-1
Inclusion Criteria
Screening
1.
Subjects who are able to provide electronic informed consent (as required by IRB) prior to the 
initiation of any protocol-required procedures.
2.
Ability, in the opinion of the principal investigator, to understand the nature of the trial and follow 
protocol requirements, including the prescribed dosage regimens, tablet/capsule ingestion, and 
discontinuation of prohibited concomitant medication; to read and understand the written word in 
order to complete subject-reported outcomes measures; and to be reliably rated on assessment 
scales.
3.
Male and female outpatients 18 to 55 years of age, inclusive, at the time of informed consent.
4.
Subjects with a primary DSM-5 diagnosis of ADHD (including predominantly inattentive
presentation, hyperactive presentation, and combined presentations) as confirmed by the ACDS
v1.2. Subjects may be currently receiving treatment for adult ADHD at screening, but it is not 
necessary that they are currently receiving treatment. The rationale to discontinue current ADHD 
treatment must include either or both suboptimal efficacy response and/or treatment limiting 
safety/tolerability.
5.
Subjects who are not currently receiving an approved pharmacological treatment for ADHD who 
have an AISRS with Adult Prompts score of ≥ 26 and subjects who are receiving any 
pharmacological treatment for ADHD at screening who have an AISRS with Adult Prompts score 
of ≥ 22.
6.
Subjects who have a score of ≥ 4 on the CGI-S.
7.
Subjects willing to discontinue all prohibited psychotropic medication starting from the time of 
signing the informed consent and up to the 30 (+ 2)-day follow-up period.
8.
Subjects must be able and willing to utilize the AiCure Platform for each daily dose.
9.
Subjects likely to possess the capacity to utilize the technology interfaces (eg, open and navigate 
software applications using the touch screen) and telephone features of a smartphone.
Baseline
10.
Subjects who have an AISRS with Adult Prompts score of ≥26.
11.
Subjects who have a score of ≥ 4 on the CGI-S.
CGI-S = Global Clinical Impression-Severity; DSM-5 = Diagnostic and Statistical Manual of Mental 
Disorders, Fifth Edition.
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3.4.3
Exclusion Criteria
Subjects will be excluded if they meet any of the exclusion criteria in Table 3.4.3-1.
Table 3.4.3-1
Exclusion Criteria
1.
Females who are breast-feeding and/or who have a positive pregnancy test result prior to receiving 
IMP.
2.
All males and WOCBP who do not agree to practice 2 methods of birth control during the trial and 
for 30 days after the last dose of IMP.  Two of the following precautions must be used: vasectomy, 
tubal ligation, vaginal diaphragm, intrauterine device, birth control pills, birth control depot 
injection, birth control implant, condom with spermicide, or sponge with spermicide.  This 
exclusion does not apply for subjects confirmed, by medical record and/or prospective assessment, 
to be sterile (ie, women who have had a bilateral oophorectomy and/or hysterectomy or who have 
been postmenopausal for at least 12 consecutive months, confirmed by FSH blood level; or men 
who have had a bilateral orchidectomy).
3.
Subjects with a history of inadequate response or suboptimal tolerability to atomoxetine. (The 
subject was treated with an adequate dose for an adequate period of time, yet failed to show 
satisfactory response.)  This will be confirmed using the MGH-ATRQ-ADHD.
4.
Criterion deleted by Amendment 2.
5.
Criterion deleted by Amendment 2.
6.
Subjects who report allergies (lifetime treatment history) to stimulant or nonstimulant ADHD 
medications.
7.
Subjects with a current need for involuntary commitment or who have been hospitalized for 
psychiatric illness within 6 months of screening.
8.
Subjects with other DSM-5 disorders including psychosis (current or lifetime), bipolar disorder
(current or lifetime), current major depressive disorder, or current panic disorder; or another 
psychiatric diagnosis that the investigator believes is primary or that will confound efficacy or 
safety assessments of the trial or interfere with participation in the trial otherwise. Psychiatric 
diagnosis will be established using the M.I.N.I.
9.
Subjects with a clinically significant current DSM-5 diagnosis of borderline, antisocial, paranoid, 
schizoid, schizotypal, histrionic, narcissistic, avoidant, obsessive compulsive, or dependent 
personality disorders.
10.
Subjects receiving new onset psychotherapy (eg, individual, group, marriage, or family therapy) 
within 42 days of screening or who will initiate psychotherapy at any time during participation in 
the trial.  Those who are receiving ongoing psychotherapy for over 42 days are permitted to enroll. 
Psychotherapy should not be started or changed during a subject’s participation in the trial.
11.
Subjects who meet criteria for C-SSRS Suicidal Ideation Items 4 or 5 within the last 6 months or
subjects who meet criteria for any of the 5 C-SSRS Suicidal Behavior Items (actual attempt, 
interrupted attempt, aborted attempt, preparatory acts, or behavior) and whose most recent episode 
meeting criteria for any of these 5 C-SSRS Suicidal Behavior Items occurred within the last 
2 years,
OR
Subjects who, in the opinion of the investigator, present a serious risk of suicide.
12.
Subjects who have met DSM-5 criteria for substance use disorder within the past 180 days; 
including all substances of potential abuse, excluding caffeine and nicotine.
13.
Subjects with hypothyroidism or hyperthyroidism (unless condition has been stabilized with 
medications for at least the past 90 days) and/or an abnormal result for free T4 at screening.
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Table 3.4.3-1
Exclusion Criteria
14.
Subjects who currently have clinically significant dermatological, neurological, hepatic, renal, 
metabolic, hematological, immunological, cardiovascular, pulmonary, or gastrointestinal disorders 
such as any history of myocardial infarction, congestive heart failure, HIV seropositive 
status/acquired immunodeficiency syndrome, or active or chronic hepatitis B or C. Medical 
conditions that are minor or well controlled may be considered acceptable if the condition does not 
expose the subject to an undue risk of a significant adverse event or interfere with assessments of 
safety or efficacy during the course of the trial. The medical monitor should be contacted in any 
instance where the investigator is uncertain regarding the stability of a subject’s medical 
condition(s) and the potential impact of the condition(s) on trial participation.
15.
Subjects with Insulin-dependent diabetes mellitus (IDDM) are excluded. Subjects with non-IDDM 
may be eligible for the trial if their condition is stable as determined by satisfying ALL of the 
following criteria:

HbA1c < 7.0%,

Screening glucose (non-fasting) < 200 mg/dL. (If the non-fasting glucose is ≥200 mg/dL, 
subjects must be retested in the fasting state. Fasting glucose must be ≤125 mg/dL.),

Subject has been maintained on a stable regimen of oral anti-diabetic medication(s) for at least 
28 days prior to screening or diabetes has been well-controlled by diet for at least 28 days prior 
to screening,

Subject has not had any hospitalizations within the 12 months prior to screening due to 
diabetes or complications related to diabetes, AND
Subject’s diabetes is not newly diagnosed during screening for the trial.
16.
Subjects presenting with, or having a history of, uncontrolled hypertension (diastolic blood 
pressure > 95 mmHg) or symptomatic hypotension, or orthostatic hypotension which is defined as 
a decrease of ≥30 mmHg in systolic blood pressure and/or a decrease of ≥ 20 mmHg in DBP after 
at least 3 minutes standing compared with the previous supine blood pressure, OR development of 
symptoms.
17.
Subjects with known ischemic heart disease or history of myocardial infarction, congestive heart 
failure (whether controlled or uncontrolled), angioplasty, stenting, or coronary artery bypass 
surgery.
18.
Subjects with epilepsy or a history of seizures, except for a single childhood febrile seizure, post 
traumatic, alcohol withdrawal, etc.
19.
Subjects with a history of obstructive sleep apnea.
20.
Subjects with known intellectual disability (intellectual developmental disorder), including mild 
adaptive functioning impairment, or clinical evidence of intellectual disability based on the opinion 
of the investigator.
21.
Subjects with a positive drug screen for cannabinoids or illicit drugs will be excluded and may not 
be retested or rescreened. There will be no exceptions, including subjects from states in which 
cannabinoids are considered legal.  Subjects with a positive urine drug screen resulting from use of 
prescription or OTC medications may be retested or rescreened, at the discretion of the 
investigator.
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Table 3.4.3-1
Exclusion Criteria
22.
The following laboratory test and ECG results are exclusionary:
1) Platelets ≤ 75,000/mm3
2) Hemoglobin ≤ 9 g/dL
3) Neutrophils, absolute ≤ 1000/mm3
4) AST > 2 × upper limit of normal
5) ALT > 2 × upper limit of normal
6) Creatinine ≥ 2 mg/dL
7) HbA1c ≥ 7%
8) Abnormal free T4 (free T4 is measured only if result for TSH is abnormal)
9) QTcF and/or QTcB > 450 msec
NOTE: In addition, subjects should be excluded if they have any other abnormal laboratory tests, 
vital sign results, or ECG findings which in the investigator’s judgment are medically significant 
and that would impact the safety of the subject or the interpretation of the trial results.  Tests with 
abnormal results should be repeated to ensure reproducibility of the abnormality before excluding a 
subject based on the criteria noted above.
23.
Subjects receiving any of the prohibited medications within the specified period prior to the first 
dose of trial medication or who would be likely to require prohibited concomitant therapy during 
the trial.
24.
Subjects who received OPC-64005 in any prior clinical trial.
25.
Subjects with a history of neuroleptic malignant syndrome.
26.
Subjects with a history of true allergic response (ie, not intolerance) to more than one class of 
medications.
27.
Prisoners or subjects who are compulsorily detained (involuntarily hospitalized or incarcerated) for 
treatment of either a psychiatric or physical (eg, infectious disease) illness must not be enrolled into 
this trial.
28.
Subjects who participated in a clinical trial within the last 180 days or who participated in more 
than 2 clinical trials within the past year.
29.
Any subject who, in the opinion of the investigator, should not participate in the trial.
30.
Employees or relatives of employees of the trial site cannot participate in the trial.
31.
Siblings and other family members, and those having the same place of residence as another 
subject, will be excluded.  Subjects whose family/household member has completed participation 
in the trial may be considered for enrollment.
ALT = alanine aminotransferase; C-SSRS = Columbia-Suicide Severity Rating Scale; DBP = diastolic 
blood pressure; DSM-5 = Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; 
FSH = follicle-stimulating hormone; HbA1c = glycated hemoglobin; HIV = human 
immunodeficiency virus; IQ = intelligence quotient; OTC = over the counter; QTcB = corrected QT 
interval, Bazett’s method; QTcF = corrected QT interval, Fridericia's method; 
TSH = thyroid-stimulating hormone; WOCBP = women of childbearing potential
Nonchildbearing potential is defined as male and female subjects who are surgically 
sterile (ie, male subjects who have undergone bilateral orchidectomy and female subjects 
who have undergone bilateral oophorectomy and/or hysterectomy) and female subjects 
who have been postmenopausal for at least 12 consecutive months (confirmed by 
follicle-stimulating hormone [FSH] blood level).
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3.5
Endpoints
3.5.1
Primary Endpoint
The primary efficacy endpoint is the change from baseline to the Day 56 Visit on the 
investigator-administered Conners' Adult ADHD Rating Scales–Observer: Screening 
Version (CAARS-O:SV) 18-item ADHD symptoms total score in the OPC-64005 group 
relative to the atomoxetine group.  
3.5.2
Other Endpoint(s)
Other efficacy endpoints are:

Change from baseline to each scheduled visit (Days 7, 14, 21, 28, 42, and 56/ET; all
visits have a ± 1-day window) in the 18-item, investigator-administered
CAARS-O:SV score in the OPC-64005 group relative to the atomoxetine and placebo 
groups

Change from baseline to the Day 28 (± 1 day) and Day 56 (± 1 day) Visits for the 
AISRS with Adult Prompts score in the OPC-64005 group relative to the atomoxetine
and placebo groups

Change from baseline to each scheduled visit (Days 7, 14, 21, 28, 42, and 56/ET; all 
visits have a ± 1-day window) in the CGI-S score in the OPC-64005 group relative to 
the atomoxetine and placebo groups

CGI-I score at each scheduled visit (Days 7, 14, 21, 28, 42, and 56/ET; all visits have 
a ± 1-day window) in the OPC-64005 group relative to the atomoxetine, and placebo 
groups

Change from baseline to each scheduled visit (Days 7, 14, 21, 28, 42, and 56/ET; all 
visits have a ± 1-day window) in the 18-item Conners' Adult ADHD Rating Scales–
Self-Report: Screening Version (CAARS-S:SV) score in the OPC-64005 group 
relative to the atomoxetine and placebo groups

Change from baseline to the Day 28 (± 1 day) and Day 56 (± 1 day) Visits in the 
Adult ADHD Quality of Life Scale (AAQoL) score in the OPC-64005 group relative 
to the atomoxetine and placebo groups

OPC-64005 potential for abuse liability and dependence as assessed by the Drug 
Effects Questionnaire (DEQ) at baseline and each scheduled visit (Days 7, 14, 21, 28,
42, and 56/ET; all visits have a ± 1-day window)
3.6
Measures to Minimize/Avoid Bias
During the entire trial, treatment will be double-blind.  In other words, neither the 
investigator nor the subject will have knowledge of the treatment assignment 
(OPC-64005, atomoxetine, or placebo) at any visit.  
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Treatment assignments will be based on a computer-generated randomization code 
provided by the Otsuka Pharmaceutical Development & Commercialization, Inc. (OPDC) 
Data Sciences Department.  Sponsor personnel, including those involved in monitoring, 
data management, and data analysis, will not have access to the treatment code during the 
trial.  Access to the treatment codes will be restricted to personnel charged with 
generating and maintaining randomization files, packaging IMP, operating the interactive 
voice response system/interactive web response system (IVRS/IWRS), and reporting 
SAEs to regulatory agencies.  The interim analysis will be conducted by an independent 
biostatistician from the OPDC Data Sciences Department and the treatment code will 
remain blinded for all others until the unblinding at the final analysis after trial 
completion.
3.7
Trial Procedures
Trial assessment time points are summarized in Table 3.7-1.
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Table 3.7-1
Schedule of Assessments
Assessment
Screening
(Day −28
to −1)
Baseline 
(Day 1)
Day 7
(± 1 day)
Day 14
(± 1 day)
Day 21
(± 1 day)
Day 28
(± 1 day)
Day 42
(± 1 day)
Day 56
(± 1 day)/ET
Follow-up
(3 ± 1 day)
Follow-up 
(30 + 2 days)
ENTRANCE CRITERIA
Inclusion/exclusion 
criteria
X
X
Demographic information
X 
Medical history
X 
Psychiatric history to 
confirm DSM-5 ADHD 
diagnosis using the 
ACDS v1.2
X 
Diagnosis confirmation 
and identification of 
comorbidities using the 
M.I.N.I.
X 
Investigator assessment of 
previous and current 
ADHD treatment using 
the MGH-ATRQ-ADHD
X
X
HIV, HBsAg, and 
anti-HCV
X 
Urine pregnancy testa
X
X
X
X
SAFETY
Physical examinationb
X 
X 
X
X
X
X
X
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
X 
X 
X 
X 
X 
Clinical laboratory
X 
X 
X 
X 
Urine alcohol and drug 
screen
X 
X
X
X
X 
X 
X 
X 
C-SSRS
X 
X 
X 
X 
X 
X 
X 
X 
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Table 3.7-1
Schedule of Assessments
Assessment
Screening
(Day −28
to −1)
Baseline 
(Day 1)
Day 7
(± 1 day)
Day 14
(± 1 day)
Day 21
(± 1 day)
Day 28
(± 1 day)
Day 42
(± 1 day)
Day 56
(± 1 day)/ET
Follow-up
(3 ± 1 day)
Follow-up 
(30 + 2 days)
EFFICACY
18-item, 
investigator-administered
CAARS-O:SVc
X 
X 
X 
X 
X 
X 
X 
X 
AISRS with Adult 
Prompts  
X 
X 
X 
X 
CGI-S
X 
X 
X 
X 
X 
X 
X 
X 
CGI-I
X 
X 
X 
X 
X 
X 
18-item CAARS-S:SVc
X
X
X
X
X
X
X
AAQoL
X
X
X
POMS
X
X
X
X
X
X
X
X
CLINIC PROCEDURES
Dispense IMP and 
download the AiCure 
platform or receive device 
with the AiCure platform
predownloaded
X
IMP administrationd
X
X
X
X
X
X
X
IMP return and 
accountability / AiCure 
compliance
X
X
X
X
X
X
PK blood samples
Xe
Xf
Xg
Xh
    
Pharmacogenomic sample 
for CYP2D6 testing
X
FBR blood samplei
X
DEQ 
X 
X
X
X
X
X
X 
Record AEs
X 
X 
X 
X 
X 
X 
X 
X 
X
X 
Record concomitant 
medication
X 
X 
X 
X 
X 
X 
X 
X 
X
X 
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Table 3.7-1
Schedule of Assessments
Assessment
Screening
(Day −28
to −1)
Baseline 
(Day 1)
Day 7
(± 1 day)
Day 14
(± 1 day)
Day 21
(± 1 day)
Day 28
(± 1 day)
Day 42
(± 1 day)
Day 56
(± 1 day)/ET
Follow-up
(3 ± 1 day)
Follow-up 
(30 + 2 days)
Return trial-provided 
mobile device (if 
applicable)
X
Telephone contact
X
X 
FBR = future biospecimen research; POMS = Profile of Mood States-Brief Form™.
aIf the urine pregnancy test is positive, the result should be confirmed with a serum pregnancy test.  Additional urine pregnancy testing may be done at the
discretion of the investigator.
bA physical examination will be performed at the Screening, Baseline, and Day 56 (± 1 day)/ET Visits.  Weight, height, and waist circumference will be 
recorded at the Screening Visit.  A focused examination for the detection of rash will be performed at the Day 7, 14, 21, 28, and 42 Visits; all visits have a 
± 1-day window.  Subjects will be instructed to contact the site if rash is noted at any other time, and an unscheduled visit will be arranged.
cThe 18-item CAARS-S:SV should be conducted before the 18-item, investigator-administered CAARS-O:SV at each scheduled assessment, giving the 
investigator a chance to review the self-report before completing their own assessment.
dSubjects will receive daily doses of IMP starting on Day 1.  At the baseline visit, subjects will receive a titration card for dosing on Days 1 to 4 and a 
treatment card for dosing on Days 5 to 6.  During the treatment period, subjects will receive a treatment card(s) for dosing on scheduled visits.  On 
scheduled visit days (Days 7, 14, 21, 28, 42, and 56), dosing should be held until the subject is in the clinic; subjects will be dosed from a newly dispensed 
blister card.
eDay 1 samples collected predose and 1 and 3 hours postdose.
fDay 7 (± 1 day) samples collected predose and 2 hours postdose.
gDay 14 (± 1 day) samples collected predose and 3 hours postdose.
hDay 21(± 1 day) samples collected predose.
iFBR sample will be collected once the subject has provided consent for FBR.
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3.7.1
Schedule of Assessments
3.7.1.1
Screening
The Screening Period begins after electronic informed consent has been obtained and will 
take place between Day −28 and Day −1 prior to enrollment.  Completion of screening 
activities may require more than 1 visit.  Screening evaluations will include the 
following:

An assessment of all inclusion and exclusion criteria will be made to determine the 
subject’s eligibility for the trial.

Demographic data will be recorded.

Medical and psychiatric history will be recorded, including the DSM-5 diagnosis of 
ADHD using the ACDS v1.2.

Comorbidities will be identified and recorded using the M.I.N.I.

The investigator will assess and record previous ADHD medications using the 
MGH-ATRQ-ADHD.  If applicable, washout from ADHD medications will begin.  
The washout period will be equivalent to 5 half-lives before Baseline (Day 1).

Blood and urine samples will be collected for clinical laboratory tests, including 
hematology, serum chemistry, urinalysis, and serology (see Table 3.7.3.2-1).  Vital 
sign and ECG assessments should be completed before any blood samples are 
collected.

A physical examination will be performed.  

Body weight, height, and waist circumference will be recorded.

Vital sign measurements (including body temperature, blood pressure, pulse, and 
respiratory rate) will be recorded.  Blood pressure and pulse are to be measured in the 
following order:  supine, sitting, and standing after the subject has been in each 
position at least 3 minutes.  Respiratory rate at each visit will be performed after the 
subject has been in the sitting position for at least 5 minutes.  A standard 12-lead 
ECG will be performed after the subject has been supine and at rest for at least 
5 minutes.

A urine pregnancy test will be performed for all women of childbearing potential 
(WOCBP).  If the urine pregnancy test is positive, the result should be confirmed with 
a serum pregnancy test.  Subjects with a positive serum test result will be excluded 
from the trial.

Urine will be collected from all potential subjects for urine screen(s) for alcohol and 
drugs of abuse, including amphetamines, barbiturates, benzodiazepines, cannabinoids,
cocaine, opiates, and phencyclidine.  

The “Baseline/Screening” Columbia-Suicide Severity Rating Scale (C-SSRS) will be 
administered.
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
The AISRS with Adult Prompts will be administered.  Subjects not currently 
receiving an approved pharmacological treatment for ADHD must have an AISRS
with Adult Prompts score of ≥ 26.  Subjects receiving any pharmacological treatment 
for ADHD at screening must have an AISRS with Adult Prompts score of ≥ 22.

The investigator (or qualified designee) will complete the CGI-S.  Subjects must have 
a CGI-S score of ≥ 4.

A qualified and certified rater will administer the investigator-rated 18-item 
CAARS-O:SV.

The Profile of Mood States-Brief Form™ (POMS) will be administered.

AEs and concomitant medications will be recorded beginning with the signing of the 
eICF.
3.7.1.2
Baseline (Day 1)

An assessment of all inclusion and exclusion criteria will be made to determine the 
subject’s eligibility for the trial.

A physical examination will be performed.  

Body weight, height, and waist circumference will be recorded.

Vital sign measurements (including body temperature, blood pressure, pulse, and 
respiratory rate) will be recorded.  Blood pressure and pulse are to be measured in the 
following order:  supine, sitting, and standing after the subject has been in each 
position at least 3 minutes.  Respiratory rate at each visit will be performed after the 
subject has been in the sitting position for at least 5 minutes.  A standard 12-lead 
ECG will be performed after the subject has been supine and at rest for at least 
5 minutes.

Blood and urine samples will be collected for clinical laboratory tests, including 
hematology, serum chemistry, and urinalysis (see Table 3.7.3.2-1).  Vital sign and 
ECG assessments should be completed before any blood samples are collected.  

A urine pregnancy test will be performed for all WOCBP.  If the urine pregnancy test 
is positive, the result should be confirmed with a serum pregnancy test.  Subjects with 
a positive serum test result will be excluded from the trial.

Urine will be collected from all potential subjects for urine screen(s) for alcohol and 
drugs of abuse, including amphetamines, barbiturates, benzodiazepines, cannabinoids, 
cocaine, opiates, and phencyclidine.

The “Since-Last-Visit” C-SSRS will be administered.

If applicable, a washout from ADHD medications equivalent to 5 half-lives must 
have been completed.

The AISRS with Adult Prompts will be administered.  Subjects must have an AISRS
with Adult Prompts score of ≥ 26.  

The investigator (or qualified designee) will complete the CGI-S.  Subjects must have 
a CGI-S score of ≥ 4.
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
The subject will complete the 18-item CAARS-S:SV.  The 18-item CAARS-S:SV 
should be conducted before the 18-item, investigator-administered CAARS-O:SV at 
each scheduled assessment, giving the investigator a chance to review the self-report 
before completing their own assessment.

A qualified and certified rater will administer the investigator-rated 18-item 
CAARS-O:SV.

Blood samples for PK analyses will be collected predose and at 1 and 3 hours 
postdose.

Blood samples for pharmacogenomic CYP2D6 testing will be collected.

Blood samples for FBR will be collected (once the subject has provided consent for 
FBR).

The subject will complete the AAQoL.

The POMS will be administered.

The DEQ will be administered to assess the potential for abuse.

AEs and concomitant medications will be recorded.

Subjects will receive a titration card for dosing on Days 1 to 4 and a treatment card 
for dosing on Days 5 to 6.

The IMP will be dispensed and the subject will download the AiCure platform or 
receive a provisioned device with the AiCure platform predownloaded, and will be 
trained on IMP compliance using this application.  Subjects will be instructed to take 
their first dose of IMP from the titration card in the clinic.
3.7.1.3
Treatment Period Visits (Day 7 through Day 56 Visits)

At each visit, a focused physical examination for the presence of rash will be 
performed.  Subjects will be instructed to contact the site if rash is noted at any other 
time, and an unscheduled visit will be arranged.  A complete physical examination 
will be performed at the Day 56 (± 1 day)/ET Visit.  See Section 3.7.3.3 for a 
description of follow-up activities to be completed if rash is detected.  The 
investigator must immediately report any instances of rash to the Clinical Research 
Organization (CRO) medical monitor.

At each visit, vital sign measurements (including body temperature, blood pressure,
pulse, and respiratory rate) will be recorded.  Blood pressure and pulse are to be 
measured after the subject has been in the sitting position at least 5 minutes.  
Respiratory rate at each visit will be performed after the subject has been in the sitting 
position for at least 5 minutes.  At the Day 14, 28, 42, and 56 Visits (all visits have a 
± 1-day window), a standard 12-lead ECG will be performed after the subject has 
been supine and at rest for at least 5 minutes.

At the Day 28 (± 1 day) and Day 56 (± 1 day)/ET Visits, blood and urine samples will 
be collected for clinical laboratory tests, including hematology, serum chemistry, and 
urinalysis (see Table 3.7.3.2-1). Vital sign and ECG assessments should be 
completed before any blood samples are collected.
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
A urine pregnancy test will be performed for all WOCBP at the Day 28 (± 1 day) and 
Day 56 (± 1 day)/ET Visits.  If the urine pregnancy test is positive, the result should 
be confirmed with a serum pregnancy test.

At each visit, urine will be collected from all potential subjects for urine screen(s) for 
alcohol and drugs of abuse, including amphetamines, barbiturates, benzodiazepines, 
cannabinoids, cocaine, opiates, and phencyclidine.

At the Day 28 (± 1 day) and Day 56 (± 1 day)/ET Visits, the AISRS with Adult 
Prompts will be administered.  

At each visit, the “Since-Last-Visit” C-SSRS will be administered.

At each visit, the investigator (or qualified designee) will complete the CGI-S and 
CGI-I. 

The subject will complete the 18-item CAARS-S:SV.  The 18-item CAARS-S:SV 
should be conducted before the 18-item, investigator-administered CAARS-O:SV at 
each scheduled assessment, giving the investigator a chance to review the self-report 
before completing their own assessment.

At each visit, a qualified and certified rater will administer the investigator-rated 
18-item CAARS-O:SV.

At each visit, the POMS will be administered.

Blood samples for PK analyses will be collected predose and at 2 hours postdose at 
the Day 7 (± 1 day) Visit, predose and at 3 hours postdose at the Day 14 (± 1 day) 
Visit, and predose at the Day 21 (± 1 day) Visit.

At the Day 28 (± 1 day) and Day 56 (± 1 day)/ET Visits, the subject will complete the 
AAQoL.

At each visit, the DEQ will be administered.

At each visit, AEs and concomitant medications will be recorded.

Subjects will receive a treatment card(s) for dosing on scheduled visits.  On scheduled 
visit days (Days 7, 14, 21, 28, 42, and 56), dosing should be held until the subject is 
in the clinic; subjects will be dosed from a newly dispensed blister card.

At each visit, IMP returns, accountability, and subject compliance with the IMP will 
be assessed.

At the Day 56 (± 1 day)/ET Visit, subjects will return the trial-provided mobile 
device (if applicable).
3.7.1.4
Safety Follow-up Period
A follow-up telephone contact will occur 3 (± 1) days and 30 (+ 2) days after the last 
dose of IMP for all subjects (completers and early withdrawals).  At this time, AEs and 
concomitant medications will be recorded.
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3.7.2
Efficacy Assessments
3.7.2.1
Conners’ Adult ADHD Rating Scale-Observer: Screening 
Version (CAARS-O:SV; Investigator-Administered)
The investigator-administered CAARS-O:SV (Appendix 4) is designed to measure a 
cross-section of ADHD-related symptoms and behaviors in adults using observer 
scales.53  The investigator-administered CAARS-O:SV consists of 30 items grouped into 
3 subscales:  Inattentive Symptoms (9 items), Hyperactive/Impulsive Symptoms 
(9 items), and ADHD Index (12 items). As is frequently done in adult ADHD trials, 
items will be modified using the Adler adult prompts and only the 18 DSM-5 criteria 
relevant items (9 Inattentive and 9 Hyperactive/Impulsive) will be administered.  The 
primary efficacy assessment of ADHD symptoms is the ADHD Symptoms Total Score, 
which consists of the combined score for the Inattentive Symptoms and 
Hyperactive/Impulsive Symptoms subscales.  The 18-item scale can be administered by 
an appropriately trained and qualified clinician in approximately 20 to 30 minutes.
3.7.2.2
Conners’ Adult ADHD Rating Scale-Self-Report: Screening 
Version (CAARS-S:SV)
The CAARS-S:SV (Appendix 5) includes the same 30 items as the
investigator-administered CAARS-O:SV, worded in the first person for the subject’s 
impressions of their own ADHD behaviors (eg, “I talk too much,” “I am always on the 
go...”).53  As with the investigator-administered CAARS-O:SV, administration of the 
CAARS-S:SV in the current trial will be limited to the 18 DSM-5 criteria relevant items 
(9 Inattentive Symptoms and 9 Hyperactive/Impulsive Symptoms subscales).  The 
evaluation of ADHD symptoms will be based on the 18-item ADHD Symptoms Total 
Score, which consists of the combined score for the Inattentive Symptoms and 
Hyperactive/Impulsive Symptoms subscales.  The CAARS-S:SV can be completed in 
approximately 10 minutes.
3.7.2.3
Adult ADHD Investigator Symptom Rating Scale (AISRS With 
Adult Prompts)
The AISRS (Appendix 6) was published in 2010 by Drs. Lenard Adler, Thomas Spencer, 
and Joseph Biederman of New York University and Massachusetts General Hospital.54  
The AISRS consists of the 18 DSM ADHD symptoms with adult-relevant wording.  It 
has been validated for use as a primary efficacy scale in adult ADHD treatment trials.  
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3.7.2.4
Clinical Global Impression - Severity of Illness Scale (CGI-S)
The CGI-S is an observer-rated scale that will be used to measure symptom severity.55  
To perform this assessment, the investigator or rater will respond to the following 
question:  “Considering your total clinical experience with the ADHD population, how 
mentally ill is the patient at this time?”  Response choices include:  1 = normal, not at all 
ill; 2 = borderline ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; 
and 7 = among the most extremely ill patients.  Suggested anchor guidance is provided in 
Appendix 7.56
3.7.2.5
Clinical Global Impression - Improvement Scale (CGI-I)
The CGI-I is an observer-rated scale that will be used to measure the efficacy of the 
IMP.55  The rater or investigator will rate whether the subject’s total improvement 
relative to baseline is due entirely to drug treatment.  Response choices include:  1 = very 
much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 
5 = minimally worse, 6 = much worse, and 7 = very much worse.  Suggested anchor 
guidance is provided in Appendix 8.56
3.7.2.6
Adult ADHD Quality of Life Scale (AAQoL)
The AAQoL (Appendix 9) is a validated, 29-item instrument for measuring the impact of 
ADHD symptoms on quality of life.57  The scale assesses 4 distinct functional domains:
life productivity, psychological health, life outlook, and relationships. Scores for 
individual items range from 1 (“never/not at all”) to 5 (“extremely/very often”). Before 
total and subscale scores can be calculated, scores for individual questions that are 
worded negatively are reversed so that a higher score indicates a greater quality of life. 
Scores for each item are then converted to a 100-point scale and averages are calculated 
to obtain total score and subscale scores.
3.7.2.7
Profile of Mood States-Brief Form (POMS)
The POMS (Appendix 10) is a 30-item self-report scale that generates the following 
subscales:  Tension or Anxiety, Anger - Hostility, Vigor - Activity, Fatigue - Inertia, 
Depression - Dejection, and Confusion - Bewilderment.58  These subscales yield an 
overall total mood score.  It will be used in the trial as an exploratory measure to assess 
potential changes in symptoms often associated with ADHD.  The time period of interest 
for this trial is “during the past week”.
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3.7.3
Safety Assessments
3.7.3.1
Adverse Events
Refer to Section 5, Reporting of Adverse Events.  
3.7.3.2
Clinical Laboratory Assessments
Table 3.7.3.2-1
Clinical Laboratory Assessments
Hematology:
Hemoglobin
Mean Corpuscular Hemoglobin Concentration 
(MCHC)
Mean Corpuscular Volume (MCV)
Red Blood Cell (RBC) count
White Blood Cell (WBC) count with differential
Platelets
Urinalysis:
Appearance
Color 
Blood
Glucose
Microscopic analysis, WBC/RBC counts per high 
powered field
pH
Protein
Specific gravity
Serology:
Hepatitis B surface antigen (HBsAg)
Human Immunodeficiency Virus (HIV)
Hepatitis C Virus Antibodies (anti HCV)
Serum Chemistry:
Alkaline Phosphatase (ALP)
Alanine Aminotransferase (ALT)
Aspartate Aminotransferase (AST)
Bilirubin, total 
Blood Urea Nitrogen (BUN) 
Calcium
Cholesterol
Creatinine
Gamma Glutamyl Transferase (GGT)
Glucose
Lactic Dehydrogenase (LDH)
Potassium
Protein, total 
Sodium
Triglycerides
Glycated Hemoglobin (HbA1c)
Thyroid-stimulating hormone (TSH)
Additional Tests:
Urine (or serum) pregnancy for WOCBP
FSH (for female subjects who have been 
postmenopausal for at least 12 consecutive months)
Free T4 (free T4 is measured only if result for TSH is 
abnormal)
Urine for alcohol and drugs of abuse, including 
amphetamines, barbiturates, benzodiazepines, 
cannabinoids, cocaine, opiates, and phencyclidine
C Reactive Protein (CRP) (if rash is detected)
Human herpes virus 6 (HHV-6) (if rash is detected
and the signs and symptoms are suggestive of drug 
rash with eosinophilia and systemic symptoms 
[DRESS] or drug-induced hypersensitivity syndrome 
[DIHS])
Complete blood count with differential (if rash is 
detected)
A pregnancy test will be conducted in WOCBP prior to trial intervention; results must be 
available prior to the administration of the IMP. 
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3.7.3.3
Physical Examination and Vital Signs
A physical examination will be performed at screening, baseline, and at Day 56 
(± 1 day)/ET.  Physical examination findings will be recorded by body system (eg, head, 
eyes, ears, nose, and throat; thorax; abdomen; extremities; neurological; skin and 
mucosae).  Body weight, height, and waist circumference will be measured and recorded 
at screening.  A focused examination for the detection of rash, defined as any type of 
newly acquired skin eruptions that are nontraumatic, will be performed at the Day 7, 14, 
21, 28, and 42 Visits; all visits have a ± 1-day window.  Subjects will be instructed to 
contact the site if rash is noted at any other time, and an unscheduled visit will be 
arranged.  If rash is detected, the IMP should be discontinued and blood drawn for 
laboratory testing, including a complete blood count with differential and chemistry with 
liver function tests.  Any rash, regardless of severity or seriousness, will lead to the 
discontinuation of IMP.  Any subject who experiences a rash will be evaluated by a 
board-certified or board-eligible dermatologist.  Depending on the severity, the subject 
will be asked to have a skin biopsy performed of the rash area(s).  At the appearance of or 
discovery of the rash, the rash will be photographed by the investigator and vital signs 
(specifically, body temperature), symptoms of hepatitis (eg, weight loss, right upper 
quadrant tenderness, malaise, jaundice, hepatomegaly, dark urine), a discussion of other 
possible causes of the rash (eg, allergic, contact dermatitis), and specific location(s) of the 
rash should be recorded.  The investigator must immediately report any instances of rash 
to the CRO medical monitor.  Refer to Appendix 11 through Appendix 14 for follow-up 
activities if rash is detected.
Vital signs will be measured and recorded at screening, baseline, and at each scheduled
visit. 
Measurement of vital signs will include body temperature, systolic and diastolic blood 
pressure, heart rate, and respiratory rate. At the Screening and Baseline Visits, blood 
pressure and pulse will be measured in the following order:  supine, sitting, and standing 
after the subject has been in each position at least 3 minutes.  Respiratory rate at each 
visit and blood pressure and heart rate at each Treatment Period visit will be performed 
after the subject has been in the sitting position for at least 5 minutes.  
Abnormal vital signs values considered to be clinically significant may be repeated for 
confirmation at the investigator’s discretion.  If a screening vital sign finding with a 
clinically significant abnormal result (eg, diastolic blood pressure > 95 mmHg) is 
identified, repeat vital sign measurements to confirm the finding may be considered 
(eg, before excluding the subject from the trial).
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3.7.3.4
Electrocardiogram Assessments
At Screening, Baseline, and the Day 14 (± 1 day), 28 (± 1 day), 42 (± 1 day), and 
56 (± 1 day) Visits, a standard 12-lead ECG will be performed after the subject has been 
supine and at rest for at least 5 minutes.
3.7.3.5
Columbia-Suicide Severity Rating Scale (C-SSRS)
Suicidality will be monitored at each visit using the C-SSRS.  
Subjects expressing any sort of suicidality or who are otherwise thought to be at any risk 
of self-harm at any time during the course of the trial or follow-up, should be referred for 
appropriate evaluation and care according to applicable local standards, according to the 
best judgment of the principal investigator and in keeping with GCP.
The C-SSRS was developed by a team of researchers at Columbia University to address 
the need for standardized classification of suicide reports to assess suicide risk.  This 
scale consists of a baseline evaluation that assesses the lifetime experience of the subject 
with suicide events and suicidal ideation, and a post baseline evaluation that focuses on 
suicidality since the last trial visit.  
The baseline/screening version of the C-SSRS will be administered at the Screening
Visit.  The since-last-visit version of the C-SSRS will be administered at the Baseline 
Visit and at each subsequent scheduled visit. 
3.7.3.6
Drug Effects Questionnaire (DEQ)
The DEQ will be used to assess the potential for abuse of the IMP.  The DEQ is a 5-item 
questionnaire completed by the subject that includes the following questions:  Do you 
FEEL a drug effect right now?, Are you HIGH right now?, Do you DISLIKE any of the 
effects you are feeling right now?, Do you LIKE any of the effects you are feeling right 
now?, and Would you like MORE of the drug you took, right now?59   
3.7.4
Pharmacokinetic and Pharmacogenomic Assessments
3.7.4.1
Pharmacokinetic Assessments 
3.7.4.1.1
Pharmacokinetic Blood Samples
Blood samples for the determination of OPC-64005 and its metabolite(s) will be collected 
at Baseline (Day 1) predose (within 15 minutes of dosing) and at 1 and 3 hours postdose, 
at the Day 7 (± 1 day) Visit predose (within 5 minutes of dosing) and at 2 hours postdose, 
at the Day 14 (± 1 day) Visit predose (within 5 minutes of dosing) and at 3 hours 
postdose, and at the Day 21 (± 1 day) Visit predose (within 5 minutes of dosing).  
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Samples may also be analyzed for atomoxetine and/or other analytes to confirm 
compliance.  In addition, every effort will be made to obtain a PK blood sample from any 
subject who experiences an SAE.  This sample should be obtained as soon as is practical 
after the onset of the SAE.
Every effort should be made to draw the sample at the appropriate time.  If a sample 
cannot be drawn at the designated time, a window of ± 3 minutes for each blood draw is 
acceptable, provided the exact time of the draw is recorded.
Processing, storage, and shipping instructions are provided in Appendix 3.
3.7.4.2
DNA Blood Samples for Pharmacogenomic Testing
A blood sample will be collected at the time point presented in the Schedule of 
Assessments (Table 3.7-1) in order to extract DNA and determine the CYP2D6 genotype 
and predicted phenotype. Genotypes for other drug metabolizing enzymes and 
transporters will also be determined and may be reported as part of a future study.  All 
samples will be shipped to the pharmacogenomics laboratory.  Detailed handling and 
shipping instructions are provided in Appendix 3.
3.7.4.3
Future Biospecimen Research
A blood sample will be collected at the time point presented in the Schedule of 
Assessments (Table 3.7-1) from consenting subjects.
Research performed on this sample may include genetic analyses (deoxyribonucleic acid 
[DNA]), gene expression profiling (ribonucleic acid [RNA]), proteomics, metabolomics 
and/or the measurement of other analytes.  Such research is for biomarker testing to 
address emergent questions not described elsewhere in the protocol (as part of the main 
trial) and will only be conducted on specimens from appropriately consented subjects. 
The objective of collecting specimens for future biomedical research is to explore and 
identify biomarkers that inform the scientific understanding of diseases and/or their 
therapeutic treatments.
Processing, storage, and shipping instructions for FBR samples are provided in 
Appendix 3.
3.7.5
End of Trial
The end of trial date is defined as the last date of contact or the date of final contact 
attempt from the post-treatment follow-up eSource for the last subject completing or 
withdrawing from the trial.
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3.8
Stopping Rules, Withdrawal Criteria, and Procedures
3.8.1
Entire Trial
If the sponsor terminates or suspends the trial for any reason, prompt notification will be 
given to investigators, IRBs, and regulatory authorities in accordance with regulatory 
requirements.
3.8.2
Individual Site
Individual trial site participation may be discontinued by the sponsor, the investigator, or 
the IRB if judged to be necessary for medical, safety, regulatory, ethical or other reasons 
consistent with applicable laws, regulations, and GCP.  The investigator will notify the 
sponsor promptly if the trial is terminated by the investigator or the IRB at the site.
3.8.3
Individual Subject Discontinuation
3.8.3.1
Down Titration of Treatment
During the Treatment Period, if a subject is not able to tolerate the 30-mg dose of 
OPC-64005, the dose may be reduced to 20 mg for the duration of the Treatment Period.  
If a subject is not able to tolerate the 80-mg dose of atomoxetine, the dose may be 
reduced to 40 mg for the duration of the Treatment Period.  Subjects are permitted to 
have one dose reduction and one titration back up to their previous dose (ie, 30 mg for 
OPC-64005 and 80 mg for atomoxetine) during the trial.  When a subject is titrated down 
to a lower dose, they should be maintained on that low dose for a minimum of 4 days 
before being titrated back up to the higher dose.  
3.8.3.2
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 
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.  
However, each investigator must comprehensively review the circumstances and offer the 
subject options for continued treatment to the degree possible as described in 
Section 3.8.3.5.
If a subject will miss/misses a trial visit, the investigator should contact the medical 
monitor to discuss the potential to retain the subject.  Depending on how many doses of 
IMP the subject will miss/misses, the sponsor, medical monitor, and investigator will 
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determine if the subject is able to continue in the trial and at which dose the subject will 
resume, taking into consideration any scheduled and unscheduled dose adjustments.  
3.8.3.3
Documenting Reasons for Treatment Discontinuation
A subject may discontinue IMP for a number of reasons including those listed below:

Reasons related to AE:

Subject decides to discontinue because of annoyance or discomfort due to a 
nonserious AE which is not otherwise determined to be an undue hazard

Continuing IMP places the subject at undue risk as determined by the investigator 
(eg, a safety concern that is possibly, probably, or likely related to IMP)

SAE 

Death

Reasons unrelated to medical condition (non-compliance with IMP, protocol 
deviation, physical decision, lack of efficacy, or other) (provide detail and review AE 
history with subject)

Withdrawal of informed consent (complete written withdrawal of consent form)

Lost to follow-up

Rash (regardless of severity or seriousness) (see Section 5.4)

Pregnancy (see Section 5.6)

Termination of all or part of the trial by the sponsor (site terminated by sponsor or 
trial terminated by sponsor)
If the subject discontinues IMP due to an AE, the investigator, or other trial personnel, 
will make every effort to follow the event until it has resolved or stabilized.  Follow-up 
procedures in Section 3.8.3.2 must be followed.
3.8.3.4
Withdrawal of Consent
All subjects have the right to withdraw their consent from further participation in the trial 
at any time without prejudice.  Subjects cannot withdraw consent for use of data already 
collected as part of the trial, but only for future participation.  The investigator 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 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.
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Complete withdrawal of consent requires a subject’s refusal of ALL of the following 
methods of follow up (these methods of follow up will also be noted in the trial eICF):

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 trial site staff).

Contact of the subject by trial personnel, even if only by telephone, to assess current 
medical condition, and obtain necessary medical or laboratory reports relevant to the 
trial’s objectives.

Contact of alternative person(s) who have been designated in source records 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 for a subject’s intended withdrawal need to be completely understood, 
documented, and managed to protect the rights of the subject and the integrity of the trial.  
A subject may initially express their desire to discontinue IMP administration, which is 
not equivalent to a complete withdrawal of consent for further participation (see 
Section 3.8.3.2).  A subject may, however, indicate that further trial participation is 
creating a burden on their work or social schedule.  Therefore, the investigator should 
follow the procedures outlined in Section 3.8.3.3 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.  If a subject will miss/misses a trial visit, the 
investigator should contact the medical monitor to discuss the potential to retain the 
subject. Depending on how many doses of IMP the subject will miss/misses, the sponsor, 
medical monitor, and investigator will determine if the subject is able to continue in the 
trial and at which dose the subject will resume, taking into consideration any scheduled 
and unscheduled dose adjustments.  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.
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3.8.3.5
Procedures to Encourage Continued Trial Participation
In all cases of impending IMP discontinuation or consent withdrawal, investigators will 
meet and discuss with the subject their options of continuing in the trial, preferably on 
therapy.  The investigator should ensure understanding and documentation of the reasons 
for the subject’s desire to withdraw consent.
3.9
Screen Failures
A screen failure subject is one from whom informed consent is obtained and is 
documented in writing (ie, subject signs an eICF), but who is not randomized or assigned 
trial treatment.  Subjects who sign an eICF but who are not started on treatment are 
permitted to be rescreened, with the exception of subjects who tested positive for drugs of 
abuse.  In the event that the subject is rescreened for trial participation, and the 
rescreening is not completed within the original screening window, a new eICF must be 
signed.  Subjects who are randomized but not treated are considered withdrawals.
3.10
Definition of Completed Subjects
The treatment period is defined as the time period during which subjects are evaluated for 
primary and/or secondary objectives of the trial irrespective of whether or not the subject 
actually consumed 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 purposes of this 
trial, subjects who complete the Day 56 (± 1 day) Visit will be defined as trial 
completers.
3.11
Definition of Subjects Lost to Follow-up
Subjects who cannot be contacted on or before the follow-up visit 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” as the reason for discontinuation.  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).
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The site will make 3 documented attempts to contact the subject by telephone and in the 
event the site is unable to reach the subject by telephone, the site will attempt to contact 
the subject via certified mail or an alternative similar method, where appropriate, before 
assigning a “lost to follow-up” status.
3.12
Subject Compliance 
Responsible trial personnel will dispense the IMP (ie, OPC-64005, atomoxetine, and 
placebo) to subjects.  Accountability and compliance verification should be documented 
in the subject’s trial records.  Subjects must be counseled on the importance of taking the 
IMP as directed at all trial visits.  If poor compliance continues (eg, multiple missed 
doses resulting in less than 80% overall compliance), discontinuation of the subject from 
the trial should be considered.
Details on the AiCure technology to be used in this trial to assess IMP compliance are
provided below.
3.12.1
IMP Adherence and Reminder System
This trial will employ an IMP adherence monitoring platform (“AiCure Platform”) for all 
subjects in the trial.  The AiCure Platform uses artificial intelligence on smartphones to 
confirm IMP ingestion.  In addition, built-in reminders and a communication system 
allow real-time intervention in case of IMP interruptions. 
Use of this AiCure Platform will in no way supersede or replace the physician and/or 
prescribed IMP protocol of the subjects.  Because the AiCure Platform does not change 
the IMP protocol of the subjects, but rather encourages adherence to the predefined 
protocol, use of this AiCure Platform presents minimal risk to the subjects.  Use of the 
AiCure Platform will be required for all subjects in the trial.
The monitoring AiCure Platform requires that all subjects take each dose of the IMP 
while using a smartphone.  The AiCure Platform will be provided to subjects preloaded 
on a smartphone, or subjects will download the AiCure Platform onto their own mobile 
device at baseline (Day 1). 
When at home, subjects will receive an IMP reminder at a time within a predefined 
window. This notification reminds subjects to take their IMP dose while using the 
AiCure Platform.  Subjects will follow a series of prescribed steps in front of the 
front-facing webcam to visually confirm their ingestion of the IMP. The application on 
the smartphone will make an automated determination of whether the subject has 
properly taken their IMP at the prescribed time. There is no need for the trial site staff to 
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review the administration, nor would the trial site staff need to be available at the time the 
subject takes their IMP. The amount of guidance that the device provides to the subjects 
is automatically reduced as the subject becomes more proficient at using the application.
After the device confirms proper IMP ingestion, video recordings will be encrypted and 
transmitted to a secure centralized location for further analysis, including testing for 
duplicate enrollment.  The captured data and video are reviewable through a roles and 
rules restricted system ensuring privacy of the information. The system is compliant with 
the Health Insurance Portability and Accountability Act (HIPAA), which protects the 
privacy and security of healthcare information.
Phone numbers of the subjects may also be collected and stored in an encrypted manner.
Storing the phone numbers will allow for direct communication with subjects, including 
automated messaging from the AiCure Platform device and contact by the trial site staff
or other monitoring personnel.  At no time is the phone number visible to the trial site 
staff or monitoring personnel on the AiCure Platform.  Individuals outside the trial sites 
will not be provided with subject names, nor will they be given access to subject medical 
records.
3.12.2
Subject Risk
The AiCure Platform provides no more than minimal risk to subjects.  This protocol only 
introduces a smartphone-based monitoring application that prompts the user to take their 
IMP, verifies ingestion, and stores encrypted data securely for analysis.  When 
functioning properly, use of the AiCure Platform does not affect titration, dosage, route 
of administration, or treatment duration, conforming to any trial requirements as noted by 
trial site staff. 
It is possible, though very unlikely, that the AiCure application can fail to remind 
subjects to take the IMP or tell them to take their IMP when not required.  To date, 
AiCure has not encountered such a malfunction.  
All trial data, including any identifiable subject information, will be obtained and 
encrypted by the application.  Subjects will be coded according to the protocol and their 
identity will not be stored with the trial data obtained.  After the subject has taken the 
IMP and confirmation of proper ingestion has been completed, the encrypted data will be 
automatically forwarded to a secure server.  The server is compliant with the HIPAA, 
which protects the privacy and security of healthcare information.  The data will be 
securely stored and only accessible to the trial site staff and other authorized personnel 
through two-way authentication. 
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The data may also be retained in a secure manner beyond the term of the trial and utilized 
to improve the operation of the AiCure Platform, categorize adherence activity by disease 
state or other useful categories, and/or for regulatory filings by the AiCure Platform 
Provider to support future applications for the AiCure Platform Provider’s product. 
Individuals who are not associated with the care and treatment of subjects will not have 
access to subject identity or any medical records.
3.12.3
Subject Confidentiality
The AiCure Platform Provider will protect subjects’ personal information to the full 
extent required by law.  However, information from this trial, including de-identified 
video recording(s) of subject performance of various actions, may be submitted to the 
trial site, and potentially to the FDA.  Both information obtained by the application, and 
information in the subject Informed Consent, may be examined by the trial site or the trial 
site’s representatives, and may also be reviewed by the FDA and other regulatory 
agencies, IRBs, and or Ethics Committee(s).  All of these parties are bound to safeguard 
the rights, safety, and well-being of all clinical trial subjects, and to maintain all 
information in confidence, with special consideration given to trials that may include 
vulnerable subjects.
The results of this trial may be presented at meetings or in publications; however, specific 
subjects will not be identified by name in these presentations and/or publications.  
Information from this trial may also be retained by the AiCure Platform Provider for the 
purpose of improving the AiCure Platform, to allow for future analysis of various facial 
and other parameters, the reporting of high level statistical analysis of the AiCure 
Platform, to improve the internal workings of the system running on the smartphone 
device, or for regulatory filings by the AiCure Platform Provider to support future 
applications for the Provider’s product.
3.13
Protocol Deviations
In the event of a significant deviation from the protocol due to an emergency, accident, or 
mistake (eg, violation of informed consent process, IMP dispensing or subject dosing 
error, treatment assignment error, subject enrolled in violation of eligibility criteria or 
concomitant medication criteria), the investigator or designee will contact the sponsor at 
the earliest possible time by telephone.  The investigator and sponsor will come as 
quickly as possible to a joint decision regarding the subject’s continuation in the trial.  
This decision will be documented by the investigator and the sponsor, and reviewed by 
the site monitor.
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4
Restrictions
4.1
Prohibited Medications
Subjects who are currently taking any therapy for adult ADHD at screening will washout 
from their current ADHD therapy for a period equivalent to 5 half-lives before the 
Baseline (Day 1) Visit. All subjects must agree to discontinue all prohibited medications 
during the Screening Period.  Table 4.1-1 provides the required duration of washout for 
selected prohibited medications.  All other prohibited medications must be discontinued 
at least 24 hours before the first dose of IMP at the Baseline (Day 1) Visit.
Table 4.1-1
List of Medications Prohibited Before the Trial
Medication
Required Washout Prior to Baseline
1.
Neuroleptic agents (depot)
One cycle plus 14 days
2.
Antidepressants
Fluoxetine
All other antidepressants
28 days
14 days
3.
Benzodiazepines
14 days
4.
Hypnotics, including non-benzodiazepine sleep aids
14 days
5.
Neuroleptic agents (oral)
14 days
6.
CYP2B6 inhibitors, CYP2D6 inhibitors, CYP2D6 
substrates with a narrow therapeutic index, and CYP3A4 
inhibitors and inducers
14 days
Table 4.1-2 lists all medications prohibited during the trial, including exceptions, where 
appropriate.
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Table 4.1-2
List of Medications Prohibited During the Trial
1.
All psychotropic agents including, but not limited to, the following:
a) Antipsychotics, including depot formulations
b) Anticonvulsants
c) Antidepressants
d) Mood stabilizers (ie, lithium)
e) Benzodiazepines
f)
Hypnotics, including non-benzodiazepine sleep aids
g) Stimulants
h) Opioid analgesics, unless permission is obtained from the medical monitor.  Permission for 
opioid use may be considered for a documented and clinically appropriate indication (eg, 
episodic pain condition, tooth extraction) if prescribed at a medically appropriate dose and 
frequency.
i)
Nutritional supplements and non-prescription herbal preparations with central nervous system 
effects (eg, St. John’s Wort, omega-3 fatty acids, kava extracts, GABA supplements, etc)
j)
Cannabinoids
2.
Investigational agents
3.
CYP2B6 inhibitors, CYP2D6 inhibitors, CYP2D6 substrates with a narrow therapeutic index, or 
CYP3A4 inhibitors and inducers.  Selected CYP2B6 inhibitor is: ticlopidine.  Selected CYP2D6 
inhibitors are: celecoxib, hydroxyzine, chloroquine, methadone, chlorpheniramine, moclobemide, 
clemastine, paroxetine, clomipramine, pyrilamine, diphenhydramine, quinidine, fluoxetine, 
terbinafine, halofantrine, tripelennamine.  Selected CYP2D6 substrates are: thioridazine, pimozide, 
desipramine, eliglustat, metoprolol, nebivolol, nortriptyline, perphenazine, tolterodine, venlafaxine, 
amitriptyline, encainide, imipramine, propafenone, propranolol, tramadol, trimipramine.  Selected 
CYP3A4 inhibitors are: amiodarone, fluvoxamine, amprenavir, indinavir, aprepitant, itraconazole, 
chloramphenicol, ketoconazole, cimetidine, nefazodone, clarithromycin, nelfinavir, clotrimazole (if 
used orally), quinupristin/dalfopristin, delavirdine, ritonavir, diltiazem, saquinavir, erythromycin, 
troleandomycin, fluconazole, verapamil.  Selected CYP3A4 inducers are: carbamazepine, 
oxcarbazepine, phenytoin, dexamethasone, primidone, efavirenz, rifampin, nevirapine, St. John’s 
Wort, phenobarbitol, troglitazone.  The medical monitor should be consulted for any questions 
regarding the potential for pharmacokinetic interactions with concomitant medications used by 
subjects during the trial.
4.
Barbiturates, except for the treatment of migraine headaches, provided that in the opinion of the 
investigator the dosing is medically appropriate.
GABA = gamma-aminobutyric acid.
4.2
Other Restrictions 
4.2.1
Restricted Therapies and Precautions
Consumption of grapefruit, grapefruit juice, Seville oranges, or Seville orange juice 
within 72 hours prior to IMP administration and during the trial is prohibited.  Also, food 
containing St. John’s Wort (Hypericum perforatum) is prohibited for 14 days prior to 
IMP administration and during the trial.  Investigators should inform subjects that normal 
consumption of caffeine is permitted.
The subject’s best medical interests should guide the investigator in the management of 
conditions that are pre-existing or that develop during the trial (intercurrent illness or 
AEs).  The investigator should examine the acceptability of all concomitant medications 
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not explicitly prohibited.  In order to ensure that appropriate concomitant therapy is 
administered, it is essential that subjects be instructed not to take any medications (either 
self-administered non-prescription drugs or prescription therapy prescribed by another 
physician) without prior consultation with the investigator.  All trial personnel should be 
familiar with the content of the OPC-64005 IB in order to manage the subject’s condition 
adequately and select appropriate concomitant medications, if needed.
4.2.2
Non-therapy Precautions and Restrictions
4.2.2.1
Precautions
Subjects should not undergo any elective medical procedure without prior consultation 
with the investigator.  An elective procedure (minor surgery, dental surgery, orthopedic 
surgery, etc) that might require hospitalization or general anesthesia should be deferred 
until after the trial whenever clinically appropriate.
4.2.2.2
Restrictions
Subjects may only receive psychotherapy (eg, individual, group, marriage, or family 
therapy) if they have been participating in the therapy regularly (ie, at consistent 
intervals) for at least 6 weeks (42 days) prior to screening and commit to maintain their 
participation during the course of the trial with no changes or unless permission is 
obtained from the medical monitor.
Subjects will be instructed to refrain from drinking alcoholic beverages or using 
cannabinoids or illicit drugs during participation in the trial.  The investigator may 
request a blood or urine drug screen at any time during the trial if there is a suspicion of 
illicit drug use.
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.  AEs would not include information recorded as medical 
history at screening for pre-planned procedures for which the underlying condition was 
known and no worsening occurred.  An adverse reaction is any untoward and unintended 
response to an IMP related to any dose administered.
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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 (IND) 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, 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 in-patient 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 non-medical need) are not 
considered SAEs.

Congenital anomaly/birth defect.

Other medically significant events that, based upon appropriate medical judgment, 
may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed above; eg, allergic bronchospasm requiring 
intensive treatment in an emergency room or home, blood dyscrasias or convulsions 
that do not result in hospitalization, or the development of drug dependency or drug 
abuse.
Nonserious adverse events 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 serious hepatotoxicity case (see Section 5.5). 

Rash (regardless of severity or seriousness) (see Section 5.4).

Pregnancies are also defined as IREs.  Although normal pregnancy is not an AE, it 
will mandate IMP discontinuation and must be reported on an IRE form to the 
sponsor.  Pregnancy will only be documented on the AE eSource if there is an 
abnormality or complication.
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Clinical Laboratory Test Value Changes:  It is the investigator’s responsibility to review 
the results of all laboratory tests as they become available.  This review will be 
documented by the investigator’s dated signature on the laboratory report.  For each 
abnormal laboratory test result, the investigator needs to ascertain if this is an abnormal 
(ie, clinically significant) 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 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 (subject is symptomatic, requiring 
corrective treatment or further evaluation), or if the laboratory value leads to 
discontinuation, and/or fulfills a seriousness criterion, this is considered an AE. 
Severity:  Adverse events will be graded on a 3-point scale and reported as indicated on 
the eSource.  The intensity of an adverse experience is defined as follows:
1 = Mild:
Discomfort noticed, but no disruption to daily activity.
2 = Moderate:
Discomfort sufficient to reduce or affect normal daily activity.
3 = Severe:
Inability to work or perform normal daily activity.
IMP Causality:  Assessment of causal relationship of an AE to the use of the IMP is 
defined as follows:
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 causal relationship between the IMP and 
the AE.
5.2
Eliciting and Reporting Adverse Events
The investigator 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 on the source documents and eSource provided by the sponsor.  Collection of 
all AEs is to begin after a subject has signed the eICF.  
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 
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experienced earlier, or not expected based on the course of the condition.  A reported AE 
that undergoes a change in severity, seriousness, or toxicity should be reported as a new 
AE on the eSource.
In addition, the sponsor must be notified immediately by telephone, fax, or e-mail of any 
IREs according to the procedure outlined below, in Section 5.3.  Special attention should 
be paid to recording hospitalization and concomitant medications.
5.3
Immediately Reportable Events 
The investigator must immediately report after either the investigator or site personnel 
become aware of any SAE, potential serious hepatotoxicity, rash, or confirmed 
pregnancy, by telephone, fax, or e-mail to the sponsor using the contact information on 
the cover page of this protocol.  An IRE form must be completed and sent by e-mail, fax, 
or overnight courier to the sponsor.  (Please note that the IRE form is NOT the AE 
eSource.) 
Subjects experiencing SAEs should be followed clinically until their health has returned 
to baseline status, or until all parameters have returned to normal or have otherwise been 
explained.  It is expected that the investigator 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
Adverse Events of Special Interest
Newly acquired skin eruptions that are nontraumatic will be considered adverse events of 
special interest (AESI).  These may include, but are not limited to, eruptions such as skin 
rashes, skin irritations, skin reactions, or acneiform lesions. 
Extra measures that must be performed to characterize any skin AESI of a newly 
acquired skin eruption that is nontraumatic are specified in Appendix 11 through
Appendix 14.  The trial site will have a local dermatologist available for immediate 
consultation during the trial for these AESIs.
5.5
Potential Serious Hepatotoxicity
For a subject who experiences an elevation in AST or ALT that is 3 times the upper 
limit of normal (ULN), a total bilirubin level should also be evaluated.  If the total 
bilirubin is 2 times the ULN, complete an IRE form with all values listed and also 
report as an AE on the eSource.
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5.6
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 [confirmed 
by FSH blood level]).
For WOCBP and for men who are sexually active, there must be a documented 
agreement that the subject and/or their partner will take effective measures 
(ie, double-barrier method) to prevent pregnancy during the course of the trial and for 
30 days after the last dose of IMP.  Unless the subject is sterile (ie, women who have had 
a bilateral oophorectomy and/or hysterectomy or who have been postmenopausal for at 
least 12 consecutive months [confirmed by FSH blood level]; or men who have had a 
bilateral orchidectomy), 2 of the following precautions must be used:  vasectomy, tubal 
ligation, vaginal diaphragm, intrauterine device, birth control pills, birth control depot 
injection, birth control implant, condom with spermicide, or sponge 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 must review the below 
guidelines about trial participation with all WOCBP.  The topics should generally 
include:

General information

Informed consent form

Pregnancy prevention information

Drug interactions with hormonal contraceptives

Contraceptives in current use

Guidelines for the follow-up of a reported pregnancy
Before trial enrollment, WOCBP must be advised of the importance of avoiding 
pregnancy during trial participation and the potential risk factors for an unintentional 
pregnancy.  The subject must sign an informed consent form stating that the above-
mentioned risk factors and the consequences were discussed with her.
A urine and/or serum pregnancy test for human chorionic gonadotropin will be performed 
at screening on all WOCBP.  If a urine test is performed and is positive, the investigator 
will follow up with a confirmatory serum test.
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During the trial, all WOCBP should be instructed to contact the investigator immediately 
if they suspect they might be pregnant (eg, missed or late menstrual cycle).
If a subject is suspected to be pregnant before she receives IMP, the IMP administration 
must be withheld until the results of serum 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 pregnancy test is known.  If pregnancy is confirmed, the IMP 
will be permanently discontinued in an appropriate manner (eg, dose tapering if 
necessary for subject safety) and the subject will be withdrawn from the trial.  
The investigator must immediately notify the sponsor of any pregnancy associated with 
IMP exposure during the trial and for 30 days after the last dose of IMP, and record the 
event on the IRE form and forward it to the sponsor.  The sponsor will forward 
Pregnancy Surveillance Form(s) for monitoring the outcome of the pregnancy. 
Protocol-required procedures for trial discontinuation and follow-up must be performed 
on the subject unless contraindicated by pregnancy (eg, x-ray studies).  Other appropriate 
pregnancy follow-up procedures should be considered, if indicated.  In addition, the 
investigator must report to the sponsor, on appropriate Pregnancy Surveillance Form(s), 
follow-up information regarding the course of the pregnancy, including perinatal and 
neonatal outcome.  Infants will be followed for a minimum of 6 months from the date of 
birth.  
5.7
Procedure for Breaking the Blind 
The investigator is encouraged to contact the sponsor/CRO medical advisor to discuss 
their rationale for unblinding.  However, to prevent delays to the investigator or medical 
personnel responding to a potentially emergent situation, unblinding of IMP will not be 
dependent upon the investigator receiving approval from the sponsor/CRO medical 
advisor (ie, the investigator will be able to obtain the code break information independent 
of the sponsor/CRO medical advisor).  The investigator must contact the sponsor/CRO 
medical advisor by telephone or e-mail with an explanation of the need for opening the 
treatment assignment code within 24 hours of opening the code.  If the blind is broken, 
the Clinical Safety and Pharmacovigilance department must be notified immediately (see 
the cover page of this protocol for contact information).  Documentation of breaking the 
blind should be recorded in the subject’s medical record with the date and time the blind 
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was broken and the names of the personnel involved.  Once the blind is broken for a 
subject, that subject may not reinitiate treatment with the IMP.
5.8
Follow-up of Adverse Events 
5.8.1
Follow-up of Nonserious Adverse Events
Nonserious AEs that are identified at any time during the trial must be recorded on the 
AE eSource with the current status (ongoing or resolved/recovered) noted.  All 
nonserious events (that are not IREs) that are ongoing at the last scheduled contact will 
be recorded as ongoing on the eSource.  For any AE having been identified throughout 
the trial, during 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).
5.8.2
Follow-up of Serious Adverse Events and Immediately 
Reportable Events
This trial requires that subjects be actively monitored for SAEs up to 30 (+ 2) days after 
the last dose of IMP is administered.
Serious AEs and nonserious IREs that are identified or ongoing at the last scheduled 
contact must be recorded on the AE eSource page.  If updated information (eg, resolved 
status) on SAE or IRE status becomes available after a subject’s last scheduled contact 
(up to last in-clinic visit for the entire trial), this must be reported to the sponsor and
recorded on the AE CRF page, according to the appropriate reporting procedures.  Every
effort will be made to obtain a PK blood sample from any subject who experiences an 
SAE.  This sample should be obtained as soon as is practical after the onset of the SAE.  
The investigator will follow SAEs until the events are resolved, stabilized, or the subject 
is lost to follow-up or has died.  Resolution means that the subject has returned to the 
baseline state of health and stabilized means that the investigator does not expect any 
further improvement or worsening of the subject’s condition.  The investigator will 
continue to report any significant follow-up information to the sponsor up to the point the 
event has resolved or stabilized, or the subject is lost to follow-up or has died.
5.8.3
Follow-up and Reporting of Serious Adverse Events and 
Immediately Reportable Events Occurring after Last Scheduled 
Contact
Any new SAEs or IREs reported to the investigator which occur after the last scheduled 
contact and are determined by the investigator to be reasonably associated with the use of 
the IMP, should be reported to the sponsor.  This may include SAEs or IREs that are 
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captured on follow-up telephone contact or at any other time point after the defined trial 
period.  The investigator should follow SAEs or 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.
6
Pharmacokinetic/Pharmacogenomic Analysis
Plasma concentrations of OPC-64005 will be summarized by time points using 
descriptive statistics. No formal statistical comparisons are planned. A separate 
population or pharmacokinetic/pharmacodynamic modeling may be performed using the 
data from this trial and other trials.
7
Statistical Analysis
7.1
Sample Size
This trial is exploratory in nature, focusing on estimation of treatment effect and its 
variability as well as collecting data for future decision making and as a result, sample 
size was chosen from practical considerations.  The trial will enroll approximately 
201 subjects in expectation to have about 150 completers at the end of the trial.  It is 
evaluated via simulations that this sample size will be sufficient for making robust further 
development decision based on data from OPC-64005 and atomoxetine arms using 
concept of posterior probability. 
7.2
Datasets for Analysis
The following analysis samples are defined for this trial:
Enrolled Sample:  Comprises all subjects who sign an eICF for the trial.
Randomized Sample:  All subjects randomized into this trial.
Safety Sample:  Comprises randomized subjects who received at least one dose of 
double-blind IMP as indicated on the dosing record.
Modified Intent-to-Treat Sample:  All subjects in the Randomized Sample who took at 
least one dose of IMP and have a baseline and at least one post randomization evaluation 
for the investigator-administered CAARS-O:SV ADHD Symptoms Total Score 
(18-items).
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7.3
Handling of Missing Data
The 18-item, investigator-administered CAARS-O:SV is utilized as the primary efficacy 
assessment of a subject’s level of ADHD.  The 18-item ADHD Symptoms Total Score 
(sum of the Inattentive Symptoms Subscale and the Hyperactive/Impulsive Symptoms 
Subscale) is considered to be the primary efficacy measure.  Each item is rated on a 0 to 3 
scale with 0 = Not at all, never; 1 = Just a little, once a while; 2 = Pretty much, often; and 
3 = Very much, very frequently.  Therefore, possible ADHD Symptoms Total Scores 
range from 0 to 54.  If more than 1 item is missing in a subscale, the subscale (and the 
total) is considered as missing.  For a single missing item, the mean score will be used to 
impute the missing item and then to compute the subscale or total scores.
In general, for primary analysis of efficacy endpoints, missing data will be handled by 
analysis of mixed-effect model repeated measures (MMRM) methodology based on 
observed case (OC) data from protocol-specified visits under the assumption of missing 
at random.  The OC dataset consists of actual observations recorded at each visit and no 
missing data will be imputed.
7.4
Endpoint Analyses
7.4.1
Primary Endpoint Analysis
The primary efficacy endpoint is the mean change from baseline to the Day 56 Visit on
the 18-item, investigator-administered CAARS-O:SV score in the OPC-64005 group 
compared with the atomoxetine group.  Analysis will be performed using modified 
intent-to-treat data set. 
Bayesian posterior probability of true baseline corrected difference at Week 8 between 
treatment arms (OPC-64005 and atomoxetine) being larger than 4 points on the 18-item, 
investigator-administered CAARS-O:SV given estimates of means and standard 
deviations (SD) in the treatment arms will be calculated.  Estimates for means and SD 
will be derived from mixed-effect model as described below.  Uninformative prior will be 
used in calculations.
The change from baseline in the 18-item, investigator-administered CAARS-O:SV will 
be analyzed using an MMRM methodology with the unstructured variance covariance 
matrix.  The model will include fixed class-effect terms for treatment, trial site, visit 
week an interaction term of treatment by visit week, and baseline 18-item, 
investigator-administered CAARS-O:SV as a covariate.  The need of additional fixed 
effects and its interactions in the model will be explored.  In case the pre-specified 
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primary efficacy model does not converge, the algorithm to deal with convergence issues 
will be stated in the Statistical Analysis Plan (SAP).
7.4.2
Other Endpoint Analysis
Other key efficacy variables are as follows:
1) Mean change from baseline to each scheduled visit (other than Day 56) in the 
18-item, investigator-administered CAARS-O:SV score in the OPC-64005 group 
relative to the atomoxetine and placebo groups
2) Mean change from baseline to the Day 28 (± 1 day) and Day 56 (± 1 day) Visits for 
the AISRS with Adult Prompts score in the OPC-64005 group relative to the 
atomoxetine and placebo groups
3) Mean change from baseline to each scheduled visit in the CGI-S score in the 
OPC-64005 group relative to the atomoxetine and placebo groups
4) Mean CGI-I score at each scheduled visit in the OPC-64005 group relative to the 
atomoxetine and placebo groups
5) Mean change from baseline to each scheduled visit in the 18-item CAARS-S:SV in 
the OPC-64005 group relative to the atomoxetine and placebo groups
6) Mean change from baseline to the Day 28 (± 1 day) and Day 56 (± 1 day) Visits in 
the AAQoL in the OPC-64005 group relative to the atomoxetine and placebo groups
Estimates in mean change from baseline and its variability of above listed endpoints will 
be calculated using MMRM model similar to one described in the primary analysis. 
Details on other analyses will be provided in the SAP.
7.4.3
Interim Analysis
An administrative interim analysis will be performed on the primary endpoint after
90 subjects complete 8 weeks of treatment. This analysis will be performed for purpose 
of planning future studies and will not change the trial conduct (ie, regardless of the 
interim analysis outcome, this trial will run to completion). Analysis methods will be the 
same as ones for the final analysis.  Analysis will be performed by the OPDC Internal 
Independent Biostatistician who is not a member of the trial team in order to 
minimize/avoid bias.
7.5
Analysis of Demographic and Baseline Characteristics
Baseline demographic characteristics including age, race, ethnicity, gender, weight, 
height, and body mass index (BMI) for the randomized subjects will be summarized by 
descriptive statistics (frequency, mean, median, standard deviation, maximum, minimum, 
and percentage when applicable).
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Baseline disease severity and psychiatric history will be also be summarized by 
descriptive statistics for safety sample to identify any potential lack of balance between 
the treatment arms.
7.6
Safety Analysis
Safety analysis regarding safety and tolerability of OPC-64005 will be conducted based 
on the safety sample, which is defined in Section 7.2.  In general, baseline measurements 
of safety variables are defined as their last measurements prior to the first dosing of IMP.  
Standard safety variables to be analyzed include AEs, clinical laboratory tests, vital signs, 
and ECGs.
7.6.1
Adverse Events
All AEs will be coded to the Lowest Level Term (LLT) in the Medical Dictionary for 
Regulatory Activities (MedDRA) that most accurately reflects the reported term.  The 
incidence of the following events will be summarized by treatment group:

TEAEs

TEAEs by severity

Potentially drug-related TEAEs

TEAEs with an outcome of death

Serious TEAEs

TEAEs leading to discontinuation of the IMP 
7.6.2
Clinical Laboratory Data
Summary statistics for changes from baseline in the routine clinical laboratory 
measurements will be provided.  Potentially clinically significant results in laboratory 
tests will also be summarized.
7.6.3
Physical Examination and Vital Signs Data
By-subject listings will be provided for physical examination.  Summary statistics for 
changes from baseline in vital signs will be provided.  Potentially clinically significant 
results in vital signs will also be summarized.
7.6.4
Electrocardiogram Data 
Mean change from baseline and incidence of clinically significant changes will be 
calculated for ECG parameters.
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For the analysis of QT and QTc, data from 3 consecutive complexes (representing 
3 consecutive heart beats) will be measured to determine average values.  The following 
QT corrections will be used for reporting purposes in the clinical study report:
1) QTcB is the length of the QT interval corrected for heart rate by the Bazett formula: 
QTcB = QT/(RR)0.5
2) QTcF is the length of the QT interval corrected for heart rate by the Fridericia 
formula: QTcF=QT/(RR)0.33
3) QTcN is the length of the QT interval corrected for heart rate by the FDA 
Neuropharm Division formula:  QTcN=QT/(RR)0.37
7.6.5
Other Safety Data
The DEQ will be completed at each scheduled visit (Days 7, 14, 21, 28, 42, and 56/ET; 
all visits have a ± 1-day window) as a measure of abuse potential and will be analyzed 
via summary statistics.
Suicidality will be monitored during the trial using the C-SSRS.  The incidence of 
suicidality, suicidal behavior, and suicidal ideation will be calculated from the potential 
suicide events recorded on the C-SSRS and summarized by trial visit.
8
Management of Investigational Medicinal Product
For full details on the IMP, please refer to the OPC-64005 IB.
8.1
Packaging and Labeling
Trial medication will be provided to the investigators and the persons designated by the 
investigator(s) or institution(s) by the sponsor or designated agent.  The IMP will be 
supplied as blister cards.  Each card used in the dosing period will be labeled to clearly 
disclose the compound identification, trial number, sponsor’s name and address, 
instructions for use, route of administration, and appropriate precautionary statements.
8.2
Storage
The IMP will be stored in a securely locked cabinet or enclosure.  Access will be limited 
to investigators and their designees.  Neither investigators nor any designees may provide 
IMP to any subject not participating in this protocol.
The IMP will be stored according to the storage conditions indicated on the clinical 
label(s).  
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The trial site staff will maintain a temperature log in the IMP storage area recording the 
temperature at least once each working day.  Temperature excursions, outside of the 
specific conditions for the IMP (as noted on the label), will be immediately reported to 
the sponsor.
8.3
Accountability
The investigator or designee must maintain an inventory record of IMP (including 
investigational, active control, and placebo) received, dispensed, administered, and 
returned.
8.4
Returns and Destruction
Upon completion or termination of the trial, all used IMP containers, unused IMP, and 
partially used IMP must be returned to the sponsor or a designated agent, or destroyed at
the trial sites.  The IMP may only be destroyed by the trial sites, if approved by the 
sponsor and if the IMP destruction meets all local regulations.
All IMP returned to the sponsor or designated agent must be accompanied by the 
appropriate documentation and be clearly identified by the protocol number and trial site
number on the outermost shipping container.  Returned supplies should be in the original 
containers.  The assigned trial monitor will facilitate the return or destruction of used 
IMP containers, unused IMP, and partially-used IMP.
8.5
Reporting of Product Quality Complaints
A Product Quality Complaint (PQC) is any written, electronic, or verbal communication 
by a healthcare professional, consumer, subject, medical representative, Competent 
Authority, regulatory agency, partner, affiliate or other third party that alleges 
deficiencies or dissatisfaction related to identity, quality, labeling, packaging, reliability, 
safety, durability, tampering, counterfeiting, theft, effectiveness or performance of a drug 
product or medical device after it is released for distribution.  Examples include, but are 
not limited to, communications involving:

Failure/malfunction of a product to meet any of its specifications

Incorrect or missing labeling

Packaging issues (eg, damaged, dirty, crushed, missing product)

Blister defects (eg, missing, empty blisters)

Bottle defects (eg, under/over-fill, no safety seal)
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
Vial defects

Product defect (eg, odor, chipped, broken, embossing illegible)

Loss or theft of product
8.5.1
Eliciting and Reporting Product Quality Complaints
The investigator 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 or 
designee must notify the sponsor (or sponsor’s designee) by e-mail or telephone within 
24 hours of becoming aware of the PQC according to the procedure outlined below.
Identification of a PQC by the subject should be reported to the site investigator, who 
should then follow one of the reporting mechanisms above.
8.5.2
Information Required for Reporting Purposes

Description of compliant

Reporter identification (eg, subject, investigator, site, etc.)

Reporter contact information (eg, address, phone number, e-mail address)

ID of material (product/compound name, coding)

Clinical protocol reference (number and/or trial name)

Dosage form/strength (if known)

Pictures (if available)

Availability for return
8.5.3
Return Process
Indicate during the report of the PQC if the complaint sample is available for return.  If 
complaint sample is available for return, return it in the product retrieval package, which 
will be provided by the sponsor.
It must be documented in the site accountability record that a complaint sample for a 
dispensed kit has been forwarded to the sponsor for complaint investigation.
8.5.4
Assessment/Evaluation
Assessment and evaluation of PQCs will be handled by the sponsor.
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9
Records Management
9.1
Source Documents
Source documents are defined as the results of original observations and activities of a 
clinical investigation.  Source documents will include but are not limited to progress 
notes, electronic data, screening logs, and recorded data from automated instruments.  All 
source documents pertaining to this trial will be maintained by the investigators and made 
available for direct inspection by authorized persons.
Investigator(s)/institution(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 eICF.  In all cases, subject confidentiality must be 
maintained in accordance with local regulatory requirements.
9.2
Data Collection
During each subject’s visit to the clinic, a clinician participating in the trial will record 
progress notes to document all significant observations.  At a minimum, these notes will 
contain:

Documentation of the informed consent process, including any revised consents;

Documentation of the investigator’s decision to enroll the subject into the trial, the 
review of all inclusion/exclusion criteria prior to IMP administration, and 
confirmation of the subject’s actual participation in the trial;

The date of the visit and the corresponding Visit or Day in the trial schedule;

General subject status remarks, including any significant medical findings.  The 
severity, frequency, duration, action taken, and outcome of any AEs and the 
investigator's assessment of relationship to IMP must also be recorded;

Any changes in concomitant medications or dosages;

A general reference to the procedures completed; 

The signature (or initials) and date of each clinician (or designee) who made an entry 
in the progress notes.
In addition, any contact with the subject via telephone or other means that provides 
significant clinical information will also be documented in the progress notes as 
described above.  
Source documents and source data will be captured electronically in this trial, and will 
meet the same fundamental elements of data quality (eg, attributable, legible, 
contemporaneous, original, and accurate) as paper records.  These data will be collected 
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into a system that is fully validated.  Changes to the data will be captured by an automatic 
audit trail.
The trial site will be given a tablet to directly record subject data and clinical 
observations on electronic forms.  Designated trial site staff will not be given access to 
the system until they have been appropriately trained.  Information to be originally 
captured and reviewed electronically shall include details of the subject visit and the 
protocol-required assessments performed as a part of these visits, medical history, AEs, 
and concomitant medications.  Because this trial is using an electronic source record as 
the original point of data capture, there is no additional data entry step for the trial site for 
data collected directly into the application – rather, the electronic source record directly 
populates the trial database.
Some data may be captured via paper and then entered into the eSource system.  These 
and any other data treated in this manner will be source data verified by the trial clinical 
research associate, and the location of the source data (ie, eSource, paper, or a local 
electronic system) will be documented before the trial start.  Any changes to information 
in paper 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 clinician.
Another exception will be safety laboratory [or central ECG data], where the official 
source documentation will be considered the report issued by the analyzing laboratory.
Remote monitoring of the original electronic source records will take place, however 
on-site monitoring inspections will continue to take place in order to review data entry of 
source documentation directly captured on paper and transcribed into the system, to 
ensure protocol adherence, to assess trial site operational capabilities and to perform 
other monitoring activities that cannot be performed remotely.
At the end of the trial, the investigator must certify that the data entered into the eSource 
application are complete and accurate.  After database lock, the investigator will receive 
an electronic copy of the subject data.
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9.3
File Management at the Trial Site
The investigator 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 investigator/institution will take measures to prevent accidental or premature 
destruction of these documents.
9.4
Records Retention at the Trial Site
Food and Drug Administration regulations require all investigators participating in 
clinical drug trials to maintain detailed clinical data for one of the following periods:

A period of at least 2 years after the date on which a New Drug Application is 
approved by the FDA;

A period of 2 years after the sponsor has notified the FDA that investigation with this 
drug is discontinued.
The investigator must not dispose of any records relevant to this trial without either 
(1) written permission from the sponsor or (2) provision of an opportunity for sponsor to 
collect such records.  The investigator will be responsible to maintain adequate and 
accurate electronic or hard copy source documents of all observations and data generated 
during this trial including any data clarification forms received from the sponsor.  Such 
documentation is subject to inspection by the sponsor and relevant regulatory authorities.  
If the investigator withdraws from the trial (eg, due to relocation or retirement), all trial-
related records should be transferred to a mutually agreed-upon designee within a 
sponsor-specified timeframe.  Notice of such transfer will be given to the sponsor in 
writing.
10
Quality Control and Quality Assurance 
10.1
Monitoring
The sponsor has ethical, legal, and scientific obligations to follow this trial in accordance 
with established research principles, the ICH E6 GCP: Consolidated Guidance, and 
applicable regulatory requirements and local 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 and 
clinical site personnel will undergo initial and ongoing training for this particular trial, 
and this training will be clearly documented.
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10.2
Auditing
The sponsor's Quality Assurance Unit (or representative) may conduct trial site audits.  
Audits will include, but are not limited to, IMP supply, presence of required documents, 
the informed consent process, and comparison of eSource with source documents.  The 
investigator agrees to participate with audits.
Regulatory authorities may inspect the investigator site during or after the trial.  The 
investigator will cooperate with such inspections and will contact the sponsor 
immediately if such an inspection occurs.
11
Ethics and Responsibility
This trial must be conducted in compliance with the protocol, FDA regulations, ICH GCP 
Guideline (E6), international ethical principles derived from the Declaration of Helsinki 
and Council for International Organizations of Medical Science (CIOMS) guidelines, and 
applicable local laws and regulations.  Each trial site will seek approval/favorable opinion 
by an IRB according to regional requirements, and the investigator 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 eSource, the investigator, 
subinvestigator and their staff will take measures to ensure adequate care in protecting 
subject privacy.  To this end, a subject number and subject identification code will be 
used to identify each subject.
Financial aspects, subject insurance and the publication policy for the trial will be 
documented in the agreement between the sponsor and the investigator.
12
Confidentiality
All information generated in this trial will be considered confidential and will not be 
disclosed to anyone not directly concerned with the trial without the sponsor’s prior 
written permission.  Subject confidentiality requirements of the region(s) 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/or 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 unique subject numbers in eSource.  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.
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13
Amendment Policy
The investigator will not make any changes to this protocol without the sponsor’s prior 
written consent and subsequent approval/favorable opinion by the IRB.  Any permanent 
change to the protocol, whether an overall change or a change for specific trial site(s), 
must be handled as a protocol amendment.  Any amendment will be written by the 
sponsor.  Each amendment will be submitted to the IRB, as required by local regulations.  
Except for “administrative” or “non-substantial” amendments, investigators 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 after agreement by the sponsor 
and investigator, followed by IRB notification within local applicable timelines.  
The sponsor will submit protocol amendments to the applicable regulatory agencies 
within local applicable timelines.
When the IRB, investigators, and/or the sponsor conclude that the protocol amendment 
substantially alters the trial design and/or increases the potential risk to the subject, the 
currently approved eICF will require similar modification.  In such cases, after 
approval/favorable opinion of the new eICF by the IRB, repeat electronic informed 
consent will be obtained from subjects enrolled in the trial before expecting continued 
participation and before the amendment-specified changes in the trial are implemented.
14
Publication Authorship Requirements
Authorship for any Otsuka-sponsored publications resulting from the conduct of this trial 
will be based on International Committee of Medical Journal Editors (ICMJE) authorship 
criteria (http://www.icmje.org/recommendations).  According to ICMJE guidelines, one 
may be considered an author only if the following criteria are met:
1) Substantial contributions to the conception or design of the work; or the acquisition, 
analysis, or interpretation of data for the work; AND
2) Drafting the work or revising it critically for important intellectual content; AND
3) Final approval of the version to be published; AND
4) Agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved.
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All authors must meet the above criteria, and all who qualify for authorship based on the 
above criteria should be listed as authors.
Investigators or other trial participants who do not qualify for authorship may be 
acknowledged in publications resulting from the trial.  By agreeing to participate in the 
trial, investigators or other trial participants consent to such acknowledgement in any 
publications resulting from its conduct.
15
References
1
 Effects of OPC-64005 on 5-hydroxytryptamine 
(5-HT), norepinephrine (NE) and dopamine (DA) uptake into rat brain synaptosome. 
Otsuka Study No. 029017, Otsuka Report No. 023563, 2009.
2
 Evaluation of binding affinities of OPC-64005 to human monoamine 
transporters. Otsuka Study No. 029930, Otsuka Report No. 024275, 2009.
3
 Effects of OPC-277 against radioligand binding to various receptors, 
channels, transporters and enzymes. Otsuka Study No. 029247, Otsuka Report No. 
023557, 2009.
4
 Effects of OPC-64005 on the extracellular serotonin, norepinephrine 
and dopamine levels in the rat medial prefrontal cortex: in vivo microdialysis study. 
Otsuka Study No. 029192, Otsuka Report No. 023766, 2009.
5
 Effects of reference compounds on the extracellular serotonin, 
norepinephrine and dopamine levels in the rat medial prefrontal cortex: in vivo 
microdialysis study. Otsuka Study No. 029875, Otsuka Report No. 023956, 2009.
6
Carboni E, Tanda GL, Frau R, Chiara GD. Blockade of the noradrenaline carrier 
increases extracellular dopamine concentrations in the prefrontal cortex: evidence that 
dopamine is taken up in vivo by noradrenergic terminals. J Neurochem. 
1990;55:1067-1070.
7
 Effect of OPC-64005 on the extracellular dopamine levels in the rat 
striatum: in vivo microdialysis study. Otsuka Study No. 029215, Otsuka Report No. 
023843, 2009.
8
 Effect of OPC-64005 on immobility time in the forced swimming test 
in rats. Otsuka Study No. 029546, Otsuka Report No. 024052, 2009.
9
 Effects of OPC-64005 and other antidepressants on spontaneous 
locomotor activity in rats. Otsuka Study No. 030257, Otsuka Report No. 024195, 
2009.
10
 Effect of repeated administration of OPC-64005 on immobility time in 
the forced swimming test in rats. Otsuka Study No. 030182, Otsuka Report No. 
024077, 2009.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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11
 Effect of repeated administration of OPC-64005 on spontaneous 
locomotor activity in rats. Otsuka Study No. 030412, Otsuka Report No. 024196, 
2009.
12
 Anxiolytic effect of OPC-64005 on the elevated plus maze test in rats. 
Otsuka Study No. 029491, Otsuka Report No. 024046, 2009.
13
 Safety pharmacology of OPC-64005: Effect of OPC-64005 on the 
general symptoms and behavior in rats. Otsuka Study No. 028887, Otsuka Report No. 
023083, 2009.
14
 Safety pharmacology of OPC-277: Effect of OPC-277 on the respiratory 
system in conscious rats. Otsuka Study No. 028858, Otsuka Report No. 023359, 
2009.
15
 Safety pharmacology of OPC-277: Effect of OPC-277 on the cardiovascular 
system in conscious monkeys. Otsuka Study No. 028859, Otsuka Report No. 023360, 
2009.
16
 Safety pharmacology of OPC-64005: Effect of OPC-64005 on hERG 
currents in CHO-K1 cells. Otsuka Study No. 028621, Otsuka Report No. 022619, 
2009.
17
 Safety pharmacology of OPC-64005: Effects of OPC-64005 on the 
action potentials in isolated guinea-pig papillary muscles. Otsuka Study No. 029560, 
Otsuka Report No. 023860, 2009.
18
 Safety pharmacology of OPC-64005: Effect of OPC-64005 on the 
beating rate and contraction force of isolated guinea-pig right atrium. Otsuka Study 
No. 030024, Otsuka Report No. 023997, 2009.
19
 Plasma concentrations of OPC-64005 following single oral/intravenous 
administration of OPC-64005 to rats. Otsuka Study No. 028770, Otsuka Report No. 
024012, 2009.
20
 Plasma concentrations of OPC-64005 and its metabolites in monkeys after 
single oral or intravenous administration of OPC-64005. Otsuka Study No. 028872, 
Otsuka Report No. 023380, 2009.
21
 Absorption, distribution and excretion of radioactivity after single oral 
administration of 14C-OPC-64005 to rats. Otsuka Study No. 028771, Otsuka Report 
No. 023484, 2009.
22
 Absorption and excretion of radioactivity after single oral 
administration of 14C-OPC-277 to cynomolgus monkeys. Otsuka Study No. 028873, 
Otsuka Report No. 023372, 2009.
23
 Protein binding of 14C-OPC-64005 in mouse, rat, rabbit, dog, monkey and 
human serum proteins by equilibrium dialysis method. Otsuka Study No. 028752, 
Otsuka Report No. 023321, 2009.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
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24
 Investigation of metabolites of OPC-64005 in rat and monkey plasma after 
oral administration of OPC-64005 and in samples produced by in vitro metabolism 
using human liver 9,000×g supernatant (S9) fraction. Otsuka Study No. 029488, 
Otsuka Report No. 024175, 2009.
25
 In vitro metabolism of 14C-OPC-64005 using mouse, rat, rabbit, dog, 
monkey and human liver 9,000×g supernatant (S9) fraction and rat, monkey and 
human hepatocyte. Otsuka Study No. 028999, Otsuka Report No. 023452, 2009.
26
 In vitro metabolism of 14C-OPC-64005 by human cytochrome P450s 
baculovirus insect cell expressed. Otsuka Study No. 029019, Otsuka Report No. 
023453, 2009.
27
 Biliary and urinary excretion and enterohepatic circulation of radioactivity 
after single oral administration of 14C-OPC-64005 to rats. Otsuka Study No. 029108, 
Otsuka Report No. 023554, 2009.
28
 A single oral dose toxicity study of OPC-64005 in rats. Otsuka Study 
No. 028416, Otsuka Report No. 022669, 2009.
29
 Single oral dose toxicity study of OPC-277 in cynomolgus monkeys. 
Otsuka Study No. 028463, Otsuka Report No. 023090, 2009.
30
 Four-week repeated oral dose toxicity study of OPC-64005 with a 
2-week recovery test in rats. Otsuka Study No. 028823, Otsuka Report No. 023123,
2009.
31
 Four-week repeated oral dose toxicity study of OPC-277 in 
cynomolgus monkeys with 2-week recovery test. Otsuka Study No. 028636, Otsuka 
Report No. 023722, 2009.
32
 Thirteen-week repeated oral dose toxicity study of OPC-64005 with a 
4-week recovery test in rats. Otsuka Study No. 029878, Otsuka Report No. 025025, 
2010.
33
 Thirteen-week repeated oral dose toxicity of OPC-277 in cynomolgus 
monkeys with 4-week recovery test. Otsuka Study No. 029877, Otsuka Report No. 
024632, 2010.
34
 OPC-64005: Reverse mutation test in Salmonella typhimurium with male 
rat liver S9 by plate incorporation method. Otsuka Study No. 029111, Otsuka Report 
No. 022933, 2009.
35
 OPC-64005: Forward mutation test at the thymidine kinase locus of 
L5178Y mouse lymphoma cells with male rat liver S9 by 96-well-plate fluctuation 
method. Otsuka Study No. 028879, Otsuka Report No. 022917, 2009.
36
 OPC-64005: Micronucleus test in rat bone marrow erythrocytes after 
oral administration for 2 consecutive days. Otsuka Study No. 029071, Otsuka Report 
No. 023147, 2009.
37
 In vivo unscheduled DNA synthesis (UDS) test of OPC-277 with rat 
hepatocytes. Otsuka Study No. 029370, Otsuka Report No. 023643, 2009.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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38
 Study for effects of OPC-277 on fertility and early embryonic 
development to implantation by oral administration in male rats. Otsuka Study No. 
029620, Otsuka Report No. 024128, 2009.
39
 Study for effects of OPC-277 on fertility and early embryonic 
development to implantation by oral administration in female rats. Otsuka Study No. 
029621, Otsuka Report No. 024131, 2009.
40
 Study for effects of OPC-277 on embryo-fetal development by oral 
administration in rats. Otsuka Study No. 029044, Otsuka Report No. 024249, 2009.
41
 Study for effects of OPC-277 on embryo-fetal development by oral 
administration in rabbits. Otsuka Study No. 029045, Otsuka Report No. 024250, 
2009.
42 Austerman J. ADHD and behavioral disorders: Assessment, management, and an 
update from DSM-5. Cleve Clin J Med. 2015 Nov;82(11 Suppl 1):S2-7.
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Attention-deficit/hyperactivity disorder in adults: an overview. Biol Psychiatry. 2000 
Jul 1;48(1):9-20.
44 Heal DJ, Smith SL, Gosden J, Nutt DJ. Amphetamine, past and present--a 
pharmacological and clinical perspective. J Psychopharmacol. 2013 
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45 Volkow ND, Wang GJ, Newcorn J, Telang F, Solanto MV, Fowler JS, et al. 
Depressed dopamine activity in caudate and preliminary evidence of limbic 
involvement in adults with attention-deficit/hyperactivity disorder. Arch Gen 
Psychiatry. 2007;64(8):932-40.
46 Wilens TE, Faraone SV, Biederman J. Attention-deficit/hyperactivity disorder in 
adults. JAMA. 2004;292:619-23.
47 Ding Y, Lin K, Logan J. PET imaging of norepinephrine transporters. Curr Pharm 
Des 2006;12:3831-45. Review.
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49 Adler L, Spencer T. The Adult ADHD Clinical Diagnostic Scale (ACDS). Version 
1.2. New York: New York University School of Medicine; 2004.
50 Sheehan DV, Lecrubier Y, Harnett-Sheehan K, Amorim P, Janavs J, Weiller E, et al. 
The Mini International Neuropsychiatric Interview (M.I.N.I): the development and 
validation of a structured diagnostic psychiatric interview. J Clin Psychiatry. 
1998;59(Suppl 20):22-33.
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Questionnaire x ADHD-Adult Version. Massachusetts General Hospital. 2014.
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Guideline; Notice of Availability, 62 Federal Register 90 (9 May 1997), 
p. 25691-709.
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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53 Conners CK, Erhardt D, Sparrow E. Conners' Adult ADHD Rating Scales (CAARS). 
North Tonawanda, NY: Multi-Health Systems Inc; 1999.
54 Spencer TJ, Adler LA, Meihua Qiao, Saylor KE, Brown TE, Holdnack JA, et al. 
Validation of the adult ADHD investigator symptom rating scale (AISRS). J Atten 
Disord. 2010;14(1):57-68.
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Health, Education, and Welfare publication (ADM) 76-338. Rockville, MD: National 
Institute of Mental Health; 1976.
56 Busner J, Targum SD. The clinical global impressions scale: applying a research tool 
in clinical practice. Psychiatry. 2007;4(7):28-37.
57 Brod M, Johnston J, Able S, Swindle R. Validation of the adult attention 
deficit/hyperactivity disorder quality-of-life scale (AAQoL): a disease-specific 
quality-of-life measure. Qual Life Res. 2006;15:117-29.
58 McNair D, Lorr M, Droppleman L. POMS Manual. North Tonawanda (NY): MHS; 
1992.
59 Morean ME, de Wit H, King AC, Sofuoglu M, Rueger SY, O'Malley SS. The drug 
effects questionnaire: psychometric support across three drug types. 
Psychopharmacology (Berl). 2013;227:177-92.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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Appendix 3
Handling and Shipment of Bioanalytical Samples
Handling of Specimens
All tubes must be labeled such that the protocol number, subject identification number, 
date of collection, and nominal sample collection time can be verified. The labels must be 
approved by the sponsor’s bioanalytical scientist prior to use. It is important to note the 
exact time of the blood collection in eSource, not the scheduled PK collection time. The 
exact time of dosing will also be noted.
Plasma Samples for Pharmacokinetic Analysis
Blood (4 mL) will be collected into 4-mL Vacutainer® tubes containing sodium heparin 
anticoagulant. The tubes should be gently inverted 3 to 4 times and then centrifuged at 
2000 to 3000 rpm for at least 10 to 15 minutes at 4°C. The rpm should be kept at the 
same setting throughout the trial. The separated plasma should then be pipetted into 2 
polypropylene tubes and stored at −70°C (± 10°C). Trial sites that do not have access to a 
−70°C (± 10°C) freezer may utilize a −20°C (± 10°C) freezer for storage. One tube will 
subsequently be shipped on dry ice to the central laboratory. The backup tube will remain 
at the trial site until the first tube is received at the central laboratory. At that time, it 
should be shipped to the central laboratory.
Whole Blood Pharmacogenomic Samples for DMET Profiling
Blood (4 mL) will be collected into a 4-mL K2EDTA Vacutainer tube. Each tube should 
be gently inverted 3 to 4 times, transferred to the barcode-labeled polypropylene tube, 
which then must be stored at −70°C (± 10°C). Trial sites that do not have access to 
a -70°C freezer may utilize a −20°C (± 10°C) freezer for storage of metabolic samples. 
The tube will be shipped on dry ice to the central laboratory.
Blood Samples for Future Biospecimen Research
Blood (~10 mL) will be collected into an evacuated collection tube. The trial sites are 
expected to follow the instructions for collection, processing, storage, and shipment of 
blood samples as specified above. The tubes will be shipped to the central laboratory 
listed in Appendix 2.
Future biospecimen research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from acquisition. The specimens will be stored under strict 
supervision in a limited access facility which operates to ensure the integrity of the 
specimens.
Shipment of the Specimens
Each frozen specimen must be sealed in a vial and labeled with a waterproof pen. The 
label must correspond to inventory sheets and must be firmly attached with transparent 
tape and should include the protocol number and subject number, plus date and nominal 
time of collection. An electronic Excel file will be provided with the header information 
that must be filled by the trial sites. Samples should be organized consecutively by 
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subject number. The inventory should contain the name, address, and telephone number 
of the contact person from the trial site. Samples must be neatly packed and restrained in 
a Styrofoam® container (place Styrofoam container supplied within a cardboard box) 
with dry ice. Boxes should be completely filled with dry ice to avoid air spaces that allow 
evaporation of the dry ice. The Styrofoam container should be sealed with tape and 
placed in a cardboard box. Packages will not be shipped on Thursdays, Fridays, 
Saturdays, or any day prior to a holiday. The central laboratory must be alerted of 
shipments. Shipments will be via an overnight carrier to the central laboratory. The 
contact for the central laboratory (Appendix 2) must be notified of each shipment via 
e-mail with the electronic manifest attached on the shipment day. For each backup 
specimen, the same procedure will be followed once confirmation is received that the 
primary tube was received at the central laboratory. The central laboratory will 
subsequently be notified by the sponsor’s bioanalytical scientist when to ship the backup 
specimens to the biorepository for longer-term storage.
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Appendix 6
Adult ADHD Investigator Symptom Rating Scale (AISRS With 
Adult Prompts)
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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Appendix 9
Adult ADHD Quality of Life Scale (AAQoL)
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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Appendix 10
Profile of Mood States-Brief Form (POMS)
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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Appendix 11
OPC-64005 Skin AESI Workup Instructions
277-201-00001 Skin Adverse Event of Special Interest (AESI) Workup Instructions
Version 2.0 dated 18 Aug 2017
At any point during the trial, upon the report by the subject or upon the observation by 
site personnel of any type of newly acquired skin eruptions that are non-traumatic, they 
will be considered adverse events of special interest (AESIs), and the investigator or 
medical professional designee will take the following steps:
1. Discontinue administration of IMP regardless of the severity and seriousness of 
rash. 
2. Collect a detailed history, including specific questioning for symptoms of 
hepatitis (eg, weight loss, right upper quadrant tenderness, malaise, jaundice, 
hepatomegaly, dark urine) or other possible causes of the rash (eg, allergic, 
contact dermatitis).
3. Perform a physical examination of the area affected by the skin rash, listing all 
body parts affected (eg, left or right hand, forearm, upper arm, etc.).
4. Obtain vital signs (including body temperature).
5. Record all concomitant medications and nutritional supplements and compare 
them with the use of IMP and the onset and resolution of skin eruptions.
6. Take a picture of the area(s) of the rash using the Clinical Ink SureSource tablet. 
If the rash area is generalized, the torso, back, abdomen, and extremities should 
be photographed.
NOTE: Photographs should not contain any personal identifiers or parts 
of the body that would identify the subject (such as unusual tattoos, 
full-face views, etc.). 
7. Contact Otsuka’s and INC’s Medical Monitor for the trial. 
8. Collect blood samples for laboratory testing, including a complete blood count 
with differential to detect lymphocytosis, atypical lymphocytes, and absolute 
(total) eosinophil count and chemistry with liver enzyme tests and C-reactive 
protein (CRP) testing (to rule out cases of systemic hypersensitivity).

Note: If the signs and symptoms are suggestive of drug rash with eosinophilia 
and systemic symptoms (DRESS) or drug-induced hypersensitivity syndrome 
(DIHS), human herpes virus 6 (HHV-6) infection should be ruled out.
9. Complete the Skin AESI Worksheet for the trial site (Appendix 12).
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277-201-00001 Skin Adverse Event of Special Interest (AESI) Workup Instructions 
Version 2.0 dated 18 Aug 2017
10. Refer the subject to a local dermatologist assigned by the trial site for a 
consultation as soon as possible (Note that after 7 days without IMP, the subject 
may not continue in the trial regardless of the outcome of the investigation of the 
rash). 
a.
For rash that is classified as SEVERE (defined as the inability to perform 
normal daily activities) or meets the definition of an SAE: If the subject 
agrees, have the local dermatologist obtain a biopsy for histopathological 
examination by a dermatopathologist. Consider direct 
immunofluorescence evaluation, particularly if the eruption is 
characterized by vesicles, bullae, or pustules. 
b. Have the local dermatologist complete the Skin AESI Worksheet (see
Appendix 13) when the subject is evaluated. 
i. The local dermatologist will contact the trial Central Dermatologist 
for consultation (see Appendix 14)
11. Monitor the subject daily via telephone contact or in-clinic visits (per the 
investigator’s discretion) to evaluate if the event is improving, unchanging, or 
worsening. When the event resolves, record the last day as the end date of the 
AE.
12. Repeat steps 3-11 as required.
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277-201-00001 Skin Adverse Event of Special Interest (AESI) Worksheet for Trial Site
Version 2.0 dated 18 Aug 2017
Trial Protocol:  277-201-00001
Adverse Event # (in SureSource): 
Site No.
Investigator: 
Subject No.
Subject Initials:
Description of Rash: 
Location(s) of Rash: 
Locations of Adenopathy (if applicable):
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277-201-00001 Skin Adverse Event of Special Interest (AESI) Worksheet for Trial Site
Version 2.0 dated 18 Aug 2017
Trial Protocol:  277-201-00001
Adverse Event # (in SureSource): 
Site No.
Investigator: 
Subject No.
Subject Initials:
NOTE: Ensure rash location(s) is clearly specified and photographed.  If the body 
location is not obvious, label the photo or include a label with the body location in the 
photo, or take a “staging” shot of the body part and then a closer shot of the rash.  
Make sure all photos are in precise focus; some cameras will focus on items in the 
background behind the subject’s skin.
*If rash location is generalized, the torso, back, abdomen, and extremities 
should be photographed. 
*Do not photograph any personal identifiers or other parts of the body.
Were pictures taken?    ☐Yes    ☐No  If no, please explain why not: 
________________________________________________________________________
________________________________________________________________________
Note:  Attach copies of adverse events, demographics, concomitant medications 
(including herbal and dietary supplements), medical history, lab reports, and vital signs
source document records to this worksheet before forwarding to the dermatologists.
Please upload the completed Skin AESI Worksheets from the local and central 
dermatologists to the SureSource portal (ie, Appendix 13 and Appendix 14).
_______________________________________________             _____________________
Signature of Investigator
Date (dd/mmm/yyyy)
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277-201-00001 Skin Adverse Event of Special Interest (AESI) Worksheet for Trial Site
Version 2.0 dated 18 Aug 2017
Trial Protocol:  277-201-00001
Adverse Event # (in SureSource):
Site No.
Investigator: 
Subject No.
Subject Initials
Final review and disposition by the investigator (to be completed AFTER receipt of 
any pertinent laboratory tests or pathology results):
After review of the dermatologic consultation and subject history, does the 
investigator consider the rash to be IMP-related?
☐Yes 
☐No (if it is determined that the rash is not related to the IMP and further treatment with 
the IMP is in the subject’s best interest, the IMP may be restarted at the same dose 
provided no more than 7 days have elapsed since the IMP was stopped)
_______________________________
___________________
Signature of Investigator
Date (dd/mmm/yyyy)
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Appendix 13
OPC-64005 Skin AESI Worksheet for Local Dermatologist
277-201-00001 Skin Adverse Event of Special Interest (AESI) Worksheet for Local Dermatologist
Version 2.0 dated 18 Aug 2017
To be completed by the Local Dermatologist assigned by the trial site
Trial Protocol:  277-201-00001
Date of Consultation:
(dd/mmm/yyyy)
Subject No./ Subject Initials
Rash Description, select all that apply:
“X” all 
that apply
Details:
Papular
Macular
Pustular 
Vesicular 
Bullous 
Urticarial
Other _________________
Erythematous
Blanchable
Pigmented
Ecchymotic
Other _________________
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277-201-00001 Skin Adverse Event of Special Interest (AESI) Worksheet for Local Dermatologist
Version 2.0 dated 18 Aug 2017
Trial Protocol:  277-201-00001
Date of Consultation:
(dd/mmm/yyyy)
Subject No./ Subject Initials:
Mark location(s) of the rash, including any urticarial lesions or swelling/edema, on
the figures below. If the subject has any visible skin rash that predates the trial 
onset, be sure to identify such rash separately on the figures below.
Please note any of the following:
Oral mucosal involvement and lip involvement   ☐No   ☐  Yes – details:  
Conjunctival involvement   ☐No   ☐  Yes – details:  
Genital involvement   ☐No   ☐  Yes – details:  
Scalp involvement   ☐No   ☐  Yes – details:  
Palmar lesions    ☐No   ☐  Yes – details:  
Plantar lesions   ☐No   ☐  Yes – details:  
Targetoid lesions   ☐No   ☐  Yes – details:  
Urticarial lesions   ☐No   ☐  Yes – details:  
Swelling/edema   ☐No   ☐  Yes – details:  
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Version 4.0, 28 Aug 2017
277-201-00001 Skin Adverse Event of Special Interest (AESI) Worksheet for Local Dermatologist
Version 2.0 dated 18 Aug 2017
Trial Protocol:  277-201-00001
Date of Consultation:
(dd/mmm/yyyy)
Subject No./ Subject Initials:
Please take pictures of the rash per the standard photography procedures at your 
office. NOTE: Ensure rash location(s) is clearly photographed. If rash location is 
generalized, the torso, back, abdomen, and extremities should be photographed. *Do 
not photograph any personal identifiers.
Were pictures taken?    ☐Yes    ☐No  If No, please explain why not:
_________________________________________________________________
Please provide narrative description of rash, as follows: 

Occupation

Exposure to dyes or toxins

Prodromal symptoms

Recent contact with anyone else who had a rash

Changes in the environment: inhalants, foods, new clothing, new skin care 
products, new detergent

Itching, burning/stinging, tenderness, color (eg, pink, red, or brown), texture 
(raised or flat), pattern (small lesions, grouped large plaques), unusual 
characteristics (scaly, peeling, follicles), size (eg, pea-sized, dime-sized, 10 mm), 
starting location (eg, nails, feet/soles, hands/palms, scalp, mouth, 
genitalia, symmetric)

Did it move or spread? Time course? 

Any signs by physical examination or subject report of associated symptoms (eg, 
respiratory, fever, systemic symptoms)
Please insert the narrative below:
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Version 4.0, 28 Aug 2017
277-201-00001 Skin Adverse Event of Special Interest (AESI) Worksheet for Local Dermatologist
Version 2.0 dated 18 Aug 2017
Trial Protocol:  277-201-00001
Date of Consultation:
(dd/mmm/yyyy)
Subject No./ Subject Initials:
For skin eruptions that are classified as SEVERE (defined as the inability to perform 
normal daily activities) or SERIOUS (life threatening, causing hospitalization, requiring 
medical/surgical intervention, medically significant), a biopsy of a representative lesion 
is encouraged.  
Was a biopsy performed?    ☐Yes    ☐No
Please mark location of biopsy on body by placing ‘Bx’ on the map above. Please 
forward a copy of the pathology report from the biopsy to your trial contact when it 
becomes available.
Final causality assessment (choose one):
☐Definite drug eruption due to IMP
☐Probably drug eruption due to IMP (the etiology of the rash has a ≥50% chance of 
being related to the IMP)
☐Possible drug eruption due to IMP (the etiology of the rash has a < 50% chance of 
being related to the IMP)
☐Not related
☐Other Diagnosis (specify):  __________________________________________
Dermatologist Disposition (choose one): 
Is the rash considered to be IMP-related? 
☐Yes 
☐No (if it is determined that the rash is not related to the IMP and further treatment with 
the IMP is in the subject’s best interest, the IMP may be restarted at the same dose 
provided no more than 7 days have elapsed since the IMP was stopped)
___________________________________
_________________
Signature of Local Dermatologist
Date (dd/mmm/yyyy)
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277-201-00001 Skin Adverse Event of Special Interest (AESI) Worksheet for Local Dermatologist
Version 2.0 dated 18 Aug 2017
Post Subject-Assessment Instructions and Reminders for Local Dermatologist
1) As soon as possible but within 24 hours following your assessment of the subject, 
please contact the central dermatologist assigned to the trial to discuss your 
findings and review lab results (if applicable). 
Central Dermatologist Contact Info
TBD
2) If a biopsy sample was obtained, please ship the sample per standard procedures 
to the histopathology laboratory noted below:
Histopathology Laboratory Info
TBD
3) REMINDER: Please scan and email the above completed forms and any 
supporting documents to your contact at the trial site as soon as possible 
following the visit. If the subject is seen more than once, the forms above should 
be completed for each visit. Forward any laboratory tests or pathology results to 
your contact at the trial site, as soon as they become available.
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Appendix 14
OPC-64005 Skin AESI Worksheet for Central Dermatologist
277-201-00001 Skin Adverse Event of Special Interest (AESI) Worksheet for Central Dermatologist
Version 2.0 dated 18 Aug 2017
To be completed by the Central Dermatologist 
Trial Protocol:  277-201-00001
Date:
(dd/mmm/yyyy)
Subject No./ Subject Initials
Narrative / Comments (including pathology results, if applicable):
Final causality assessment (choose one):
☐Definite drug eruption due to IMP
☐Probably drug eruption due to IMP (the etiology of the rash has a ≥50% chance of 
being related to the IMP)
☐Possible drug eruption due to IMP (the etiology of the rash has a < 50% chance of 
being related to the IMP)
☐Not related
☐Other Diagnosis (specify):  ______________________________________________
Reminder: Please scan and email completed form(s) to the Local Dermatologist and trial 
site contacts.
_________________________________________
_______________________
Signature of Central Dermatologist
Date (dd/mmm/yyyy)
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Appendix 15
Protocol Amendment(s)/Administrative Change(s)
Administrative Change Number:               1
Issue Date:                                                     25 Apr 2017
PURPOSE:
The purpose of this administrative change is to update the IND number for the protocol and the 
approximate number of trial sites.
BACKGROUND:
Due to the change in indication, a new IND is being submitted for this compound and a revised 
IND number has been provided.
Also, based on further analysis of enrollment rates in similar trials, it was determined that 
additional sites are required in order to meet enrollment objectives and timelines. 
GENERAL CHANGES:
Description of Change
Rationale for Change
Section Affected by Change
Changed IND number
Change in indication
Cover page; and Protocol 
Synopsis (page 2)
Updated number of US trial 
sites
Increased number from 21 to 
approximately 40 US trial sites
Protocol Synopsis (page 3) 
ADDITIONAL RISK TO THE SUBJECT:
There is no additional risk to the subjects.
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Amendment Number:
1
Issue Date:
29 Jun 2017 
PURPOSE:
The purpose of this protocol amendment is to:

Replace 1 of the scales used for diagnosis and 2 of the scales used for efficacy 
assessments

Modify the investigator-administered CAARS-O:SV so that only the 
18 DSM-relevant items are administered to the subject

Modify the CAARS-S:SV so that only the 18 items that comprise the ADHD 
Symptoms Total Score will be administered to the subjects

Add a ± 1-day window around the Day 7 through Day 56 trial visits to allow for 
flexibility around the trial visits

Add IMP administration details to the schedule of assessments for clarity

Clarify that the first follow-up takes place 3 days after the last dose for subjects who 
complete the trial and for subjects who terminate early from the trial

Add how to handle missed trial visits/doses and clarify contact with the medical 
monitor in such cases

Add that subjects are permitted to titrate back up one time to allow subjects to return 
to their maintenance dose

Modify the steps required for subjects with a rash and add that any instances of rash 
must be reported to the CRO medical monitor

Clarify and modify the inclusion and exclusion criteria

Change the trial duration from 11 to 9 months based on when the first subject will be 
enrolled to when the last subject will complete the trial

Add details around the timing of PK blood sampling for clarity

Add a pregnancy test at Day 28 to assess pregnancy at the midpoint of the trial

Clarify that any rash, regardless of severity or seriousness, will lead to 
discontinuation of IMP

Clarify that normal consumption of caffeine is permitted

Clarify adverse events of special interest (ie, newly acquired skin eruptions that are 
nontraumatic)

Clarify IMP storage details

Clarify safety analyses for standard safety variables and the C-SSRS

Add that CYP2D6 substrates with a narrow therapeutic index are prohibited, as 
requested by the FDA

Reduce the number of trial sites from 40 to approximately 25
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
Add the IRB, CRO, and central laboratory information to Appendix 2

Add all of the efficacy scales as appendices

Add appendices for follow-up activities if rash is detected to clarify the process to be 
followed for rash evaluation
BACKGROUND:
The rationale for the changes in this protocol amendment is as follows:

The ADHD RS-5 was replaced with the AISRS as the AISRS already has language 
built in for adults and has been validated in multiple adult ADHD treatment trials.

The CAADID was replaced with the ACDS (version 1.2) as the ACDS v1.2 is 
specifically designed to generate DSM-5 ADHD diagnoses and may be faster for the 
clinic staff to administer.

The POMS 2-A was replaced with the POMS-Brief as the POMS-Brief contains 
items sufficient to capture symptoms often viewed as residual after ADHD treatment.  
Additionally, the POMS 2-A contained an adolescent scale, which is not relevant to 
this trial.

The text regarding rash was modified to be consistent with the informed consent form
and to add clarity around the process of rash review.

Inclusion criterion #4 was modified to replace the CAADID with the ACDS v1.2 and 
was revised for clarity.

Inclusion criterion #5 was modified to replace the ADHD RS-5 with the AISRS and 
to clarify the ADHD treatment.

Inclusion criterion #7 was revised for clarification only.

Inclusion criterion #8 was modified to replace the ADHD RS-5 with the AISRS.

Exclusion criterion #3 was modified to add that subjects with suboptimal tolerability 
to atomoxetine are also excluded and to remove “after 18 years of age”.

Exclusion criterion #6 was modified to remove intolerability (lifetime treatment 
history) to stimulant or nonstimulant ADHD medications.

Exclusion criteria #8 was modified to remove Axis I/II terminology and specify that 
current or lifetime bipolar disorder is excluded.

Exclusion criterion #9 was modified to add additional DSM-5 diagnoses for 
clarification to the investigator.

Exclusion criteria #10, #11, #12, and #27 were revised for clarification only.

Exclusion criterion #14 was modified to include dermatological disorders and active 
hepatitis B or C.

Exclusion criterion #20 was modified to be consistent with DSM-5 terminology and 
requirements for diagnosis.
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
Exclusion criterion #21 was modified to allow retesting or rescreening based on the 
opinion of the investigator.
MODIFICATIONS TO PROTOCOL:
Sectional Revisions:
Location
Old Text
Updated Text
Synopsis, Trial 
Design
The trial includes a Screening Period 
(≤28 days), a 4-day titration period, a 
52-day treatment period, a follow-up 
telephone contact to occur at Day 59 or 
discontinuation (± 1 day), and a 
follow-up telephone contact to occur 
30 (+ 2) days after the last treatment.
The trial includes a Screening Period 
(≤28 days), a 4-day titration period, a 
52-day treatment period, a follow-up 
telephone contact to occur at 3 (± 1) days 
after the last dose, and a follow-up 
telephone contact to occur 30 (+ 2) days 
after the last dose.
Synopsis, Subject 
Population
Approximately 201 adult male and 
female subjects with ADHD will be 
randomized (1:1:1) to be administered 
OPC-64005, atomoxetine, or placebo 
(50 completers per arm).
Approximately 201 adult male and female 
subjects with ADHD will be randomized 
(1:1:1) to be administered OPC-64005, 
atomoxetine, or placebo.
Synopsis, Inclusion 
Criteria

Subjects with a primary Diagnostic 
and Statistical Manual of Mental 
Disorders, Fifth Edition (DSM-5) 
diagnosis of ADHD (including 
inattentive, hyperactive, and 
combined subtypes) as confirmed 
by the Conners’ Adult ADHD 
Diagnostic Interview for 
Diagnostic and Statistical Manual 
of Mental Disorders, Fourth 
Edition (DSM-IV) (CAADID) 
(The CAADID will be adapted to 
be consistent with the DSM-5).  
Subjects may have received prior 
treatment for adult ADHD or may 
be currently receiving treatment for 
adult ADHD at screening.

Subjects with a primary Diagnostic 
and Statistical Manual of Mental 
Disorders, Fifth Edition (DSM-5) 
diagnosis of ADHD (including 
predominantly inattentive
presentation, hyperactive
presentation, and combined 
presentations) as confirmed by the 
Adult ADHD Clinical Diagnostic 
Scale, version 1.2 (ACDS v1.2).  
Subjects must have received prior 
successful treatment 
(pharmacotherapy) for adult ADHD 
based on medical records and the 
principal investigator’s judgment.  
Subjects may be currently receiving 
treatment for adult ADHD at 
screening, but it is not necessary 
that they are currently receiving 
treatment.  The rationale to 
discontinue current ADHD 
treatment must include either or 
both suboptimal efficacy response 
and/or treatment limiting 
safety/tolerability.
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Location
Old Text
Updated Text
Synopsis, Inclusion 
Criteria

Subjects who are not currently 
receiving treatment for ADHD who 
have an ADHD Rating Scale based 
on DSM-5 criteria (ADHD RS-5) 
with Adult Prompts score of ≥ 26 
and subjects who are receiving any 
treatment for ADHD at screening 
who have an ADHD RS-5 with 
Adult Prompts score of ≥ 22.

Subjects who are not currently 
receiving an approved 
pharmacological treatment for 
ADHD who have an Adult ADHD 
Investigator Symptom Rating Scale 
(AISRS) with Adult Prompts score of 
≥ 26 and subjects who are receiving 
any pharmacological treatment for 
ADHD at screening who have an 
AISRS with Adult Prompts score of 
≥ 22.
Synopsis, Trial 
Site(s)
Approximately 40 trial sites in the 
United States
Approximately 25 trial sites in the United 
States
Synopsis, 
Investigational 
Medicinal 
Product(s), Dose, 
Dosage regimen, 
Treatment period, 
Formulation, Mode 
of Administration:
During the Titration Period (Days 1 -
4), subjects randomized to the 
OPC-64005 arm will receive 20 mg 
OPC-64005 daily (ie, two 10 mg 
OPC-64005 tablets); subjects 
randomized to the atomoxetine arm 
will receive 40 mg of atomoxetine 
daily, and subjects randomized to the 
placebo arm will receive daily placebo 
only.
During the Titration Period (Days 1 - 4), 
subjects randomized to the OPC-64005 
arm will receive 20 mg OPC-64005 (ie, 
two 10 mg OPC-64005 tablets) and 
atomoxetine placebo daily, subjects 
randomized to the atomoxetine arm will 
receive 40 mg of atomoxetine and 
OPC-64005 placebo daily, and subjects 
randomized to the placebo arm will 
receive both OPC-64005 placebo and 
atomoxetine placebo daily.
Synopsis, 
Investigational 
Medicinal 
Product(s), Dose, 
Dosage regimen, 
Treatment period, 
Formulation, Mode 
of Administration:
During the Treatment Period (Days 5 -
56), subjects randomized to the 
OPC-64005 arm will receive 30 mg 
OPC-64005 daily; subjects randomized 
to the atomoxetine arm will receive 
80 mg of atomoxetine daily, and 
subjects randomized to the placebo arm 
will receive daily placebo only.  If a 
subject is not able to tolerate the 30-mg 
dose of OPC-64005, the dose may be 
reduced to 20 mg for the duration of the 
Treatment Period.  If a subject is not 
able to tolerate the 80-mg dose of 
atomoxetine, the dose may be reduced 
to 40 mg of atomoxetine for the 
duration of the Treatment Period.
During the Treatment Period (Days 5 -
56), subjects randomized to the 
OPC-64005 arm will receive 30 mg 
OPC-64005 and atomoxetine placebo
daily, subjects randomized to the 
atomoxetine arm will receive 80 mg of 
atomoxetine and OPC-64005 placebo
daily, and subjects randomized to the 
placebo arm will receive both 
OPC-64005 placebo and atomoxetine 
placebo daily.  If a subject is not able to 
tolerate the 30-mg dose of OPC-64005, 
the dose may be reduced to 20 mg for the 
duration of the Treatment Period.  If a 
subject is not able to tolerate the 80-mg 
dose of atomoxetine, the dose may be 
reduced to 40 mg of atomoxetine for the 
duration of the Treatment Period.  
Subjects are permitted to have one dose 
reduction and one titration back up to 
their previous dose (ie, 30 mg for 
OPC-64005 and 80 mg for atomoxetine) 
during the trial.
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Location
Old Text
Updated Text
Synopsis, Trial
Assessments
Efficacy:  Conners' Adult ADHD 
Rating Scales–Observer: Screening 
Version (CAARS-O:SV), Conners' 
Adult ADHD Rating Scales–Self-
Report: Screening Version 
(CAARS-S:SV), ADHD RS-5 with 
Adult Prompts, CGI-S, Global Clinical 
Impression-Improvement (CGI-I), 
Adult ADHD Quality of Life Scale 
(AAQoL), and Profile of Mood States 
2nd Edition™ (POMS 2-A).
Efficacy:  18-item, investigator-
administered Conners' Adult ADHD 
Rating Scales–Observer: Screening 
Version (CAARS-O:SV), 18-item 
Conners' Adult ADHD Rating Scales–
Self-Report: Screening Version 
(CAARS-S:SV), AISRS with Adult 
Prompts, CGI-S, Global Clinical 
Impression-Improvement (CGI-I), Adult 
ADHD Quality of Life Scale (AAQoL), 
and Profile of Mood States-Brief Form™ 
(POMS).
Synopsis, Trial 
Assessments
Screening/Other:  Demographic 
information; medical, medication, and 
psychiatric history; identification of 
comorbidities; HIV, hepatitis B surface 
antigen (HBsAg), and anti hepatitis C 
virus (HCV) status; urine alcohol and 
drug screen; urine pregnancy test.
Screening/Other:  Demographic 
information; medical, medication, and 
psychiatric history; identification of 
comorbidities (in part, using the Mini 
International Neuropsychiatric 
Interview); HIV, hepatitis B surface 
antigen (HBsAg), and anti hepatitis C 
virus (HCV) status; urine alcohol and 
drug screen; urine pregnancy test.
Synopsis, Criteria 
for Evaluation
Primary Endpoint:  The primary 
efficacy endpoint is the change from 
baseline to the Day 56 Visit in the 
CAARS-O:SV 18-item ADHD 
symptoms total score in the 
OPC-64005 group relative to the 
atomoxetine group. 
Primary Endpoint:  The primary 
efficacy endpoint is the change from 
baseline to the Day 56 (± 1 day) Visit in 
the investigator-administered
CAARS-O:SV 18-item ADHD symptoms 
total score in the OPC-64005 group 
relative to the atomoxetine group. 
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Location
Old Text
Updated Text
Synopsis, Criteria 
for Evaluation
Other Endpoint(s):   

Change from baseline to each 
weekly visit (Days 7, 14, 21, 28, 
42, and 56/early termination [ET]) 
in the CAARS-O:SV score in the 
OPC-64005 group relative to the 
atomoxetine and placebo groups

Change from baseline to the Day 
28 and Day 56 Visits for the 
ADHD RS-5 with Adult Prompts 
score in the OPC-64005 group 
relative to the atomoxetine and 
placebo groups

Change from baseline to each 
weekly visit (Days 7, 14, 21, 28, 
42, and 56/ET) in the CGI-S score 
in the OPC-64005 group relative to 
the atomoxetine and placebo 
groups

CGI-I score at each weekly visit 
(Days 7, 14, 21, 28, 42, and 56/ET) 
in the OPC-64005 group relative to 
the atomoxetine and placebo 
groups

Change from baseline to each 
weekly visit (Days 7, 14, 21, 28, 
42, and 56/ET) in the CAARS–
S:SV score in the OPC-64005 
group relative to the atomoxetine 
and placebo groups

Change from baseline to the 
Day 28 and Day 56 Visits in the 
AAQoL score in the OPC-64005, 
atomoxetine, and placebo groups

OPC-64005 potential for abuse 
liability and dependence as 
assessed by the DEQ at baseline 
and each weekly visit (Days 7, 14, 
21, 28, 42, and 56/ET).
Other Endpoint(s):   

Change from baseline to each 
scheduled visit (Days 7, 14, 21, 28, 
42, and 56/early termination [ET]; all 
visits have a ± 1-day window) in the 
18-item, investigator-administered
CAARS-O:SV score in the 
OPC-64005 group relative to the 
atomoxetine and placebo groups

Change from baseline to the Day 28 
(± 1 day) and Day 56 (± 1 day)
Visits for the AISRS with Adult 
Prompts score in the OPC-64005 
group relative to the atomoxetine and 
placebo groups

Change from baseline to each 
scheduled visit (Days 7, 14, 21, 28, 
42, and 56/ET; all visits have a 
± 1-day window) in the CGI-S score 
in the OPC-64005 group relative to 
the atomoxetine and placebo groups

CGI-I score at each scheduled visit 
(Days 7, 14, 21, 28, 42, and 56/ET;
all visits have a ± 1-day window) in 
the OPC-64005 group relative to the 
atomoxetine and placebo groups

Change from baseline to each 
scheduled visit (Days 7, 14, 21, 28, 
42, and 56/ET; all visits have a 
± 1-day window) in the 18-item 
CAARS–S:SV score in the 
OPC-64005 group relative to the 
atomoxetine and placebo groups

Change from baseline to the Day 28 
(± 1 day) and Day 56 (± 1 day)
Visits in the AAQoL score in the 
OPC-64005, atomoxetine, and 
placebo groups

OPC-64005 potential for abuse 
liability and dependence as assessed 
by the DEQ at baseline and each 
scheduled visit (Days 7, 14, 21, 28, 
42, and 56/ET; all visits have a 
± 1-day window).
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Version 4.0, 28 Aug 2017
Location
Old Text
Updated Text
Synopsis, 
Statistical Methods
Primary:  The primary efficacy 
endpoint is the change from baseline to 
the Day 56 Visit in the CAARS-O:SV 
18-item ADHD symptoms total score 
in the OPC-64005 group relative to the 
atomoxetine group.  Bayesian posterior 
probability of true baseline corrected 
difference at Day 56 between treatment 
arms (OPC-64005 and atomoxetine) 
being larger than 4 points on 
CAARS-O:SV given estimates of 
means and SD in the treatment arms 
will be calculated. ...
The change from baseline in 
CAARS-O:SV will be analyzed using a 
mixed-effect model repeated measures 
(MMRM) methodology with the 
unstructured variance covariance 
matrix.  The model will include fixed 
class-effect terms for treatment, trial 
site, visit week, an interaction term of 
treatment by visit week, and baseline 
CAARS-O:SV as covariate. ...
Primary:  The primary efficacy endpoint 
is the change from baseline to the Day 56 
(± 1 day) Visit in the investigator-
administered CAARS-O:SV 18-item 
ADHD symptoms total score in the 
OPC-64005 group relative to the 
atomoxetine group.  Bayesian posterior 
probability of true baseline corrected 
difference at Day 56 (± 1 day) between 
treatment arms (OPC-64005 and 
atomoxetine) being larger than 4 points on 
the 18-item, investigator-administered
CAARS-O:SV given estimates of means 
and SD in the treatment arms will be 
calculated. ...
The change from baseline in the 18-item, 
investigator-administered
CAARS-O:SV will be analyzed using a 
mixed-effect model repeated measures 
(MMRM) methodology with the 
unstructured variance covariance matrix.  
The model will include fixed class-effect 
terms for treatment, trial site, visit week, 
an interaction term of treatment by visit 
week, and baseline 18-item, investigator-
administered CAARS-O:SV as 
covariate. ...
Synopsis, Trial 
Duration
The duration of this trial from first 
subject enrolled to last subject 
completed is estimated to be 
approximately 11 months.   The 
duration of the trial for each subject is 
estimated to be up to 16 weeks 
(Screening Period of up to 28 days, 
56 days of dosing, a safety follow-up 
phone call at Day 59 or discontinuation 
(± 1 day), and a 30 (+ 2)-day safety 
follow-up phone call).
The duration of this trial from first subject 
enrolled to last subject completed is 
estimated to be approximately 9 months.  
The duration of the trial for each subject 
is estimated to be up to 16 weeks 
(Screening Period of up to 28 days, 
56 days of dosing, a 3 [± 1]-day safety 
follow-up phone call, and a 30 [+ 2]-day 
safety follow-up phone call).
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Section 1.1.1, 
Efficacy 
Pharmacology
OPC-64005 also shows selective 
affinities for human 5-HT, NE, and DA 
transporters (inhibition constant values 
= 1.62, 6.57, and 123.06 nmol/L, 
respectively).2,3  In addition, 
OPC-64005 has the potential to 
modulate monoamine systems.  An in 
vivo microdialysis study demonstrated 
that extracellular 5-HT, NE, and DA 
levels in the rat medial prefrontal 
cortex were dose dependent and 
simultaneously increased by 
OPC-64005 from lower doses than 
paroxetine, sertraline, duloxetine, and
bupropion.4,5  In addition, OPC-64005, 
orally administered at doses of 
0.2 mg/kg and greater, produced 
statistically significant increases in 
extracellular 5-HT, NE, and DA (area 
under the curve as an integrated 
measurement of percent of basal values 
during 0 to 360 minutes after 
administration) to 206.7%, 176.5%, and 
164.8%, respectively, of the vehicle 
group.  In the medial prefrontal cortex, 
where there is a low density of 
dopamine transporter (DAT), 
extracellular DA levels are thought to 
be regulated by norepinephrine 
transporter (NET).6  The effects of 
DAT inhibition on the extracellular DA 
level were therefore evaluated in the 
striatum, where there is a high density 
of DAT.  OPC-64005 significantly 
increased extracellular DA levels in the 
rat striatum at 2.5 mg/kg and greater.7
OPC-64005 shows selective affinities for 
human 5-HT, NE, and DA transporters 
(inhibition constant values = 1.62, 6.57, 
and 123.06 nmol/L, respectively).2,3  In 
addition, OPC-64005 has demonstrated
the potential to modulate monoamine 
systems.  In vivo microdialysis 
demonstrated that extracellular 5-HT, NE, 
and DA levels in the rat medial prefrontal 
cortex were dose dependent and 
simultaneously increased by OPC-64005 
with greater potency relative to
paroxetine, sertraline, duloxetine, and 
bupropion.4,5  In addition, OPC-64005, 
orally administered at doses of 0.2 mg/kg 
and greater, produced statistically 
significant increases in extracellular 
5-HT, NE, and DA (area under the curve 
as an integrated measurement of percent 
of basal values during 0 to 360 minutes 
after administration) to 206.7%, 176.5%, 
and 164.8%, respectively, compared to
the vehicle group.  In the medial 
prefrontal cortex, where there is a low 
density of dopamine transporter (DAT), 
extracellular DA levels are thought to be 
regulated by norepinephrine transporter 
(NET).6  The effects of DAT inhibition 
on the extracellular DA level were 
therefore evaluated in the striatum, where 
there is a high density of DAT.  
OPC-64005 significantly increased 
extracellular DA levels in the rat striatum 
at 2.5 mg/kg and higher doses.7
Section 1.1.1, 
Efficacy 
Pharmacology
From the results of these nonclinical 
pharmacology studies, OPC-64005 may 
have the potential to improve 
depression related to monoamine 
dysfunction.
From the results of these nonclinical 
pharmacology studies, OPC-64005 may 
have the potential to improve depressive
symptoms related to monoamine 
imbalance.
Section 1.1.4.2, 
Repeated-dose 
Toxicity
Limb tremor in both sexes and 
decreased body weight or suppressed 
body weight gain in females were 
observed at 10 mg/kg/day.
Limb tremor (males and females),
decreased body weight, or suppressed 
body weight gain in females were 
observed at 10 mg/kg/day.
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Section 1.2.2, 
Phase 1 
Single-Dose 
Trial in Healthy 
Adult Male 
Subjects (Japan,
Trial 277-10-001)
This trial was designed to administer a 
single dose of OPC-64005 at doses of 
1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, 
15 mg, 20 mg, 25 mg, 30 mg, 40 mg, 
50 mg, 60 mg, 70 mg, or placebo to 
healthy adult males, and to randomize 
8 subjects each (6 subjects for 
OPC-64005 and 2 subject for placebo) 
and 9 subjects each (6 subjects for 
OPC-64005 and 3 subjects for placebo) 
to the 1 to 20 mg groups and the 
25 to 70 mg groups, respectively.  
However, only up to the 60 mg dose 
was used.
This trial was designed to assess the 
pharmacokinetics (PK), safety, and 
tolerability of a single dose of 
OPC-64005 at doses of 1 mg, 2 mg, 4 mg, 
6 mg, 8 mg, 10 mg, 15 mg, 20 mg, 25 mg, 
30 mg, 40 mg, 50 mg, 60 mg, 70 mg, or 
placebo to healthy adult males, and to 
randomize 8 subjects each (6 subjects for 
OPC-64005 and 2 subject for placebo) 
and 9 subjects each (6 subjects for 
OPC-64005 and 3 subjects for placebo) to 
the 1 to 20 mg groups and the 25 to 70 mg 
groups, respectively.  However, 60 mg 
was the highest dose assessed in this 
trial.
Section 1.2.2, 
Phase 1 
Single-Dose 
Trial in Healthy 
Adult Male 
Subjects (Japan, 
Trial 277-10-001)
Therefore, another cohort for 60 mg 
OPC-64005 was established again for 
further assessment to determine the 
maximum tolerated dose (MTD).  As a 
result, the MTD was considered hardly 
possible to determine in this trial for 
the following reasons: The dosage in 
this cohort did not violate the MTD 
defined in the protocol; 
supraventricular tachycardia observed 
in this subject was difficult to assess; 
and the investigator and subinvestigator 
did not change the assessment of 
‘nonserious’ for supraventricular 
tachycardia even after the Sponsor had 
assessed the event as serious.  Although 
the result suggested the possibility to 
proceed to the next dose step of 70 mg, 
the dose escalation in this trial was 
terminated at a dose of 60 mg.
The MTD was not determined in this 
trial for the following reasons:  this cohort 
did not meet the definition of MTD as 
defined in the protocol; supraventricular 
tachycardia observed in this subject was 
difficult to assess; and the investigator 
and subinvestigator did not change the 
assessment of ‘nonserious’ for 
supraventricular tachycardia even after 
the Sponsor had assessed the event as 
‘serious’.  Although the result suggested 
the possibility to proceed to the next dose 
step of 70 mg, dose escalation in this trial 
was terminated at a dose of 60 mg.
Section 1.2.3, 
Phase 1 
Multiple-Dose 
Trial to Evaluate 
Pharmacokinetics, 
Safety, and 
Pharmacodynamics 
in Healthy Adult 
Male and Female 
Subjects 
(United States, 
277-10-206)
The 30-mg dose of OPC-64005 
demonstrated significant effects in 
cerebrospinal fluid (CSF) reuptake in 
NE and 5-HT, but no statistically 
significant effect on DA.  Plasma 
monoamine changes for OPC-64005 in 
the NE and 5-HT systems were 
consistent with those found in CSF.  
Bupropion, which was believed to be a 
comparator for DA activity, showed no 
statistically significant activity on any 
of the monoamine transmitters or their 
metabolites in CSF.
Assays to detect the presence of 
neurotransmitter metabolites in 
cerebrospinal fluid (CSF) suggested that
the 30 mg dose of OPC-64005 had a
significant impact on reuptake inhibition 
for NE and 5-HT.  However, there was 
no clear evidence of DA related 
metabolites in CSF in either OPC-64005 
samples or in those collected from 
subjects who received bupropion 
(positive control).
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Section 1.2.4, 
Phase 1, Multiple 
Ascending Dose 
Trial in Healthy 
Adult Male 
Subjects (Japan, 
Trial 277-12-001)
After the completion of Cohort 2 
(30 mg), it was decided not to proceed 
with Cohort 3 (60 mg), because 
sufficient data for pharmacokinetic 
(PK) and safety were obtained from 
Cohorts 1 and 2.  
After the completion of Cohort 2 (30 mg), 
the decision was made not to proceed 
with Cohort 3 (60 mg) because sufficient 
data for PK and safety were obtained 
from Cohorts 1 and 2.  
Section 1.2.4, 
Phase 1, Multiple 
Ascending Dose 
Trial in Healthy 
Adult Male 
Subjects (Japan, 
Trial 277-12-001)
The TEAEs observed during the trial 
were nausea, somnolence, and rash 
pruritic and all were reported in the 
OPC-64005 group:  rash pruritic, 
1 subject (1/6) in the 20 mg 
OPC-64005 group:  nausea, 2 subjects 
(2/6) in the 30 mg OPC-64005 group:  
somnolence, 1 subject (1/6) in the 
30 mg OPC-64005 group.  
The TEAEs observed during the trial were 
nausea, somnolence, and pruritic rash
and all were reported in the OPC-64005 
group:  pruritic rash, 1 subject (1/6) in 
the 20 mg OPC-64005 group:  nausea, 
2 subjects (2/6) in the 30 mg OPC-64005 
group:  somnolence, 1 subject (1/6) in the 
30 mg OPC-64005 group.
Section 1.2.5, 
Phase 1 Trial to 
Evaluate Serotonin, 
Norepinephrine, 
and Dopamine 
Transporter 
Occupancy in 
Healthy Adult Male 
Subjects (United 
States, 277-10-205)
The times of postdose scans were to be 
at approximately 3 hours and at 16 to 
24 hours postdose, as feasible.  
The times of postdose scans occurred at 
approximately 3 hours and at 16 to 
24 hours postdose, as feasible.  
Section 1.3, Known 
and Potential Risks 
and Benefits
The subjects will not derive any benefit 
from this trial.  
The subjects may or may not derive any 
benefit from this trial.  
Section 3.1, 
Type/Design of 
Trial
The trial includes a Screening Period 
(≤28 days), a 4-day titration period, a 
52-day treatment period, a follow-up 
telephone contact to occur at Day 59 or 
discontinuation (± 1 day), and a 
follow-up telephone contact to occur 30 
(+ 2) days after the last treatment.  
The trial includes a Screening Period 
(≤28 days), a 4-day titration period, a 
52-day treatment period, a follow-up 
telephone contact to occur 3 (± 1) days 
after the last dose, and a follow-up 
telephone contact to occur 30 (+ 2) days 
after the last dose.  
Section 3.1,
Type/Design of 
Trial
During the Treatment Period (Days 5 -
56), subjects who were randomized to 
the OPC-64005 arm for Titration will 
continue in the OPC-64005 arm for 
Treatment. ... During the 8-week 
Titration/Treatment Period, subjects 
will have visits to the clinical site.  
Critical and non-standard trial 
assessments to be performed during the 
trial are listed in Table 3.7-1.
During the Treatment Period (Days 5 -
56), subjects who are randomized to the 
OPC-64005 arm for Titration will 
continue in the OPC-64005 arm for 
Treatment. ... During the 8-week 
Titration/Treatment Period, subjects will 
have weekly or biweekly visits to the 
clinical site.  Assessments to be 
performed during the trial are listed in 
Table 3.7-1.
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Section 3.1, 
Type/Design of 
Trial
If any subject discontinues the trial 
early, every effort should be made to 
complete the Day 56/early termination 
(ET) evaluations.  All subjects 
(completers and early withdrawals) will 
be contacted to monitor for safety 
events via telephone or clinic visit at 
Day 59 or discontinuation (± 1 day) and 
30 (+ 2) days after the last dose of 
OPC-64005, atomoxetine, or placebo.
The total duration of this trial for each 
subject is estimated to be up to 16 
weeks (Screening Period of up to 
28 days, 56 days of dosing, a safety 
follow-up phone call at Day 59 or 
discontinuation (± 1 day),  and a 30 
(+ 2)-day safety follow-up phone call).
If any subject discontinues the trial early, 
every effort should be made to complete 
the Day 56 (± 1 day)/early termination 
(ET) evaluations.  All subjects 
(completers and early withdrawals) will 
be contacted to monitor for safety events 
via telephone at 3 (± 1) days and 30 (+ 2) 
days after the last dose of OPC-64005, 
atomoxetine, or placebo.
The total duration of this trial for each 
subject is estimated to be up to 16 weeks 
(Screening Period of up to 28 days, 
56 days of dosing, a 3 [± 1]-day safety 
follow-up phone call, and a 30 [+ 2]-day 
safety follow-up phone call).
Figure 3.1-1, Trial 
Design Schematic
Changes to Figure 3.1-1 are summarized on the next page and are indicated by bold, 
underlined text.
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Section 3.2, Trial 
Treatments
During the Treatment Period, subjects 
in the OPC-64005 group will receive 
daily 30-mg oral doses of OPC-64005.  
During the Treatment Period, if a 
subject is not able to tolerate the 30-mg 
dose of OPC-64005, the dose may be 
reduced to 20 mg for the duration of the 
Treatment Period.  Subjects in the 
atomoxetine group will receive daily 
80-mg oral doses of atomoxetine.  
During the Treatment Period, if a 
subject is not able to tolerate the 80-mg 
dose of atomoxetine, the dose may be 
reduced to 40 mg of atomoxetine for 
the duration of the Treatment Period. 
Subjects in the placebo group will 
receive daily oral doses of both 
OPC-64005 and atomoxetine placebo.
All tablets/capsules are to be taken 
together orally once daily and can be 
taken without regard to meals.  Every 
effort should be made to take the IMP 
at the same time every day.
During the Treatment Period, subjects in 
the OPC-64005 group will receive daily 
30-mg oral doses of OPC-64005 and 
atomoxetine placebo.  During the 
Treatment Period, if a subject is not able 
to tolerate the 30-mg dose of OPC-64005, 
the dose may be reduced to 20 mg for the 
duration of the Treatment Period.  
Subjects in the atomoxetine group will 
receive daily 80-mg oral doses of 
atomoxetine and OPC-64005 placebo.  
During the Treatment Period, if a subject 
is not able to tolerate the 80-mg dose of 
atomoxetine, the dose may be reduced to 
40 mg of atomoxetine for the duration of 
the Treatment Period.  Subjects are 
permitted to have one dose reduction 
and one titration back up to their 
previous dose (ie, 30 mg for OPC-64005 
and 80 mg for atomoxetine) during the 
trial.  Subjects in the placebo group will 
receive daily oral doses of both 
OPC-64005 placebo and atomoxetine 
placebo.
All tablets/capsules are to be taken 
together orally once daily and can be 
taken without regard to meals.  Every 
effort should be made to take the IMP at 
the same time every morning, every day.
Table 3.2-1, Dosing 
Schedule
Time
8:00am
Time
8:00 am
(AM dosing)
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Table 3.2-1, Dosing 
Schedule
aBlood samples for PK analyses will be 
collected predose and at 1 and 3 hours 
postdose at the Baseline (Day 1) Visit, 
predose and at 2 hours postdose at the 
Day 7 Visit, predose and at 3 hours 
postdose at the Day 14 Visit, and 
predose at the Day 21 Visit.
bMay be reduced to 20 mg if 40 mg 
dose is not tolerable.
cMay be reduced to 40 mg if 80 mg 
dose is not tolerable. 
aBlood samples for PK analyses will be 
collected predose and at 1 and 3 hours 
postdose at the Baseline (Day 1) Visit, 
predose and at 2 hours postdose at the 
Day 7 (± 1 day) Visit, predose and at 
3 hours postdose at the Day 14 (± 1 day)
Visit, and predose at the Day 21 (± 1 day)
Visit.
bMay be reduced to 20 mg if the 30 mg 
dose is not tolerable.  Subjects are 
permitted to have one dose reduction 
and one titration back up to their 
previous dose (ie, 30 mg for 
OPC-64005) during the trial.
cMay be reduced to 40 mg if the 80 mg 
dose is not tolerable.  Subjects are 
permitted to have one dose reduction 
and one titration back up to their 
previous dose (ie, 80 mg for 
atomoxetine) during the trial.
Section 3.3.1, 
Number of Subjects 
and Description of 
Population
Approximately 252 adult 
(18 - 55 years) subjects with a 
diagnosis of ADHD will be screened to 
randomize approximately 201 subjects 
to have approximately 150 completers 
(50 completers per arm). 
Approximately 252 adult (18 - 55 years) 
subjects with a diagnosis of ADHD will 
be screened to randomize approximately 
201 subjects to yield approximately 
150 completers.
Section 3.3.1, 
Number of Subjects 
and Description of 
Population
Subjects must meet the Diagnostic and 
Statistical Manual of Mental Disorders, 
Fifth Edition (DSM-5) criteria for 
ADHD (any type) as confirmed by the 
Conners’ Adult ADHD Diagnostic 
Interview for Diagnostic and Statistical 
Manual of Mental Disorders, Fourth 
Edition (DSM-IV) (CAADID) (The 
CAADID will be adapted to be 
consistent with the DSM-5) to be 
considered for enrollment.49  
Subjects must meet the Diagnostic and 
Statistical Manual of Mental Disorders, 
Fifth Edition (DSM-5) criteria for ADHD 
(any presentation) as confirmed by the 
Adult ADHD Clinical Diagnostic Scale, 
version 1.2 (ACDS v1.2).49
Section 3.3.1, 
Number of Subjects 
and Description of 
Population
Subjects identified with bipolar 
disorder, schizophrenia, or other 
psychotic disorder or current Axis II 
personality disorder will not be eligible 
for enrollment.  Subjects must have a 
history of successful treatment with 
stimulants or nonstimulant ADHD 
medication.  
Subjects identified with a current or 
lifetime history of bipolar disorder, 
schizophrenia, other psychotic disorder, 
or personality disorder will not be eligible 
for enrollment.  Subjects must have a 
history of adequate symptom reduction 
with stimulants or nonstimulant ADHD 
medication.  
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Section 3.3.1, 
Number of Subjects 
and Description of 
Population
At screening, subjects not currently 
receiving treatment for ADHD must 
have an ADHD Rating Scale based on 
DSM-5 criteria (ADHD RS-5) with 
Adult Prompts score of ≥ 26.  Subjects 
receiving any treatment for ADHD at 
screening must have an ADHD RS-5 
with Adult Prompts score of ≥ 22 and 
will wash out from their current ADHD 
therapy prior to the baseline (ie, Day 1) 
evaluations for a period equivalent to 
5 half-lives.  At baseline, all subjects 
must have an ADHD RS-5 with Adult 
Prompts score of ≥26 to be enrolled.
At screening, subjects not currently 
receiving an approved pharmacological 
treatment for ADHD must have an Adult 
ADHD Investigator Symptom Rating 
Scale (AISRS) with Adult Prompts score 
of ≥ 26.  Subjects receiving any 
pharmacological treatment for ADHD at 
screening must have an AISRS with 
Adult Prompts score of ≥ 22 and will 
wash out from their current ADHD 
therapy prior to the baseline (ie, Day 1) 
evaluations for a period equivalent to 
5 half-lives.  At baseline, all subjects must 
have an AISRS with Adult Prompts score 
of ≥26 to be enrolled.
Section 3.3.2, 
Subject Selection 
and Numbering
Subjects will be assigned a unique 
subject number upon enrollment, prior 
to dosing on Day 1.
Subjects will be assigned a unique subject 
number upon randomization, prior to 
dosing on Day 1.  
Table 3.4.2-1, 
Inclusion Criteria
4. Subjects with a primary DSM-5 
diagnosis of ADHD (including 
inattentive, hyperactive, and combined 
subtypes) as confirmed by the 
CAADID (The CAADID will be 
adapted to be consistent with the 
DSM-5).  Subjects may have received 
prior treatment for adult ADHD or may 
be currently receiving treatment for 
adult ADHD at screening.
4. Subjects with a primary DSM-5 
diagnosis of ADHD (including 
predominantly inattentive presentation, 
hyperactive presentation, and combined 
presentations) as confirmed by the 
ACDS v1.2.  Subjects must have received 
prior successful treatment 
(pharmacotherapy) for adult ADHD 
based on medical records and the 
principal investigator’s judgment.
Subjects may be currently receiving 
treatment for adult ADHD at screening, 
but it is not necessary that they are
currently receiving treatment.  The 
rationale to discontinue current ADHD 
treatment must include either or both 
suboptimal efficacy response and/or 
treatment limiting safety/tolerability.
Table 3.4.2-1, 
Inclusion Criteria
5. Subjects who are not currently 
receiving treatment for ADHD who 
have an ADHD RS-5 with Adult 
Prompts score of ≥ 26 and subjects who 
are receiving any treatment for ADHD 
at screening who have an ADHD RS-5 
with Adult Prompts score of ≥ 22.
5. Subjects who are not currently 
receiving an approved pharmacological 
treatment for ADHD who have an AISRS
with Adult Prompts score of ≥26 and 
subjects who are receiving any 
pharmacological treatment for ADHD at 
screening who have an AISRS with Adult 
Prompts score of ≥ 22.
Table 3.4.2-1, 
Inclusion Criteria
7. Subjects willing to discontinue all 
prohibited psychotropic medication 
starting from the time of signing the 
informed consent and during the trial 
period.
7. Subjects willing to discontinue all 
prohibited psychotropic medication 
starting from the time of signing the 
informed consent and up to the 
30 (+ 2)-day follow-up period.
Table 3.4.2-1, 
Inclusion Criteria
8. Subjects who have an ADHD RS-5 
with Adult Prompts score of ≥26.
8. Subjects who have an AISRS with 
Adult Prompts score of ≥26.
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Table 3.4.3-1, 
Exclusion Criteria
3. Subjects with an inadequate response 
to atomoxetine taken after 18 years of 
age (ie, in the investigator’s opinion, 
the subject was treated with an 
adequate dose for an adequate period of 
time, yet failed to show satisfactory 
response).
3. Subjects with a history of inadequate 
response or suboptimal tolerability to 
atomoxetine.  (In the investigator’s 
opinion, the subject was treated with an 
adequate dose for an adequate period of 
time, yet failed to show satisfactory 
response.)
Table 3.4.3-1, 
Exclusion Criteria
6. Subjects who report allergies or an 
intolerability (lifetime treatment 
history) to stimulant or nonstimulant 
ADHD medications.
6. Subjects who report allergies (lifetime 
treatment history) to stimulant or 
nonstimulant ADHD medications.
Table 3.4.3-1, 
Exclusion Criteria
8. Subjects with other DSM-5 Axis I 
disorders including history of psychosis 
(current or lifetime), current bipolar 
disorder, current major depressive 
disorder, or current panic disorder; or 
subject has a controlled (requiring a 
prohibited medication) or uncontrolled 
comorbid psychiatric condition with 
significant symptoms such as any 
severe DSM-5 Axis I or II disorders or 
other psychopathological or abnormal 
behavioral manifestations that, in the 
opinion of the principal investigator, 
will confound efficacy or safety 
assessments of the trial, or interfere 
with participation in the trial otherwise.  
Psychiatric diagnosis will be 
established using the M.I.N.I.
8. Subjects with other DSM-5 disorders 
including psychosis (current or lifetime), 
bipolar disorder (current or lifetime), 
current major depressive disorder, or 
current panic disorder; or another 
psychiatric diagnosis that the investigator
believes is primary or that will 
confound efficacy or safety assessments 
of the trial or interfere with participation 
in the trial otherwise.  Psychiatric 
diagnosis will be established using the 
M.I.N.I.
Table 3.4.3-1, 
Exclusion Criteria
9. Subjects with a clinically significant 
current Axis II (DSM-5) diagnosis of 
borderline, antisocial, paranoid, 
schizoid, schizotypal, or histrionic 
personality disorder.
9. Subjects with a clinically significant 
current DSM-5 diagnosis of borderline, 
antisocial, paranoid, schizoid, schizotypal, 
histrionic, narcissistic, avoidant, 
obsessive compulsive, or dependent 
personality disorders.
Table 3.4.3-1, 
Exclusion Criteria
10. Subjects receiving new onset 
psychotherapy (individual, group, 
marriage, or family therapy) within 
42 days of screening or at any time 
during participation in the trial.  
10. Subjects receiving new onset 
psychotherapy (eg, individual, group, 
marriage, or family therapy) within 
42 days of screening or who will initiate 
psychotherapy at any time during 
participation in the trial.  Those who are 
receiving ongoing psychotherapy for 
over 42 days are permitted to enroll.  
Psychotherapy should not be started or 
changed during a subject’s 
participation in the trial.
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Table 3.4.3-1, 
Exclusion Criteria
11. Subjects who answer “Yes” on the 
C-SSRS Suicidal Ideation Item 4 
(Active Suicidal Ideation with Some 
Intent to Act, Without Specific Plan) 
and whose most recent episode meeting 
criteria for this C-SSRS Item 4 
occurred within the last 6 months, OR 
Subjects who answer “Yes” on the C-
SSRS Suicidal Ideation Item 5 (Active 
Suicidal Ideation with Specific Plan 
and Intent) and whose most recent 
episode meeting criteria for this 
C-SSRS Item 5 occurred within the last 
6 months OR Subjects who answer 
“Yes” on any of the 5 C-SSRS Suicidal 
Behavior Items (actual attempt, 
interrupted attempt, aborted attempt, 
preparatory acts, or behavior) and 
whose most recent episode meeting 
criteria for any of these 5 C-SSRS 
Suicidal Behavior Items occurred 
within the last 2 years,
OR
Subjects who, in the opinion of the 
investigator, present a serious risk of 
suicide.
11. Subjects who meet criteria for
C-SSRS Suicidal Ideation Items 4 or 5
within the last 6 months or subjects who 
meet criteria for any of the 5 C-SSRS 
Suicidal Behavior Items (actual attempt, 
interrupted attempt, aborted attempt, 
preparatory acts, or behavior) and whose 
most recent episode meeting criteria for 
any of these 5 C-SSRS Suicidal Behavior 
Items occurred within the last 2 years,
OR
Subjects who, in the opinion of the 
investigator, present a serious risk of 
suicide.
Table 3.4.3-1, 
Exclusion Criteria
12. Subjects who have met DSM-5 
criteria for substance use disorder 
within the past 180 days; including 
alcohol and benzodiazepines, but 
excluding caffeine and nicotine.
12. Subjects who have met DSM-5 
criteria for substance use disorder within 
the past 180 days; including all 
substances of potential abuse, excluding 
caffeine and nicotine.
Table 3.4.3-1, 
Exclusion Criteria
14. Subjects who currently have 
clinically significant neurological, 
hepatic, renal, metabolic, 
hematological, immunological, 
cardiovascular, pulmonary, or 
gastrointestinal disorders such as any 
history of myocardial infarction, 
congestive heart failure, HIV 
seropositive status/acquired 
immunodeficiency syndrome, chronic 
hepatitis B or C.  
14. Subjects who currently have clinically 
significant dermatological, neurological, 
hepatic, renal, metabolic, hematological, 
immunological, cardiovascular, 
pulmonary, or gastrointestinal disorders 
such as any history of myocardial 
infarction, congestive heart failure, HIV 
seropositive status/acquired 
immunodeficiency syndrome, or active 
or chronic hepatitis B or C.  
Table 3.4.3-1, 
Exclusion Criteria
20. Subjects with known mental 
retardation defined as an IQ less than 
75, or clinical evidence of mental 
retardation based on the opinion of the 
investigator.
20. Subjects with known intellectual 
disability (intellectual developmental 
disorder), including mild adaptive 
functioning impairment, or clinical 
evidence of intellectual disability based 
on the opinion of the investigator.
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Table 3.4.3-1, 
Exclusion Criteria
21. Subjects with a positive drug screen 
for cocaine or other illicit drugs will be 
excluded and may not be retested or 
re-screened.  Subjects with a positive 
urine drug screen resulting from use of 
prescription or OTC medications.
21. Subjects with a positive drug screen 
for cocaine or other illicit drugs will be 
excluded and may not be retested or 
rescreened.  Subjects with a positive urine 
drug screen resulting from use of 
prescription or OTC medications may be 
retested or rescreened, at the discretion
of the investigator.
Table 3.4.3-1, 
Exclusion Criteria
27. Prisoners or subjects who are 
compulsorily detained (involuntarily 
incarcerated) for treatment of either a 
psychiatric or physical (eg, infectious 
disease) illness must not be enrolled 
into this trial.
27. Prisoners or subjects who are 
compulsorily detained (involuntarily 
hospitalized or incarcerated) for 
treatment of either a psychiatric or 
physical (eg, infectious disease) illness 
must not be enrolled into this trial.
Section 3.5.1, 
Primary Endpoint
The primary efficacy endpoint is the 
change from baseline to the Day 56 
Visit in the Conners' Adult ADHD 
Rating Scales–Observer: Screening 
Version (CAARS-O:SV) 18-item 
ADHD symptoms total score in the 
OPC-64005 group relative to the 
atomoxetine group.  
The primary efficacy endpoint is the 
change from baseline to the Day 56 
(± 1 day) Visit in the investigator-
administered Conners' Adult ADHD 
Rating Scales–Observer: Screening 
Version (CAARS-O:SV) 18-item ADHD 
symptoms total score in the OPC-64005 
group relative to the atomoxetine group.  
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Section 3.5.2, 
Other Endpoint(s)
Other efficacy endpoints are

Change from baseline to each 
weekly visit (Days 7, 14, 21, 28, 
42, and 56/ET) in the 
CAARS-O:SV score in the 
OPC-64005 group relative to the 
atomoxetine and placebo groups

Change from baseline to the 
Day 28 and Day 56 Visits for the 
ADHD RS-5 with Adult Prompts 
score in the OPC-64005 group 
relative to the atomoxetine and 
placebo groups

Change from baseline to each 
weekly visit (Days 7, 14, 21, 28, 
42, and 56/ET) in the CGI-S score 
in the OPC-64005 group relative to 
the atomoxetine and placebo 
groups

CGI-I score at each weekly visit 
(Days 7, 14, 21, 28, 42, and 56/ET) 
in the OPC-64005 group relative to 
the atomoxetine, and placebo 
groups

Change from baseline to each 
weekly visit (Days 7, 14, 21, 28, 
42, and 56/ET) in the Conners' 
Adult ADHD Rating Scales–
Self-Report: Screening Version
(CAARS-S:SV) score in the 
OPC-64005 group relative to the 
atomoxetine and placebo groups

Change from baseline to the Day 
28 and Day 56 Visits in the Adult 
ADHD Quality of Life Scale 
(AAQoL) score in the OPC-64005 
group relative to the atomoxetine 
and placebo groups

OPC-64005 potential for abuse 
liability and dependence as 
assessed by the Drug Effects 
Questionnaire (DEQ) at baseline 
and each weekly visit (Days 7, 14, 
21, 28, 42, and 56/ET)
Other efficacy endpoints are

Change from baseline to each 
scheduled visit (Days 7, 14, 21, 28, 
42, and 56/ET; all visits have a 
± 1-day window) in the 18-item, 
investigator-administered
CAARS-O:SV score in the 
OPC-64005 group relative to the 
atomoxetine and placebo groups

Change from baseline to the Day 28 
(± 1 day) and Day 56 (± 1 day)
Visits for the AISRS with Adult 
Prompts score in the OPC-64005 
group relative to the atomoxetine and 
placebo groups

Change from baseline to each 
scheduled visit (Days 7, 14, 21, 28, 
42, and 56/ET; all visits have a 
± 1-day window) in the CGI-S score 
in the OPC-64005 group relative to 
the atomoxetine and placebo groups

CGI-I score at each scheduled visit 
(Days 7, 14, 21, 28, 42, and 56/ET; 
all visits have a ± 1-day window) in 
the OPC-64005 group relative to the 
atomoxetine, and placebo groups

Change from baseline to each 
scheduled visit (Days 7, 14, 21, 28, 
42, and 56/ET; all visits have a 
± 1-day window) in the 18-item 
Conners' Adult ADHD Rating 
Scales–Self-Report: Screening 
Version (CAARS-S:SV) score in the 
OPC-64005 group relative to the 
atomoxetine and placebo groups

Change from baseline to the Day 28 
(± 1 day) and Day 56 (± 1 day)
Visits in the Adult ADHD Quality of 
Life Scale (AAQoL) score in the 
OPC-64005 group relative to the 
atomoxetine and placebo groups

OPC-64005 potential for abuse 
liability and dependence as assessed 
by the Drug Effects Questionnaire 
(DEQ) at baseline and each 
scheduled visit (Days 7, 14, 21, 28, 
42, and 56/ET; all visits have a 
± 1-day window)
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Section 3.6, 
Measures to 
Minimize/Avoid 
Bias
Access to the treatment codes will be 
restricted to personnel charged with 
generating and maintaining 
randomization files, packaging IMP, 
operating the interactive voice response 
system/interactive web response system 
(IVRS/IWRS), and reporting SAEs to 
regulatory agencies.  
Access to the treatment codes will be 
restricted to personnel charged with 
generating and maintaining randomization 
files, packaging IMP, operating the 
interactive voice response 
system/interactive web response system 
(IVRS/IWRS), and reporting SAEs to 
regulatory agencies.  The interim 
analysis will be conducted by an 
independent biostatistician from the 
OPDC Data Sciences Department and 
the treatment code will remain blinded 
for all others until the unblinding at the 
final analysis after trial completion.
Table 3.7-1, 
Schedule of 
Assessments
Changes to Table 3.7-1 are summarized on the next page and are indicated by bold, 
underlined text.
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Table 3.7-1
Schedule of Assessments
Assessment
Screening
(Day −28 
to −1)
Baseline 
(Day 1)
Day 7
(± 1 day)
Day 14
(± 1 day)
Day 21
(± 1 day)
Day 28
(± 1 day)
Day 42
(± 1 day)
Day 56
(± 1 day)/ET
Follow-up
(3 ± 1 day)
Follow-up 
(30 + 2 days)
ENTRANCE CRITERIA
Inclusion/exclusion 
criteria
X
X
Demographic information
X 
Medical history
X 
Psychiatric history to 
confirm DSM-5 ADHD 
diagnosis using the 
ACDS v1.2
X 
Identification of 
comorbidities using the 
M.I.N.I.
X 
Investigator assessment of 
previous and current 
ADHD treatment 
X
X
HIV, HBsAg, and 
anti-HCV
X 
Urine pregnancy testa
X
X
X
X
SAFETY
Physical examinationb
X 
X 
X
X
X
X
X
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
X 
X 
X 
X 
X 
Clinical laboratory
X 
X 
X 
X 
Urine alcohol and drug 
screen
X 
X 
C-SSRS
X 
X 
X 
X 
X 
X 
X 
X 
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Table 3.7-1
Schedule of Assessments
Assessment
Screening
(Day −28 
to −1)
Baseline 
(Day 1)
Day 7
(± 1 day)
Day 14
(± 1 day)
Day 21
(± 1 day)
Day 28
(± 1 day)
Day 42
(± 1 day)
Day 56
(± 1 day)/ET
Follow-up
(3 ± 1 day)
Follow-up 
(30 + 2 days)
EFFICACY
18-item, investigator-
administered
CAARS-O:SVc
X 
X 
X 
X 
X 
X 
X 
X 
AISRS with Adult 
Prompts  
X 
X 
X 
X 
CGI-S
X 
X 
X 
X 
X 
X 
X 
X 
CGI-I
X 
X 
X 
X 
X 
X 
18-item CAARS-S:SVc
X
X
X
X
X
X
X
AAQoL
X
X
X
POMS
X
X
X
X
X
X
X
X
CLINIC PROCEDURES
IMP administrationd
X
X
X
X
X
X
X
PK blood samples
Xe
Xf
Xg
Xh
    
Pharmacogenomic sample 
for CYP2D6 testing
X
FBR blood samplei
X
DEQ 
X 
X
X
X
X
X
X 
Record AEs
X 
X 
X 
X 
X 
X 
X 
X 
X
X 
Record concomitant 
medication
X 
X 
X 
X 
X 
X 
X 
X 
X
X 
Telephone contact
X
X 
FBR = future biospecimen research; POMS = Profile of Mood States-Brief Form™.
...
bA physical examination will be performed at the Screening, Baseline, and Day 56 (± 1 day)/ET Visits.  Weight, height, and waist circumference will be 
recorded at the Screening Visit.  A focused examination for the detection of rash will be performed at the Day 7, 14, 21, 28, and 42 Visits; all visits have a 
± 1-day window.  Subjects will be instructed to contact the site if rash is noted at any other time, and an unscheduled visit will be arranged.
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cThe 18-item CAARS-S:SV should be conducted before the 18-item, investigator-administered CAARS-O:SV at each scheduled assessment, giving the 
investigator a chance to review the self-report before completing their own assessment.
dSubjects will receive daily doses of IMP starting on Day 1.  At the baseline visit, subjects will receive a titration card for dosing on Days 1 to 4 and a 
treatment card for dosing on Days 5 to 7.  During the treatment period, subjects will receive a treatment card(s) for dosing on scheduled visits.
eDay 1 samples collected predose and 1 and 3 hours postdose.
fDay 7 (± 1 day) samples collected predose and 2 hours postdose.
gDay 14(± 1 day) samples collected predose and 3 hours postdose.
hDay 21 (± 1 day) samples collected predose.
iFBR sample will be collected once the subject has provided consent for FBR.
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Section 3.7.1.1, 
Screening

Medical and psychiatric history 
will be recorded, including the 
DSM-5 diagnosis of ADHD using 
the CAADID (The CAADID will 
be adapted to be consistent with 
the DSM-5).

Medical and psychiatric history will 
be recorded, including the DSM-5 
diagnosis of ADHD using the 
ACDS v1.2.
Section 3.7.1.1, 
Screening

The investigator will assess and 
record previous ADHD 
medications.  Subjects must have a 
history of successful treatment 
with stimulants or nonstimulant 
ADHD medication.  

The investigator will assess and 
record previous ADHD medications.  
Subjects must have a history of 
adequate symptom reduction with 
stimulants or nonstimulant ADHD 
medication.  
Section 3.7.1.1, 
Screening

A complete physical examination 
will be performed.  

A physical examination will be 
performed. 
Section 3.7.1.1, 
Screening

Vital sign measurements 
(including blood pressure and 
pulse) will be recorded.  Blood 
pressure and pulse are to be 
measured in the following order:  
supine, sitting, and standing after 
the subject has been in each 
position at least 3 minutes.  A 
standard 12-lead ECG will be 
performed after the subject has 
been supine and at rest for at least 
5 minutes.  Respiratory rate at each 
visit will be performed after the 
subject has been in the sitting 
position for at least 5 minutes.

Vital sign measurements (including 
body temperature, blood pressure, 
pulse, and respiratory rate) will be 
recorded.  Blood pressure and pulse 
are to be measured in the following 
order:  supine, sitting, and standing 
after the subject has been in each 
position at least 3 minutes.  
Respiratory rate at each visit will be 
performed after the subject has been 
in the sitting position for at least 
5 minutes.  A standard 12-lead ECG 
will be performed after the subject 
has been supine and at rest for at least 
5 minutes. 
Section 3.7.1.1, 
Screening

The ADHD RS-5 with Adult 
Prompts will be administered.  
Subjects not currently receiving 
treatment for ADHD must have an 
ADHD RS-5 with Adult Prompts 
score of ≥ 26.  Subjects receiving 
any treatment for ADHD at 
screening must have an ADHD 
RS-5 with Adult Prompts score of 
≥ 22.

The AISRS with Adult Prompts will 
be administered.  Subjects not 
currently receiving an approved 
pharmacological treatment for 
ADHD must have an AISRS with 
Adult Prompts score of ≥ 26.  
Subjects receiving any 
pharmacological treatment for 
ADHD at screening must have an 
AISRS with Adult Prompts score of 
≥ 22.
Section 3.7.1.1, 
Screening

A qualified and certified rater will 
administer the investigator-rated 
CAARS-O:SV.

A qualified and certified rater will 
administer the investigator-rated 
18-item CAARS-O:SV.
Section 3.7.1.1, 
Screening

The Profile of Mood States 2nd 
Edition™ (POMS 2-A) will be 
administered.

The Profile of Mood States-Brief
Form™ (POMS) will be 
administered.
Section 3.7.1.2, 
Baseline (Day 1)

A complete physical examination 
will be performed.  

A physical examination will be 
performed. 
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Section 3.7.1.2, 
Baseline (Day 1)

Vital sign measurements 
(including blood pressure and 
pulse) will be recorded.  Blood 
pressure and pulse are to be 
measured in the following order:  
supine, sitting, and standing after 
the subject has been in each 
position at least 3 minutes.  A 
standard 12-lead ECG will be 
performed after the subject has 
been supine and at rest for at least 
5 minutes.  Respiratory rate at each 
visit will be performed after the 
subject has been in the sitting 
position for at least 5 minutes.  

Vital sign measurements (including 
body temperature, blood pressure, 
pulse, and respiratory rate) will be 
recorded.  Blood pressure and pulse 
are to be measured in the following 
order:  supine, sitting, and standing 
after the subject has been in each 
position at least 3 minutes.  
Respiratory rate at each visit will be 
performed after the subject has been 
in the sitting position for at least 
5 minutes.  A standard 12-lead ECG 
will be performed after the subject 
has been supine and at rest for at least 
5 minutes.
Section 3.7.1.2, 
Baseline (Day 1)

The ADHD RS-5 with Adult 
Prompts will be administered.  
Subjects must have an ADHD 
RS-5 with Adult Prompts score of 
≥ 26.  

The AISRS with Adult Prompts will 
be administered.  Subjects must have 
an AISRS with Adult Prompts score 
of ≥ 26.  
Section 3.7.1.2, 
Baseline (Day 1)

The subject will complete the 
CAARS-S:SV.  The CAARS-S:SV 
should be conducted before the 
CAARS-O:SV at each scheduled 
assessment, giving the investigator 
a chance to review the self-report 
before completing their own 
assessment.

The subject will complete the 
18-item CAARS-S:SV.  The 18-item 
CAARS-S:SV should be conducted 
before the 18-item, investigator-
administered CAARS-O:SV at each 
scheduled assessment, giving the 
investigator a chance to review the 
self-report before completing their 
own assessment.
Section 3.7.1.2, 
Baseline (Day 1)

A qualified and certified rater will 
administer the investigator-rated 
CAARS-O:SV.

A qualified and certified rater will 
administer the investigator-rated 
18-item CAARS-O:SV.
Section 3.7.1.2, 
Baseline (Day 1)

Blood samples for FBR will be 
collected. 

Blood samples for FBR will be 
collected (once the subject has 
provided consent for FBR).
Section 3.7.1.2, 
Baseline (Day 1)

The POMS 2-A will be 
administered.

The POMS will be administered.
Section 3.7.1.2, 
Baseline (Day 1)
Not applicable (newly added text)

Subjects will receive a titration 
card for dosing on Days 1 to 4 and 
a treatment card for dosing on 
Days 5 to 7.
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Section 3.7.1.3, 
Treatment Period 
Visits (Day 7 
through Day 56 
Visits)

At each visit, a focused physical 
examination for the presence of 
rash will be performed.  Subjects 
will be instructed to contact the site 
if rash is noted at any other time, 
and an unscheduled visit will be 
arranged.  A complete physical 
examination will be performed at 
the Day 56/ET Visit.  See Section 
3.7.3.3 for a description of 
follow-up activities to be 
completed if rash is detected.  

At each visit, a focused physical 
examination for the presence of rash 
will be performed.  Subjects will be 
instructed to contact the site if rash is 
noted at any other time, and an 
unscheduled visit will be arranged.  A 
complete physical examination will 
be performed at the Day 56
(± 1 day)/ET Visit.  See Section 
3.7.3.3 for a description of follow-up 
activities to be completed if rash is 
detected.  The investigator must 
immediately report any instances 
of rash to the Clinical Research 
Organization (CRO) medical 
monitor.
Section 3.7.1.3, 
Treatment Period 
Visits (Day 7 
through Day 56 
Visits)

At each visit, vital sign 
measurements (including blood 
pressure and pulse) will be 
recorded.  Blood pressure and 
pulse are to be measured after the 
subject has been in the sitting 
position at least 5 minutes.  At the 
Day 14, 28, 42, and 56 Visits, a 
standard 12-lead ECG will be 
performed after the subject has 
been supine and at rest for at least 
5 minutes.  Respiratory rate at each 
visit will be performed after the 
subject has been in the sitting 
position for at least 5 minutes.  

At each visit, vital sign 
measurements (including body
temperature, blood pressure, pulse, 
and respiratory rate) will be 
recorded.  Blood pressure and pulse 
are to be measured after the subject 
has been in the sitting position at 
least 5 minutes.  Respiratory rate at 
each visit will be performed after the 
subject has been in the sitting 
position for at least 5 minutes.  At the 
Day 14, 28, 42, and 56 Visits (all 
visits have a ± 1-day window), a 
standard 12-lead ECG will be 
performed after the subject has been 
supine and at rest for at least 
5 minutes.
Section 3.7.1.3, 
Treatment Period 
Visits (Day 7 
through Day 56 
Visits)

At the Day 28 and 56 Visits, blood 
and urine samples will be collected 
for clinical laboratory tests, 
including hematology, serum 
chemistry, and urinalysis (see 
Table 3.7.3.2-1). 

At the Day 28 (± 1 day) and Day 56 
(± 1 day) Visits, blood and urine 
samples will be collected for clinical 
laboratory tests, including 
hematology, serum chemistry, and 
urinalysis (see Table 3.7.3.2-1). 
Section 3.7.1.3, 
Treatment Period 
Visits (Day 7 
through Day 56 
Visits)

A urine pregnancy test will be 
performed for all WOCBP at the 
Day 56/ET Visit.  If the urine 
pregnancy test is positive, the 
result should be confirmed with a 
serum pregnancy test.

A urine pregnancy test will be 
performed for all WOCBP at the 
Day 28 (± 1 day) and Day 56 
(± 1 day)/ET Visits.  If the urine 
pregnancy test is positive, the result 
should be confirmed with a serum 
pregnancy test.
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Section 3.7.1.3, 
Treatment Period 
Visits (Day 7 
through Day 56 
Visits)
Not applicable (newly added text)

Urine will be collected from all 
potential subjects for urine 
screen(s) for alcohol and drugs of 
abuse, including amphetamines, 
barbiturates, benzodiazepines, 
cannabinoids, cocaine, opiates, 
phencyclidine, and marijuana at 
the Day 56 (± 1 day)/ET Visit.
Section 3.7.1.3, 
Treatment Period 
Visits (Day 7 
through Day 56 
Visits)

At the Day 28 and 56 Visits, the 
ADHD RS-5 with Adult Prompts 
will be administered.  

At the Day 28 (± 1 day) and Day 56 
(± 1 day) Visits, the AISRS with 
Adult Prompts will be administered.  
Section 3.7.1.3, 
Treatment Period 
Visits (Day 7 
through Day 56 
Visits)

The subject will complete the 
CAARS-S:SV.  The CAARS-S:SV 
should be conducted before the 
CAARS-O:SV at each scheduled 
assessment, giving the investigator 
a chance to review the self-report 
before completing their own 
assessment.

The subject will complete the 
18-item CAARS-S:SV.  The 18-item 
CAARS-S:SV should be conducted 
before the 18-item, investigator-
administered CAARS-O:SV at each 
scheduled assessment, giving the 
investigator a chance to review the 
self-report before completing their 
own assessment.
Section 3.7.1.3, 
Treatment Period 
Visits (Day 7 
through Day 56 
Visits)

At each visit, a qualified and 
certified rater will administer the 
investigator-rated CAARS-O:SV.

At each visit, a qualified and certified 
rater will administer the investigator-
rated 18-item CAARS-O:SV.
Section 3.7.1.3, 
Treatment Period 
Visits (Day 7 
through Day 56 
Visits)

At each visit, the POMS 2-A will 
be administered.

At each visit, the POMS will be 
administered.
Section 3.7.1.3, 
Treatment Period 
Visits (Day 7 
through Day 56 
Visits)

Blood samples for PK analyses 
will be collected predose and at 
2 hours postdose at the Day 7 
Visit, predose and at 3 hours 
postdose at the Day 14 Visit, and 
predose at the Day 21 Visit.

Blood samples for PK analyses will 
be collected predose and at 2 hours 
postdose at the Day 7 (± 1 day) Visit, 
predose and at 3 hours postdose at the 
Day 14 (± 1 day) Visit, and predose 
at the Day 21 (± 1 day) Visit.
Section 3.7.1.3, 
Treatment Period 
Visits (Day 7 
through Day 56 
Visits)

At the Day 28 and 56 Visits, the 
subject will complete the AAQoL.

At the Day 28 (± 1 day) and Day 56 
(± 1 day) Visits, the subject will 
complete the AAQoL.
Section 3.7.1.3, 
Treatment Period 
Visits (Day 7 
through Day 56 
Visits)
Not applicable (newly added text)

Subjects will receive a treatment 
card(s) for dosing on scheduled 
visits.
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Section 3.7.1.4, 
Safety Follow-up 
Period
A follow-up telephone contact will 
occur at Day 59 or discontinuation 
(± 1 day).  A follow-up telephone 
contact will occur 30 (+ 2) days after 
the last dose of IMP for all subjects 
(completers and early withdrawals).
A follow-up telephone contact will occur 
3 (± 1) days and 30 (+ 2) days after the 
last dose of IMP for all subjects 
(completers and early withdrawals).  
Section 3.7.2.1, 
Conners’ Adult 
ADHD Rating 
Scale-Observer:  
Screening Version 
(CAARS-O:SV)
3.7.2.1  Conners’ Adult ADHD Rating 
Scale-Observer:  Screening Version 
(CAARS-O:SV)
The CAARS-O:SV is designed to 
measure a cross-section of 
ADHD-related symptoms and 
behaviors in adults using observer 
scales.52  The screening version of the 
CAARS that is being used to monitor 
ADHD symptoms in this trial can be 
administered by an appropriately 
trained and qualified clinician in
approximately 10 minutes.  The 
CAARS-O:SV consists of 30 items that 
are each scored on a 4-point scale as 
follows:  0 = not at all, never; 1 = just a 
little, once in a while; 2 = pretty much, 
often; and 3 = very much, very 
frequently based on the extent to which 
the item is applicable to the individual 
being evaluated.  For analysis purposes, 
the 30 items of the scale are grouped 
into 3 subscales:  Inattentive Symptoms 
(9 items), Hyperactive/Impulsive 
Symptoms (9 items), and ADHD Index 
(12 items).  The primary evaluation of 
ADHD will be based on the 18-item 
ADHD Symptoms Total Score, which 
consists of the combined score for the 
Inattentive Symptoms and 
Hyperactive/Impulsive Symptoms 
subscales.
3.7.2.1  Conners’ Adult ADHD Rating 
Scale-Observer:  Screening Version 
(CAARS-O:SV; Investigator-
Administered)
The investigator-administered
CAARS-O:SV (Appendix 4) is designed 
to measure a cross-section of 
ADHD-related symptoms and behaviors 
in adults using observer scales.52  The 
investigator-administered
CAARS-O:SV consists of 30 items
grouped into 3 subscales:  Inattentive 
Symptoms (9 items), 
Hyperactive/Impulsive Symptoms 
(9 items), and ADHD Index (12 items).
As is frequently done in adult ADHD 
trials, items will be modified using the 
Adler adult prompts and only the 
18 DSM-5 criteria relevant items 
(9 Inattentive and 
9 Hyperactive/Impulsive) will be 
administered.  The primary efficacy 
assessment of ADHD symptoms is the 
ADHD Symptoms Total Score, which 
consists of the combined score for the 
Inattentive Symptoms and 
Hyperactive/Impulsive Symptoms 
subscales.  The 18-item scale can be 
administered by an appropriately trained 
and qualified clinician in approximately 
20 to 30 minutes.
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Section 3.7.2.2, 
Conners’ Adult 
ADHD Rating 
Scale-Self Report:  
Screening Version 
(CAARS-S:SV)
The CAARS-S:SV includes the same 
30 items used for the CAARS-O:SV, 
worded in the first person for the 
subject’s impressions of ADHD 
behaviors (eg, “I talk too much,” “I am 
always on the go...”etc).  The subjects 
will score each of the items on a 
4-point scale as follows:  0 = Not at all, 
never; 1 = Just a little, once in a while; 
2 = Pretty much, often; and 3 = Very 
much, very frequently.52  For analysis 
purposes, the 30 items of the scale are 
grouped into 3 subscales:  Inattentive 
Symptoms (9 items), 
Hyperactive/Impulsive Symptoms 
(9 items), and ADHD Index (12 items).  
The evaluation of ADHD will be based 
on the 18-item ADHD Symptoms Total 
Score which consists of the combined 
score for the Inattentive Symptoms and 
Hyperactive/Impulsive Symptoms 
subscales.  The screening version of the 
CAARS-S:SV that is being used to 
monitor self-reported ADHD 
symptoms in this trial can be completed 
in approximately 10 minutes.
The CAARS-S:SV (Appendix 5) includes 
the same 30 items as the investigator-
administered CAARS-O:SV, worded in 
the first person for the subject’s 
impressions of their own ADHD 
behaviors (eg, “I talk too much,” “I am 
always on the go...”).52  As with the 
investigator-administered
CAARS-O:SV, administration of the 
CAARS-S:SV in the current trial will 
be limited to the 18 DSM-5 criteria 
relevant items (9 Inattentive Symptoms 
and 9 Hyperactive/Impulsive 
Symptoms subscales).  The evaluation of 
ADHD symptoms will be based on the 
18-item ADHD Symptoms Total Score, 
which consists of the combined score for 
the Inattentive Symptoms and 
Hyperactive/Impulsive Symptoms 
subscales.  The CAARS-S:SV can be 
completed in approximately 10 minutes.
Section 3.7.2.3, 
ADHD Rating 
Scale based on 
DSM-5 Criteria 
(ADHD RS-5 with 
Adult Prompts)
3.7.2.3  ADHD Rating Scale based on 
DSM-5 Criteria (ADHD RS-5 with 
Adult Prompts
The ADHD RS-5 with Adult Prompts 
is an 18-item scale based on the DSM-5 
criteria for ADHD that provides a 
rating of the severity of symptoms.53  
The first 9 items assess inattentive 
symptoms, and the last 9 items assess 
hyperactive-impulsive symptoms.  
Scoring is based on a 4-point severity 
scale:  0 = none, 1 = mild, 
2 = moderate, 3 = severe.
3.7.2.3  Adult ADHD Investigator 
Symptom Rating Scale (AISRS With 
Adult Prompts
The AISRS (Appendix 6) was published 
in 2010 by Drs. Lenard Adler, Thomas 
Spencer, and Joseph Biederman of New 
York University and Massachusetts 
General Hospital.53  The AISRS 
consists of the 18 DSM ADHD 
symptoms with adult-relevant wording.  
It has been validated for use as a 
primary efficacy scale in adult ADHD 
treatment trials.
Section 3.7.2.4, 
Clinical Global 
Impression -
Severity of Illness 
Scale (CGI-S)
To perform this assessment, the 
investigator or rater will respond to the 
following question:  “Considering your 
total clinical experience with this 
particular population, how mentally ill 
is the patient at this time?”  Response 
choices include:  0 = not assessed; 
1 = normal, not at all ill; 2 = borderline 
mentally ill; 3 = mildly ill; 
4 = moderately ill; 5 = markedly ill; 
6 = severely ill; and 7 = among the 
most extremely ill patients.
To perform this assessment, the 
investigator or rater will respond to the 
following question:  “Considering your 
total clinical experience with the ADHD
population, how mentally ill is the patient
at this time?”  Response choices include:  
1 = normal, not at all ill; 2 = borderline 
ill; 3 = mildly ill; 4 = moderately ill; 
5 = markedly ill; 6 = severely ill; and 
7 = among the most extremely ill patients.  
Suggested anchor guidance is provided 
in Appendix 7.55
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Section 3.7.2.5, 
Clinical Global 
Impression -
Improvement Scale 
(CGI-I)
The rater or investigator will rate 
whether the subject’s total 
improvement relative to baseline is due 
entirely to drug treatment.  Response 
choices include:  0 = not assessed; 
1 = very much improved, 2 = much 
improved, 3 = minimally improved, 
4 = no change, 5 = minimally worse, 
6 = much worse, and 7 = very much 
worse.
The rater or investigator will rate whether 
the subject’s total improvement relative to 
baseline is due entirely to drug treatment.  
Response choices include:  1 = very much 
improved, 2 = much improved, 
3 = minimally improved, 4 = no change, 
5 = minimally worse, 6 = much worse, 
and 7 = very much worse.  Suggested 
anchor guidance is provided in 
Appendix 8.55
Section 3.7.2.6, 
Adult ADHD 
Quality of Life 
Scale (AAQoL)
The AAQoL is a validated, 29-item 
instrument for measuring the impact of 
ADHD symptoms on quality of life.55
The AAQoL (Appendix 9) is a validated, 
29-item instrument for measuring the 
impact of ADHD symptoms on quality of 
life.56
Section 3.7.2.7, 
Profile of Mood 
States 2nd Edition 
(POMS 2-A)
3.7.2.7  Profile of Mood States 2nd 
Edition (POMS 2-A)
The Profile of Mood States™ (POMS) 
self-report scales are a collection of 
tools that allow for the quick
assessment of transient, fluctuating 
feelings, and enduring affect states.  
The tool is applicable in clinical, 
medical, research, and athletic settings, 
where its sensitivity to change makes 
the assessment ideal for treatment 
monitoring and evaluation, as well as 
clinical trials.  The POMS 2-A is 
comprised of 65 items.  This full length 
version yields several scale scores:  
Anger-Hostility, Confusion 
Bewilderment, Depression-Dejection, 
Fatigue-Inertia, Tension-Anxiety, and 
Vigor-Activity.  Total Mood 
Disturbance is a function of these 6 
scale scores.  The Friendliness scale is 
scored separately.  These 
comprehensive versions are 
recommended for use when a thorough 
evaluation of mood is desired.
3.7.2.7  Profile of Mood States-Brief 
Form (POMS)
The POMS (Appendix 10) is a 30-item 
self-report scale that generates the 
following subscales:  Tension or 
Anxiety, Anger - Hostility, Vigor -
Activity, Fatigue - Inertia, Depression -
Dejection, and Confusion -
Bewilderment.57  These subscales yield 
an overall total mood score.  It will be 
used in the trial as an exploratory 
measure to assess potential changes in 
symptoms often associated with ADHD.  
The time period of interest for this trial 
is “during the past week”.
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Section 3.7.3.3, 
Physical 
Examination and 
Vital Signs
A physical examination will be 
performed at screening and at each 
weekly visit. ... In addition, at each visit 
during the Treatment Period (ie, 
beginning with the Day 7 Visit), the 
physical examination will include a 
focused examination for the presence 
of rash. ...  The subject should be 
evaluated by a dermatologist.  The rash 
should be photographed and a punch 
biopsy performed.  At the appearance 
of or discovery of the rash, vital signs 
(specifically, body temperature), 
symptoms of hepatitis (eg, weight loss, 
right upper quadrant tenderness, 
malaise, jaundice, hepatomegaly, dark 
urine), a discussion of other possible 
causes of the rash (eg, allergic, contact 
dermatitis), and specific location(s) of 
the rash should be recorded.
A physical examination will be performed 
at screening, baseline, and at Day 56 
(± 1 day). ... A focused examination for 
the detection of rash, defined as any 
type of newly acquired skin eruptions 
that are nontraumatic, will be 
performed at the Day 7, 14, 21, 28, and 
42 Visits; all visits have a ± 1-day 
window. ... Any rash, regardless of 
severity or seriousness, will lead to the 
discontinuation of IMP.  Any subject 
who experiences a rash will be evaluated 
by a board-certified or board-eligible 
dermatologist. Depending on the 
severity, the subject will be asked to 
have a skin biopsy performed of the rash 
area(s).  At the appearance of or 
discovery of the rash, the rash will be 
photographed by the investigator and
vital signs (specifically, body 
temperature), symptoms of hepatitis (eg, 
weight loss, right upper quadrant 
tenderness, malaise, jaundice, 
hepatomegaly, dark urine), a discussion of 
other possible causes of the rash (eg, 
allergic, contact dermatitis), and specific 
location(s) of the rash should be recorded.  
The investigator must immediately 
report any instances of rash to the 
CRO medical monitor.  Refer to 
Appendix 11 through Appendix 14 for 
follow-up activities if rash is detected.
Section 3.7.3.3, 
Physical 
Examination and 
Vital Signs
Vital signs will be measured and 
recorded at screening, baseline, and at 
each weekly visit.
Vital signs will be measured and recorded 
at screening, baseline, and at each 
scheduled visit.
Section 3.7.3.4, 
Electrocardiogram 
Assessments
At Screening, Baseline, and the Day 
14, 28, 42, and 56 Visits, a standard 
12-lead ECG will be performed after 
the subject has been supine and at rest 
for at least 5 minutes.
At Screening, Baseline, and the Day 14 
(± 1 day), 28 (± 1 day), 42 (± 1 day), and 
56 (± 1 day) Visits, a standard 12-lead 
ECG will be performed after the subject 
has been supine and at rest for at least 
5 minutes.
Section 3.7.3.5, 
Columbia-Suicide 
Severity Rating 
Scale (C-SSRS)
The since-last-visit version of the 
C-SSRS will be administered at the 
Baseline Visit and at each subsequent 
weekly visit.
The since-last-visit version of the C-SSRS 
will be administered at the Baseline Visit 
and at each subsequent scheduled visit.
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Section 3.7.4.1.1, 
Pharmacokinetic 
Blood Samples
Blood samples for the determination of 
OPC-64005 and its metabolite(s) will 
be collected at Baseline (Day 1) 
predose and at 1 and 3 hours postdose, 
at the Day 7 Visit predose and at 2 
hours postdose, at the Day 14 Visit 
predose and at 3 hours postdose, and at 
the Day 21 Visit predose.  In addition, 
every effort will be made to obtain a 
PK blood sample from any subject who 
experiences an SAE.  This sample 
should be obtained as soon as is 
practical after the onset of the SAE.
Blood samples for the determination of
OPC-64005 and its metabolite(s) will be 
collected at Baseline (Day 1) predose 
(within 15 minutes of dosing) and at 
1 and 3 hours postdose, at the Day 7 
(± 1 day) Visit predose (within 
5 minutes of dosing) and at 2 hours 
postdose, at the Day 14 (± 1 day) Visit 
predose (within 5 minutes of dosing) and 
at 3 hours postdose, and at the Day 21 
(± 1 day) Visit predose (within 
5 minutes of dosing).  In addition, every 
effort will be made to obtain a PK blood 
sample from any subject who experiences 
an SAE.  This sample should be obtained 
as soon as is practical after the onset of 
the SAE.
Every effort should be made to draw 
the sample at the appropriate time.  If a 
sample cannot be drawn at the 
designated time, a window of 
± 3 minutes for each blood draw is 
acceptable, provided the exact time of 
the draw is recorded.
Section 3.8.3.1, 
Down Titration of 
Treatment
During the Treatment Period, if a 
subject is not able to tolerate the 30-mg 
dose of OPC-64005, the dose may be 
reduced to 20 mg for the duration of the 
Treatment Period.  If a subject is not 
able to tolerate the 80-mg dose of 
atomoxetine, the dose may be reduced 
to 40 mg for the duration of the 
Treatment Period.
During the Treatment Period, if a subject 
is not able to tolerate the 30-mg dose of 
OPC-64005, the dose may be reduced to 
20 mg for the duration of the Treatment 
Period.  If a subject is not able to tolerate 
the 80-mg dose of atomoxetine, the dose 
may be reduced to 40 mg for the duration 
of the Treatment Period.  Subjects are 
permitted to have one dose reduction 
and one titration back up to their 
previous dose (ie, 30 mg for OPC-64005 
and 80 mg for atomoxetine) during the 
trial.
Section 3.8.3.2, 
Treatment 
Discontinuation
Not applicable (newly added text)
If a subject will miss/misses a trial visit,
the investigator should contact the 
medical monitor to discuss the potential 
to retain the subject.  Depending on 
how many doses of IMP the subject will 
miss/misses, the sponsor, medical 
monitor, and investigator will 
determine if the subject is able to 
continue in the trial and at which dose 
the subject will resume, taking into 
consideration any scheduled and 
unscheduled dose adjustments.
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Section 3.8.3.3, 
Documenting 
Reasons for 
Treatment 
Discontinuation
A subject may discontinue IMP for a 
number of reasons including those 
listed below:
...

Rash (see Section 5.3).
A subject may discontinue IMP for a 
number of reasons including those listed 
below:
...

Rash (regardless of severity or 
seriousness) (see Section 5.4)
Section 3.8.3.4, 
Withdrawal of 
Consent
A subject may, however, indicate that 
further trial participation is creating a 
burden on their work or social 
schedule.  Therefore, the investigator 
should follow the procedures outlined 
in Section 3.8.3.3 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.
A subject may, however, indicate that 
further trial participation is creating a 
burden on their work or social schedule.  
Therefore, the investigator should follow 
the procedures outlined in Section 3.8.3.3
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.  If a 
subject will miss/misses a trial visit, the 
investigator should contact the medical 
monitor to discuss the potential to 
retain the subject.  Depending on how 
many doses of IMP the subject will 
miss/misses, the sponsor, medical 
monitor, and investigator will 
determine if the subject is able to 
continue in the trial and at which dose 
the subject will resume, taking into 
consideration any scheduled and 
unscheduled dose adjustments.  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.
Section 3.10, 
Definition of 
Completed 
Subjects
For purposes of this trial, subjects who 
complete Day 56 Visit will be defined 
as trial completers.
For purposes of this trial, subjects who 
complete Day 56 (± 1 day) Visit will be 
defined as trial completers.
Table 4.1-1, List of 
Medications 
Prohibited Before 
the Trial
6.  CYP2B6 inhibitors, CYP2D6 
inhibitors, and CYP3A4 inhibitors and 
inducers
6.  CYP2B6 inhibitors, CYP2D6 
inhibitors, CYP2D6 substrates with a 
narrow therapeutic index, and CYP3A4 
inhibitors and inducers
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Table 4.1-2, List of 
Medications 
Prohibited During 
the Trial
3.  CYP2B6 inhibitors, CYP2D6 
inhibitors, or CYP3A4 inhibitors and 
inducers.  Selected CYP2B6 inhibitor 
is: ticlopidine.  Selected CYP2D6 
inhibitors are: celecoxib, hydroxyzine, 
chloroquine, methadone, 
chlorpheniramine, moclobemide, 
clemastine, paroxetine, clomipramine, 
pyrilamine, diphenhydramine, 
quinidine, fluoxetine, terbinafine, 
halofantrine, tripelennamine.  Selected 
CYP3A4 inhibitors are ....  
3.  CYP2B6 inhibitors, CYP2D6 
inhibitors, CYP2D6 substrates with a 
narrow therapeutic index, or CYP3A4 
inhibitors and inducers.  Selected 
CYP2B6 inhibitor is: ticlopidine.  
Selected CYP2D6 inhibitors are: 
celecoxib, hydroxyzine, chloroquine, 
methadone, chlorpheniramine, 
moclobemide, clemastine, paroxetine, 
clomipramine, pyrilamine, 
diphenhydramine, quinidine, fluoxetine, 
terbinafine, halofantrine, tripelennamine.  
Selected CYP2D6 substrates are: 
thioridazine, pimozide, desipramine, 
eliglustat, metoprolol, nebivolol, 
nortriptyline, perphenazine, 
tolterodine, venlafaxine, amitriptyline, 
encainide, imipramine, propafenone, 
propranolol, tramadol, trimipramine.  
Selected CYP3A4 inhibitors are ....  
Section 4.2.1, 
Restricted 
Therapies and 
Precautions
Investigators should discourage the use 
of caffeine and caffeine-containing 
products.
Investigators should inform subjects that 
normal consumption of caffeine is 
permitted.
Section 5.1, 
Definitions
Immediately Reportable Event (IRE):  
...

Rash (see Section 5.3).
Immediately Reportable Event (IRE):  
...

Rash (regardless of severity or 
seriousness) (see Section 5.4).
Section 5.4, 
Adverse Events of 
Special Interest
Not applicable (newly added section)
5.4  Adverse Events of Special Interest
Newly acquired skin eruptions that are 
nontraumatic will be considered 
adverse events of special interest 
(AESI).  These may include, but are not 
limited to, eruptions such as skin 
rashes, skin irritations, skin reactions, 
or acneiform lesions. 
Extra measures that must be 
performed to characterize any skin 
AESI of a newly acquired skin eruption 
that is nontraumatic are specified in
Appendix 11 through Appendix 14.  
The trial site will have a local 
designated dermatologist available for 
immediate consultation during the trial 
for these AESIs.
Section 7.1, Sample 
Size
The trial will enroll approximately 
201 subjects in expectation to have 
about 150 completers (50 per arm) at 
the end of the trial.  
The trial will enroll approximately 
201 subjects in expectation to have about 
150 completers at the end of the trial.  
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Section 7.2, 
Datasets for 
Analysis
Modified Intent-to-Treat Sample: All 
subjects in the Randomized Sample 
who took at least one dose of IMP and 
have a baseline and at least one post 
randomization evaluation for the 
CAARS-O:SV ADHD Symptoms Total 
Score (18-items).
Modified Intent-to-Treat Sample:  All 
subjects in the Randomized Sample who 
took at least one dose of IMP and have a 
baseline and at least one post 
randomization evaluation for the 
investigator-administered
CAARS-O:SV ADHD Symptoms Total 
Score (18-items).
Section 7.3, 
Handling of 
Missing Data
The CAARS-O:SV is utilized as the 
primary efficacy assessment of a 
subject’s level of ADHD.  The 
CAARS-O:SV is a 30-item scale 
containing 3 subscales:  the 9-item 
Inattentive Symptoms Subscale (sum of 
items 1, 9, 13, 14, 19, 21, 26, 29, and 
30), the 9-item Hyperactive/Impulsive 
Symptoms Subscale (sum of items 2, 4, 
6, 8, 16, 18, 22, 25, and 27), and the 
12-item ADHD Index (sum of items 3, 
5, 7, 10, 11, 12, 15, 17, 20, 23, 24, and 
28).  The 18-item ADHD Symptoms 
Total Score (sum of the Inattentive 
Symptoms Subscale and the 
Hyperactive/Impulsive Symptoms 
Subscale) is considered to be the 
primary efficacy measure.  
The 18-item, investigator-administered
CAARS-O:SV is utilized as the primary 
efficacy assessment of a subject’s level of 
ADHD.  The 18-item ADHD Symptoms 
Total Score (sum of the Inattentive 
Symptoms Subscale and the 
Hyperactive/Impulsive Symptoms 
Subscale) is considered to be the primary 
efficacy measure.
Section 7.3, 
Handling of 
Missing Data
In general, missing data will be handled 
by analysis of mixed-effect model 
repeated measures (MMRM) 
methodology based on observed case 
(OC) data from protocol-specified 
visits under the assumption of missing 
at random.  
In general, for primary analysis of 
efficacy endpoints, missing data will be 
handled by analysis of mixed-effect 
model repeated measures (MMRM) 
methodology based on observed case 
(OC) data from protocol-specified visits 
under the assumption of missing at 
random.  
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Section 7.4.1, 
Primary Endpoint 
Analysis
The primary efficacy endpoint is the 
mean change from baseline to the 
Day 56 Visit in the CAARS-O:SV 
score in the OPC-64005 group 
compared with the atomoxetine group.  
Analysis will be performed using 
modified intent-to-treat data set. 
Bayesian posterior probability of true 
baseline corrected difference at Week 8 
between treatment arms (OPC-64005 
and atomoxetine) being larger than 
4 points on CAARS-O:SV given 
estimates of means and standard 
deviations (SD) in the treatment arms 
will be calculated. ...
The change from baseline in 
CAARS-O:SV will be analyzed using
an MMRM methodology with the 
unstructured variance covariance 
matrix.  The model will include fixed 
class-effect terms for treatment, trial 
site, visit week an interaction term of 
treatment by visit week, and baseline 
CAARS-O:SV as a covariate. ...
The primary efficacy endpoint is the mean 
change from baseline to the Day 56 
(± 1 day) Visit in the 18-item, 
investigator-administered
CAARS-O:SV score in the OPC-64005 
group compared with the atomoxetine 
group.  Analysis will be performed using 
modified intent-to-treat data set. 
Bayesian posterior probability of true 
baseline corrected difference at Week 8 
between treatment arms (OPC-64005 and 
atomoxetine) being larger than 4 points on 
the 18-item, investigator-administered
CAARS-O:SV given estimates of means 
and standard deviations (SD) in the 
treatment arms will be calculated. ...
The change from baseline in the 18-item, 
investigator-administered
CAARS-O:SV will be analyzed using an 
MMRM methodology with the 
unstructured variance covariance matrix.  
The model will include fixed class-effect 
terms for treatment, trial site, visit week 
an interaction term of treatment by visit 
week, and baseline 18-item, investigator-
administered CAARS-O:SV as a 
covariate. ...
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Section 7.4.2, 
Other Endpoint 
Analysis
Other key efficacy variables are as 
follows:
1)
Mean change from baseline to each 
weekly visit (other than Day 56) in 
the CAARS-O:SV score in the 
OPC-64005 group relative to the 
atomoxetine and placebo groups
2)
Mean change from baseline to the 
Day 28 and Day 56 Visits for the 
ADHD RS-5 with Adult Prompts 
score in the OPC-64005 group 
relative to the atomoxetine and 
placebo groups
3)
Mean change from baseline to each 
weekly visit in the CGI-S score in 
the OPC-64005 group relative to 
the atomoxetine and placebo 
groups
4)
Mean CGI-I score at each weekly 
visit in the OPC-64005 group 
relative to the atomoxetine and 
placebo groups
5)
Mean change from baseline to each 
weekly visit in the CAARS-S:SV
in the OPC-64005 group relative to 
the atomoxetine and placebo 
groups
6)
Mean change from baseline to the 
Day 28 and Day 56 Visits in the 
AAQoL in the OPC-64005 group 
relative to the atomoxetine and 
placebo groups
Other key efficacy variables are as 
follows:
1)
Mean change from baseline to each 
scheduled visit (other than Day 56) 
in the 18-item, investigator-
administered CAARS-O:SV score in 
the OPC-64005 group relative to the 
atomoxetine and placebo groups
2)
Mean change from baseline to the 
Day 28 (± 1 day) and Day 56 
(± 1 day) Visits for the AISRS with 
Adult Prompts score in the 
OPC-64005 group relative to the 
atomoxetine and placebo groups
3)
Mean change from baseline to each 
scheduled visit in the CGI-S score in 
the OPC-64005 group relative to the 
atomoxetine and placebo groups
4)
Mean CGI-I score at each scheduled
visit in the OPC-64005 group relative 
to the atomoxetine and placebo 
groups
5)
Mean change from baseline to each 
scheduled visit in the 18-item 
CAARS-S:SV in the OPC-64005 
group relative to the atomoxetine and 
placebo groups
6)
Mean change from baseline to the 
Day 28 (± 1 day) and Day 56 
(± 1 day) Visits in the AAQoL in the 
OPC-64005 group relative to the 
atomoxetine and placebo groups
Section 7.4.2, 
Other Endpoint 
Analysis
The placebo group is included in this 
trial to provide direct estimates of 
effect for powering a Phase 3 trial.
Details on other analyses will be 
provided in the SAP.
Section 7.6, Safety 
Analysis
Standard safety variables to be 
analyzed include AEs, clinical 
laboratory tests, vital signs, ECGs, 
body weight, waist circumference, and 
BMI (derived programmatically from 
body weight and height measurements).
Standard safety variables to be analyzed 
include AEs, clinical laboratory tests, 
vital signs, and ECGs.
Section 7.6.1, 
Adverse Events
The incidence of the following events 
will be summarized by treatment 
group:

TEAEs

TEAEs by severity
...
The above summaries will also be 
prepared for TEAEs potentially 
causally related to the IMP.
The incidence of the following events will 
be summarized by treatment group:

TEAEs

TEAEs by severity

Potentially drug-related TEAEs
...
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Appendix 8, 
Clinical Global 
Impression -
Improvement Scale 
(CGI-I)
Not applicable
Newly added appendix
Appendix 9, Adult 
ADHD Quality of 
Life Scale 
(AAQoL)
Not applicable
Newly added appendix
Appendix 10, 
Profile of Mood 
States-Brief Form 
(POMS)
Not applicable
Newly added appendix
Appendix 11, 
OPC-64005 Skin 
AESI Workup 
Instructions 
Not applicable
Newly added appendix
Appendix 12, 
OPC-64005 Skin 
AESI Worksheet 
for Trial Site 
Not applicable
Newly added appendix
Appendix 13, 
OPC-64005 Skin 
AESI Worksheet 
for Local 
Dermatologist 
Not applicable
Newly added appendix
Appendix 14, 
OPC-64005 Skin 
AESI Worksheet 
for Central 
Dermatologist 
Not applicable
Newly added appendix
ADDITIONAL RISK TO THE SUBJECT:
There is no additional risk to the subjects.
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Amendment Number:
2
Issue Date:
28 Aug 2017
PURPOSE:
The purpose of this protocol amendment is to:

Remove abstinence as a method of birth control

Add a urine alcohol and drug screen at each scheduled visit

Add an IMP compliance application (AiCure platform)

Add the MGH-ATRQ-ADHD

Modify inclusion criterion #4 

Add inclusion criteria regarding the use of the AiCure platform and a smartphone

Modify exclusion criterion #2, #3, and #21

Remove exclusion criteria #4 and #5

Add an exclusion criterion to note that employees or relatives of employees of the 
trial site cannot participate in the trial

Add an exclusion criterion to note that family members or cohabitants of currently 
enrolled subjects will be excluded

Add FSH as a laboratory test

Add additional laboratory tests to Table 3.7.3.2-1

Add additional analyses for PK blood samples

Add cannabinoids to the list of prohibited medications
The following additional changes were made for clarification or administrative purposes:

Updated Appendix 11 through Appendix 14 (skin AESI workup instructions and 
worksheets)

Removed “designated” for “local designated dermatologist”

Added that a subject who is titrated down to a lower dose should be maintained on 
that low dose for a minimum of 4 days before being titrated back up to the higher 
dose  

Added that dosing should be held on scheduled visit days until the subject is in the 
clinic and that subjects will be dosed from a newly dispensed blister card

Clarified that a treatment card will be issued at baseline for Days 5 to 6

Removed the specific time required for dosing

Modified restrictions around psychotherapy

Corrected a typographical error in reference #39
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BACKGROUND:
The rationale for the changes in this protocol amendment is as follows:

Abstinence was removed as requested by the FDA (given reliability concerns)

A urine and alcohol drug screen was added at each scheduled visit as requested by the 
FDA

The AiCure platform was added to assess compliance with the IMP

The MGH-ATRQ-ADHD was added to assess medication history, specifically for the 
treatment of ADHD

Inclusion criterion #4 was modified to remove prior successful treatment for ADHD

Inclusion criteria #8 and #9 were added for consistency with the AiCure platform (the 
previous inclusion criteria #8 and #9 were renumbered to #10 and #11, respectively)

Exclusion criterion #2 was modified for consistency with the rest of the protocol

Exclusion criterion #3 was modified to include the MGH-ATRQ-ADHD

Exclusion criterion #4 was removed as requested by the FDA (newly diagnosed 
subjects are now permitted to enroll in the trial)

Exclusion criterion #5 was removed as newly diagnosed subjects are now permitted 
to enroll in the trial

Exclusion criterion #21 was modified to replace “cocaine” with “cannabinoids”
(which includes marijuana) and add that there are no exceptions

Exclusion criterion #30 was added to reduce bias in the trial

Exclusion criterion #31 was added to exclude enrollment of family members or 
cohabitants of currently enrolled subjects in order to reduce bias and risk of 
unblinding

FSH was added as a laboratory test for female subjects who have been 
postmenopausal for at least 12 consecutive months

Additional laboratory tests were added to Table 3.7.3.2-1 for consistency with the rest 
of the protocol

Added that PK blood samples may be analyzed for atomoxetine and/or other analytes 
to confirm compliance

Cannabinoids was added to the list of prohibited medications for consistency
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MODIFICATIONS TO PROTOCOL:
Sectional Revisions:
Location
Old Text
Updated Text
Synopsis, Inclusion 
Criteria
Subjects with a primary Diagnostic and 
Statistical Manual of Mental Disorders, 
Fifth Edition (DSM-5) diagnosis of 
ADHD (including predominantly 
inattentive presentation, hyperactive 
presentation, and combined 
presentations) as confirmed by the 
Adult ADHD Clinical Diagnostic 
Scale, version 1.2 (ACDS v1.2).  
Subjects must have received prior 
successful treatment (pharmacotherapy) 
for adult ADHD based on medical 
records and the principal investigator’s 
judgment.  Subjects may be currently 
receiving treatment for adult ADHD at 
screening, but it is not necessary that 
are currently receiving treatment.
Subjects with a primary Diagnostic and 
Statistical Manual of Mental Disorders, 
Fifth Edition (DSM-5) diagnosis of 
ADHD (including predominantly 
inattentive presentation, hyperactive 
presentation, and combined presentations) 
as confirmed by the Adult ADHD Clinical 
Diagnostic Scale, version 1.2 (ACDS 
v1.2).  Subjects may be currently 
receiving treatment for adult ADHD at 
screening, but it is not necessary that they 
are currently receiving treatment.
Synopsis, 
Investigational 
Medicinal 
Product(s), Dose, 
Dosage regimen, 
Treatment period, 
Formulation, Mode 
of Administration:
During the Treatment Period (Days 5 -
56), subjects randomized to the 
OPC-64005 arm will receive 30 mg 
OPC-64005 and atomoxetine placebo 
daily, subjects randomized to the 
atomoxetine arm will receive 80 mg of 
atomoxetine and OPC-64005 placebo 
daily, and subjects randomized to the 
placebo arm will receive both 
OPC-64005 placebo and atomoxetine 
placebo daily.  If a subject is not able to 
tolerate the 30-mg dose of OPC-64005, 
the dose may be reduced to 20 mg for 
the duration of the Treatment Period.  If 
a subject is not able to tolerate the 
80-mg dose of atomoxetine, the dose 
may be reduced to 40 mg of 
atomoxetine for the duration of the 
Treatment Period.  Subjects are 
permitted to have one dose reduction 
and one titration back up to their 
previous dose (ie, 30 mg for 
OPC-64005 and 80 mg for 
atomoxetine) during the trial.
During the Treatment Period (Days 5 -
56), subjects randomized to the 
OPC-64005 arm will receive 30 mg 
OPC-64005 and atomoxetine placebo 
daily, subjects randomized to the 
atomoxetine arm will receive 80 mg of 
atomoxetine and OPC-64005 placebo 
daily, and subjects randomized to the 
placebo arm will receive both OPC-64005 
placebo and atomoxetine placebo daily.  
If a subject is not able to tolerate the 
30-mg dose of OPC-64005, the dose may 
be reduced to 20 mg for the duration of 
the Treatment Period.  If a subject is not 
able to tolerate the 80-mg dose of 
atomoxetine, the dose may be reduced to 
40 mg of atomoxetine for the duration of 
the Treatment Period.  Subjects are 
permitted to have one dose reduction and 
one titration back up to their previous 
dose (ie, 30 mg for OPC-64005 and 
80 mg for atomoxetine) during the trial.  
When a subject is titrated down to a 
lower dose, they should be maintained
on that low dose for a minimum of 4 
days before being titrated back up to 
the higher dose.  On scheduled visit 
days (Days 7, 14, 21, 28, 42, and 56), 
dosing should be held until the subject 
is in the clinic; subjects will be dosed 
from a newly dispensed blister card.
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Synopsis, Criteria 
for Evaluation
Primary Endpoint:  The primary 
efficacy endpoint is the change from 
baseline to the Day 56 (± 1 day) Visit 
in the investigator-administered 
CAARS-O:SV 18-item ADHD 
symptoms total score in the 
OPC-64005 group relative to the 
atomoxetine group. 
Primary Endpoint:  The primary 
efficacy endpoint is the change from 
baseline to the Day 56 Visit on the 
investigator-administered CAARS-O:SV 
18-item ADHD symptoms total score in 
the OPC-64005 group relative to the 
atomoxetine group. 
Synopsis, 
Statistical Methods
Details of the planned statistical 
analysis will be presented in the 
protocol and in the statistical analysis 
plan (SAP).
Details of the planned statistical analysis 
will be presented in the statistical analysis 
plan (SAP).
Synopsis, 
Statistical Methods
Primary:  The primary efficacy 
endpoint is the change from baseline to 
the Day 56 (± 1 day) Visit in the 
investigator-administered CAARS-
O:SV 18-item ADHD symptoms total 
score in the OPC-64005 group relative 
to the atomoxetine group.  
Primary:  The primary efficacy endpoint 
is the change from baseline to the Day 56 
Visit on the investigator-administered 
CAARS-O:SV 18-item ADHD symptoms 
total score in the OPC-64005 group 
relative to the atomoxetine group.  
Section 3.1, 
Type/Design of 
Trial
Treatment Period:  During the 
Treatment Period (Days 5 - 56), 
subjects who are randomized to the 
OPC-64005 arm for Titration will 
continue in the OPC-64005 arm for 
Treatment.  Subjects randomized to the 
atomoxetine arm for Titration will 
continue in the atomoxetine arm for
Treatment. Subjects randomized to the 
placebo arm for Titration will continue 
in the placebo arm for Treatment.  
During the 8-week Titration/Treatment 
Period, subjects will have weekly or 
biweekly visits to the clinical site.  
Assessments to be performed during 
the trial are listed in Table 3.7-1.
Treatment Period:  During the Treatment 
Period (Days 5 - 56), subjects who are 
randomized to the OPC-64005 arm for 
Titration will continue in the OPC-64005 
arm for Treatment.  Subjects randomized 
to the atomoxetine arm for Titration will 
continue in the atomoxetine arm for 
Treatment. Subjects randomized to the 
placebo arm for Titration will continue in 
the placebo arm for Treatment.  During 
the 8-week Titration/Treatment Period, 
subjects will have weekly or biweekly 
visits to the clinical site.  On scheduled 
visit days (Days 7, 14, 21, 28, 42, and 
56), dosing should be held until the 
subject is in the clinic; subjects will be 
dosed from a newly dispensed blister 
card.  Assessments to be performed 
during the trial are listed in Table 3.7-1.
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Section 3.2, Trial 
Treatments
During the Treatment Period, subjects 
in the OPC-64005 group will receive 
daily 30-mg oral doses of OPC-64005 
and atomoxetine placebo.  During the 
Treatment Period, if a subject is not 
able to tolerate the 30-mg dose of 
OPC-64005, the dose may be reduced 
to 20 mg for the duration of the 
Treatment Period.  Subjects in the 
atomoxetine group will receive daily 
80-mg oral doses of atomoxetine and 
OPC-64005 placebo.  During the 
Treatment Period, if a subject is not 
able to tolerate the 80-mg dose of 
atomoxetine, the dose may be reduced 
to 40 mg of atomoxetine for the 
duration of the Treatment Period.  
Subjects are permitted to have one dose 
reduction and one titration back up to 
their previous dose (ie, 30 mg for 
OPC-64005 and 80 mg for 
atomoxetine) during the trial.  Subjects 
in the placebo group will receive daily 
oral doses of both OPC-64005 placebo 
and atomoxetine placebo.
During the Treatment Period, subjects in 
the OPC-64005 group will receive daily 
30-mg oral doses of OPC-64005 and 
atomoxetine placebo.  During the 
Treatment Period, if a subject is not able 
to tolerate the 30-mg dose of OPC-64005, 
the dose may be reduced to 20 mg for the 
duration of the Treatment Period.  
Subjects in the atomoxetine group will 
receive daily 80-mg oral doses of 
atomoxetine and OPC-64005 placebo.  
During the Treatment Period, if a subject 
is not able to tolerate the 80-mg dose of 
atomoxetine, the dose may be reduced to 
40 mg of atomoxetine for the duration of 
the Treatment Period.  Subjects are 
permitted to have one dose reduction and 
one titration back up to their previous 
dose (ie, 30 mg for OPC-64005 and 
80 mg for atomoxetine) during the trial.  
When a subject is titrated down to a 
lower dose, they should be maintained
on that low dose for a minimum of 4 
days before being titrated back up to 
the higher dose.  Subjects in the placebo 
group will receive daily oral doses of both 
OPC-64005 placebo and atomoxetine 
placebo.  On scheduled visit days 
(Days 7, 14, 21, 28, 42, and 56), dosing 
should be held until the subject is in the 
clinic; subjects will be dosed from a 
newly dispensed blister card.  
Table 3.2-1, Dosing 
Schedule
Time
8:00 am
(AM dosing)
Time
AM dosing
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Table 3.2-1, Dosing 
Schedule
bMay be reduced to 20 mg if the 30 
mg dose is not tolerable.  Subjects 
are permitted to have one dose 
reduction and one titration back 
up to their previous dose (ie, 30 
mg for OPC-64005) during the 
trial.  
cMay be reduced to 40 mg if the 80 
mg dose is not tolerable.  Subjects 
are permitted to have one dose 
reduction and one titration back 
up to their previous dose (ie, 80 
mg for atomoxetine) during the 
trial.  
bMay be reduced to 20 mg if the 30 
mg dose is not tolerable.  Subjects 
are permitted to have one dose 
reduction and one titration back up 
to their previous dose (ie, 30 mg for 
OPC-64005) during the trial.  When 
a subject is titrated down to a 
lower dose, they should be 
maintained on that low dose for a 
minimum of 4 days before being 
titrated back up to the higher 
dose.  
cMay be reduced to 40 mg if the 80 mg 
dose is not tolerable.  Subjects are 
permitted to have one dose 
reduction and one titration back up 
to their previous dose (ie, 80 mg for 
atomoxetine) during the trial.  
When a subject is titrated down to 
a lower dose, they should be 
maintained on that low dose for a 
minimum of 4 days before being 
titrated back up to the higher 
dose.  
Section 3.3.1, 
Number of Subjects 
and Description of 
Population
To assure that ADHD is the primary 
diagnosis, the Mini International 
Neuropsychiatric Interview (M.I.N.I.) 
will be used to identify and exclude 
other psychiatric conditions.50  
Subjects identified with a current or 
lifetime history of bipolar disorder, 
schizophrenia, other psychotic disorder, 
or personality disorder will not be 
eligible for enrollment.  Subjects must 
have a history of adequate symptom 
reduction with stimulants or 
nonstimulant ADHD medication.  
To confirm that ADHD is the primary 
diagnosis, the Mini International 
Neuropsychiatric Interview (M.I.N.I.) will 
be used to identify and exclude other 
psychiatric conditions.50  Subjects 
identified with a current or lifetime 
history of bipolar disorder, schizophrenia, 
other psychotic disorder, or personality 
disorder will not be eligible for 
enrollment.  Medication history, 
specifically for the treatment of ADHD, 
will be assessed using the 
Massachusetts General Hospital 
Treatment Response Questionnaire 
(ATRQ) - ADHD 
(MGH-ATRQ-ADHD).51
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Table 3.4.2-1, 
Inclusion Criteria
4. Subjects with a primary DSM-5 
diagnosis of ADHD (including 
predominantly inattentive presentation, 
hyperactive presentation, and combined 
presentations) as confirmed by the 
ACDS v1.2.  Subjects must have 
received prior successful treatment 
(pharmacotherapy) for adult ADHD 
based on medical records and the 
principal investigator’s judgment.  
Subjects may be currently receiving 
treatment for adult ADHD at screening, 
but it is not necessary that they are 
currently receiving treatment.  The 
rationale to discontinue current ADHD 
treatment must include either or both 
suboptimal efficacy response and/or 
treatment limiting safety/tolerability.
4. Subjects with a primary DSM-5 
diagnosis of ADHD (including 
predominantly inattentive presentation, 
hyperactive presentation, and combined 
presentations) as confirmed by the ACDS 
v1.2.  Subjects may be currently receiving 
treatment for adult ADHD at screening, 
but it is not necessary that they are 
currently receiving treatment.  The 
rationale to discontinue current ADHD 
treatment must include either or both 
suboptimal efficacy response and/or 
treatment limiting safety/tolerability.
Table 3.4.2-1, 
Inclusion Criteria
Not applicable (newly added inclusion 
criterion)
8. Subjects must be able and willing to 
utilize the AiCure Platform for each 
daily dose.
Table 3.4.2-1, 
Inclusion Criteria
Not applicable (newly added inclusion 
criterion)
9. Subjects likely to possess the capacity 
to utilize the technology interfaces (eg, 
open and navigate software 
applications using the touch screen) 
and telephone features of a 
smartphone.
Table 3.4.2-1, 
Inclusion Criteria
8. Subjects who have an AISRS with 
Adult Prompts score of ≥26.
10. Subjects who have an AISRS with 
Adult Prompts score of ≥26.
Table 3.4.2-1, 
Inclusion Criteria
9. Subjects who have a score of ≥ 4 on 
the CGI-S.
11. Subjects who have a score of ≥ 4 on 
the CGI-S.
Table 3.4.3-1, 
Exclusion Criteria
2. Sexually active males or WOCBP 
who do not agree to practice 2 different 
methods of birth control or remain 
abstinent during the trial and for 
30 days after the last dose of IMP.  If 
employing birth control, 2 of the 
following precautions must be used: 
vasectomy, tubal ligation, vaginal 
diaphragm, intrauterine device, birth 
control pill, birth control implant, birth 
control depot injection, condom with 
spermicide, or sponge with spermicide.
2. All males and WOCBP who do not 
agree to practice 2 methods of birth 
control during the trial and for 30 days 
after the last dose of IMP.  Two of the 
following precautions must be used: 
vasectomy, tubal ligation, vaginal 
diaphragm, intrauterine device, birth 
control pills, birth control depot injection, 
birth control implant, condom with 
spermicide, or sponge with spermicide.  
This exclusion does not apply for 
subjects confirmed, by medical record 
and/or prospective assessment, to be 
sterile (ie, women who have had a 
bilateral oophorectomy and/or 
hysterectomy or who have been 
postmenopausal for at least 12 
consecutive months, confirmed by FSH 
blood level; or men who have had a 
bilateral orchidectomy).
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Table 3.4.3-1, 
Exclusion Criteria
3. Subjects with a history of inadequate 
response or suboptimal tolerability to 
atomoxetine.  (In the investigator’s 
opinion, the subject was treated with an 
adequate dose for an adequate period of 
time, yet failed to show satisfactory 
response.)  
3. Subjects with a history of inadequate 
response or suboptimal tolerability to 
atomoxetine.  (The subject was treated 
with an adequate dose for an adequate 
period of time, yet failed to show 
satisfactory response.)  This will be 
confirmed using the 
MGH-ATRQ-ADHD.
Table 3.4.3-1, 
Exclusion Criteria
4. Subjects who are newly diagnosed, 
and have not received treatment for 
ADHD.
4. Criterion deleted by Amendment 2.
Table 3.4.3-1, 
Exclusion Criteria
5. Subjects who have an existing 
diagnosis of ADHD, and who have not 
demonstrated clinical improvement on 
an approved treatment for ADHD.
5. Criterion deleted by Amendment 2.
Table 3.4.3-1, 
Exclusion Criteria
21. Subjects with a positive drug screen 
for cocaine or other illicit drugs will be 
excluded and may not be retested or 
rescreened.  Subjects with a positive 
urine drug screen resulting from use of 
prescription or OTC medications may 
be retested or rescreened, at the 
discretion of the investigator.
21. Subjects with a positive drug screen 
for cannabinoids or illicit drugs will be 
excluded and may not be retested or 
rescreened.  There will be no exceptions, 
including subjects from states in which 
cannabinoids are considered legal.  
Subjects with a positive urine drug screen 
resulting from use of prescription or OTC 
medications may be retested or 
rescreened, at the discretion of the 
investigator.
Table 3.4.3-1, 
Exclusion Criteria
Not applicable (newly added exclusion 
criterion)
30. Employees or relatives of employees 
of the trial site cannot participate in the 
trial.
Table 3.4.3-1, 
Exclusion Criteria
Not applicable (newly added exclusion 
criterion)
31. Siblings and other family members, 
and those having the same place of 
residence as another subject, will be 
excluded.  Subjects whose 
family/household member has 
completed participation in the trial 
may be considered for enrollment.
Section 3.4.3, 
Exclusion Criteria
Nonchildbearing potential is defined as 
male and female subjects who are 
surgically sterile (ie, male subjects who 
have undergone bilateral orchidectomy 
and female subjects who have 
undergone bilateral oophorectomy 
and/or hysterectomy) and female 
subjects who have been 
postmenopausal for at least 
12 consecutive months.
Nonchildbearing potential is defined as 
male and female subjects who are 
surgically sterile (ie, male subjects who 
have undergone bilateral orchidectomy 
and female subjects who have undergone 
bilateral oophorectomy and/or 
hysterectomy) and female subjects who 
have been postmenopausal for at least 
12 consecutive months (confirmed by 
follicle-stimulating hormone [FSH] 
blood level).
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Section 3.5.1, 
Primary Endpoint
The primary efficacy endpoint is the 
change from baseline to the Day 56 
(± 1 day) Visit in the 
investigator-administered Conners' 
Adult ADHD Rating Scales–Observer: 
Screening Version (CAARS-O:SV) 
18-item ADHD symptoms total score 
in the OPC-64005 group relative to the 
atomoxetine group.  
The primary efficacy endpoint is the 
change from baseline to the Day 56 Visit 
on the investigator-administered Conners' 
Adult ADHD Rating Scales–Observer: 
Screening Version (CAARS-O:SV) 
18-item ADHD symptoms total score in 
the OPC-64005 group relative to the 
atomoxetine group.  
Table 3.7-1, 
Schedule of 
Assessments
Changes to Table 3.7-1 are summarized on the next page and are indicated by bold, 
underlined text.
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Table 3.7-1
Schedule of Assessments
Assessment
Screening
(Day −28 
to −1)
Baseline 
(Day 1)
Day 7 
(± 1 day)
Day 14 
(± 1 day)
Day 21 
(± 1 day)
Day 28 
(± 1 day)
Day 42 
(± 1 day)
Day 56 
(± 1 day)/ET
Follow-up
(3 ± 1 day)
Follow-up 
(30 + 2 days)
ENTRANCE CRITERIA
Inclusion/exclusion 
criteria
X
X
Demographic information
X 
Medical history
X 
Psychiatric history to 
confirm DSM-5 ADHD 
diagnosis using the 
ACDS v1.2
X 
Diagnosis confirmation 
and identification of 
comorbidities using the 
M.I.N.I.
X 
Investigator assessment of 
previous and current 
ADHD treatment using 
the MGH-ATRQ-ADHD
X
X
HIV, HBsAg, and 
anti-HCV
X 
Urine pregnancy testa
X
X
X
X
SAFETY
Physical examinationb
X 
X 
X
X
X
X
X
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
X 
X 
X 
X 
X 
Clinical laboratory
X 
X 
X 
X 
Urine alcohol and drug 
screen
X 
X
X
X
X 
X 
X 
X 
C-SSRS
X 
X 
X 
X 
X 
X 
X 
X 
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Table 3.7-1
Schedule of Assessments
Assessment
Screening
(Day −28 
to −1)
Baseline 
(Day 1)
Day 7 
(± 1 day)
Day 14 
(± 1 day)
Day 21 
(± 1 day)
Day 28 
(± 1 day)
Day 42 
(± 1 day)
Day 56 
(± 1 day)/ET
Follow-up
(3 ± 1 day)
Follow-up 
(30 + 2 days)
EFFICACY
18-item, 
investigator-administered 
CAARS-O:SVc
X 
X 
X 
X 
X 
X 
X 
X 
AISRS with Adult 
Prompts  
X 
X 
X 
X 
CGI-S
X 
X 
X 
X 
X 
X 
X 
X 
CGI-I
X 
X 
X 
X 
X 
X 
18-item CAARS-S:SVc
X
X
X
X
X
X
X
AAQoL
X
X
X
POMS
X
X
X
X
X
X
X
X
CLINIC PROCEDURES
Dispense IMP and 
download the AiCure 
platform or receive  
device with the AiCure 
platform predownloaded
X
IMP administrationd
X
X
X
X
X
X
X
IMP return and 
accountability / AiCure
compliance
X
X
X
X
X
X
PK blood samples
Xe
Xf
Xg
Xh
    
Pharmacogenomic sample 
for CYP2D6 testing
X
FBR blood samplei
X
DEQ 
X 
X
X
X
X
X
X 
Record AEs
X 
X 
X 
X 
X 
X 
X 
X 
X
X 
Record concomitant 
medication
X 
X 
X 
X 
X 
X 
X 
X 
X
X 
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Table 3.7-1
Schedule of Assessments
Assessment
Screening
(Day −28 
to −1)
Baseline 
(Day 1)
Day 7 
(± 1 day)
Day 14 
(± 1 day)
Day 21 
(± 1 day)
Day 28 
(± 1 day)
Day 42 
(± 1 day)
Day 56 
(± 1 day)/ET
Follow-up
(3 ± 1 day)
Follow-up 
(30 + 2 days)
Return trial-provided 
mobile device (if 
applicable)
X
Telephone contact
X
X 
FBR = future biospecimen research; POMS = Profile of Mood States-Brief Form™.
aIf the urine pregnancy test is positive, the result should be confirmed with a serum pregnancy test.  Additional urine pregnancy testing may be done at the 
discretion of the investigator.
bA physical examination will be performed at the Screening, Baseline, and Day 56 (± 1 day)/ET Visits.  Weight, height, and waist circumference will be 
recorded at the Screening Visit.  A focused examination for the detection of rash will be performed at the Day 7, 14, 21, 28, and 42 Visits; all visits have a 
± 1-day window.  Subjects will be instructed to contact the site if rash is noted at any other time, and an unscheduled visit will be arranged.
cThe 18-item CAARS-S:SV should be conducted before the 18-item, investigator-administered CAARS-O:SV at each scheduled assessment, giving the 
investigator a chance to review the self-report before completing their own assessment.
dSubjects will receive daily doses of IMP starting on Day 1.  At the baseline visit, subjects will receive a titration card for dosing on Days 1 to 4 and a 
treatment card for dosing on Days 5 to 6.  During the treatment period, subjects will receive a treatment card(s) for dosing on scheduled visits.  On 
scheduled visit days (Days 7, 14, 21, 28, 42, and 56), dosing should be held until the subject is in the clinic; subjects will be dosed from a newly 
dispensed blister card.
eDay 1 samples collected predose and 1 and 3 hours postdose.
fDay 7 (± 1 day) samples collected predose and 2 hours postdose.
gDay 14 (± 1 day) samples collected predose and 3 hours postdose.
hDay 21(± 1 day) samples collected predose.
iFBR sample will be collected once the subject has provided consent for FBR.
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Section 3.7.1.1, 
Screening

The investigator will assess and 
record previous ADHD medications.  
Subjects must have a history of 
adequate symptom reduction with 
stimulants or nonstimulant ADHD 
medication.  If applicable, washout 
from ADHD medications will begin.  
The washout period will be 
equivalent to 5 half-lives before 
Baseline (Day 1).

The investigator will assess and 
record previous ADHD medications 
using the MGH-ATRQ-ADHD.  If 
applicable, washout from ADHD 
medications will begin.  The 
washout period will be equivalent to 
5 half-lives before Baseline (Day 1).
Section 3.7.1.1, 
Screening

Urine will be collected from all 
potential subjects for urine screen(s) 
for alcohol and drugs of abuse, 
including amphetamines, 
barbiturates, benzodiazepines, 
cannabinoids, cocaine, opiates, 
phencyclidine, and marijuana

Urine will be collected from all 
potential subjects for urine screen(s) 
for alcohol and drugs of abuse, 
including amphetamines, 
barbiturates, benzodiazepines, 
cannabinoids, cocaine, opiates, and 
phencyclidine
Section 3.7.1.2, 
Baseline (Day 1)
Not applicable (newly added bullet)

Urine will be collected from all 
potential subjects for urine 
screen(s) for alcohol and drugs of 
abuse, including amphetamines, 
barbiturates, benzodiazepines, 
cannabinoids, cocaine, opiates, 
and phencyclidine.
Section 3.7.1.2, 
Baseline (Day 1)

Subjects will receive a titration card 
for dosing on Days 1 to 4 and a 
treatment card for dosing on Days 5 
to 7.

Subjects will receive a titration card 
for dosing on Days 1 to 4 and a 
treatment card for dosing on Days 5 
to 6.
Section 3.7.1.2, 
Baseline (Day 1)
Not applicable (newly added bullet)

The IMP will be dispensed and the 
subject will download the AiCure 
platform or receive a provisioned
device with the AiCure platform
predownloaded and will be trained 
on IMP compliance using this 
application.  Subjects will be 
instructed to take their first dose 
of IMP from the titration card in 
the clinic.
Section 3.7.1.3, 
Treatment Period 
Visits (Day 7 
Through Day 56 
Visits)

At the Day 28 (± 1 day) and Day 56 
(± 1 day) Visits, blood and urine 
samples will be collected for clinical 
laboratory tests, including 
hematology, serum chemistry, and 
urinalysis (see Table 3.7.3.2-1).

At the Day 28 (± 1 day) and Day 56 
(± 1 day)/ET Visits, blood and urine 
samples will be collected for clinical 
laboratory tests, including 
hematology, serum chemistry, and 
urinalysis (see Table 3.7.3.2-1).
Section 3.7.1.3, 
Treatment Period 
Visits (Day 7 
Through Day 56 
Visits)

Urine will be collected from all 
potential subjects for urine screen(s) 
for alcohol and drugs of abuse, 
including amphetamines, 
barbiturates, benzodiazepines, 
cannabinoids, cocaine, opiates, 
phencyclidine, and marijuana at the 
Day 56 (± 1 day)/ET Visit.

At each visit, urine will be collected 
from all potential subjects for urine 
screen(s) for alcohol and drugs of 
abuse, including amphetamines, 
barbiturates, benzodiazepines, 
cannabinoids, cocaine, opiates, and 
phencyclidine.
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Section 3.7.1.3, 
Treatment Period 
Visits (Day 7 
Through Day 56 
Visits)

At the Day 28 (± 1 day) and Day 56 
(± 1 day) Visits, the AISRS with 
Adult Prompts will be administered.

At the Day 28 (± 1 day) and Day 56 
(± 1 day)/ET Visits, the AISRS with 
Adult Prompts will be administered.
Section 3.7.1.3, 
Treatment Period 
Visits (Day 7 
Through Day 56 
Visits)

At the Day 28 (± 1 day) and Day 56 
(± 1 day) Visits, the subject will 
complete the AAQoL.

At the Day 28 (± 1 day) and Day 56 
(± 1 day)/ET Visits, the subject will 
complete the AAQoL.
Section 3.7.1.3, 
Treatment Period 
Visits (Day 7 
Through Day 56 
Visits)

Subjects will receive a treatment 
card(s) for dosing on scheduled 
visits.

Subjects will receive a treatment 
card(s) for dosing on scheduled 
visits.  On scheduled visit days 
(Days 7, 14, 21, 28, 42, and 56), 
dosing should be held until the 
subject is in the clinic; subjects 
will be dosed from a newly 
dispensed blister card.
Section 3.7.1.3, 
Treatment Period 
Visits (Day 7 
Through Day 56 
Visits)
Not applicable (newly added bullet)

At each visit, IMP returns, 
accountability, and subject 
compliance with the IMP will be 
assessed.
Section 3.7.1.3, 
Treatment Period 
Visits (Day 7 
Through Day 56 
Visits)
Not applicable (newly added bullet)

At the Day 56 (± 1 day)/ET Visit, 
subjects will return the 
trial-provided mobile device (if 
applicable).
Table 3.7.3.2-1, 
Clinical 
Laboratory 
Assessments
Additional Tests:
Urine [or serum] pregnancy for WOCBP
Free T4 (free T4 is measured only if 
result for TSH is abnormal)
Additional Tests:
Urine (or serum) pregnancy for WOCBP
FSH (for female subjects who have 
been postmenopausal for at least 
12 consecutive months)
Free T4 (free T4 is measured only if 
result for TSH is abnormal)
Urine for alcohol and drugs of abuse, 
including amphetamines, barbiturates, 
benzodiazepines, cannabinoids, 
cocaine, opiates, and phencyclidine
C Reactive Protein (CRP) (if rash is 
detected)
Human herpes virus 6 (HHV-6) (if 
rash is detected and the signs and 
symptoms are suggestive of drug rash 
with eosinophilia and systemic 
symptoms [DRESS] or drug-induced 
hypersensitivity syndrome [DIHS])
Complete blood count with differential 
(if rash is detected)
Section 3.7.3.3, 
Physical 
Examination and 
Vital Signs
A physical examination will be performed 
at screening, baseline, and at Day 56 
(± 1 day).  
A physical examination will be 
performed at screening, baseline, and at 
Day 56 (± 1 day)/ET.  
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Section 3.7.4.1.1, 
Pharmacokinetic 
Blood Samples
Blood samples for the determination of 
OPC-64005 and its metabolite(s) will be 
collected at Baseline (Day 1) predose 
(within 15 minutes of dosing) and at 1 
and 3 hours postdose, at the Day 7 (± 1 
day) Visit predose (within 5 minutes of 
dosing) and at 2 hours postdose, at the 
Day 14 (± 1 day) Visit predose (within 5 
minutes of dosing) and at 3 hours 
postdose, and at the Day 21 (± 1 day) 
Visit predose (within 5 minutes of 
dosing).  In addition, every effort will be 
made to obtain a PK blood sample from 
any subject who experiences an SAE.  
Blood samples for the determination of 
OPC-64005 and its metabolite(s) will be 
collected at Baseline (Day 1) predose 
(within 15 minutes of dosing) and at 1 
and 3 hours postdose, at the Day 7 (± 1 
day) Visit predose (within 5 minutes of 
dosing) and at 2 hours postdose, at the 
Day 14 (± 1 day) Visit predose (within 5 
minutes of dosing) and at 3 hours 
postdose, and at the Day 21 (± 1 day) 
Visit predose (within 5 minutes of 
dosing).  Samples may also be analyzed 
for atomoxetine and/or other analytes 
to confirm compliance.  In addition, 
every effort will be made to obtain a PK 
blood sample from any subject who 
experiences an SAE.  
Section 3.8.3.1, 
Down Titration of 
Treatment
During the Treatment Period, if a subject 
is not able to tolerate the 30-mg dose of 
OPC-64005, the dose may be reduced to 
20 mg for the duration of the Treatment 
Period.  If a subject is not able to tolerate 
the 80-mg dose of atomoxetine, the dose 
may be reduced to 40 mg for the duration 
of the Treatment Period.  Subjects are 
permitted to have one dose reduction and 
one titration back up to their previous 
dose (ie, 30 mg for OPC-64005 and 80 
mg for atomoxetine) during the trial. 
During the Treatment Period, if a subject 
is not able to tolerate the 30-mg dose of 
OPC-64005, the dose may be reduced to 
20 mg for the duration of the Treatment 
Period.  If a subject is not able to tolerate 
the 80-mg dose of atomoxetine, the dose 
may be reduced to 40 mg for the duration 
of the Treatment Period.  Subjects are 
permitted to have one dose reduction and 
one titration back up to their previous 
dose (ie, 30 mg for OPC-64005 and 
80 mg for atomoxetine) during the trial.  
When a subject is titrated down to a 
lower dose, they should be maintained
on that low dose for a minimum of
4 days before being titrated back up to 
the higher dose.  
Section 3.12, 
Subject 
Compliance
Responsible trial personnel will dispense 
the IMP (ie, OPC-64005, atomoxetine, 
and placebo) to subjects.  Accountability 
and compliance verification should be 
documented in the subject’s trial records.  
Subjects must be counseled on the 
importance of taking the IMP as directed 
at all trial visits.  If poor compliance 
continues (eg, multiple missed doses 
resulting in less than 80% overall 
compliance), discontinuation of the 
subject from the trial should be 
considered.
Responsible trial personnel will dispense 
the IMP (ie, OPC-64005, atomoxetine, 
and placebo) to subjects.  Accountability 
and compliance verification should be 
documented in the subject’s trial records.  
Subjects must be counseled on the 
importance of taking the IMP as directed 
at all trial visits.  If poor compliance 
continues (eg, multiple missed doses 
resulting in less than 80% overall 
compliance), discontinuation of the 
subject from the trial should be 
considered.
Details on the AiCure technology to be 
used in this trial to assess IMP 
compliance are provided below. 
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Section 3.12.1, 
IMP Adherence 
and Reminder 
System
Not applicable (newly added section)
This trial will employ an IMP 
adherence monitoring platform 
(“AiCure Platform”) for all subjects in 
the trial.  The AiCure Platform uses 
artificial intelligence on smartphones 
to confirm IMP ingestion.  In addition, 
built-in reminders and a 
communication system allow real-time 
intervention in case of IMP 
interruptions. 
Use of this AiCure Platform will in no 
way supersede or replace the physician 
and/or prescribed IMP protocol of the 
subjects.  Because the AiCure 
Platform does not change the IMP 
protocol of the subjects, but rather 
encourages adherence to the 
predefined protocol, use of this AiCure 
Platform presents minimal risk to the 
subjects.  Use of the AiCure Platform 
will be required for all subjects in the 
trial.
The monitoring AiCure Platform 
requires that all subjects take each 
dose of the IMP while using a 
smartphone.  The AiCure Platform 
will be provided to subjects preloaded 
on a smartphone, or subjects will 
download the AiCure Platform onto 
their own mobile device at baseline 
(Day 1). 
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When at home, subjects will receive an 
IMP reminder at a time within a 
predefined window.  This notification 
reminds subjects to take their IMP 
dose while using the AiCure Platform.  
Subjects will follow a series of 
prescribed steps in front of the 
front-facing webcam to visually 
confirm their ingestion of the IMP.  
The application on the smartphone 
will make an automated determination 
of whether the subject has properly 
taken their IMP at the prescribed 
time.  There is no need for the trial site 
staff to review the administration, nor 
would the trial site staff need to be 
available at the time the subject takes 
their IMP.  The amount of guidance 
that the device provides to the subjects 
is automatically reduced as the subject 
becomes more proficient at using the 
application.
After the device confirms proper IMP 
ingestion, video recordings will be 
encrypted and transmitted to a secure 
centralized location for further 
analysis, including testing for duplicate 
enrollment.  The captured data and 
video are reviewable through a roles 
and rules restricted system ensuring 
privacy of the information.  The 
system is compliant with the Health 
Insurance Portability and 
Accountability Act (HIPAA), which 
protects the privacy and security of 
healthcare information.
Phone numbers of the subjects may 
also be collected and stored in an 
encrypted manner.  Storing the phone 
numbers will allow for direct 
communication with subjects, 
including automated messaging from 
the AiCure Platform device and 
contact by the trial site staff or other 
monitoring personnel.  At no time is 
the phone number visible to the trial 
site staff or monitoring personnel on 
the AiCure Platform.  Individuals 
outside the trial sites will not be 
provided with subject names, nor will 
they be given access to subject medical 
records.
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Section 3.12.2, 
Subject Risk
Not applicable (newly added section)
The AiCure Platform provides no 
more than minimal risk to subjects.  
This protocol only introduces a 
smartphone-based monitoring 
application that prompts the user to 
take their IMP, verifies ingestion, and 
stores encrypted data securely for 
analysis.  When functioning properly, 
use of the AiCure Platform does not 
affect titration, dosage, route of 
administration, or treatment duration, 
conforming to any trial requirements 
as noted by trial site staff. 
It is possible, though very unlikely, 
that the AiCure application can fail to 
remind subjects to take the IMP or tell 
them to take their IMP when not 
required.  To date, AiCure has not 
encountered such a malfunction.  
All trial data, including any 
identifiable subject information, will 
be obtained and encrypted by the 
application.  Subjects will be coded 
according to the protocol and their 
identity will not be stored with the trial 
data obtained.  After the subject has 
taken the IMP and confirmation of 
proper ingestion has been completed, 
the encrypted data will be 
automatically forwarded to a secure 
server.  The server is compliant with 
the HIPAA, which protects the privacy 
and security of healthcare information.  
The data will be securely stored and 
only accessible to the trial site staff and 
other authorized personnel through 
two-way authentication. 
The data may also be retained in a 
secure manner beyond the term of the 
trial and utilized to improve the 
operation of the AiCure Platform, 
categorize adherence activity by 
disease state or other useful categories, 
and/or for regulatory filings by the 
AiCure Platform Provider to support 
future applications for the AiCure 
Platform Provider’s product.  
Individuals who are not associated 
with the care and treatment of subjects 
will not have access to subject identity 
or any medical records.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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Section 3.12.3, 
Subject 
Confidentiality
Not applicable (newly added section)
The AiCure Platform Provider will 
protect subjects’ personal information 
to the full extent required by law.  
However, information from this trial, 
including de-identified video 
recording(s) of subject performance of 
various actions, may be submitted to 
the trial site, and potentially to the 
FDA.  Both information obtained by 
the application, and information in the 
subject Informed Consent, may be 
examined by the trial site or the trial 
site’s representatives, and may also be 
reviewed by the FDA and other 
regulatory agencies, IRBs, and or 
Ethics Committee(s).  All of these 
parties are bound to safeguard the 
rights, safety, and well-being of all 
clinical trial subjects, and to maintain 
all information in confidence, with 
special consideration given to trials 
that may include vulnerable subjects.
The results of this trial may be 
presented at meetings or in 
publications; however, specific 
subjects will not be identified by name 
in these presentations and/or 
publications.  Information from this 
trial may also be retained by the 
AiCure Platform Provider for the 
purpose of improving the AiCure 
Platform, to allow for future analysis 
of various facial and other parameters, 
the reporting of high level statistical 
analysis of the AiCure Platform, to 
improve the internal workings of the 
system running on the smartphone 
device, or for regulatory filings by the 
AiCure Platform Provider to support 
future applications for the Provider’s 
product.
Table 4.1-2, List 
of Medications 
Prohibited During 
the Trial
All psychotropic agents including, but not 
limited to, the following:
...
i)
Nutritional supplements and non-
prescription herbal preparations with 
central nervous system effects (eg, St. 
John’s Wort, omega-3 fatty acids, 
kava extracts, GABA supplements, 
etc)
All psychotropic agents including, but 
not limited to, the following:
i)
Nutritional supplements and non-
prescription herbal preparations with 
central nervous system effects (eg, 
St. John’s Wort, omega-3 fatty acids, 
kava extracts, GABA supplements, 
etc)
j)
Cannabinoids
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Section 4.2.2.2, 
Restrictions
Subjects may only receive psychotherapy 
(eg, individual, group, marriage, or family 
therapy) if they have been participating in 
the therapy regularly (ie, weekly) for at 
least 6 weeks (42 days) prior to screening 
and commit to maintain their participation 
during the course of the trial at the current 
frequency or unless permission is 
obtained from the medical monitor.
Subjects will be instructed to refrain from 
drinking alcoholic beverages or using 
illicit drugs during participation in the 
trial.  
Subjects may only receive psychotherapy 
(eg, individual, group, marriage, or 
family therapy) if they have been 
participating in the therapy regularly (ie, 
at consistent intervals) for at least 
6 weeks (42 days) prior to screening and 
commit to maintain their participation 
during the course of the trial with no 
changes or unless permission is obtained 
from the medical monitor.
Subjects will be instructed to refrain 
from drinking alcoholic beverages or 
using cannabinoids or illicit drugs 
during participation in the trial.  
Section 5.4, 
Adverse Events 
of Special Interest
The trial site will have a local designated 
dermatologist available for immediate 
consultation during the trial for these 
AESIs.
The trial site will have a local 
dermatologist available for immediate 
consultation during the trial for these 
AESIs.
Section 5.6, 
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.
... Unless the subject is sterile (ie, women 
who have had a bilateral oophorectomy 
and/or hysterectomy or who have been 
postmenopausal for at least 
12 consecutive months; or men who have 
had a bilateral orchidectomy) or remains 
abstinent, 2 of the following precautions 
must be used:  vasectomy, tubal ligation, 
vaginal diaphragm, intrauterine device, 
birth control pills, birth control depot 
injection, birth control implant, condom 
with spermicide, or sponge with 
spermicide.
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 
[confirmed by FSH blood level]).
... Unless the subject is sterile (ie, women 
who have had a bilateral oophorectomy 
and/or hysterectomy or who have been 
postmenopausal for at least 
12 consecutive months [confirmed by 
FSH blood level]; or men who have had 
a bilateral orchidectomy), 2 of the 
following precautions must be used:  
vasectomy, tubal ligation, vaginal 
diaphragm, intrauterine device, birth 
control pills, birth control depot
injection, birth control implant, condom 
with spermicide, or sponge with 
spermicide.
Section 7.4.1, 
Primary Endpoint 
Analysis
The primary efficacy endpoint is the 
mean change from baseline to the Day 56 
(± 1 day) Visit in the 18-item, 
investigator-administered CAARS-O:SV 
score in the OPC-64005 group compared 
with the atomoxetine group.  Analysis 
will be performed using modified intent-
to-treat data set. 
The primary efficacy endpoint is the 
mean change from baseline to the Day 56 
Visit on the 18-item, 
investigator-administered CAARS-O:SV 
score in the OPC-64005 group compared 
with the atomoxetine group.  Analysis 
will be performed using modified intent-
to-treat data set. 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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Section 15, 
References
39. 
 Study for effects of 
OPC-266 on fertility and early embryonic 
development to implantation by oral 
administration in female rats. Otsuka 
Study No. 029621, Otsuka Report No. 
024131, 2009.
39. 
 Study for effects of 
OPC-277 on fertility and early 
embryonic development to implantation 
by oral administration in female rats. 
Otsuka Study No. 029621, Otsuka Report 
No. 024131, 2009.
Section 15, 
References
Not applicable (newly added reference -
note that all subsequent references were 
automatically renumbered accordingly)
51. Fava M. Massachusetts General 
Hospital Antidepressant Treatment 
Response Questionnaire x ADHD-
Adult Version. Massachusetts General 
Hospital. 2014.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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Appendix 11, 
OPC-64005 Skin 
AESI Workup 
Instructions
277-201-00001 Skin Adverse Event of 
Special Interest (AESI) Instructions
Version 1.0 dated 25 Jun 2017
At any point during the study, upon the 
report by the subject or upon the 
observation by site personnel of any type 
of newly acquired skin eruptions that are 
non-traumatic (considered adverse events 
of special interest [AESIs]), and the 
Investigator or medical professional 
designee will take the following steps:
1. Discontinue administration of IMP 
regardless of the severity and seriousness 
of rash. 
2. Collect a detailed history, including 
specific questioning for symptoms of 
hepatitis (eg, weight loss, right upper 
quadrant tenderness, malaise, jaundice, 
hepatomegaly, dark urine) or other 
possible causes of the rash (eg, allergic, 
contact dermatitis); perform a physical 
examination of the area affected by the 
skin rash, including vital signs 
(specifically, body temperature); record 
all concomitant medications and 
nutritional supplements and compare 
them with the use of investigational 
medicinal product (IMP) and the onset 
and resolution of skin eruptions.
3. Take a picture of the area(s) of the rash 
using the Clinical Ink tablet. If the rash 
area is generalized, torso, back, abdomen 
and extremities should be photographed.
NOTE: Photographs should not contain 
any personal identifiers or other parts of 
the body. 
4. Contact the CRO Medical Monitor for 
the study. 
277-201-00001 Skin Adverse Event of 
Special Interest (AESI) Workup 
Instructions
Version 2.0 dated 18 Aug 2017
At any point during the trial, upon the 
report by the subject or upon the 
observation by site personnel of any type 
of newly acquired skin eruptions that are 
non-traumatic, they will be considered
adverse events of special interest 
(AESIs), and the investigator or medical 
professional designee will take the 
following steps:
1. Discontinue administration of IMP 
regardless of the severity and seriousness 
of rash. 
2. Collect a detailed history, including
specific questioning for symptoms of 
hepatitis (eg, weight loss, right upper 
quadrant tenderness, malaise, jaundice, 
hepatomegaly, dark urine) or other 
possible causes of the rash (eg, allergic, 
contact dermatitis).
3. Perform a physical examination of the 
area affected by the skin rash, listing all 
body parts affected (eg, left or right 
hand, forearm, upper arm, etc.).
4. Obtain vital signs (including body 
temperature).
5. Record all concomitant medications 
and nutritional supplements and compare 
them with the use of IMP and the onset 
and resolution of skin eruptions.
6. Take a picture of the area(s) of the 
rash using the Clinical Ink SureSource
tablet. If the rash area is generalized, the 
torso, back, abdomen, and extremities 
should be photographed.
NOTE:  Photographs should not contain 
any personal identifiers or parts of the 
body that would identify the subject 
(such as unusual tattoos, full-face 
views, etc.). 
7. Contact Otsuka’s and INC’s Medical 
Monitor for the trial. 
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5. Collect blood samples for laboratory 
testing, including a complete blood count 
with differential to detect lymphocytosis, 
atypical lymphocytes, and absolute (total) 
eosinophil count and chemistry with liver 
enzyme tests and C-reactive protein 
(CRP) testing [to rule out cases of 
systemic hypersensitivity].

(Note: If the signs and symptoms are 
suggestive of drug rash with 
eosinophilia and systemic symptoms 
(DRESS) or drug-induced 
hypersensitivity syndrome (DIHS), 
human herpes virus 6 (HHV-6) 
infection should be ruled out.)
6. Complete Skin AESI Worksheet for 
study site (Appendix 12).
7. Refer the subject to the local 
dermatologist assigned to the study site as 
soon as possible for consultation. 
a.
For rash that is classified as SEVERE 
(defined as the inability to perform 
normal daily activities) or meets the 
definition of an SAE: If subject 
agrees, have the local dermatologist 
obtain a biopsy for histopathological 
examination by a dermatopathologist. 
Consider direct immunofluorescence 
evaluation, particularly if the 
eruption is characterized by vesicles, 
bullae, or pustules. 
b.
Have the local dermatologist 
complete Skin AESI Worksheet (see 
Appendix 13) when the subject is 
evaluated. 
i. The local dermatologist will 
contact the study Central 
Dermatologist for consultation 
(see Appendix 14)
8. Monitor the subject daily via telephone 
contact or in-clinic visits (per the PI’s 
discretion) to evaluate if the event is 
improving, unchanging, or worsening. 
When the event resolves, record the last 
day as the end date of the AE.
9. Repeat steps 3-7 as required.
8. Collect blood samples for laboratory 
testing, including a complete blood count 
with differential to detect lymphocytosis, 
atypical lymphocytes, and absolute 
(total) eosinophil count and chemistry 
with liver enzyme tests and C-reactive 
protein (CRP) testing (to rule out cases of 
systemic hypersensitivity).

(Note:  If the signs and symptoms 
are suggestive of drug rash with 
eosinophilia and systemic symptoms 
(DRESS) or drug-induced 
hypersensitivity syndrome (DIHS), 
human herpes virus 6 (HHV-6) 
infection should be ruled out.
9. Complete the Skin AESI Worksheet 
for the trial site (Appendix 12).
10. Refer the subject to a local 
dermatologist assigned by the trial site 
for a consultation as soon as possible 
(Note that after 7 days without IMP, 
the subject may not continue in the 
trial regardless of the outcome of the 
investigation of the rash). 
a.
For rash that is classified as 
SEVERE (defined as the inability to 
perform normal daily activities) or 
meets the definition of an SAE: If 
the subject agrees, have the local 
dermatologist obtain a biopsy for 
histopathological examination by a 
dermatopathologist.  Consider direct 
immunofluorescence evaluation, 
particularly if the eruption is 
characterized by vesicles, bullae, or 
pustules. 
b.
Have the local dermatologist 
complete the Skin AESI Worksheet 
(see Appendix 13) when the subject 
is evaluated. 
i.
The local dermatologist will 
contact the trial Central 
Dermatologist for consultation 
(see Appendix 14)
11. Monitor the subject daily via 
telephone contact or in-clinic visits (per 
the investigator’s discretion) to evaluate 
if the event is improving, unchanging, or 
worsening.  When the event resolves, 
record the last day as the end date of the 
AE.
12. Repeat steps 3-11 as required.
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Description of Rash: 
Location(s) of Rash: 
*If rash location is generalized, torso, 
back, abdomen and extremities should 
be photographed. 
*Do not photograph any personal 
identifiers or other parts of the body.
Were pictures taken?    ☐Yes    ☐No  
If no, please explain why: 
Note:  Attach copies of Adverse Events, 
Demographics, Concomitant Medications 
(including herbal and dietary 
supplements), and Medical History 
source document records to this 
worksheet before forwarding to the
dermatologist.
Final review and disposition by the 
Investigator (to be completed AFTER 
receipt of any pertinent laboratory 
tests or pathology results):
After review of the dermatologic 
consultation and subject history, does 
the Investigator consider the rash to be 
study drug-related?
Description of Rash: 
Location(s) of Rash: 
Locations of Adenopathy (if 
applicable):
NOTE: Ensure rash location(s) is 
clearly specified and photographed.  If 
the body location is not obvious, label 
the photo or include a label with the 
body location in the photo, or take a 
“staging” shot of the body part and then 
a closer shot of the rash.  Make sure all 
photos are in precise focus; some 
cameras will focus on items in the 
background behind the subject’s skin.
*If rash location is generalized, the 
torso, back, abdomen, and extremities 
should be photographed. 
*Do not photograph any personal 
identifiers or other parts of the body.
Were pictures taken?    ☐Yes    ☐No  
If no, please explain why not:
Note:  Attach copies of adverse events, 
demographics, concomitant medications 
(including herbal and dietary 
supplements), medical history, lab 
reports, and vital signs source document 
records to this worksheet before 
forwarding to the dermatologists.
Please upload the completed Skin AESI 
Worksheets from the local and central 
dermatologists to the SureSource portal 
(ie, Appendix 13 and Appendix 14).
Final review and disposition by the 
investigator (to be completed AFTER 
receipt of any pertinent laboratory 
tests or pathology results):
After review of the dermatologic 
consultation and subject history, does 
the investigator consider the rash to be 
IMP-related?
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☐Yes 
☐No (if it is determined that the rash is 
not related to the study drug and further 
treatment with the study drug is in the 
subject’s best interest, the study drug may 
be restarted at the same dose provided no 
more than 7 days have elapsed since the 
study drug was stopped)
☐Yes 
☐No (if it is determined that the rash is 
not related to the IMP and further 
treatment with the IMP is in the subject’s 
best interest, the IMP may be restarted at 
the same dose provided no more than 
7 days have elapsed since the IMP was 
stopped)
Appendix 13, 
OPC-64005 Skin 
AESI Worksheet 
for Local 
Dermatologist
277-201-00001 Skin Adverse Event of 
Special Interest (AESI) Worksheet for 
Local Dermatologist
Version 1.0 dated 25 Jun 2017
To be completed by the Local 
Dermatologist assigned to study site
Study Protocol:  277-201-00001
Date of 
Consultation:
(dd/mm/yyyy)
Subject No./ 
Subject Initials
...
Mark location(s) of the rash, including 
any urticarial lesions or 
swelling/edema, on the figures below:
Oral Mucosal involvement   ☐No   ☐  
Yes – details:  
Palmar lesions    ☐No   ☐  Yes –
details:  
Plantar lesions   ☐No   ☐  Yes – details:  
Targetoid lesions   ☐No   ☐  Yes –
details:  
Urticarial lesions   ☐No   ☐  Yes –
details:  
Swelling/edema   ☐No   ☐  Yes –
details:  
277-201-00001 Skin Adverse Event of 
Special Interest (AESI) Worksheet for 
Local Dermatologist
Version 2.0 dated 18 Aug 2017
To be completed by the Local 
Dermatologist assigned by the trial site
Trial Protocol:  277-201-00001
Date of Consultation:
(dd/mmm/yyyy)
Subject No./ 
Subject 
Initials
...
Mark location(s) of the rash, including 
any urticarial lesions or 
swelling/edema, on the figures below.  
If the subject has any visible skin rash 
that predates the trial onset, be sure to 
identify such rash separately on the 
figures below.
Oral mucosal involvement and lip 
involvement   ☐No   ☐  Yes – details:  
Conjunctival involvement   ☐No   ☐  
Yes – details:  
Genital involvement   ☐No   ☐  Yes –
details:  
Scalp involvement   ☐No   ☐  Yes –
details:  
Palmar lesions    ☐No   ☐  Yes –
details:  
Plantar lesions   ☐No   ☐  Yes –
details:  
Targetoid lesions   ☐No   ☐  Yes –
details:  
Urticarial lesions   ☐No   ☐  Yes –
details:  
Swelling/edema   ☐No   ☐  Yes –
details:  
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Please take pictures of the rash per the 
standard photography procedures at 
your office.  NOTE: Ensure rash 
location(s) is clearly photographed. If 
rash location is generalized, torso, back, 
abdomen and extremities should be 
photographed. *Do not photograph any 
personal identifiers or other parts of the 
body
Were pictures taken?    ☐Yes    ☐No  
If No, please explain why:
Please provide narrative description of 
rash, as follows: 

Occupation

prodromal symptoms

Recent contact with anyone else who 
had a rash

Changes in the environment: 
inhalants, foods, new clothing, new 
skin care products, new detergent

Itching, burning/stinging, tenderness,
color (eg, pink, red, or brown), 
texture (raised or flat), pattern (small 
lesions, grouped large plaques), 
unusual characteristics (scaly, 
peeling, follicles), size (eg, pea-sized, 
dime-sized, 10mm), starting location 
(eg, nails, feet/soles hands/palms, 
scalp, mouth, genitalia, symmetric)

Did it move or spread? Time course? 

Any signs by physical examination, 
associated symptoms (eg, respiratory, 
fever, systemic symptoms)
...
Please take pictures of the rash per the 
standard photography procedures at 
your office.  NOTE:  Ensure rash 
location(s) is clearly photographed.  If 
rash location is generalized, the torso, 
back, abdomen, and extremities should 
be photographed.  *Do not photograph 
any personal identifiers. 
Were pictures taken?    ☐Yes    ☐No  
If No, please explain why not:
Please provide narrative description of 
rash, as follows: 

Occupation

Exposure to dyes or toxins

Prodromal symptoms

Recent contact with anyone else who 
had a rash

Changes in the environment:  
inhalants, foods, new clothing, new 
skin care products, new detergent

Itching, burning/stinging, 
tenderness, color (eg, pink, red, or 
brown), texture (raised or flat), 
pattern (small lesions, grouped large 
plaques), unusual characteristics 
(scaly, peeling, follicles), size (eg, 
pea-sized, dime-sized, 10 mm), 
starting location (eg, nails, 
feet/soles, hands/palms, scalp, 
mouth, genitalia, symmetric)

Did it move or spread? Time course? 

Any signs by physical examination 
or subject report of associated 
symptoms (eg, respiratory, fever, 
systemic symptoms)
...
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Please mark location of biopsy on body 
by placing an ‘X’ on the map above. 
Please forward a copy of the pathology 
report from the biopsy to your study 
contact when it becomes available.
Final causality assessment (choose 
one):
☐Definite drug eruption due to study 
drug
☐Probably drug eruption due to study 
drug (the etiology of the rash has a ≥50% 
chance of being related to the drug)
☐Possible drug eruption due to study 
drug (the etiology of the rash has a <50% 
chance of being related to the drug)
☐Other Diagnosis:  
Dermatologist Disposition (choose one): 
Is the rash considered to be study drug-
related? 
☐Yes 
☐No (if it is determined that the rash is 
not related to the study drug and further 
treatment with the study drug is in the 
subject’s best interest, the study drug may 
be restarted at the same dose provided no 
more than 7 days have elapsed since the 
study drug was stopped)
Post Subject-Assessment Instructions 
and Reminders for Local 
Dermatologist
1) As soon as possible but within 24 
hours following your assessment of the 
subject, please contact the central 
dermatologist assigned to the study to 
discuss your findings and review lab 
results (if applicable). 
...
3) REMINDER:  Please scan and email 
the above completed forms and any 
supporting documents to your contact at 
the Study Site as soon as possible 
following the visit.  The forms above 
should be completed for each visit (if 
subject is seen more than once).  Forward 
any laboratory tests or pathology results, 
as soon as they become available.
Please mark location of biopsy on body 
by placing ‘Bx’ on the map above.  
Please forward a copy of the pathology 
report from the biopsy to your trial 
contact when it becomes available.
Final causality assessment (choose 
one):
☐Definite drug eruption due to IMP
☐Probably drug eruption due to IMP
(the etiology of the rash has a ≥ 50% 
chance of being related to the IMP)
☐Possible drug eruption due to IMP 
(the etiology of the rash has a < 50% 
chance of being related to the IMP)
☐Not related
☐Other Diagnosis (specify):  
Dermatologist Disposition (choose 
one): 
Is the rash considered to be IMP-
related? 
☐Yes 
☐No (if it is determined that the rash is 
not related to the IMP and further 
treatment with the IMP is in the subject’s 
best interest, the IMP may be restarted at 
the same dose provided no more than 
7 days have elapsed since the IMP was 
stopped)
Post Subject-Assessment Instructions 
and Reminders for Local 
Dermatologist
1) As soon as possible but within 24 
hours following your assessment of the 
subject, please contact the central 
dermatologist assigned to the trial to 
discuss your findings and review lab 
results (if applicable). 
...
3) REMINDER:  Please scan and email 
the above completed forms and any 
supporting documents to your contact at 
the trial site as soon as possible 
following the visit.  If the subject is seen 
more than once, the forms above should 
be completed for each visit.  Forward any 
laboratory tests or pathology results to 
your contact at the trial site, as soon as 
they become available.
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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Appendix 14, 
OPC-64005 Skin 
AESI Worksheet 
for Central 
Dermatologist
277-201-00001 Skin Adverse Event of 
Special Interest (AESI) Worksheet for 
Central Dermatologist
Version 1.0 dated 25 Jun 2017
To be completed by the Central 
Dermatologist
Study Protocol:  277-201-00001
Date of 
Consultation:
(dd/mm/yyyy)
Subject No./ 
Subject Initials
...
Final causality assessment (choose 
one):
☐Definite drug eruption due to study 
drug
☐Probably drug eruption due to study 
drug (the etiology of the rash has a ≥50% 
chance of being related to the drug)
☐Possible drug eruption due to study 
drug (the etiology of the rash has a <50% 
chance of being related to the drug)☐
☐Other Diagnosis:  
Reminder: Please scan and email 
completed form(s) to the Local 
Dermatologist and Study Site contacts.
277-201-00001 Skin Adverse Event of 
Special Interest (AESI) Worksheet for 
Central Dermatologist
Version 2.0 dated 18 Aug 2017
To be completed by the Central 
Dermatologist 
Trial Protocol:  277-201-00001
Date of Consultation:
(dd/mmm/yyyy)
Subject No./ 
Subject 
Initials
...
Final causality assessment (choose 
one):
☐Definite drug eruption due to IMP
☐Probably drug eruption due to IMP 
(the etiology of the rash has a ≥ 50% 
chance of being related to the IMP)
☐Possible drug eruption due to IMP
(the etiology of the rash has a < 50% 
chance of being related to the IMP)
☐Not related
☐Other Diagnosis (specify):  
Reminder:  Please scan and email 
completed form(s) to the Local 
Dermatologist and trial site contacts.
ADDITIONAL RISK TO THE SUBJECT:
There is no additional risk to the subjects.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 277-201-00001
16.1.1 Protocol and Protocol Amendments
199

Protocol 277-201-00001
Confidential - Proprietary Information
200
Version 4.0, 28 Aug 2017
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-64005, 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-64005 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 electronic 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 
research sites, whenever applicable. I agree to allow sponsor and designee monitors and 
auditors full access to all medical records at the research facility 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 experiences 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 results on an individual basis may occur, and I consent to 
be acknowledged in any such cooperative publications that result.
____________________________
_____________________________
___________
Principal Investigator Print Name
Signature
Date
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 277-201-00001
16.1.1 Protocol and Protocol Amendments
200