Conditions: Attention Deficit Disorder Attention Deficit Hyperactivity Disorder
Keywords: Centanafadine ADD ADHD
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 662
Healthy volunteers: no

Brief summary:
This study evaluated the long-term safety and tolerability of centanafadine sustained-release (SR) tablets, administered twice daily (BID) in the treatment of adults with attention deficit hyperactivity disorder (ADHD).

Detailed description:
This open-label study assessed the overall safety and tolerability of 400 mg total daily dose centanafadine SR tablets in participants, over the course of approximately 52 weeks. This study has accepted rollover participants from both the 405-201-00013 and 405-201-00014 trials. For individuals that did not participate in one of the studies mentioned above, they will be able to enroll if they meet the inclusion criteria as outlined below.

Arms:
arm 1: 400 mg total daily dose

Interventions: intervention 1: Centanafadine SR
Intervention descriptions: intervention 1: 200mg, BID, oral tablets

Protocol document:
Prot_000.pdf: 
NCT Number: 
Document Date: 
An Open-label, 52-Week, Multicenter Trial Evaluating the 
Long-term Safety and Tolerability of Centanafadine 
Sustained-Release Tablets in Adults with Attention-
Deficit/Hyperactivity Disorder
NCT03605849
Protocol Amendment Version 2: 02 Jun 2020
Official Title: 


Table of Contents
Table of Contents.............................................................................................................
1
Study 405-201-00015 Protocol Amendment 2; 02 Jun 2020...........................................
2
Study 405-201-00015 Protocol Addendum; 02 Jun 2020................................................
109
Clinical Study Report 405-201-00015
16.1.1 Protocol and Protocol Amendments
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
1


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Otsuka Pharmaceutical Development & Commercialization, Inc
Investigational Medicinal Product
Centanafadine (EB-1020)
REVISED CLINICAL PROTOCOL
An Open-label, 52-Week, Multicenter Trial Evaluating the Long-term Safety and 
Tolerability of Centanafadine Sustained-Release Tablets in Adults with 
Attention-Deficit/Hyperactivity Disorder 
Protocol No. 405-201-00015
IND No. 119,361
CONFIDENTIAL – PROPRIETARY INFORMATION
Clinical Development Phase:
3
Sponsor:
Otsuka Pharmaceutical Development & 
Commercialization, Inc
2440 Research Boulevard
Rockville, Maryland 20850
Immediately Reportable Event 
Syneos Health Pharmacovigilance & Drug 
Safety
Issue Date:
07 Mar 2018
Version No.:
4.0
CCI
CCI


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16.1.1 Protocol and Protocol Amendments
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Trial Conduct for COVID-19
All procedures and assessments in this protocol are to be followed to the fullest 
extent possible. The sponsor, in coordination with the site, investigator(s), and 
medical monitor, will continuously monitor and evaluate the benefits and risks to 
subject participation in the clinical trial as it relates to COVID-19. If any 
protocol-specified activities were not able to be performed, or cannot be performed 
due to COVID-19 considerations, refer to the COVID-19 Addendum for the 
appropriate measures to be followed. Appropriate measures may include replacing 
in-person visits with virtual visits (phone or video) as deemed necessary by the 
investigator to ensure subject safety and maintain protocol requirements.


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16.1.1 Protocol and Protocol Amendments
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Protocol Synopsis 
Name of Sponsor: Otsuka Pharmaceutical 
Development & Commercialization, Inc
Name of Investigational Medicinal Product: 
Centanafadine (EB-1020)
Protocol No.: 405-201-00015
IND No.:119,361
Protocol Title:
An Open-label, 52-Week, Multicenter Trial Evaluating the 
Long-term Safety and Tolerability of Centanafadine 
Sustained-Release Tablets in Adults with 
Attention-Deficit/Hyperactivity Disorder
Clinical Phase/Trial 
Type:
3
Treatment Indication: Adults with attention-deficit/hyperactivity disorder (ADHD)
Objective:
To assess the long-term safety and tolerability of centanafadine 
sustained-release (SR) tablets administered twice daily (BID) 
(400 mg total daily dose [TDD]) in the treatment of adults with 
ADHD.
Trial Design:
Multicenter, open-label
Subject Population:
The trial population will include rollover subjects from 
Trial 405-201-00013 or Trial 405-201-00014 and de novo 
subjects. 
De novo subjects must meet the Diagnostic and Statistical 
Manual of Mental Disorders, Fifth Edition (DSM-5) criteria 
for ADHD (including predominantly inattentive presentation, 
hyperactive presentation, or combined presentation) as 
confirmed by the Adult ADHD Clinical Diagnostic Scale 
(ACDS) Version 1.2. To confirm that ADHD is the primary 
diagnosis, the Mini International Neuropsychiatric Interview 
(MINI) will be used to identify and exclude other psychiatric 
conditions which would preclude enrollment.
Approximately 720 subjects will be enrolled in this trial, with 
the expectation that approximately 300 subjects will achieve 
6-month exposure and approximately 100 subjects will achieve
52-week exposure.


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Inclusion/Exclusion 
Criteria:
Key inclusion criteria for rollover subjects from double-blind 
phase 3 trial (ie, Trial 405-201-00013 or Trial 405-201-00014) 
include the following:

Subjects who completed the 6-week double-blind treatment 
period and 7-day follow-up after last dose of 
investigational medicincal product (IMP) in double-blind 
trials and who, in the opinion of the investigator, could 
potentially benefit from centanafadine for ADHD.

Subjects who, during the double-blind trials, demonstrated 
adequate compliance with medication and protocol 
requirements, per investigator’s judgment.
Key inclusion criteria for de novo subjects include the 
following (other than the key criteria described under Subject 
Population in this Synopsis):

Subjects are 18 to 55 years of age, inclusive, at the time of 
consent.

Subjects have BMI of 18 to 40, inclusive.

Subjects are willing to discontinue all prohibited 
psychotropic medications starting from the time of signing 
the informed consent and up to the 10-day safety follow-up 
period.
Key exclusion criteria for rollover subjects from double-blind 
phase 3 trial (ie, Trial 405-201-00013 or Trial 405-201-00014) 
include the following:

Subjects who experienced, in the opinion of the 
investigator, poor tolerability to trial medication or whose 
safety assessments resulted in new concerns that would 
suggest the subject may not be appropriate for a 52-week 
treatment with trial medication.

Subjects who have re-initiated any therapy for adult ADHD 
during the 7-day follow-up period after the Week 6 visit of 
the double-blind phase 3 trial.

Subjects that have a positive alcohol test (via breathalyzer 
or blood), a positive drug screen for cocaine, or other illicit 
drugs (excluding marijuana). Subjects with a positive drug 
screen for confirmed prescription medications at baseline
will not be permitted to continue participation in 
Trial 405-201-00015. 


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NOTE: Subjects that test positive for marijuana may be 
permitted to be enrolled if they have no evidence of a 
substance use disorder, and if they agree to refrain from 
use for the duration of the trial. Allowance for subjects 
testing positive for marijuana at screening require explicit 
approval from the medical monitor.
Key exclusion criteria for de novo subjects include the 
following:

Subject has a DSM-5 diagnosis of Other Specified or 
Unspecified Attention-Deficit/Hyperactivity Disorder as 
confirmed by ACDS Version 1.2.

Subject has a current comorbid psychiatric disorder that is 
either controlled with medications prohibited in this trial or 
is uncontrolled and associated with significant symptoms, 
including but not limited to: a current major depressive 
episode (as per DSM-5 criteria), current symptoms (past 
90 days) meeting the DSM-5 criteria for a diagnosis of 
generalized anxiety disorder, obsessive-compulsive 
disorder, panic disorder, or posttraumatic stress disorder, as 
established by the MINI. 
Note: Subjects with mild mood or anxiety symptoms that 
do not meet criteria for diagnosis, who do not require 
treatment based on the Investigator’s assessment, and do 
not confound efficacy or safety assessments in the opinion 
of the examining Investigator, may be included.

Subjects that have a positive alcohol test (via breathalyzer 
or blood), a positive drug screen for cocaine, or other illicit 
drugs (excluding marijuana). Subjects with a positive drug 
screen for confirmed prescription or over-the-counter 
(OTC) use of ADHD medications at screening will be 
required to undergo a washout period. 
NOTE: Subjects that test positive for marijuana may be 
permitted to be enrolled if they have no evidence of a 
substance use disorder, and if they agree to refrain from 
use for the duration of the trial. Allowance for subjects 
testing positive for marijuana at screening require explicit 
approval from the medical monitor.
Trial Site(s):
An estimated 115 sites in the United States (US) will enroll 
subjects.


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Investigational 
Medicinal Product(s), 
Dose, Dosage 
regimen, Treatment 
period, Formulation, 
Mode of 
Administration:
Centanafadine will be provided as 100 mg SR tablets.
After the completion of baseline evaluations (Day -1), all 
subjects will receive a starting dose of 200 mg TDD of 
centanafadine SR tablets from Days 1 to 7, followed by a 
titration to 400 mg TDD of centanafadine SR tablets on Day 8.
Subjects will continue at 400 mg TDD for the rest of the 
open-label treatment period.
From Days 1 to 7, all doses of open-label IMP will be taken 
orally BID, with 1 centanafadine SR tablet taken in the 
morning and 1 centanafadine SR tablet taken 4 to 6 hours after 
the first dose.
From Day 8 to Week 52/early termination (ET), all doses of 
open-label IMP will be taken orally BID, with 2 centanafadine 
SR tablets taken in the morning and 2 centanafadine SR tablets 
taken 4 to 6 hours after the first dose. 
Every effort should be made to administer the IMP at the same 
times every day. 
Trial Assessments:
Primary: Adverse event (AE) reporting.
Additional Safety: Clinical laboratory tests, 12-lead 
electrocardiogram (ECG), vital signs, physical examination, 
Columbia-Suicide Severity Rating Scale (C-SSRS), and Study 
Medication Withdrawal Questionnaire (SMWQ).
Efficacy: Adult ADHD Investigator Symptom Rating Scale
(AISRS), Clinical Global Impression-Severity of Illness Scale
(CGI-S) and ADHD Impact Module - Adult (AIM-A).
Screening/Other: Medical, psychiatric, and medication history, 
urine drug and alcohol screening, urine pregnancy test, MINI,
and ACDS Version 1.2.


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Criteria for 
Evaluations:
Primary Endpoint:
The long-term safety and tolerability of centanafadine SR
tablets administered BID (400 mg TDD) will be assessed by 
the frequency and severity of treatment-emergent AEs
(TEAEs).
Additional Safety Endpoints:
Additional safety variables will include clinically significant 
changes in: laboratory tests (hematology, serum chemistry, 
coagulation parameters, and urinalysis), physical 
examinations, vital sign measurements, electrocardiograms 
(ECGs).
The C-SSRS will be used to assess and classify reported 
suicidal behavior. By-subject listings of physical examination 
findings will be provided as a further assessment of safety.
Assessments of withdrawal symptoms will be evaluated using 
SMWQ.
Abuse-related AEs and AEs involving medication 
irregularities will be recorded verbatim on source 
documentation with detailed narratives. 


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Statistical Methods:
The sample size is not based on statistical power 
considerations but on International Council for
Harmonisation/Good Clinical Practice (ICH/GCP) 
requirements. The trial population will be derived from 
eligible subjects from double-blind phase 3 trial (ie, 
Trial 405-201-00013 or Trial 405-201-00014) and de novo 
subjects from selected sites. It is expected that approximately 
560 completing subjects from double-blind phase 3 trial 
(Trial 405-201-00013 or Trial 405-201-00014) and 
approximately 145 de novo subjects will be enrolled into this 
trial.
Primary Endpoint Analysis:
The primary safety analysis is the frequency and severity of 
AEs in this trial. All AEs will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA) preferred 
term. The incidence of TEAEs will include the following 
summaries:

TEAEs

TEAEs by severity

TEAEs potentially causally related to the IMP

TEAEs with an outcome of death

Serious TEAEs

TEAEs leading to discontinuation of the IMP

Abuse-related AEs and AEs involving medication handling 
irregularities
A TEAE is defined as an AE that starts after the first dose of 
IMP or an AE that is reported at baseline and increases in 
intensity or becomes serious or trial drug-related or results in 
death, discontinuation, interruption, or reduction of IMP.
Descriptive statistics will be provided for each endpoint, and 
will be summarized at each trial visit using the observed cases 
(OC) dataset and at the last visit using the last observation 
carried forward (LOCF) dataset. Baseline is defined as the last 
available measurement prior to the first dose of open-label 
IMP in the open-label treatment phase.


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Trial Duration:
Individual participation for rollover subjects who complete the 
trial without early withdrawal will be approximately 54 weeks, 
consisting of a 52-week open-label treatment period, and
10-day safety follow-up after the last dose of IMP.
Individual participation for de novo subjects who complete the 
trial without early withdrawal will be approximately 58 weeks, 
consisting of a screening period of up to 28 days, a 52-week 
open-label treatment period, and a 10-day safety follow-up
after the last dose of IMP.


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16.1.1 Protocol and Protocol Amendments
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Table of Contents 
Trial Conduct for COVID-19.......................................................................2
Protocol Synopsis...........................................................................................3
Table of Contents.........................................................................................10
List of In-text Tables ...................................................................................15
List of In-text Figures..................................................................................16
List of Appendices........................................................................................17
List of Abbreviations and Definitions of Terms .......................................18
1
Introduction ........................................................................................20
1.1
Nonclinical Data................................................................................................21
1.2
Clinical Data......................................................................................................22
1.3
Known and Potential Risks and Benefits ..........................................................22
2
Trial Rationale and Objectives..........................................................24
2.1
Trial Rationale...................................................................................................24
2.2
Dosing Rationale...............................................................................................24
2.3
Trial Objective...................................................................................................25
2.3.1
Primary Objective...........................................................................................25
3
Trial Design.........................................................................................25
3.1
Type/Design of Trial .........................................................................................25
3.2
Trial Treatments ................................................................................................31
3.3
Trial Population.................................................................................................31
3.3.1
Number of Subjects and Description of Population .......................................31
3.3.2
Subject Selection and Numbering ..................................................................32
3.4
Eligibility Criteria..............................................................................................32
3.4.1
Informed Consent ...........................................................................................32
3.4.2
Inclusion Criteria ............................................................................................33
3.4.2.1
Rollover Subjects ........................................................................................33
3.4.2.2
De Novo Subjects........................................................................................34
3.4.3
Exclusion Criteria...........................................................................................34
3.4.3.1
Rollover Subjects ........................................................................................34
3.4.3.2
De Novo Subjects........................................................................................37


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3.5
Endpoints...........................................................................................................39
3.5.1
Primary Endpoint............................................................................................39
3.5.2
Secondary Endpoints ......................................................................................39
3.5.3
Exploratory Endpoint(s) .................................................................................40
3.5.4
Additional Safety Endpoints...........................................................................40
3.6
Measures to Minimize/Avoid Bias....................................................................40
3.7
Trial Procedures ................................................................................................41
3.7.1
Schedule of Assessments................................................................................50
3.7.1.1
Screening and Baseline ...............................................................................50
3.7.1.1.1
Rollover Subjects.....................................................................................50
3.7.1.1.2
De Novo Subjects....................................................................................51
3.7.1.1.2.1
Screening..............................................................................................51
3.7.1.1.2.2
Baseline................................................................................................52
3.7.1.2
Open-label Treatment Period......................................................................53
3.7.1.2.1
Weeks 1 and 2 .........................................................................................53
3.7.1.2.2
Weeks 4, 8, 12 and 16 .............................................................................54
3.7.1.2.3
Week 20...................................................................................................54
3.7.1.2.4
Week 26...................................................................................................55
3.7.1.2.5
Week 32...................................................................................................56
3.7.1.2.6
Week 38...................................................................................................56
3.7.1.2.7
Week 44...................................................................................................57
3.7.1.2.8
Week 48...................................................................................................57
3.7.1.2.9
Week 52/Early Termination (End of Treatment) ....................................57
3.7.1.3
Follow-up Period.........................................................................................58
3.7.2
Efficacy Assessments .....................................................................................59
3.7.2.1
Adult Attention-deficit/Hyperactivity Disorder Investigator Symptom 
Rating Scale ................................................................................................59
3.7.2.2
Clinical Global Impression-Severity of Illness Scale - Modified for 
Attention-deficit/Hyperactivity Disorder....................................................60
3.7.3
Other Assessments..........................................................................................60
60
3.7.3.2
Mini International Neuropsychiatric Interview...........................................60
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3.7.3.3
Adult Attention-deficit/Hyperactivity Disorder Clinical Diagnostic 
Scale............................................................................................................60
3.7.3.4
Attention-Deficit Hyperactivity Disorder Impact Module - Adult .............61
3.7.3.5
Prior and Concomitant Medications............................................................61
3.7.4
Safety Assessments.........................................................................................61
3.7.4.1
Adverse Events............................................................................................61
3.7.4.2
Clinical Laboratory Assessments................................................................61
3.7.4.3
Physical Examination and Vital Signs........................................................64
3.7.4.3.1
Physical Examination..............................................................................64
3.7.4.4
Vital Signs...................................................................................................65
3.7.4.5
Electrocardiogram Assessments..................................................................65
3.7.4.6
Other Safety Assessments...........................................................................66
3.7.4.6.1
Study Medication Withdrawal Questionnaire .........................................66
3.7.4.6.2
Suicidality................................................................................................66
3.7.5
Pharmacokinetic/Pharmacodynamic Assessments .........................................67
3.7.5.1
Pharmacokinetic Assessment......................................................................67
...........................67
3.7.6
End of Trial.....................................................................................................67
3.8
Stopping Rules, Withdrawal Criteria, and Procedures......................................67
3.8.1
Entire Trial or Treatment Arm(s) ...................................................................67
3.8.2
Individual Site.................................................................................................68
3.8.3
Individual Subject Discontinuation ................................................................68
3.8.3.1
Treatment Interruption ................................................................................68
3.8.3.2
Treatment Discontinuation..........................................................................68
3.8.3.3
Documenting Reasons for Treatment Discontinuation...............................69
3.8.3.4
Withdrawal of Consent ...............................................................................70
3.8.3.5
Procedures to Encourage Continued Trial Participation.............................71
3.9
Screen Failures ..................................................................................................71
3.10
Definition of Completed Subjects.....................................................................72
3.11
Definition of Subjects Lost to Follow-up..........................................................72
3.12
Subject Compliance...........................................................................................72
3.13
Protocol Deviations...........................................................................................72
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4
Restrictions..........................................................................................73
4.1
Prohibited Medications......................................................................................73
4.2
Other Restrictions..............................................................................................74
4.2.1
Restricted Therapies and Precautions.............................................................74
4.2.2
Non-therapy Precautions and Restrictions......................................................75
4.2.2.1
Precautions..................................................................................................75
4.2.2.2
Restrictions..................................................................................................75
5
Reporting of Adverse Events.............................................................75
5.1
Definitions.........................................................................................................75
5.2
Eliciting and Reporting Adverse Events ...........................................................77
5.3
Immediately Reportable Events ........................................................................78
5.4
Adverse Events of Special Interest....................................................................78
5.5
Abuse Potential Monitoring Plan, Events Subject to Additional 
Monitoring, and Medication Handling Irregularities ........................................78
5.6
Potential Serious Hepatotoxicity.......................................................................79
5.7
Pregnancy..........................................................................................................79
5.8
Procedure for Breaking the Blind......................................................................81
5.9
Follow-up of Adverse Events............................................................................81
5.9.1
Follow-up of Nonserious Adverse Events......................................................81
5.9.2
Follow-up of Serious Adverse Events and Immediately Reportable 
Events .............................................................................................................81
5.9.3
Follow-up and Reporting of Serious Adverse Events and Immediately 
Reportable Events Occurring after Last Scheduled Contact ..........................82
6
Pharmacokinetic/Pharmacogenomic Analysis ................................82
7
Statistical Analysis..............................................................................82
7.1
Sample Size.......................................................................................................82
7.2
Datasets for Analysis.........................................................................................82
7.3
Handling of Missing Data .................................................................................83
7.4
Primary, Secondary, and Exploratory Endpoint Analyses................................83
7.4.1
Primary Endpoint Analysis.............................................................................83
7.4.2
Secondary Endpoint Analysis.........................................................................83
7.4.3
Exploratory Endpoint Analysis.......................................................................84
7.4.4
Interim Analysis..............................................................................................84


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7.5
Analysis of Demographic and Baseline Characteristics....................................84
7.6
Additional Safety Endpoint Analysis................................................................84
7.6.1
Abuse Liability Analysis ................................................................................85
7.6.2
Clinical Laboratory Data ................................................................................85
7.6.3
Physical Examination and Vital Signs Data ...................................................85
7.6.4
Electrocardiogram Data..................................................................................85
7.6.5
Study Medication Withdrawal Symptoms......................................................86
7.6.6
Columbia-Suicide Severity Rating Scale........................................................86
8
Management of Investigational Medicinal Product........................86
8.1
Packaging and Labeling ....................................................................................86
8.2
Storage...............................................................................................................86
8.3
Accountability ...................................................................................................86
8.4
Returns and Destruction....................................................................................87
8.5
Reporting of Product Quality Complaints.........................................................87
8.5.1
Eliciting and Reporting Product Quality Complaints.....................................88
8.5.2
Information Required for Reporting Purposes ...............................................88
8.5.3
Return Process ................................................................................................88
8.5.4
Assessment/Evaluation...................................................................................88
9
Records Management.........................................................................89
9.1
Source Documents.............................................................................................89
9.2
Data Collection..................................................................................................89
9.3
File Management at the Trial Site.....................................................................91
9.4
Records Retention at the Trial Site....................................................................91
10
Quality Control and Quality Assurance...........................................91
10.1
Monitoring.........................................................................................................91
10.2
Auditing.............................................................................................................92
11
Ethics and Responsibility...................................................................92
12
Confidentiality ....................................................................................92
13
Amendment Policy..............................................................................93
14
Publication Authorship Requirements.............................................94
15
References............................................................................................95


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List of In-text Tables
Table 3.2-1
Titration Schedule for Centanafadine SR Tablets .........................31
Table 3.4.2.1-1
Inclusion Criteria for Rollover Subjects from 
Trial 405-201-00013 or Trial 405-201-00014 ...............................33
Table 3.4.2.2-1
Inclusion Criteria for De Novo Subjects........................................34
Table 3.4.3.1-1
Exclusion Criteria for Rollover Subjects from 
Trial 405-201-00013 or Trial 405-201-00014 ...............................34
Table 3.4.3.2-1
Exclusion Criteria for De Novo Subjects.......................................37
Table 3.7-1
Schedule of Assessments - Rollover Subjects from 
Trial 405-201-00013 or Trial 405-201-00014 - Baseline 
Through End of Treatment.............................................................42
Table 3.7-2
Schedule of Assessments - Rollover Subjects from 
Trial 405-201-00013 or Trial 405-201-00014 - Follow-up ...........45
Table 3.7-3
Schedule of Assessments - De Novo Subjects - Baseline 
Through End of Treatment.............................................................46
Table 3.7-4
Schedule of Assessments - De Novo Subjects - Follow-up...........49
Table 3.7.4.2-1
Clinical Laboratory Assessments...................................................63
Table 4.1-1
Washout of Prohibited Medications Required Before the 
Trial - De Novo Subjects ...............................................................73
Table 4.1-2
List of Medications Prohibited During the Trial............................74


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List of In-text Figures
Figure 3.1-1
Trial Design Schematic - Rollover Subjects from 
Trial 405-201-00013 or Trial 405-201-00014 ...............................29
Figure 3.1-2
Trial Design Schematic - De Novo Subjects .................................30


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List of Appendices
..98
Appendix 2
Criteria for Identifying Laboratory Values of Potential 
Clinical Relevance .........................................................................99
Appendix 3
Criteria for Identifying Vital Signs of Potential 
Clinical Relevance .......................................................................100
Appendix 4
Criteria for Identifying ECG Measurements of Potential 
Clinical Relevance .......................................................................101
CCI
CCI


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List of Abbreviations and Definitions of Terms
Abbreviation
Definition
ACDS
Adult ADHD Clinical Diagnostic Scale
ADHD
Attention-deficit hyperactivity disorder
ADHD-RS-IV
ADHD Rating Scale Version IV
AE
Adverse event
AESI
Adverse event of special interest
AIM-A
ADHD Impact Module - Adult
AISRS
Adult ADHD Investigator Symptom Rating Scale
ALT
Alanine aminotransferase
Anti-HCV
Hepatitis C antibodies
APMP
Abuse Potential Monitoring Plan
AST
Aspartate aminotransferase
BID
Twice daily
BMI
Body mass index
CGI-S
Clinical Global Impression-Severity of Illness Scale
CPK
Creatine phosphokinase
C-SSRS
Columbia-Suicide Severity Rating Scale
CYP
Cytochrome P450
DSM
Diagnostic and Statistical Manual of Mental Disorders
DSM-IV
Diagnostic and Statistical Manual of Mental Disorders, Fourth
Edition
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
DRESS
Drug rash with eosinophilia and systemic symptoms
ECG
Electrocardiogram
eCRF
Electronic case report form
eICF
Electronic informed consent form
ESAM
Events Subject to Additional Monitoring
ET
Early termination
FDA
Food and Drug Administration
FOCBP
Females of childbearing potential
GCP
Good Clinical Practice 
HbA1c
Glycosylated hemoglobin
HBsAg
Hepatitis B surface antigen
HCV
Hepatitis C virus
HDL
High-density lipoprotein
HIV
Human immunodeficiency virus
IB
Investigator’s Brochure
ICH
International Council for Harmonisation
ICMJE
International Committee of Medical Journal Editors
ID
Identification
IEC
Independent Ethics Committee
IMP
Investigational medicinal product
CCI
CCI


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IND
Investigatinal new drug
IR
Immediate-release
IRB
Institutional review board
IRE
Immediately reportable event
LDL
Low-density lipoprotein
LOCF
Last observation carried forward
MedDRA
Medical Dictionary for Regulatory Activities
MHI
medication handling irregularities
MINI
Mini International Neuropsychiatric Interview
OC
Observed-case
OPDC
Otsuka Pharmaceutical Development & Commercialization, Inc
OTC
Over-the-counter
PK
Pharmacokinetic
PO
by mouth
PQC
Product quality complaint
PT
Preferred terms/international normalized ratio
PT/INR
prothrombin time
QTcB
QT interval corrected for heart rate by Bazett’s formula
QTcF
QT interval corrected for heart rate by Fridericia’s formula
QTcN
QT interval corrected for heart rate by the FDA Neuropharm 
Division formula
RBC
Red blood cell
SAE
Serious adverse event
SAP
Statistical analysis plan
SMWQ
Study Medication Withdrawal Questionnaire
SR
Sustained-release
T4
Free thyroxine
TDD
Total daily dose
TEAE
Treatment-emergent adverse event
TSH
Thyroid-stimulating hormone
ULN
Upper limit of normal
US
United States of America/United States
WBC
White blood cell


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1
Introduction
Attention-deficit hyperactivity disorder (ADHD) is an increasingly recognized and 
heterogeneous disorder characterized by 3 core symptoms of hyperactivity, 
inattentiveness, and impulsivity.1 Depending on the ADHD subtype, sex, and presence of 
comorbid disorders, individuals with ADHD may display considerably different 
symptomatology, even within a particular age cohort.2
Although ADHD is still considered primarily a childhood disorder, the advent of 
consensus diagnostic criteria for ADHD in conjunction with more rigorous prospective 
research has documented the persistence of this disorder into adolescence in up to 70% 
and into adulthood in up to 66% of childhood cases.3,4 More recently, 2 follow-up trials 
of children with ADHD from child mental health clinics in southeast England and the 
Netherlands showed persistence of ADHD into young adulthood in 79% to 85% of 
individuals, respectively.5,6 Long-term follow-up trials report the persistence of this 
disorder into adulthood in as many as 65% of childhood cases.7,8 There is mounting 
evidence that supports adult ADHD is a combination of both childhood ADHD persisting 
into adulthood and adult-onset ADHD without childhood diagnosis.9 Fayyad et al (2007) 
estimated adult (18 to 44 years) ADHD prevalence determined by Diagnostic and 
Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria to be 3.4%.10
Kessler et al determined adult ADHD prevalence to be 4.4% using the National 
Comorbidity Survey Replication, a lay-administered household survey.11
The exact pathophysiology of ADHD remains uncertain although it is believed that a 
dysregulation of neurotransmitters, specifically dopamine and norepinephrine, in the 
frontostriatal region of the brain are involved.12,13 This hypothesis is based primarily on 
knowledge of the mechanism of action of drugs found to be effective in treating ADHD 
and further supported by molecular genetics and neuroimaging studies.12,14
Environmental and perinatal complications may also be contributing factors.15,16
The pharmacotherapy of ADHD consequently relies on 2 major classes of drugs: (1) 
stimulants, such as methylphenidate and amphetamines, and (2) nonstimulants, such as 
atomoxetine17 and alpha-adrenergic agonists such as guanfacine and clonidine.18
Stimulants have a rapid onset of action in ADHD, are effective in all 3 core deficits of the 
disorder17, and have a response rate of about 70%.19 However, their usefulness is limited 
by adverse reactions, by lack of effect on or exacerbation of comorbidities, and by abuse 


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liability (ie, risks of abuse, dependence, and diversion) with resultant drug prescribing 
restrictions.17
The first nonstimulant drug approved in the United States (US) was atomoxetine. 
Although atomoxetine is an acceptable option for some patients with ADHD, it is 
generally less effective than treatment with stimulant therapy. In an 
atomoxetine/methylphenidate comparison trial, the response rate for atomoxetine was 
superior to placebo, 45% to 24%, respectively. However, the response rate for 
methylphenidate was superior to atomoxetine (56% to 45%).20 In addition, atomoxetine 
is associated with cardiovascular and nervous system adverse events (AEs) and has a 
boxed warning from the Food and Drug Administration (FDA) for increased risk of 
suicidal ideation in children or adolescents.21
Immediate-release clonidine and guanfacine have been evaluated as monotherapy in 
ADHD, however rapid clearance and absorption, negative side effects, and reduced 
efficacy compared with stimulants has limited their usage.22 In addition, patient 
responses to alpha-2 adrenergic agonists have been shown to be not as strong as 
stimulants. An effect size of 0.58 for clonidine was seen compared to 0.82 for stimulants 
in a meta-analysis of ADHD treatment trials. Therefore, as a first-line treatment 
immediate release alpha-2 adrenergic agonists are usually not considered for ADHD.23,24
Clinical data available to date suggest that centanafadine sustained release (SR) has the 
potential to be more effective than nonstimulant therapies, with a better side-effect 
profile, and lower abuse potential than currently available stimulant therapies. This 
52-week, open-label, multicenter, trial will evaluate the long-term safety and tolerability 
of a 400 mg total daily dose (TDD) of centanafadine SR for the treatment of adult 
subjects with ADHD.
Please refer to the Investigator’s Brochure (IB) for more detailed information about the 
investigational medicinal product (IMP).25
1.1
Nonclinical Data
A complete description of the available efficacy and safety pharmacology data from 
nonclinical studies, including pharmacokinetic (PK) and toxicology studies in different 
animal species can be found in the current IB.25


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1.2
Clinical Data
As of the IB data cutoff of 01 Apr 2017, 7 clinical trials in 260 subjects have been 
conducted with centanafadine. A total of 140 healthy subjects or recreational stimulant 
users received centanafadine in 5 phase 1 trials and 120 subjects with ADHD received 
centanafadine in 2 phase 2 trials.
Data from the 2 completed phase 2 trials (EB-1020-SR-ADHD-201 and 
NVI-EB-1020-202) demonstrated the efficacy of centanafadine SR in the treatment of 
adult subjects with ADHD. Trial EB-1020-SR-ADHD-201 was an exploratory, 
single-blind pilot trial to evaluate flexible doses (100 to 500 mg) of centanafadine SR. 
Trial NVI-EB-1020-202 was a randomized, double-blind, multicenter, 2-period, 
2-treatment, crossover trial. Due to tolerability issues observed at high doses of 
centanafadine SR (800 and 600 mg), the trial was amended to the maximum TDD of 
400 mg for further evaluation. For both trials, there was a statistically significant 
difference in the primary endpoint using the adult ADHD Rating Scale Version IV
(ADHD-RS-IV) for subjects that received centanafadine SR compared to placebo 
(p < 0.001). Safety data collected from the complete phase 2 trials indicated that 
centanafadine SR is well-tolerated up to 400 mg in adult subjects with ADHD.
Refer to the IB for a detailed summary of available clinical data.25
1.3
Known and Potential Risks and Benefits
Based on the IB, data from the completed phase 1 and 2 trials indicate that centanafadine 
is safe and well-tolerated in healthy adult subjects and adult subjects with ADHD. Data 
from the completed phase 2 trials demonstrate that centanafadine is effective in treating 
symptoms of ADHD; based on the positive effect of centanafadine SR on the primary 
efficacy measure, the adult ADHD-RS-IV. Centanafadine may also confer an improved 
safety profile and lower potential for abuse compared to currently approved Schedule II 
stimulant treatments for ADHD. The abuse potential for centanafadine is continuing to be 
evaluated.
Seven clinical trials in 260 subjects and subjects with ADHD have been conducted with 
centanafadine. A total of 140 healthy subjects received centanafadine in 5 phase 1 trials 
and 120 subjects with ADHD received centanafadine in 2 phase 2 trials. The most 
common AEs reported in trials with centanafadine SR at TDDs ranging from 25 to 
800 mg were gastrointestinal (nausea, diarrhea, and dry mouth), 
metabolism/nutrition-related (decreased appetite), and nervous system disorders 
(headache, dizziness, and insomnia). In general, these AEs were mild and resolved. 


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To date, 1 serious AE (SAE) (ischemic cardiovascular accident) occurred in a subject 
with ADHD (initial dosage of centanafadine SR 100 mg, titrated to 500 mg) 6 days after 
completing treatment, but it was not considered related to centanafadine treatment.
Based on the outcome of the phase 2 trials, treatment with centanafadine may be 
associated with increases in blood pressure, heart rate and orthostatic blood pressure 
changes. Increases in blood pressure and heart rate were usually modest and 
asymptomatic; however, hypertension, tachycardia, and orthostasis have occurred. 
During clinical trials, heart rate and blood pressure will be measured prior to initiation of 
therapy, and periodically while on therapy. Subjects will also be monitored for 
tachycardia or hypertension. Centanafadine should be used with caution in subjects with 
hypertension, tachycardia, or cerebrovascular disease or cardiovascular disease 
(eg, known serious structural cardiac abnormalities, cardiomyopathy, serious heart 
rhythm abnormalities, or other serious cardiac problems that may place a subject at 
increased vulnerability to noradrenergic effects).
Rash has been observed in subjects who received centanafadine. One subject experienced 
mild rash that was considered related to treatment after taking 500 mg centanafadine SR 
TDD for 4 days (Trial NVI-EB-1020-201). The rash resolved in 8 days with no change in 
the dose and the subject completed the trial. Eight subjects reported rash after multiple 
doses of centanafadine SR in Trial NVI-EB-1020-202. Rashes resulted in discontinuation 
of dosing for 5 subjects and dose interruption and/or dose reduction for 3 subjects. The 
severity of the rash in subjects who discontinued IMP ranged from moderate to severe. 
The majority of subjects who experienced rash were exposed to doses greater than 
400 mg/day (2 subjects received 800 mg/day; 4 subjects received 600 mg/day; 2 subjects 
received 400 mg/kg). Neither subject who received 400 mg/day discontinued dosing due 
to the rash nor were the rashes in these subjects consistent with the drug eruptions seen in 
subjects who received 600 mg or 800 mg. All of the rashes were nonserious and all but 1 
resolved within 12 days of treatment with IMP withdrawal or dose reduction. The one 
exception was a severe rash lasting over 2 months that was considered likely due to an 
existing cutaneous condition and exacerbated by the drug eruption. The dermatologic 
experts who reviewed these AEs concluded that none exhibited a profile consistent with a 
rash that would progress to a serious or otherwise life-threatening AE.
Considering that rash can be a sign of an allergic reaction, subjects will be monitored 
closely for other symptoms of allergic reaction, including shortness of breath, itching and 
swelling of the throat or mouth, or difficulty breathing (see Section 5.4). A 
comprehensive rash monitoring plan will be followed.


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Please refer to the IB for more detailed information about the known and potential risks 
and benefits of centanafadine.25
2
Trial Rationale and Objectives
2.1
Trial Rationale
Attention-deficit hyperactivity disorder is an increasingly recognized and heterogeneous 
disorder characterized by the 3 core symptoms of hyperactivity, inattentiveness, and 
impulsivity1. Recent estimates of the prevalence of adult ADHD range from 2% to 6% of 
the adult population.26
While the currently recommended treatments for ADHD include stimulants 
(eg, methylphenidate and amphetamines) and nonstimulants (eg, atomoxetine, 
guanfacine, and clonidine)17,18 there still remains a need for safer, more effective 
therapies to expand the current options.
Centanafadine SR is a novel triple reuptake inhibitor developed for the treatment of 
ADHD. The purpose of this proposed open-label, multicenter trial is to evaluate the 
long-term safety and tolerability of a 400 mg TDD centanafadine SR in adult subjects
with ADHD.
2.2
Dosing Rationale
In this trial, centanafadine will be provided as 100 mg SR tablets.
After the completion of baseline evaluations (Day -1), all subjects will receive a starting 
dose of 200 mg TDD of centanafadine SR tablets from Days 1 to 7, followed by a 
titration to 400 mg TDD of centanafadine SR tablets on Day 8. Subjects will continue at 
400 mg TDD for the rest of the open-label treatment period until Week 52/ET.
From Days 1 to 7, all doses of open-label IMP will be taken orally twice daily (BID),
with 1 centanafadine SR tablet taken in the morning and 1 centanafadine SR tablet taken 
4 to 6 hours after the first dose.
From Day 8 to Week 52/ET, all doses of open-label IMP will be taken orally BID, with
2 centanafadine SR tablets taken in the morning and 2 centanafadine SR tablets taken 4 to
6 hours after the first dose. 
During the treatment period, subjects should make every effort to administer the 
open-label IMP at the same times every day.


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In the phase 2 NVI-EB-1020-202 trial, centanafadine SR was initially administered at a 
target dose of 800 mg/day. This dose was revised down to 600 mg/day given the 
incidence of gastrointestinal AEs and 3 reported cases of rash. After an additional 5 cases 
of rash were reported at the revised maximal dose of 600 mg/day centanafadine SR, the 
dose was further reduced to 400 mg/day. The primary endpoint, ADHD Rating Scale IV 
(ADHD-RS-IV) total score, was met in subjects that received 400 mg TDD centanafadine 
compared to those that received placebo (p < 0.001). Given the separation of 400 mg 
centanafadine from placebo, and the positive benefit/risk profile, it was concluded that 
the maximum tolerated dose is 400 mg/day. A TDD of 400 mg centanfadine will be 
included in this study to confirm the long-term safety and tolerability of the 
previously-established maximum tolerated dose.
Please refer to the IB for additional information about the IMP.25
2.3
Trial Objective
2.3.1
Primary Objective
The primary objective of this trial is to assess the safety and tolerability of centanafadine 
SR tablets administered BID (400 mg TDD) in the treatment of adults with ADHD.
3
Trial Design
3.1
Type/Design of Trial
This is a phase 3, 52-week, open-label, multicenter trial to assess the long-term safety and 
tolerability of centanafadine SR tablets (400 mg TDD) for the treatment of adults with 
ADHD. The trial population will include male and female subjects 18 to 55 years of age 
(inclusive) who meet Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition (DSM-5) criteria for ADHD (including predominantly inattentive presentation, 
hyperactive presentation, and combined presentations) as confirmed by the Adult ADHD 
Clinical Diagnostic Scale (ACDS) Version 1.2. Subjects who rollover from the 
double-blind phase 3 trial (ie, Trial 405-201-00013 or Trial 405-201-00014) and de novo 
subjects from selected sites are permitted to enroll in this trial.
This trial will have 3 periods for rollover subjects:
1. Baseline;
2. Open-label treatment; and
3. Follow-up.


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The trial will have 4 periods for de novo subjects: 
1. Screening and washout; 
2. Baseline; 
3. Open-label treatment; and 
4. Follow-up. 
The trial will be organized as follows:
Rollover Subjects from Double-blind Phase 3 Trial (ie, Trial 405-201-00013 or
Trial 405-201-00014)
Open-label Screening/Baseline: Subjects who completed one of the double-blind phase 3 
trials may be eligible to enroll in this trial; subjects who discontinued will not be eligible.
Subjects who complete both the 6-week double-blind treatment period and the 7-day 
follow-up visit are eligible to enroll into this trial. Subjects will be evaluated for 
eligibility at the 7-day follow-up visit of the double-blind phase 3 trial, and informed 
consent will be obtained before any procedures for the open-label trial are conducted. 
Therefore the assessments from the 7-day follow-up visit of the double-blind phase 3 trial 
may serve as the baseline assessments for the open-label trial.
 
Open-label Treatment: Eligible subjects from the double-blind phase 3 trial will receive 
daily treatment with open-label centanafadine SR tablets as described in Section 3.2.
During the open-label treatment period, subjects will return to the clinic for evaluations at 
the end of Weeks 1, 2, 4, 8, 12, 16, 20, 26, 32, 38, 44, and 52/ET. A Week 48 visit will be 
conducted via telephone, web, or other acceptable means of contact.
Follow-up: If any subject discontinues the trial early, every effort should be made to 
complete the early termination (ET) evaluations as soon as possible and, whenever 
possible, prior to starting any new medication or treatment. All subjects (completers and 
early withdrawals) will be evaluated for safety during a 10-day follow up (follow-up 
telephone calls at 1, 3, and 5 days after the last dose of IMP, in-clinic visits 2 and 7 days
after the last dose of IMP, and a follow-up telephone call [or web, or other acceptable 
means of contact] 10 days after the last dose of IMP).
CCI


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De Novo Subjects
Screening and Washout: De novo subjects must meet the DSM-5 criteria for ADHD 
(including predominantly inattentive presentation, hyperactive presentation, and 
combined presentations) as confirmed by the ACDS Version 1.2. To confirm that ADHD 
is the primary diagnosis, the Mini International Neuropsychiatric Interview (MINI) will 
be used to identify and exclude other psychiatric conditions. 
Subjects will be screened to establish eligibility for trial participation. The length of 
screening (Day –28 to Day –2) will include a washout period (if needed), which will 
range from 7 to 28 days. The investigator or his/her designee must obtain informed 
consent from the subject prior to any trial-related procedures being performed. An 
identification (ID) number will be assigned for each subject with documented consent.
Those subjects who meet eligibility requirements will undergo ADHD medication 
washout, if applicable. If subjects are taking disallowed medications and are able to taper 
appropriately and safely, they will do so during the screening period. If medication taken 
is for ADHD, a minimum of 7 days off stimulants and 21 days off nonstimulants will be 
required before baseline. A complete washout schedule, including common excluded 
medications and herbal preparations, is provided in Table 4.1-1 of the protocol. The 
screening visit may take place over multiple days to accommodate the subject’s schedule, 
if needed.
Baseline: Following medication washout, subjects will return to the clinic for 
reassessment of eligibility criteria and establishment of baseline measurements. The 
interval between the first day of the screening visit (informed consent date) and the 
baseline visit (Day –1) must not exceed 28 days. Subjects who meet relevant entry 
criteria by the time they leave the clinic on the day of the baseline visit will be dispensed 
the trial medication. 
 
Open-Label Treatment: After completing the baseline assessments, eligible subjects will 
receive daily treatment with open-label centanafadine SR tablets during the open-label 
treatment period, as described in Section 3.2.
During the open-label treatment period, subjects will return to the clinic for evaluations at 
the end of Weeks 1, 2, 4, 8, 12, 16, 20, 26, 32, 38, 44, and 52/ET. A Week 48 visit will be 
conducted via telephone, the web, or other acceptable means of contact.
CCI


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Follow-up: If any subject discontinues the trial early, every effort should be made to 
complete the Week 52/ET evaluations as soon as possible and whenever possible prior to 
starting any new medication or treatment. All subjects (completers and early 
withdrawals) will be evaluated for safety during a 10-day follow up (follow-up telephone 
calls at 1, 3, and 5 days after the last dose of IMP, in-clinic visits 2 and 7 days after the 
last dose of IMP, and a follow-up telephone call [or web, or other acceptable means of 
contact] 10 days after the last dose of IMP).
See Figure 3.1-1 and Figure 3.1-2 for schematics of the trial design for rollover and 
de novo subjects, respectively.


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Figure 3.1-1
Trial Design Schematic - Rollover Subjects from Trial 405-201-00013 or Trial 405-201-00014
Eligible rollover subjects 
who completed one of the 
double-blind phase 3 trials 
(ie, Trial 405-201-000013 or 
Trial 405-201-00014) and 
would potentially benefit 
from treatment with 
centanafadine SR for adult 
ADHD per investigator
Baseline
(7-day follow-up visit for 
Trial 405-201-00013 or 
Trial 405-201-00014)
Open-label Treatment Period
Follow-up Period
Open-label Centanafadine SR 400 mg (TDD)
Weeks 1, 2, 4, 8, 12, 16, 20, 26, 32, 38, and 44: clinic visits
Week 48: telephone, web, or other means of contact
(unscheduled visits as necessary)
Safety follow-up on 1, 2, 3, 5, 
7, and 10 days after the last 
dose of IMP
•
1-day, 3-day, and 5-day 
follow-up: telephone
•
2-day and 7-day 
follow-up: clinic visits
•
10-day follow-up: 
telephone, web, or other 
means of contact
Day -1
Baseline
Week 52/ET  
Screening/baseline values 
will be derived from the  
double-blind phase 3 trials 
(ie, Trial 405-201-000013 
or Trial 405-201-00014), 
as required
Day 1
First dose  


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Figure 3.1-2
Trial Design Schematic - De Novo Subjects
Eligible de novo 
subjects who could 
potentially benefit from 
treatment with 
centanafadine SR for 
ADHD per investigator
One or more visits 
as needed
(Days -28 to -2)
Day -1
Baseline
Screening Period
Week 52/ET  
Weeks 1, 2, 4, 8, 12, 16, 20, 26, 32, 38, and 44: clinic visits
Week 48: telephone, web, or other means of contact
(unscheduled visits as necessary)
Open-label Treatment Period
Follow-up Period
Open-label Centanafadine SR 400 mg/day (TDD)
Safety follow-up on 1, 2, 3, 5, 
7, and 10 days after the last 
dose of IMP
•
1-day, 3-day, and 5-day 
follow-up: telephone
•
2-day and 7-day 
follow-up: clinic visits
•
10-day follow-up: 
telephone, web, or other 
means of contact
Day 1
First dose  


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3.2
Trial Treatments
After the completion of baseline evaluations on Day -1, all subjects will follow a 
dose-escalation schedule starting on Day 1 (the day after the baseline visit) to increase 
their dose of the IMP to the target dose of 400 mg TDD by Day 8, as presented in 
Table 3.2-1 below:
Table 3.2-1
Titration Schedule for Centanafadine SR Tablets
Days
Time
Total Daily Dose
1 to 7
1 tablet PO in morning
1 tablet PO 4 to 6 hours later
1 × 100 mg tablet
1 × 100 mg tablet
200 mg
8 and thereafter
2 tablets PO in morning
2 tablets PO 4 to 6 hours later
2 × 100 mg tablets
2 × 100 mg tablets
400 mg
PO = by mouth.
Subjects will continue to dose with 400 mg TDD for the remainder of the open-label 
treatment period starting on Day 8. If there are any tolerability issues at the 400 mg TDD, 
the dose may be temporarily decreased to 200 mg TDD, based on the clinical judgment of 
the investigator. If an investigator reduces the TDD of a subject due to an adverse event, 
once the AE resolves, the dose should increase back to 400mg TDD. If tolerability issues 
emerge once the dose has been brought back to 400mg TDD, then the dose may be 
reduced again. If the dose is reduced from 400mg for ≥5 days in total, the medical 
monitor should be contacted to discuss continuation in the study.
Every effort should be made to administer the IMP at the same times every day. 
3.3
Trial Population
3.3.1
Number of Subjects and Description of Population
A total of approximately 720 male and female subjects with a current diagnosis of ADHD 
are anticipated to be enrolled with the expectation that at least 300 subjects will achieve 
6-month exposure and 100 subjects will achieve 52-week exposure.
The trial population will include approximately 560 completing rollover subjects from 
double-blind phase 3 trials (ie, Trial 405-201-00013 or Trial 405-201-00014) and 
approximately 145 de novo subjects between the ages of 18 and 55 years, inclusive, at the 
time of informed consent; de novo subjects must meet the DSM-5 criteria for ADHD 
including predominantly inattentive presentation, hyperactive presentation, or combined 
presentation) as confirmed by the ACDS Version 1.2. To confirm that ADHD is the 
primary diagnosis, the Mini International Neuropsychiatric Interview (MINI) will be used 
to identify and exclude other psychiatric conditions which would preclude enrollment.


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De novo subjects must washout of any prohibited medications prior to baseline 
(Table 4.1-2). Rollover subjects have already met the diagnostic criteria for ADHD
(ie, DSM-5 criteria for ADHD as confirmed by the ACDS Version 1.2) as a part of their 
screening for the double-blind phase 3 trial (ie, Trial 405-201-00013 or 
Trial 405-201-00014) and have already been washed out of any prohibited medications 
prior to the start of the double-blind trial treatment phase, which will be confirmed prior 
to baseline of Trial 405-201-00015 via concomitant medication reporting and urine drug 
screening.
Subjects who roll over from Trial 405-201-00013 or Trial 405-201-00014 who turned 
56 years old during that trial are also permitted to enroll in this trial.
3.3.2
Subject Selection and Numbering
At screening, only de novo subjects will be assigned a unique subject ID number upon 
signing the electronic informed consent form (eICF) based on sequential enrollment in 
the trial. The clinical site will maintain a list identifying all subjects by their subject ID
number and initials. Subjects that rollover from Trials 405-201-00013 or 405-201-00014 
will retain their subject ID number from the prior trial upon entry in to 
Trial 405-201-00015.
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). 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) Guideline27 and local regulatory requirements. The investigator 
will ensure that the sponsor reviews and authorizes any written site-specific eICF used in 
the trial prior to 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 subject 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 result in additional information that needs to be provided to the 
subjects, so that they can make a knowledgeable and voluntary decision on continued 
trial participation.
3.4.2
Inclusion Criteria
3.4.2.1
Rollover Subjects
Subjects are required to meet the inclusion criteria presented in Table 3.4.2.1-1.
Table 3.4.2.1-1
Inclusion Criteria for Rollover Subjects from 
Trial 405-201-00013 or Trial 405-201-00014
1.
Subjects who completed the 6-week double-blind treatment period and 7-day follow-up after last 
dose of IMP in double-blind phase 3 trial, (ie, Trial 405-201-00013 or Trial 405-201-00014) and 
who, in the opinion of the investigator, could potentially benefit from centanafadine for ADHD.
2.
Subjects who are able to complete the consent process and/or consent obtained from a legally 
acceptable representative (as required by IRB) prior to the initiation of any protocol-required 
procedures.
3.
Subjects who, during the double-blind trials, demonstrated adequate compliance with medication 
and protocol requirements, per investigator’s judgment.
4.
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 ingestion, and 
discontinuation of prohibited medication, and to read and understand the written word in order to 
be reliably rated on assessment scales.
FOCBP = females of childbearing potential.


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3.4.2.2
De Novo Subjects
Subjects are required to meet the inclusion criteria presented in Table 3.4.2.2-1.
Table 3.4.2.2-1
Inclusion Criteria for De Novo Subjects
1.
Subjects with a current primary DSM-5 diagnosis of ADHD (including predominantly 
inattentive presentation, hyperactive presentation, and combined presentations) as confirmed by 
the ACDS Version 1.2.
2.
Subjects are 18 to 55 years of age, inclusive, at the time of consent.
3.
Subjects have BMI of 18 to 40, inclusive.
4.
Subjects are able to swallow multiple tablets.
5.
Subjects are willing and able to comply with all testing and requirements as defined in this 
protocol.
6.
Subjects are able to provide electronic informed consent to participate in the trial in accordance 
with the ICH GCP Guidance E6 and applicable regulations before completing any trial-related 
procedures.
7.
Subjects are willing to discontinue all prohibited psychotropic medications (Section 4) starting 
from the time of signing the informed consent and up to the 10-day safety follow-up period.
8.
Subjects are able to read English or Spanish well enough to understand the nature of the trial and 
to read and understand the written word in order to complete subject-reported outcome measures 
and be able to communicate effectively to be reliably rated on assessment scales; must be able 
and agree to comply with all protocol requirements, including the prescribed dosage regimens, 
discontinuation of prohibited medications, and report for regularly scheduled office visits.
BMI = body mass index.
3.4.3
Exclusion Criteria
3.4.3.1
Rollover Subjects
Subjects will be excluded if they meet any of the exclusion criteria in Table 3.4.3.1-1.
Table 3.4.3.1-1
Exclusion Criteria for Rollover Subjects from 
Trial 405-201-00013 or Trial 405-201-00014
1.
Subjects who, during the double-blind phase 3 trial, (ie, Trial 405-201-00013 or 
Trial 405-201-00014), experienced, in the opinion of the investigator, poor tolerability to trial 
medication or whose safety assessments resulted in new concerns that would suggest the subject 
may not be appropriate for a 52-week treatment with trial medication.
2.
Subjects who have demonstrated noncompliance, based on investigator’s judgment to follow 
trial procedures during the course of their participation in the double-blind phase 3 trial, (ie, 
Trial 405-201-00013 or Trial 405-201-00014). The medical monitor should be contacted if the 
investigator is unsure of a subject’s eligibility.
3.
Subjects who have re-initiated any therapy for adult ADHD during the 7-day follow-up period 
after the Week 6 visit in Trial 405-201-00013 or Trial 405-201-00014.
4.
Females who have a positive pregnancy test result prior to receiving IMP.


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Table 3.4.3.1-1
Exclusion Criteria for Rollover Subjects from 
Trial 405-201-00013 or Trial 405-201-00014
5.
Sexually active males or FOCBP who do not agree to practice 2 different methods of birth 
control or remain abstinent during the course of the trial and for 30 days after the last dose of 
IMP for female subjects, and 90 days after the last dose of IMP for male subjects and their 
partners who are FOCBP. Unless the subject is sterile (ie, females who have had a bilateral 
oophorectomy or hysterectomy or who have been postmenopausal for at least 12 consecutive 
months; or males 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 injection, birth control implant, birth control patch, 
condom with spermicide, or sponge with spermicide. Male subjects who do not agree to refrain 
from donating sperm from screening through 90 days after the last dose of IMP.
6.
Following responses from the “Since Last Visit” version of the C-SSRS 7-day follow-up visit of 
double-blind pahse 3 trial, (ie, Trial 405-201-00013 or Trial 405-201-00014):

Subjects with a response of “Yes” on the C-SSRS Suicidal Ideation Item 4 (Active Suicidal 
Ideation with Some Intent to Act, Without Specific Plan) at entry, OR

Subjects with a response of “Yes” on the C-SSRS Suicidal Ideation Item 5 (Active Suicidal 
Ideation with Specific Plan and Intent) at entry, OR

Subjects with a response of “Yes” on any of the 5 C-SSRS Suicidal Behavior Items (actual 
attempt, interrupted attempt, aborted attempt, preparatory acts, or behavior) at entry, 
OR
Subjects who, in the opinion of the investigator (including consideration of responses on the 
C-SSRS throughout Trial 405-201-00013 or Trial 405-201-00014), present a serious risk of 
suicide.
Note: “Entry” is defined as the 7-day follow-up of Trial 405-201-00013 or Trial 405-201-00014.
7.
Subjects with newly developed psychiatric or medical condition that would be exclusionary 
under the criteria listed for Trial 405-201-00013 or Trial 405-201-00014.
8.
Subjects that have a positive alcohol test (via breathalyzer or blood), a positive drug screen for 
cocaine, or other illicit drugs (excluding marijuana). Subjects with a positive drug screen for 
confirmed prescription medications at baseline will not be permitted to continue participation in 
Trial 405-201-00015.
NOTE: Subjects that test positive for marijuana may be permitted to be enrolled if they have no 
evidence of a substance use disorder, and if they agree to refrain from use for the duration of the 
trial. Allowance for subjects testing positive for marijuana at screening require explicit approval 
from the medical monitor.
9.
Any new or developing safety concerns related to vital signs in the opinion of the investigator 
during the baseline visit.


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Table 3.4.3.1-1
Exclusion Criteria for Rollover Subjects from 
Trial 405-201-00013 or Trial 405-201-00014
10.
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 for males or > 470 msec for females
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. Eligibility should be based on the last 
available measurement during Trial 405-201-00013 or Trial 405-201-00014, as applicable. The 
medical monitor should be contacted if the investigator is unsure of a subject’s eligibility.
11.
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 (Section 4).
12.
Subjects who have previously been enrolled in this trial and subsequently withdrawn.
13.
Any subject who, in the opinion of the investigator, should not participate in the trial.
ALT = alanine aminotransferase; anti-HCV = hepatitis C antibodies; AST = asparatate 
aminotransferase; C-SSRS = Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; 
HbA1c = glycosylated hemoglobin; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; 
HIV = human immunodeficiency virus; OTC = over-the-counter; QTcB = QT interval corrected using 
Bazett's formula; QTcF = QT interval corrected using Fridericia's formula; T4 = free thyroxin; 
TSH = thyroid stimulating hormone.


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3.4.3.2
De Novo Subjects
Subjects will be excluded if they meet any of the exclusion criteria in Table 3.4.3.2-1.
Table 3.4.3.2-1
Exclusion Criteria for De Novo Subjects
1.
Females who are breast-feeding and/or who have a positive pregnancy test result prior to
receiving IMP.
2.
Sexually active males or FOCBP who do not agree to practice 2 different methods of birth control 
or remain abstinent during the course of the trial and for 30 days after the last dose of IMP for 
female subjects, and 90 days after the last dose of IMP for male subjects and their partners who 
are FOCBP. Unless the subject is sterile (ie, females who have had a bilateral oophorectomy or 
hysterectomy or who have been postmenopausal for at least 12 consecutive months; or males 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 injection, birth control implant, birth control patch, condom with spermicide, or sponge 
with spermicide. Male subjects who do not agree to refrain from donating sperm from screening 
through 90 days after the last dose of IMP.
3.
Subjects with DSM-5 diagnosis of Other Specified or Unspecified 
Attention-Deficit/Hyperactivity Disorder as confirmed by ACDS Version 1.2.
4.
Subjects with life-time history of electroconvulsive therapy, or a life-time history of vagal nerve 
stimulation or deep brain stimulation for the treatment of depression.
5.
Subjects with current comorbid psychiatric disorder that either could be expected to require 
treatment with medications prohibited in this trial, or to confound efficacy or safety assessments. 
Examples include, but are not limited to, psychotic disorder (current or lifetime), bipolar disorder 
(current or lifetime), generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, 
a current major depressive episode, or posttraumatic stress disorder, as established by the MINI.
6.
Subjects with a clinically significant current DSM-5 diagnosis of borderline, antisocial, paranoid, 
schizoid, schizotypal, histrionic, narcissistic, avoidant, or dependent personality disorders.
7.
Subjects who meet the following criteria for “Baseline/Screening” version of the C-SSRS:

Suicidal Ideation Items 4 or 5 within the last 6 months OR

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.
8.
Subject has any medical or psychological condition(s) or state(s) that in the investigator’s opinion 
would prohibit the subject from completing the trial or would go against the subject’s best interest 
with his/her participation in the trial. This would include any significant illness or unstable 
medical condition that could lead to difficulty complying with the protocol.
9.
Subject has a history of epilepsy, seizures (other than infantile febrile seizures), syncope, 
Tourette’s Disorder, serious neurological disease, history of significant head trauma with 
clinically significant loss of consciousness, dementia, cerebrovascular disease, Parkinson’s 
disease, or intracranial lesions.
10.
Subject has a life-time history of a pattern of abuse or diversion of stimulants.
11.
Subjects with any current or suspected drug or alcohol use disorder or have met the DSM-5 
criteria for a substance use disorder in the past 6 months. Nicotine use disorder is not 
exclusionary.


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Table 3.4.3.2-1
Exclusion Criteria for De Novo Subjects
12.
Subjects that have a positive alcohol test (via breathalyzer or blood), a positive drug screen for 
cocaine, or other illicit drugs (excluding marijuana). Subjects with a positive drug screen for 
confirmed prescription or OTC use of ADHD medications at screening will be required to 
undergo a washout period (Section 4).
NOTE: Subjects that test positive for marijuana may be permitted to be enrolled if they have no 
evidence of a substance use disorder, and if they agree to refrain from use for the duration of the
trial. Allowance for subjects testing positive for marijuana at screening require explicit approval 
from the medical monitor.
13.
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.
14.
Subjects with insulin-dependent diabetes mellitus are excluded. Subjects with 
non- insulin-dependent diabetes mellitus may be eligible for the trial if their condition is stable as 
determined by satisfying ALL of the following criteria:

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.
15.
Subjects presenting with, or having a history of, uncontrolled hypertension (systolic blood 
pressure > 140 mmHg and/or diastolic blood pressure > 90 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 diastolic blood pressure after at least 3 minutes 
standing compared with the previous supine blood pressure, OR development of symptoms.
16.
Subjects with known ischemic heart disease or history of myocardial infarction, congestive heart 
failure (whether controlled or uncontrolled), angioplasty, stenting, coronary artery bypass surgery, 
or other serious cardiac problems that would place him/her at increased vulnerability to the 
sympathomimetic effects of a stimulant medication.
17.
The following laboratory test and ECG results are exclusionary at screening:
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) QTcF and/or QTcB > 450 msec for males or > 470 msec for females
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.
18.
Subjects with hypothyroidism or hyperthyroidism (unless condition has been stabilized with 
medications for at least the past 90 days) or an abnormal result for free T4 at screening (free T4 is 
measured only if result for TSH is abnormal).


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Table 3.4.3.2-1
Exclusion Criteria for De Novo Subjects
19.
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 (Section 4).
20.
Subjects with a history of prior exposure to centanafadine.
21.
Subjects with a history of dermatologic adverse reactions or anaphylaxis secondary to drug 
exposure.
22.
Subjects with HIV seropositive status/acquired immunodeficiency syndrome, seropositive status 
for hepatitis B (ie, HBsAg positive), or hepatitis C (ie, anti-HCV positive and HCV RNA 
positive).
23.
Subjects who have previously been enrolled in this trial and subsequently withdrawn.
24.
Subject has participated in a clinical trial involving either an investigational medication or a 
non-medication intervention within the last 60 days prior to screening or has participated in more 
than 2 clinical trials involving either an investigational medication or non-medication intervention 
within the past year.
25.
Any subject who, in the opinion of the investigator, should not participate in the trial.
See Section 3.9 for details regarding screen failures.
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 or hysterectomy) and female subjects who 
have been postmenopausal for at least 12 consecutive months.
Subjects must agree to restrictions to medications and lifestyle as described in Section 4.
3.5
Endpoints
3.5.1
Primary Endpoint
The primary endpoint in this trial is the long-term safety and tolerability of centanafadine 
SR tablets administered BID (400 mg TDD), as assessed by the frequency and severity of 
treatment-emergent adverse events (TEAEs).
3.5.2
Secondary Endpoints
None.


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3.5.3
Exploratory Endpoint(s)
Exploratory efficacy endpoints for the open-label treatment period are as follows:
!
Change from baseline in Adult ADHD Investigator Symptom Rating Scale (AISRS)
Total Score, by trial visit and at the last visit (ie, Week 52/ET);
!
Change from baseline Clinical Global Impression-Severity of Illness Scale (CGI-S), 
by trial visit and at the last visit (ie, Week 52/ET); 
!
Change from baseline in ADHD Impact Module - Adult (AIM-A) Score by trial visit
and at the last visit;
3.5.4
Additional Safety Endpoints
Additional safety variables will include clinically significant changes in: clinical 
laboratory tests (hematology, serum chemistry, coagulation parameters, and urinalysis), 
physical examinations, vital sign measurements, and electrocardiograms (ECGs). 
The Columbia-Suicide Severity Rating Scale (C-SSRS) will be used to assess and 
classify reported suicidal behavior. By-subject listings of physical examination findings 
will be reviewed as a further assessment of safety.
Assessments of withdrawal symptoms will be performed using Study Medication
Withdrawal Questionnaire (SMWQ).
Abuse-related AEs and AEs involving medication irregularities will be recorded verbatim 
on source documentation with detailed narratives (Section 5.5).
3.6
Measures to Minimize/Avoid Bias
Not applicable; this is an open-label trial.
CCI


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3.7
Trial Procedures
Individual participation for rollover subjects who complete the trial without early 
withdrawal will be approximately 54 weeks, consisting of a 52-week open-label
treatment period, and 10-day safety follow-up period after the last dose of IMP.
Individual participation for de novo subjects who complete the trial without early 
withdrawal will be approximately 58 weeks, consisting of a screening period of up to 
28 days, a 52-week open-label treatment period, and a 10-day safety follow-up after the 
last dose of IMP.
Trial assessment time points are summarized in Table 3.7-1 and Table 3.7-2 (rollover 
subjects from Trial 405-201-00013 or Trial 405-201-00014) and Table 3.7-3 and 
Table 3.7-4 (de novo subjects).
In addition to the trial assessment time points summarized (Table 3.7-1 and Table 3.7-2
for rollover subjects and Table 3.7-3 and Table 3.7-4 for de novo subjects 
 
 
 
CCI


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Table 3.7-1
Schedule of Assessments - Rollover Subjects from Trial 405-201-00013 or Trial 405-201-00014 -
Baseline Through End of Treatment
Baseline
7-day follow-up visit 
from
Trial 405-201-00013 or 
Trial 405-201-00014/
Baseline for
Trial 405-201-00015a
52-Week Open-label Treatment Period
W 1 & 
2
(3
days)
W 4, 8, 12 & 
16
(3 days)
W 20
(3
days)
W 26
(3
days)
W 32
(3
days)
W 38
(3
days)
W 44
(3
days)
W 48b
(3
days)
End of 
Treatment
W 52/ET
(3 days)
Visit
1
2 & 3
4, 5, 6, & 7
8
9
10
11
12
13
14
ENTRANCE/HISTORY
Informed consent
X
Inclusion/exclusion 
criteria
X
Concomitant 
medication(s)
Xc
X
X
X
X
X
X
X
X
X
HIV/HBsAg/
anti-HCV
X
Urine pregnancy testd
X
X
X
X
X
X
X
X
X
SAFETY
Adverse events
Xc
X
X
X
X
X
X
X
X
X
Physical examination
Xe
Xf
X
X
Vital signs
Xc
X
X
X
X
X
X
X
X
12-lead ECG
X
X
Xg
X
X
X


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
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Table 3.7-1
Schedule of Assessments - Rollover Subjects from Trial 405-201-00013 or Trial 405-201-00014 -
Baseline Through End of Treatment
Baseline
7-day follow-up visit 
from
Trial 405-201-00013 or 
Trial 405-201-00014/
Baseline for
Trial 405-201-00015a
52-Week Open-label Treatment Period
W 1 & 
2
(∀3
days)
W 4, 8, 12 & 
16
(∀3 days)
W 20
(∀3
days)
W 26
(∀3
days)
W 32
(∀3
days)
W 38
(∀3
days)
W 44
(∀3
days)
W 48b
(∀3
days)
End of 
Treatment
W 52/ET
(∀3 days)
Visit
1
2 & 3
4, 5, 6, & 7
8
9
10
11
12
13
14
Clinical laboratory 
tests (hematology, 
serum chemistry 
[including HbA1c and 
TSH], and urinalysis)
X
Xf
X
X
X
PT/INR
X
X
X
SMWQ
X
Urine drug screen
Xc
Xh
X
X
Alcohol testingi
Xc
Xh
X
X
C-SSRS
Xc
X
X
X
X
X
X
X
X
EFFICACY
AISRS
Xc
X
X
X
X
X
X
X
X
CGI-S
X
X
X
X
X
X
X
X
X
AIM-A
X
X
X
CCI


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
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Table 3.7-1
Schedule of Assessments - Rollover Subjects from Trial 405-201-00013 or Trial 405-201-00014 -
Baseline Through End of Treatment
Baseline
7-day follow-up visit 
from
Trial 405-201-00013 or 
Trial 405-201-00014/
Baseline for
Trial 405-201-00015a
52-Week Open-label Treatment Period
W 1 & 
2
(∀3
days)
W 4, 8, 12 & 
16
(∀3 days)
W 20
(∀3
days)
W 26
(∀3
days)
W 32
(∀3
days)
W 38
(∀3
days)
W 44
(∀3
days)
W 48b
(∀3
days)
End of 
Treatment
W 52/ET
(∀3 days)
Visit
1
2 & 3
4, 5, 6, & 7
8
9
10
11
12
13
14
OTHER
IMP dispensing
X
X
X
X
X
X
X
X
IMP return and 
accountability
X
X
X
X
X
X
X
X
AIM-A = ADHD Impact Module – Adult; AISRS = Adult ADHD Investigator Rating Scale; C-SSRS = Columbia-Suicide Severity Rating Scale; 
ECG=electrocardiogram; PT/INR = prothrombin time/international normalized ratio; W = week.
aDosing will commence the day after the baseline visit.
bTelephone, web, or other acceptable means of contact.
cAssessments may be conducted at the 7-day follow-up visits of Trial 405-201-00013 or Trial 405-201-00014, and the information can be carried over into 
Trial 405-201-00015 for the baseline visit.
dIf the urine pregnancy test is positive, the result will be confirmed with a serum pregnancy test.
ePhysical examination at baseline will include height measurements.
fWeek 8 only.
gWeeks, 4, 8, and 16 only.
hWeeks 4 and 12 only.
iAlcohol testing may be conducted via a blood test or using a breathalyzer.
CCI
CCI


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Table 3.7-2
Schedule of Assessments - Rollover Subjects from Trial 405-201-00013 or Trial 405-201-00014 -
Follow-up
Period
Follow-upa
1 (+1) days after 
the last dose of 
IMP
2 (+1) 
days 
after the 
last dose 
of IMP
3 (+ 1) 
days after 
the last 
dose of 
IMP
5 (+ 1) 
days after 
the last 
dose of 
IMP
7 (+ 2) days 
after the last
dose of IMP
10 (+ 2) 
days after 
the last 
dose of 
IMP
Visit
15
16
17
18
19
20
ENTRANCE/HISTORY
Concomitant medication(s)
X
X
X
X
X
X
EFFICACY
AISRS
X
X
SAFETY
Adverse events
X
X
X
X
X
X
Vital signs
X
X
SMWQ
X
X
X
X
X
X
Urine drug screen
X
X
Alcohol testingb
X
X
C-SSRS
X
X
aFollow-up telephone calls will be conducted at 1, 3, and 5 days after the last dose of IMP, in-clinic visits on 2 and 7 days after the last dose of IMP, and a 
follow-up telephone call [or web, or other acceptable means of contact] 10 days after the last dose of IMP).
bAlcohol testing may be conducted via a blood test or using a breathalyzer.


Clinical Study Report 405-201-00015
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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Table 3.7-3
Schedule of Assessments - De Novo Subjects - Baseline Through End of Treatment
Screeninga
Baselineb
52-Week Open-label Treatment Period
W 1 & 2
(3
days)
W 4, 8, 12, 
& 16
(3 days)
W 20
(3 
days)
W 26
(3
days)
W 32
(3
days)
W 38
(3 
days)
W 44
(3
days)
W 48c
(3 
days)
End of 
Treatment
W 52/ET
(3 days)
Visit
1
2
3 & 4
5, 6, 7, & 8
9
10
11
12
13
14
15
ENTRANCE/HISTORY
Informed consent
X
Inclusion/exclusion 
criteria
X
X
Demography
X
Concomitant 
medication(s)
X
X
X
X
X
X
X
X
X
X
X
Medical history
X
ACDS
X
Identification of 
comorbidities using 
MINI
X
Psychiatric history
X
HIV/HBsAg/
anti-HCV
X
Urine pregnancy testd
X
X
X
X
X
X
X
X
X
X
SAFETY
Adverse events
X
X
X
X
X
X
X
X
X
X
X
Physical examination
Xe
X
Xf
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X
X
X
Xg
X
X
X


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
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Table 3.7-3
Schedule of Assessments - De Novo Subjects - Baseline Through End of Treatment
Screeninga
Baselineb
52-Week Open-label Treatment Period
W 1 & 2
(∀3
days)
W 4, 8, 12, 
& 16
(∀3 days)
W 20
(∀3 
days)
W 26
(∀3
days)
W 32
(∀3
days)
W 38
(∀3 
days)
W 44
(∀3
days)
W 48c
(∀3 
days)
End of 
Treatment
W 52/ET
(∀3 days)
Visit
1
2
3 & 4
5, 6, 7, & 8
9
10
11
12
13
14
15
Clinical laboratory 
tests
(hematology, serum 
chemistry [including 
HbA1c and TSH], and 
urinalysis)
X
X
Xf
X
X
X
PT/INR
X
X
X
SMWQ
X
Urine drug screen
X
X
Xh
X
X
Alcohol testingi
X
X
Xh
X
X
C-SSRS
X
X
X
X
X
X
X
X
X
X
EFFICACY
AISRS
X
X
X
X
X
X
X
X
X
CGI-S
X
X
X
X
X
X
X
X
X
AIM-A
X
X
X
CCI


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Table 3.7-3
Schedule of Assessments - De Novo Subjects - Baseline Through End of Treatment
Screeninga
Baselineb
52-Week Open-label Treatment Period
W 1 & 2
(∀3
days)
W 4, 8, 12, 
& 16
(∀3 days)
W 20
(∀3 
days)
W 26
(∀3
days)
W 32
(∀3
days)
W 38
(∀3 
days)
W 44
(∀3
days)
W 48c
(∀3 
days)
End of 
Treatment
W 52/ET
(∀3 days)
Visit
1
2
3 & 4
5, 6, 7, & 8
9
10
11
12
13
14
15
OTHER
IMP dispensing
X
X
X
X
X
X
X
X
IMP return and 
accountability
X
X
X
X
X
X
X
X
aScreening will include a washout period that can range from 7 to 28 days.
bDosing will commence the day after the Baseline visit.
cTelephone, web, or other acceptable means of contact.
dIf the urine pregnancy test is positive, the result will be confirmed with a serum pregnancy test.
ePhysical examination at screening will include height measurements.
fWeek 8 only.
gWeeks 4, 8, and 16 only.
hWeeks 4 and 12 only.
iAlcohol testing may be conducted via a blood test or using a breathalyzer.
CCI
CCI


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Table 3.7-4
Schedule of Assessments - De Novo Subjects - Follow-up
Period
Follow-upa
1 (+1) days after 
the last dose of 
IMP
2 (+1) 
days 
after the 
last dose 
of IMP
3 (+ 1) 
days after 
the last 
dose of 
IMP
5 (+ 1) 
days after 
the last 
dose of 
IMP
7 (+ 2) days 
after the last 
dose of IMP
10 (+ 2) 
days after 
the last 
dose of 
IMP
Visit
16
17
18
19
20
21
ENTRANCE/HISTORY
Concomitant medication(s)
X
X
X
X
X
X
EFFICACY
AISRS
X
X
SAFETY
Adverse events
X
X
X
X
X
X
Vital signs
X
X
SMWQ
X
X
X
X
X
X
Urine drug screen
X
X
Alcohol testingb
X
X
C-SSRS
X
X
aFollow-up telephone calls will be conducted at 1, 3, and 5 days after the last dose of IMP, in-clinic visits on 2 and 7 days after the last dose of IMP, and a 
follow-up telephone call [or web, or other acceptable means of contact] 10 days after the last dose of IMP).
bAlcohol testing may be conducted via a blood test or using a breathalyzer.


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3.7.1
Schedule of Assessments
3.7.1.1
Screening and Baseline
3.7.1.1.1
Rollover Subjects
Screening for rollover subjects occurs simultaneously with baseline at the 7-day 
follow-up visit after Week 6/ET visit (Week 6) of double-blind phase 3 trial, 
(ie, Trial 405-201-00013 or Trial 405-201-00014) (Table 3.7-1) (Visit 1). Rollover 
subjects entering from double-blind phase 3 trial must sign the eICF for the open-label 
trial (ie, Trial 405-201-00015), before any procedures specific to Trial 405-201-00015 
can be performed. Subjects will retain the same subject ID number assigned in 
Trial 405-201-00013 or Trial 405-201-00014. The following screening/baseline 
assessments may be conducted at the 7-day follow-up visits of Trial 405-201-00013 or 
Trial 405-201-00014, and the information can be carried over into Trial 405-201-00015 
for the baseline visit: concomitant medications, AEs, vital signs, urine drug screen, 
alcohol testing, C-SSRS, and AISRS. The additional procedures to be performed for 
rollover subjects at baseline of the open-label trial are as follows:
!
An assessment of all inclusion and exclusion criteria will be made to determine the 
subject’s eligibility for the trial.
!
Medical history from Trial 405-201-00013 or Trial 405-201-00014 will be retained, 
but will be updated if necessary.
!
A qualified rater will administer the CGI-S.
!
Subjects will complete the AIM-A.
!
 
!
A physical examination including height measurements will be performed.
!
A standard 12-lead ECG will be performed after the subject has been supine and at 
rest for at least 5 minutes. The ECG is to be completed before any blood is drawn.
!
Blood samples will be collected for clinical laboratory tests, including hematology
and serum chemistry (with glycosylated hemoglobin [HbA1c], and 
thyroid-stimulating hormone [TSH and free thyroxine [T4]). Blood will be drawn 
after a minimum 8-hour fast, if at all possible (see Section 3.7.4.2). 
See Table 3.4.3.1-1 for exclusions based on outcome of screening clinical laboratory 
tests. Vital sign and ECG assessments should be completed before any blood samples 
are collected.
!
Blood samples will be drawn for human immunodeficiency virus (HIV) serology and 
the presence of hepatitis B surface antigen (HBsAg) and antibodies to hepatitis C 
virus (anti-HCV).
!
A urine pregnancy test will be performed for all females of childbearing potential 
(FOCBP). If the urine pregnancy test is positive, the result should be confirmed with 
CCI


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
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a serum pregnancy test. Subjects with a positive serum test result will be excluded 
from the trial.
!
.AE recording will begin with the signing of the eICF for Trial 405-201-00015.
!
Open-label centanafadine SR will be dispensed to the subject and subjects will be 
instructed to take their 2 doses at approximately the same time every day starting 
from Day 1 (day after baseline visit).
3.7.1.1.2
De Novo Subjects
De novo subjects did not participate in Trial 405-201-00013 or Trial 405-201-00014; 
therefore, they must attend separate screening and baseline visits to allow for completion 
of eligibility assessments and washout of prohibited concomitant medications, if 
applicable (Table 3.7-3).
3.7.1.1.2.1
Screening
For de novo subjects, the screening period begins after informed consent has been 
obtained and will take place between Day –28 and Day –1 prior to enrollment (Visit 1). 
Although the screening period continues up to administration of the first dose of IMP, 
screening procedures should be initiated with a sufficient amount of time allotted in order 
to obtain laboratory results and ECG results from the central reader prior to dosing.
Completion of screening activities may require more than 1 visit. All procedures outlined 
for screening in the Schedule of Assessments (Table 3.7-3) will be performed. 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 Version 1.2 and MINI will be administeered to rule out other 
comorbid diagnoses.
!
The investigator (or qualified designee) will complete the “Baseline/Screening” 
C-SSRS form.
!
A physical examination including height measurements will be performed.
!
Vital sign measurements will be recorded. See Table 3.4.3.2-1 for exclusions based 
on outcome of screening vital sign measurements.
!
A standard 12-lead ECG will be performed after the subject has been supine and at 
rest for at least 5 minutes. The ECG is to be completed before any blood is drawn.
CCI


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!
Blood samples will be collected for clinical laboratory tests, including hematology
and serum chemistry (with HbA1c and TSH and T4). Blood will be drawn after a 
minimum 8-hour fast, if at all possible (see Section 3.7.4.2). See Table 3.4.3.2-1 for 
exclusions based on outcome of screening clinical laboratory tests. Vital sign and 
ECG assessments should be completed before any blood samples are collected.
!
Blood samples will be drawn for HIV serology and the presence of HBsAg and 
anti-HCV.
!
Alcohol testing will be conducted via a blood test or using a breathalyzer.
!
A urine pregnancy test will be performed for all FOCBP. 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 urinalysis and urine screen(s) 
for drugs of abuse. See Table 3.4.3.2-1 for exclusions based on outcome of urine drug 
screen(s).
!
If subjects are taking disallowed medications and they are able to taper appropriately 
and safely, they will do so during the screening period. If medication taken is for 
ADHD, a minimum of 1 week off stimulants and 3 weeks off nonstimulants will be 
required before baseline. A complete washout schedule, including common excluded 
medications and herbal preparations, is provided in Section 4.1.
!
AE recording will begin with the signing of the eICF for Trial 405-201-00015.
The sponsor reserves the right to utilize external quality oversight methods to ensure the 
validity of diagnosis, severity of illness, and other factors determining appropriateness of 
subject selection.
3.7.1.1.2.2
Baseline
If the subject is found to be eligible for the trial during the screening, the subject will 
attend a baseline visit (Visit 2) during which the following procedures will be completed 
prior to the subject starting open-label IMP:
!
Inclusion/exclusion criteria will be verified. Review of inclusion/exclusion criteria at 
the baseline visit will be based on assessments performed during screening.
!
Medications taken during the screening period will be reviewed and documented.
!
A qualified rater will administer the AISRS.
!
A qualified rater will administer the CGI-S.
!
The investigator (or qualified designee) will complete the “Since Last Visit” C-SSRS 
form.
!
Subjects will complete the AIM-A.
!
 
!
A physical examination will be performed.
CCI


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
Vital sign measurements will be recorded.

A standard 12-lead ECG will be performed after the subject has been supine and at 
rest for at least 5 minutes. The ECG is to be completed before any blood is drawn.

Blood samples will be collected for clinical laboratory tests (hematology and serum 
chemistry [including HbA1c, TSH, and PT/INR]) after a minimum 8-hour fast. Vital 
sign and ECG assessments should be completed before any blood samples are 
collected.

Alcohol testing will be conducted via a blood test or using a breathalyzer.

Urine will be collected from all potential subjects for urinalysis and urine screen(s) 
for drugs of abuse. See Table 3.4.3.2-1 for exclusions based on outcome of urine drug 
screen(s). 

A urine pregnancy test will be performed for all FOCBP. The result must be negative 
prior to dosing. If the urine pregnancy test is positive, the result should be confirmed 
with a serum pregnancy test.

Blood samples for FBR will be collected, if FBR consent was obtained.

AEs and concomitant medications will be recorded.

Open-label centanafadine SR will be dispensed to the subject and subjects will be 
instructed to take their 2 doses at approximately the same time every day starting on 
Day 1 (the day after the baseline visit).
3.7.1.2
Open-label Treatment Period
3.7.1.2.1
Weeks 1 and 2
Weeks 1 and 2 (± 3 days) will be Visits 2 and 3 for rollover subjects and Visits 3 and 4 
for de novo subjects. 
The following procedures will be performed at Week 1 and 2 visits (± 3 days):

A qualified rater will administer the AISRS.

A qualified rater will administer the CGI-S.

The investigator (or qualified designee) will complete the “Since Last Visit” C-SSRS 
form.

Vital sign measurements will be recorded.

A standard 12-lead ECG will be performed after the subject has been supine and at 
rest for at least 5 minutes. The ECG is to be completed before any blood is drawn.

A urine pregnancy test will be performed for all FOCBP. If the urine pregnancy test is 
positive, the result should be confirmed with a serum pregnancy test.

AEs and concomitant medications will be recorded.

Drug accountability will be performed.


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16.1.1 Protocol and Protocol Amendments
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
Open-label centanafadine SR will be dispensed to the subject and subjects will be 
instructed to take their 2 doses at approximately the same time every day.
3.7.1.2.2
Weeks 4, 8, 12 and 16
Weeks 4, 8, 12 and 16 (± 3 days) will be Visits 4, 5, 6, and 7 for rollover subjects and 
Visits 5, 6, 7, and 8 for de novo subjects.
The following procedures will be performed at the Week 4, 8, 12, and 16 visits
(± 3 days):

A qualified rater will administer the AISRS.

A qualified rater will administer the CGI-S.

The investigator (or qualified designee) will complete the “Since Last Visit” C-SSRS 
form.

A physical examination will be performed (Week 8 only).

Vital sign measurements will be recorded.

A standard 12-lead ECG will be performed after the subject has been supine and at 
rest for at least 5 minutes. The ECG is to be completed before any blood is drawn
(Weeks 4, 8, and 16 only).

Blood samples will be collected for clinical laboratory tests (hematology and serum 
chemistry [including HbA1c, and TSH]) after a minimum 8-hour fast. Vital sign and 
ECG assessments should be completed before any blood samples are collected
(Week 8 only).

Alcohol testing may be conducted via a blood test or using a breathalyzer (Weeks 4 
and 12 only).

Urine will be collected for urinalysis (Week 8 only).

Urine will be collected for urine screen(s) for drugs of abuse (Weeks 4 and 12 only).

A urine pregnancy test will be performed for all FOCBP. If the urine pregnancy test is 
positive, the result should be confirmed with a serum pregnancy test.

AEs and concomitant medications will be recorded.

Drug accountability will be performed.

Open-label centanafadine SR will be dispensed to the subject and subjects will be 
instructed to take their 2 doses at approximately the same time every day.
3.7.1.2.3
Week 20
Week 20 (± 3 days) will be Visit 8 for rollover subjects and Visit 9 for de novo subjects.
The following procedures will be performed at the Week 20 visit (± 3 days):

A qualified rater will administer the AISRS.


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!
A qualified rater will administer the CGI-S.
!
The investigator (or qualified designee) will complete the “Since Last Visit” C-SSRS 
form.
!
Vital sign measurements will be recorded.
!
A urine pregnancy test will be performed for all FOCBP. If the urine pregnancy test is 
positive, the result should be confirmed with a serum pregnancy test.
!
AEs and concomitant medications will be recorded.
!
Drug accountability will be performed.
!
Open-label centanafadine SR will be dispensed to the subject and subjects will be 
instructed to take their 2 doses at approximately the same time every day.
3.7.1.2.4
Week 26
Week 26 (± 3 days) will be Visit 9 for rollover subjects and Visit 10 for de novo subjects.
The following procedures will be performed at the Week 26 visit (± 3 days):
!
A qualified rater will administer the AISRS.
!
A qualified rater will administer the CGI-S.
!
The investigator (or qualified designee) will complete the “Since Last Visit” C-SSRS 
form.
!
Subjects will complete the AIM-A.
!
 
!
A physical examination will be performed.
!
Vital sign measurements will be recorded. 
!
A standard 12-lead ECG will be performed after the subject has been supine and at 
rest for at least 5 minutes. The ECG is to be completed before any blood is drawn.
!
Blood samples will be collected for clinical laboratory tests (hematology and serum 
chemistry [including HbA1c, TSH, and PT/INR]) after a minimum 8-hour fast. Vital 
sign and ECG assessments should be completed before any blood samples are 
collected.
!
Alcohol testing may be conducted via a blood test or using a breathalyzer.
!
Urine will be collected for urinalysis and urine screen(s) for drugs of abuse.
!
A urine pregnancy test will be performed for all FOCBP. If the urine pregnancy test is 
positive, the result should be confirmed with a serum pregnancy test.
!
AEs and concomitant medications will be recorded.
!
Drug accountability will be performed.
!
Open-label centanafadine SR will be dispensed to the subject and subjects will be 
instructed to take their 2 doses at approximately the same time every day.
CCI


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3.7.1.2.5
Week 32
Week 32 (± 3 days) will be Visit 10 for rollover subjects and Visit 11 for de novo 
subjects.
The following procedures will be performed at the Week 32 visit (± 3 days):

A qualified rater will administer the AISRS.

A qualified rater will administer the CGI-S.

The investigator (or qualified designee) will complete the “Since Last Visit” C-SSRS 
form.

Vital sign measurements will be recorded. 

A urine pregnancy test will be performed for all FOCBP. If the urine pregnancy test is 
positive, the result should be confirmed with a serum pregnancy test.

AEs and concomitant medications will be recorded.

Drug accountability will be performed.

Open-label centanafadine SR will be dispensed to the subject and subjects will be 
instructed to take their 2 doses at approximately the same time every day.
3.7.1.2.6
Week 38
Week 38 (± 3 days) will be Visit 11 for rollover subjects and Visit 12 for de novo 
subjects.
The following procedures will be performed at the Week 38 visit (± 3 days):

A qualified rater will administer the AISRS.

A qualified rater will administer the CGI-S.

The investigator (or qualified designee) will complete the “Since Last Visit” C-SSRS 
form.

Vital sign measurements will be recorded.

A standard 12-lead ECG will be performed after the subject has been supine and at 
rest for at least 5 minutes. The ECG is to be completed before any blood is drawn.

Blood samples will be collected for clinical laboratory tests (hematology and serum 
chemistry [including HbA1c and TSH]) after a minimum 8-hour fast. Vital sign and 
ECG assessments should be completed before any blood samples are collected.

A urine pregnancy test will be performed for all FOCBP. If the urine pregnancy test is 
positive, the result should be confirmed with a serum pregnancy test.

AEs and concomitant medications will be recorded.

Drug accountability will be performed.

Open-label centanafadine SR will be dispensed to the subject and subjects will be 
instructed to take their 2 doses at approximately the same time every day.


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3.7.1.2.7
Week 44
Week 44 (± 3 days) will be Visit 12 for rollover subjects and Visit 13 for de novo 
subjects.
The following procedures will be performed at the Week 44 visit (± 3 days):

A qualified rater will administer the AISRS.

A qualified rater will administer the CGI-S.

The investigator (or qualified designee) will complete the “Since Last Visit” C-SSRS 
form.

Vital sign measurements will be recorded. 

A urine pregnancy test will be performed for all FOCBP. The result must be negative 
prior to dosing. If the urine pregnancy test is positive, the result should be confirmed 
with a serum pregnancy test.

AEs and concomitant medications will be recorded.

Drug accountability will be performed.

Open-label centanafadine SR will be dispensed to the subject and will be instructed to 
take their 2 doses at approximately the same time every day.
3.7.1.2.8
Week 48
Week 48 (± 3 days) will be Visit 13 for rollover subjects and Visit 14 for de novo 
subjects.
Week 48 visit (± 3 days) will be conducted via telephone, web, or other acceptable means 
of contact. The following procedures will occur for all subjects:

AEs and concomitant medications will be recorded.
3.7.1.2.9
Week 52/Early Termination (End of Treatment)
Week 52/ET (3 days) will be Visit 14 for rollover subjects and Visit 15 for de novo 
subjects.
The following procedures will be performed at the Week 52/ET visit (3 days):

A qualified rater will administer the AISRS.

A qualified rater will administer the CGI-S.

The SMWQ questionnaire will be completed.


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!
The investigator (or qualified designee) will complete the “Since Last Visit” C-SSRS
form.
!
Subjects will complete the AIM-A.
!
 
!
A physical examination will be performed.
!
Vital sign measurements will be recorded.
!
A standard 12-lead ECG will be performed after the subject has been supine and at 
rest for at least 5 minutes. The ECG is to be completed before any blood is drawn.
!
Blood samples will be collected for clinical laboratory tests (hematology and serum 
chemistry [including HbA1c, TSH, and PT/INR]) after a minimum 8-hour fast. Vital 
sign and ECG assessments should be completed before any blood samples are 
collected.
!
Alcohol testing will be conducted via a blood test or using a breathalyzer.
!
Urine will be collected from all subjects for urinalysis and urine screen(s) for drugs of 
abuse.
!
A urine pregnancy test will be performed for all FOCBP. If the urine pregnancy test is 
positive, the result should be confirmed with a serum pregnancy test.
!
AEs and concomitant medications will be recorded.
!
Drug accountability will be performed.
!
Subjects will be instructed not to initiate a different ADHD therapy until follow-up 
visit is completed 10 days after the last dose of IMP (Week 52/ET + 14 days).
3.7.1.3
Follow-up Period
All subjects, whether they complete the trial or are withdrawn prematurely for any 
reason, will be followed up for a safety evaluation during a 10-day follow up period 
(follow-up telephone calls at 1, 3, and 5 days after the last dose of IMP, in-clinic visits 2
and 7 days after the last dose of IMP, and a follow-up telephone call [or web, or other 
acceptable means of contact] 10 days after the last dose of IMP). 
The following procedures will be performed at the 1-day, 3-day, and 5-day follow-up 
visit:
!
The SMWQ questionnaire will be completed remotely.
!
AEs will be recorded.
!
Concomitant medications will be recorded.
The following procedures will be performed at the 2-day and 7-day follow-up visit:
CCI


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
A qualified rater will administer the AISRS.

The SMWQ questionnaire will be completed in-clinic.

Vital sign measurements will be recorded.

Alcohol testing may be conducted via a blood test or using a breathalyzer.

Urine will be collected for urine screen(s) for drugs of abuse.

The investigator (or qualified designee) will complete the “Since Last Visit” C-SSRS 
form.

AEs and concomitant medications will be recorded.
The following procedures will be performed at 10-day follow-up contact:

The SMWQ questionnaire will be completed remotely.

AEs and concomitant medications will be recorded.
Depending upon the type of follow-up required, other evaluations or tests may be 
conducted or performed.
3.7.2
Efficacy Assessments
It is required that adequately trained and experienced clinicians administer the AISRS, 
CGI-S, MINI, and ACDS Version 1.2. All individuals performing these assessments must 
be pre-approved by the sponsor or designee.
3.7.2.1
Adult Attention-deficit/Hyperactivity Disorder Investigator 
Symptom Rating Scale
The AISRS is a modified version of the ADHD Rating Scale that more accurately reflects 
the impact and severity of ADHD among adults. The scale will be administered as 
described in the Schedule of Assessments (Table 3.7-1 and Table 3.7-2 for rollover 
subjects and Table 3.7-3 and Table 3.7-4 for de novo subjects). It is a 
clinician-administered scale that measures all 18 symptoms of adult ADHD using a 
Likert scale: 0 (none); 1 (mild); 2 (moderate); and 3 (severe), and uses a semi-structured 
interview methodology with suggested prompts for each item to improve interrater 
reliability. The scale's 18 items directly correspond to the 18 DSM-5 symptoms of 
ADHD where 9 inattentive items alternate with 9 hyperactive impulsive items. The 
maximum total score for the scale is 54 points, with 27 points for each subscale. The total 
score is the sum of both the inattentive and hyperactive impulsive subscales.28


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3.7.2.2
Clinical Global Impression-Severity of Illness Scale - Modified 
for Attention-deficit/Hyperactivity Disorder
The CGI-S modified (Table 3.7-1 for rollover subjects and Table 3.7-3 for de novo 
subjects) is an observer-rated scale that will be used to measure symptom severity.29 To 
perform this assessment, the investigator or rater will respond to the following question: 
“Considering your total clinical experience with the ADHD, how mentally ill is the 
patient at this time?” Response choices include: 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.30
3.7.3
Other Assessments
3.7.3.2
Mini International Neuropsychiatric Interview
The MINI31,32,33 will be conducted for de novo subjects at screening to rule out 
exclusionary comorbid psychiatric diagnoses. Detailed instructions for administration of 
this structured interview will be provided.
3.7.3.3
Adult Attention-deficit/Hyperactivity Disorder Clinical 
Diagnostic Scale
The ACDS Version 1.2 is a clinician-administered semistructured interview assessment 
used to establish the presence of current adult symptoms of ADHD, with suggested 
age-specific prompts for rating both childhood and adult symptoms. The ACDS includes 
a retrospective assessment of all childhood ADHD symptoms as well as an assessment of 
recent (last 6 months) adult ADHD symptoms that includes 9 criterion symptoms of 
inattention, 9 criterion symptoms of hyperactivity and impulsivity, and 14 non-DSM 
CCI


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symptoms believed to be relevant to adult ADHD.34 The ACDS will be administered to 
de novo subjects at screening.
3.7.3.4
Attention-Deficit Hyperactivity Disorder Impact Module - Adult
The AIM-A is a subject self-report questionnaire which assesses quality of life in adults 
with ADHD. The questionnaire has 4 global quality of life items, 5 economic impact 
items, and 5 multi-item scales that assess the following key concepts: Living with 
ADHD, General Well-Being, Work, Home and School Performance and Daily 
Functioning. Additionally, Relationships and Communication, and Impact of Symptoms 
are also included.35
3.7.3.5
Prior and Concomitant Medications
The investigator will record all medications and therapies taken by the subject from 
30 days prior to signing of informed consent through the end of the evaluation period 
(defined as the time period during which subjects are evaluated for primary and/or
secondary objectives) on the electronic case report form (eCRF). Details of prohibited 
and restricted medications are provided in Section 4.1. The investigator will record all 
medications and therapies taken by the subject until the end of the trial (defined as the 
last date of contact or date of final contact attempt) on the eCRF.
3.7.4
Safety Assessments
3.7.4.1
Adverse Events
Refer to Section 5, Reporting of Adverse Events.
3.7.4.2
Clinical Laboratory Assessments
A central laboratory designated by the sponsor will be used for all laboratory testing 
required during the trial. The central laboratory should be used for all laboratory testing 
whenever possible (including unscheduled and follow-up, if needed). In cases where an 
immediate result is required for a particular laboratory test, the sample should be divided 
and sent to both a local laboratory and the designated central laboratory. Urine will be 
collected and blood will be drawn from each subject prior to treatment with the IMP. 
Subjects should be fasting for a minimum of 8 hours prior to the blood draws, if possible. 
If fasting blood samples are not feasible, non-fasting blood samples may be obtained 
initially for determining eligibility for the trial. A fasting blood sample is required at 
baseline prior to dosing. Clinical laboratory tests at other visits should be drawn fasting, 
if possible, but must be drawn after a minimum 8-hour fast at Week 52/ET. Vital sign 
measurements and ECG assessments should be completed before any blood samples are 


Clinical Study Report 405-201-00015
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collected. See exclusion criteria (Section 3.4.3) for laboratory tests. For de novo subjects, 
if a fasting blood sample was obtained at the screening visit and less than 14 days have 
elapsed since the screening visit, clinical laboratory tests (hematology, serum chemistry, 
and urinalysis) do not need to be repeated at the baseline visit. The results of these tests 
must be reviewed by the investigator prior to initiation of the administration of the IMP. 
Additional urine and blood samples may be collected for further evaluation of safety as 
warranted by the investigator’s judgment. Reports from the central laboratory will be 
retained electronically within the lab vendor's online portal and assessed by the 
investigator or qualified designee for clinical significance within eCRF.


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Table 3.7.4.2-1
Clinical Laboratory Assessments
Hematology:
Hematocrit
Hemoglobin
Mean corpuscular hemoglobin concentration
Mean corpuscular hemoglobin
Mean corpuscular volume
Platelet count
RBC count
WBC count with differential
Urinalysis:
Color
Bilirubin
Blood
Glucose
Ketones
Leukocyte esterase
Microscopic analysis, WBC/RBC counts per high 
powered field
Nitrite
pH
Protein
Specific gravity
Urobilinogen
Urine Drug Screen
Amphetamines
Barbiturates
Benzodiazepines
Cannabinoids
Cocaine
Marijuana
Methadone
Methylphenidate (ritalinic acid)
Opiates
Phencyclidine
Propoxyphene
Other
Blood alcohol test or breathalyzer
Serum Chemistry:
Albumin
Alkaline phosphatase
ALT
AST
Bicarbonate
Bilirubin, total 
Blood urea nitrogen
Calcium
Cholesterol (total, HDL, LDL)
Chloride
CPK
Creatinine
Gamma glutamyl transferase 
Glucose
Magnesium
Potassium
Phosphorus
Protein, total 
Sodium
Triglycerides
Uric acid
Additional Tests:
Urine pregnancy (females of childbearing 
potential), serum test will confirm positive urine 
test results
PT/INR
TSH, with reflex to free T4 if TSH is abnormal
HbA1c
CPK reflex for isoenzymes if CPK > 3 × ULN; 
serum and urine myogloblin collected if 
CPK > 5 × ULN
Additional Tests (Baseline Only for Rollover 
Subjects and Screening Only for De Novo 
Subjects):
HBsAg
Anti-HCV
HIV
CPK = creatine phosphokinase; HDL = high-density lipoprotein; LDL = low-density lipoprotein; 
RBC = red blood cell; WBC = white blood cell.
The total volume of blood to be collected during the trial will be documented in the eICF.
Any value outside the normal range will be flagged for the attention of the investigator 
who must indicate whether or not a flagged value is of clinical significance. If one or 
more values are questionable, the test(s) may be repeated. For de novo subjects, if the 


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result of any test (or repeat test, if done) is indicated as clinically significant in the 
samples taken during the screening period, the subject will NOT be enrolled into the trial 
without the permission of the medical monitor. The baseline laboratory test results will be 
available after the subject has initiated the IMP; therefore, if results come back meeting 
any of the ‘exclusionary’ ranges (see Table 3.4.3.1-1 for rollover subjects and
Table 3.4.3.2-1 for de novo subjects), the subject’s eligibility to continue the trial will be 
determined after discussing with the medical monitor. In addition, unscheduled 
laboratory tests should be performed if clinically significant abnormalities are observed. 
Unscheduled laboratory tests may be repeated at any time at the discretion of the 
investigator for appropriate medical care. Refer to Appendix 2 for criteria for identifying 
values of potential clinical relevance.
A pregnancy test will be conducted in all FOCBP prior to trial intervention; results must 
be available prior to the administration of the IMP. All positive urine pregnancy test 
results must be confirmed by a serum test. Subjects with a positive serum pregnancy test 
result at screening must not be enrolled. Subjects with a positive serum pregnancy test 
result during the trial must discontinue treatment and be withdrawn from the trial. 
Pregnancy tests can be performed at any point during the trial if pregnancy is suspected.
Urine pregnancy tests will be conducted in FOCBP per the Schedule of Assessments 
(Table 3.7-1 and Table 3.7-2 for rollover subjects and Table 3.7-3 and Table 3.7-4 for de 
novo subjects).
3.7.4.3
Physical Examination and Vital Signs
3.7.4.3.1
Physical Examination
A complete physical examination will be performed at screening for de novo subjects and 
at baseline for rollover subjects (ie, Trial 405-201-00013 or Trial 405-201-00014), and a 
targeted physical examination to address any new concerns will be performed at all other 
visits indicated in the Schedule of Assessments (Table 3.7-1 for rollover subjects and 
Table 3.7-3 for de novo subjects). A complete physical examination will include height 
(baseline and screening only for rollover subjects and de novo subjects, respectively), 
weight, waist circumference, and calculation of body mass index (BMI) (baseline and 
screening only for rollover subjects and de novo subjects, respectively, and Week 52/ET 
for all subjects); and assessment of the head, eyes, ears, nose, throat, thorax, abdomen, 
urogenital, skin and mucosae, neurological, and extremities. Any abnormalities 
considered by the investigator to be clinically significant are to be recorded as AEs on the 
AE eCRF.


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3.7.4.4
Vital Signs
Vital signs including systolic blood pressure and diastolic blood pressure, heart rate, 
respiratory rate, and body temperature will be measured at the time points described in 
the Schedule of Assessments (Table 3.7-1 and Table 3.7-2 for rollover subjects and 
Table 3.7-3 and Table 3.7-4 for de novo subjects). Blood pressure and heart rate 
measurements will be made in the supine and standing positions after the subject has 
been in each position for at least 3 minutes. The supine measurements will be performed 
first followed by the standing measurements. Temperature and respiratory rate will be 
taken with the subject in the supine position. At baseline, predose vital signs will be 
measured before dosing. Vital signs are to be completed before any blood is drawn.
Subjects should be monitored for potentially clinically significant vital signs values 
(Appendix 3). Abnormal results that are deemed clinically significant should be repeated 
to ensure reproducibility of the abnormality. Any abnormalities considered by the 
investigator to be clinically significant are to be recorded as AEs on the AE eCRF
(Section 5.2).
3.7.4.5
Electrocardiogram Assessments
The 12-lead ECGs will be performed in the supine position at the time points described in 
the Schedule of Assessments (Table 3.7-1 for rollover subjects and Table 3.7-3 for de 
novo subjects). All ECG recordings will be obtained after the subject has been supine and 
at rest for at least 5 minutes. Additional 12-lead ECGs may be obtained at the 
investigator’s discretion and should always be obtained in the event of an ET. 
Electrocardiogram results will be evaluated at the investigational site to determine the 
subject’s eligibility and to monitor safety during the trial. The principal investigator or 
qualified designee will review, sign, and date each ECG reading, noting whether or not 
any abnormal results are of clinical significance. The ECG will be repeated if any results 
are considered to be clinically significant. A central ECG service will be utilized for 
reading all ECGs in order to standardize interpretations for the safety analysis.
If, according to the investigator's judgment, any abnormal ECG finding is deemed 
medically significant (impacting the safety of the subject and/or the interpretation of the 
trial results) or meets an exclusion criterion (see Table 3.4.3.1-1 for rollover subjects and 
Table 3.4.3.2-1 for de novo subjects), the subject should be excluded from the trial. For 
de novo subjects, abnormal results for ECGs should be repeated once at screening with 
3 consecutive ECG recordings to ensure reproducibility of the abnormality before 
excluding a subject based on the criteria noted above. Each ECG recording should be 
taken approximately 5 minutes apart (the ECG result reported will be evaluated at each 


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time point). The central ECG service will provide the corrections for the 3 ECGs 
performed. Based on the QT interval corrected for heart rate by Fridericia’s formula 
(QTcF) reported by the central service, a subject will be excluded if the corrections are 
≥450 msec in men and ≥ 470 msec in women for 2 of the 3 time points of the ECGs 
done, unless due to ventricular pacing. If only 1 ECG time point has a QTcF of 
≥450 msec in men and ≥ 470 msec in women, and this is not reproduced at either of the 
other 2 time points, the subject can be included in the trial.
Subjects should be monitored for potentially clinically significant ECG results
Appendix 4. Tests with abnormal results that are deemed clinically significant should be 
repeated to ensure reproducibility of the abnormality. Any abnormalities considered by 
the investigator to be clinically significant are to be recorded as AEs on the AE eCRF.
3.7.4.6
Other Safety Assessments
3.7.4.6.1
Study Medication Withdrawal Questionnaire
The SMWQ is a questionnaire to assess withdrawal symptoms that will be completed as 
described in the Schedule of Assessments (Table 3.7-1 and Table 3.7-2 for rollover 
subjects and Table 3.7-3 and Table 3.7-4 for de novo subjects). The SMWQ is a 
modification of the Amphetamine Withdrawal Questionnaire in which the terms 
“amphetamines and methamphetamine” are replaced with the term “the study 
medication.”36,37,38 At the site, the subject will complete the SMWQ, and on non-site 
days, subjects will complete the SMWQ remotely.
3.7.4.6.2
Suicidality
Suicidality will be monitored during the trial (Table 3.7-1 and Table 3.7-2 for rollover 
subjects and Table 3.7-3 and Table 3.7-4 for de novo subjects) using the C-SSRS.39 The 
C-SSRS is a semi-structured interview that captures the occurrence, severity, and 
frequency of suicide-related thoughts and behaviors during the assessment period.39 The 
interview includes definitions and suggested questions to solicit the type of information 
needed to determine if a suicide-related thought or behavior has occurred. The interview 
and rating for the C-SSRS must be completed by a licensed clinician who has been 
successfully trained to rate this scale by the sponsor or a designee, and is medically 
responsible for the subject. Documentation of trial training should be maintained in the 
investigational site’s files.
This trial will use the “Baseline/Screening” and “Since Last Visit” versions of the scale.
The “Baseline/Screening” version, which assesses the life-time experience of the subject 
with suicide events and suicidal ideation and the occurrence of suicide events or ideation 


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within a specified time period prior to entry into the trial, will be completed for all 
de novo subjects at the screening visit to determine the eligibility. Any subject with 
active suicidal ideation within the last 30 days, suicidal behaviors within the last year, or 
who in the clinical judgment of the investigator presents a serious risk of suicide should 
be excluded from the trial (see Table 3.4.3.1-1 for rollover subjects and Table 3.4.3.2-1
for de novo subjects). The “Since Last Visit” C-SSRS form will be completed at all other 
in-clinic visits for all subjects (rollover and de novo).
3.7.5
Pharmacokinetic/Pharmacodynamic Assessments
3.7.5.1
Pharmacokinetic Assessment
Not applicable.
3.7.6
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 eCRF page for the last subject completing or 
withdrawing from the trial.
3.8
Stopping Rules, Withdrawal Criteria, and Procedures
3.8.1
Entire Trial or Treatment Arm(s)
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.
CCI


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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
Treatment Interruption
All attempts should be made to avoid treatment interruption during the trial. For subjects 
who have an interruption of treatment, the investigator or designee will contact the 
sponsor at the earliest possible time to discuss. The sponsor should be notified when there 
is a planned or inadvertent treatment interruption of 4 days or more in a 7-day period. 
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. The treatment interruption 
will be recorded in the eCRF and also recorded as a protocol deviation (Section 3.13).
3.8.3.2
Treatment Discontinuation
After starting open-label IMP, 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. Refer to the Schedule of Assessments (Table 3.7-1 and Table 3.7-2 for 
rollover subjects and Table 3.7-3 and Table 3.7-4 for de novo subjects ) for a description 
of follow-up procedures.
If a subject discontinues from the trial prematurely, the reason must be fully evaluated 
and recorded appropriately in source documents and in eCRF. If the subject is being 
withdrawn because of an AE, that AE should be indicated as the reason for withdrawal. 
All subjects have the right to withdraw at any point during treatment without prejudice. 
The investigator can discontinue a subject’s participation in the trial at any time if 
medically necessary.


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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 
non-serious 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 

Other potentially IMP-related safety concerns or AEs

Death

Reasons unrelated to medical condition (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 5.7)

Termination of all or part of the trial by the sponsor

Lack of efficacy
Subjects withdrawn prior to Week 52 must complete the Week 52/ET evaluations at the 
time of withdrawal. In addition, all subjects who withdraw prematurely from the trial will 
be assessed by telephone 1, 3, and 5 days after the last dose of IMP, in the clinic 2 days 
and 7 days after the last dose of the IMP, and 10 days via telephone, web, or other 
acceptable means of contact after the last dose of the IMP. Three attempts will be made 
to contact the subject by telephone; 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.
Meeting a screening exclusion criterion after enrollment does not require an automatic 
discontinuation of the subject. The investigator should assess the change for clinical 
significance, determine if an AE should be reported, and make a determination of subject 
continuation based on subject safety. The investigator will consult with the medical 
monitor to determine subject continuation in the trial.
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 5.9 must be followed. Subjects will be instructed not to start 


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alternative ADHD therapy until Week 52/ET visit and appropriate follow-up visits are 
completed.
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.
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 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 [interrupt or] discontinue IMP 
administration, which is not equivalent to a complete withdrawal of consent for further 
participation (see Section 3.8.3.1 and 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 


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determine if the subject can continue participation in the trial if modifications to his/her 
treatment and/or schedule of assessments can be accommodated. Only subjects who 
withdraw their permission for all of the above degrees of follow-up are considered to 
have completely withdrawn their consent to participate in the trial.
3.8.3.5
Procedures to Encourage Continued Trial Participation
In all cases of impending IMP discontinuation or consent withdrawal, investigators will 
be given instructions to 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 started on open-label 
treatment. For the purposes of this trial, treatment begins with the first dose of open-label 
oral centanafadine SR.
Subjects who sign an eICF but who are not started on-treatment may be permitted to be 
rescreened. 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.
De Novo Subjects
If a subject fails to qualify for the trial during the 28-day screening period for a reason 
other than a positive screen for cocaine, or other illicit drugs (excluding marijuana), the 
subject is permitted to be rescreened at a later date. Screen failures previously excluded 
for a positive blood alcohol test or breath alcohol test or a positive urine drug screen due 
to use of prescription or over-the-counter (OTC) medications or products may be retested 
or rescreened for participation in the trial only with the explicit consent of the medical 
monitor. Subjects that test positive for marijuana may be permitted to be enrolled if they 
have no evidence of a substance use disorder, and if they agree to refrain from use for the 
duration of the trial. Allowance for subjects testing positive for marijuana at screening 
require explicit approval from the medical monitor. Subjects that test positive for 
confirmed prescription use of ADHD medications at screening will be required to 
undergo a washout period (Section 4.1). If subjects again test positive at baseline visit, 
authorization to proceed for an additional washout and continuation to the treatment
period requires explicit authorization from the medical monitor. Screen failures excluded 
for any other reasons may be rescreened at any time if the exclusion characteristic has 


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changed. In the event that the subject is rescreened for trial participation, a new eICF 
must be signed, a new screening number assigned, and all screening procedures repeated.
3.10
Definition of Completed Subjects
The treatment period is defined as the time period during which subjects are evaluated for 
primary objective 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 Week 52/ET visit will be defined as trial completers.
3.11
Definition of Subjects Lost to Follow-up
Subjects who cannot be contacted on or before Week 52/ET 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).
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 according to the visits outlined in the 
Schedule of Assessments (Table 3.7-1 for rollover subjects and Table 3.7-3 for de novo 
subjects). 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.
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 


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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.
4
Restrictions
4.1
Prohibited Medications
Rollover subjects who enrolled from Trial 405-201-00013 or Trial 405-201-00014 will 
washout from centanafadine for at least one week before the baseline visit of the 
open-label trial. Rollover subjects who are willing to enroll in this trial must not start any 
new medication for ADHD after the Week 6 visit in Trial 405-201-00013 or
Trial 405-201-00014.
De novo subjects who are currently taking any medication for adult ADHD at screening 
will washout from their current ADHD medication before the baseline (Day -1) visit. 
De novo 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.
Table 4.1-1
Washout of Prohibited Medications Required Before the 
Trial - De Novo Subjects
Medication
Required Washout Prior to Dosing
1.
Antidepressants
Fluoxetine
All other antidepressants
28 days
14 days
2.
Benzodiazepines
7 days
3.
Hypnotics, including non-benzodiazepine sleep aids
7 days
4.
ADHD medications
Stimulants
Nonstimulants
7 days
21 days
5.
Sedating antihistamines (eg, diphenhydramine, 
hydroxyzine, chlorpheniramine), unless meeting 
critieria in Table 4.1-2 (1. [j])
7 days
7.
Antihypertensives
Clonidine
Propranolol
Guanfacine
21 days
8.
Anorexics (weight loss supplements)
7 days


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Table 4.1-2 lists all medications prohibited during the trial, including exceptions, where 
appropriate. Prohibited medications may be considered for a documented and clinically 
appropriate indication (eg, episodic pain condition, tooth extraction) in short-term basis 
and must not be prescribed as a treatment for a chronic disease.
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) Benzodiazepinesa
f)
Hypnotics
g) All medications intended for the treatment or management of ADHD symptoms (on or off 
label use), including but not limited to any form of: amphetamine (mixed salts), atomoxetine, 
clonidine, dexmethylphenidate, guanfacine, lisdexamfetamine, and methylphenidate
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, melatonin, kava extracts, GABA 
supplements, etc)
j)
Antihistamines: 
Sedating (eg, diphenhydramine, hydroxyzine, chlorpheniramine): Permitted if subject can 
provide a valid prescription, or if taken OTC to treat an established medical history of 
insomnia or as a decongestant.
Non-sedating (eg, Claritin, Alegra): Subjects are permitted to use during trial
2.
Investigational agents
3.
Barbiturates, except for the treatment of migraine headaches, provided that in the opinion of the 
investigator the dosing is medically appropriate
4.
The following antihypertensive medications: propranolol, clonidine, guanfacine
5.
Varenicline or similar medications, excluding nicotine replacement products
6.
Anorexics (weight loss supplements)
aLimited use of oral benzodiazapines as rescue medication for the short-term management of AEs of 
anxiety, agitation, and insomnia will be allowed during the trial. The prescribed benzodiazepine 
should be discontinued as soon as the AE for which it was initiated subsides, as per the investigator’s 
discretion to avoid any withdrawal effects. Non-benzodiazepine sleep aids (ie, zolpidem, zaleplon, 
zopiclone, and eszopiclone only) are permitted for the treatment of insomnia AEs.
4.2
Other Restrictions
4.2.1
Restricted Therapies and Precautions
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 centanafadine 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 will be instructed to refrain from drinking alcoholic beverages or using illicit 
drugs (including marijuana) during participation in the trial. The investigator may request 
a blood or urine drug screen or breathalyzer at any time during the trial if there is a 
suspicion of illicit drug or alcohol 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. The AEs would not include information recorded as 
medical history at screening for preplanned 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.
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.


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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:

Any SAE.

Any AE of special interest (AESI) (see Section 5.4)

Any AE related to occupational exposure.

Potential serious hepatotoxicity (see Section 5.6).

Pregnancies are also defined as immediately reportable events (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 eCRF if there is an abnormality or complication.
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 


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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 eCRF. 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 eCRF provided by the sponsor. Serious AE 
collection 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 
experienced earlier, or not expected based on the course of the condition.
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.


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5.3
Immediately Reportable Events 
The investigator must immediately report after either the investigator or site personnel 
become aware of any SAE, AE related to occupational exposure, AESI, potential serious 
hepatotoxicity, 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 eCRF).
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 non-traumatic will be considered AESIs. These 
may include, but are not limited to eruptions such as skin rashes, skin irritations, skin 
reactions, or acneiform lesions. This does not include localized contact irritation at ECG 
lead sites due to application/removal of lead adhesive.
Refer to the separate rash workup plan for complete details, including reporting forms, 
and extra measures that must be performed to characterize any skin AESI of a newly 
acquired skin eruption that is non-traumatic. The trial site will have a local designated 
dermatologist available for immediate consultation during the trial for these AESI.
All AESI should be reported as IREs (Section 5.3).
5.5
Abuse Potential Monitoring Plan, Events Subject to Additional 
Monitoring, and Medication Handling Irregularities
A key objective of the Abuse Potential Monitoring Plan (APMP) is to monitor for 
instances of abuse or diversion of the trial medication and other psychoactive substances. 
In addition to monitoring for irregularities in medication handling, AEs that may be 
suggestive of a developing abuse issue will also receive special attention. As part of the 
APMP, medication handling irregularities (MHIs) must be reported, and AEs related to 
abuse potential and AEs involving MHIs must be reported as Events Subject to 
Additional Monitoring (ESAMs) with detailed narratives. 
Investigators and site staff at each trial site will be trained on reporting potentially 
abuse-related AEs (eg, recording a description of the event in the subject’s own words in 


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the source documents as well as the eCRF, in addition to the clinical term, and to be 
aware that a subject’s report may encompass more than one event and that these should 
be recorded separately). The investigators will be provided with examples of potentially 
abuse-related AEs, and trained on how to handle such events (eg, additional monitoring). 
While the investigators will be provided with examples of AE terms as a guide during 
trial conduct, the analysis of potentially abuse-related AEs will be based on a search of all 
Medical Dictionary for Regulatory Activities (MedDRA) preferred terms, all verbatim 
terms, and any open text fields within the AE data to identify text strings suggestive of 
abuse potential, in line with the 2017 FDA guidance (Assessment of Abuse Potential of 
Drugs).40 Refer to the separate APMP documentation for complete details on MHIs and 
ESAMs, including documenting and reporting procedures, examples of potentially 
abuse-related AE terms that meet the criteria for ESAM reporting, and guidance for the 
training of investigators and trial site staff.
5.6
Potential Serious Hepatotoxicity
For a subject who experiences an elevation in aspartate aminotransferase (AST) or 
alanine aminotransferase (ALT) that is 3 times the upper limit of normal (ULN), 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 eCRF.
5.7
Pregnancy
Females 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 consecutive 
months).
For FOCBP 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 for female subjects, and 90 days after the last dose of IMP for male subjects 
and their partners who are FOCBP. Unless the subject is sterile (ie, females who have had 
a bilateral oophorectomy and/or hysterectomy or who have been postmenopausal for at 
least 12 consecutive months; or males 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 injection, birth control 
implant, birth control patch, condom with spermicide, or sponge with spermicide. Any 
single method of birth control, including vasectomy and tubal ligation, may fail, leading 


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to pregnancy. The contraceptive method will be documented at each trial visit. Male 
subjects must also agree not to donate sperm from screening through 90 days after the 
last dose of IMP.
Before enrolling FOCBP in this clinical trial, investigators must review the below 
guidelines about trial participation with all FOCBP. 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, FOCBP 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 FOCBP subjects. If a urine test is performed and is positive, the 
investigator will follow up with a confirmatory serum test.
During the trial, all FOCBP 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 for female 
subjects, and for 90 days after the last dose of IMP for partners of male subjects, 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.


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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.
5.8
Procedure for Breaking the Blind
Not applicable; this is an open-label trial.
5.9
Follow-up of Adverse Events 
5.9.1
Follow-up of Nonserious Adverse Events
Nonserious AEs that are identified at any time during the trial must be recorded on the 
AE eCRF 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 eCRF. 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).
5.9.2
Follow-up of Serious Adverse Events and Immediately 
Reportable Events
This trial requires that subjects be actively monitored for SAEs and IREs up to 10 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 as such on the AE eCRF 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 according to the appropriate reporting procedures. 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.


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5.9.3
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 
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
No PK or pharmacogenomic analysis is planned.
7
Statistical Analysis
7.1
Sample Size
The sample size is not based on statistical power considerations but on ICH/GCP 
requirements. The trial population will be derived from eligible subjects from the,
double-blind phase 3 trial (ie, Trial 405-201-00013 or Trial 405-201-00014) and de novo 
subjects from selected sites. It is expected that approximately 560 completing rollover 
subjects from double-blind phase 3 trial (Trial 405-201-00013 or Trial 405-201-00014)
and approximately 145 de novo subjects will be enrolled into this trial.
7.2
Datasets for Analysis
The following samples are defined for this trial:

Enrolled Sample, which comprises all subjects who sign an eICF for the trial;

Safety Sample, which comprises all subjects that will receive at least 1 dose of IMP;

Efficacy Sample, which comprises those subjectsin the Safety Sample who have at 
least 1 post baseline efficacy evaluation of AISRS Total Score.


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7.3
Handling of Missing Data
In order to assess the sensitivity of results due to missing data, 2 types of analyses will be 
performed: last observation carried forward (LOCF) and observed cases (OC). The OC 
dataset will consist of the actual observations recorded at each visit. The LOCF dataset 
will include data recorded at a scheduled visit, ie, all OC data, or, if no observation is 
recorded at that visit, data will be carried forward from the previously scheduled visit. 
Baseline data will not be carried forward to impute missing values for the LOCF dataset. 
The OC dataset will be used for analyzes at each trial visit and the LOCF dataset will be 
used for analyzes at the last visit.
7.4
Primary, Secondary, and Exploratory Endpoint Analyses
7.4.1
Primary Endpoint Analysis
The primary (safety) endpoint analysis is the frequency and severity of AEs (including 
evaluations of rash and abuse potential) in the open-label treatment period. All AEs will 
be coded using the MedDRA PTs. The incidence of TEAEs will include the following 
summaries:

TEAEs

TEAEs by severity

TEAEs potentially causally related to the IMP

TEAEs with an outcome of death

Serious TEAEs

TEAEs leading to discontinuation of the IMP

Abuse-related AEs and AEs involving medication handling irregularities
A TEAE is defined as an AE that starts after the first dose of IMP or an AE that is 
reported at baseline and increases in intensity or becomes serious or trial drug-related or 
results in death, discontinuation, interruption, or reduction of IMP.
7.4.2
Secondary Endpoint Analysis
Not applicable.


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7.4.3
Exploratory Endpoint Analysis
Exploratory (efficacy) endpoints for the open-label trial are:
!
Change from baseline in AISRS Total Score, by trial visit and at the last visit 
(ie, Week 52/ET);
!
Change from baseline CGI-S, by trial visit and at the last visit (ie, Week 52/ET); 
!
Change from baseline in AIM-A Score by trial visit and at the last visit;
 
 
 
Descriptive statistics will be provided for each endpoint, and will be summarized at each 
trial visit based on the Efficacy Sample using the OC dataset and at the last visit using the 
LOCF dataset. Baseline is defined as the last available measurement prior to the first dose 
of open-label IMP in the open-label treatment period.
7.4.4
Interim Analysis
No interim analysis is planned for this trial.
7.5
Analysis of Demographic and Baseline Characteristics
Baseline demographic characteristics including age, race, ethnicity, gender, weight, 
height, and BMI will be summarized by descriptive statistics (frequency, mean, median, 
standard deviation, maximum, minimum, and percentage when applicable).
7.6
Additional Safety Endpoint Analysis
Standard safety variables to be analyzed include clinical laboratory tests, vital signs, 
ECGs, and physical examinations. In addition, data from the following safety scales will 
be evaluated: abuse liability, assessments of suicidality (C-SSRS), and assessment of 
withdrawal (SMWQ).
Safety analysis will be conducted based on the Safety Sample defined in Section 7.2. In 
general, baseline of a safety variable is defined as the last observation of the variable 
before taking the first dose of IMP, unless specified otherwise. Prospectively defined 
criteria will be used to identify potentially clinically relevant abnormal values for clinical 
CCI
C
C
I


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laboratory tests, vital signs, ECGs and body weight. Details of safety analyzes are
provided in the statistical analysis plan (SAP).
7.6.1
Abuse Liability Analysis
Abuse potential will be assessed through the active monitoring of ESAMs (eg, AEs 
related to abuse potential and AEs involving MHI).
7.6.2
Clinical Laboratory Data
Summary statistics for changes from baseline in the routine clinical laboratory 
measurements will be provided. In addition, the incidence of potentially clinically 
relevant values identified using prospectively defined in the SAP criteria for laboratory 
tests will be summarized.
7.6.3
Physical Examination and Vital Signs Data
Physical examination findings will be listed by-subject. Potentially clinically relevant 
results in vital signs and body weight will also be summarized.
Summary statistics for change from baseline in vital signs and body weight will be 
provided.
7.6.4
Electrocardiogram Data 
Mean change from baseline will be summarized by visit.
The incidence of clinically relevant changes will be calculated for ECG parameters and 
summarized by visit.
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:
1) QTcB is the length of the QT interval corrected for heart rate by the Bazett’s 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
Results will be summarized by visit.


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7.6.5
Study Medication Withdrawal Symptoms
Medication withdrawal symptoms for all subjects will be assessed using SMWQ. 
Summary statistics for SMWQ total scores at the scheduled visit(s) will be provided.
7.6.6
Columbia-Suicide Severity Rating Scale
Suicidality (eg, C-SSRS) will be summarized by treatment group by descriptive statistics. 
Details are described in the SAP.
8
Management of Investigational Medicinal Product
For full details on IMP management, please refer to the centanafadine IB.25
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. Trial medication will 
be labeled to clearly disclose the subject ID, compound ID, 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 at controlled room temperature conditions as per the clinical label 
on the IMP. The clinical site staff will ensure that the temperature log is maintained in the 
drug storage area and that the temperature is recorded at least once each working day.
The clinical site staff will maintain a temperature log in the IMP storage area recording 
the temperature at least once each working day.
8.3
Accountability
The investigator or designee must maintain an inventory record of IMP (including 
investigational or active control) received, dispensed, administered, and returned.


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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 site(s). The IMP may only be destroyed by the trial site(s), if approved by the 
sponsor and if the IMP destruction meets all local regulations.
All IMP returned to the sponsor must be accompanied by the appropriate documentation 
and be clearly identified by protocol number and trial site number on the outermost 
shipping container. Returned supplies should be in the original containers (eg, subject 
kits). 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 is any written, electronic, or verbal communication by a 
healthcare professional, consumer, subject, medical representative, Competent Authority, 
regulatory agency, partner, affiliate or other third party that alleges deficiencies or 
dissatisfaction related to identity, quality, labeling, packaging, reliability, safety, 
durability, tampering, counterfeiting, theft, effectiveness or performance of a drug 
product or medical device after it is released for distribution. Examples include, but are 
not limited to, communications involving:

Failure/malfunction of a product to meet any of its specifications

Incorrect or missing labeling

Packaging issues (eg, damaged, dirty, crushed, missing product)

Blister defects (eg, missing, empty blisters)

Bottle defects (eg, under/over-fill, no safety seal)

Vial defects

Product defect (eg, odor, chipped, broken, embossing illegible)

Loss or theft of product


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8.5.1
Eliciting and Reporting Product Quality Complaints
The investigator or designee must record all Product Quality Complaint (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.
!
Online: Send information required for reporting purposes (listed below) to 
!
Phone: 
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 complaint
!
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.
CCI
CCI


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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 eCRF 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 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 eCRF, the investigator, 
sub-investigator and their staff will take measures to ensure adequate care in protecting 
subject privacy. To this end, a subject number and subject ID 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.


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Subjects will be identified only by unique subject numbers in eCRF. If further subject ID
is required, subjects’ full names may be made known to a regulatory agency or other 
authorized officials if necessary, subject to local regulations.
13
Amendment Policy
The investigator will not make any changes to this protocol without the sponsor’s prior 
written consent and subsequent approval/favorable opinion by the IRB. Any permanent 
change to the protocol, whether an overall change or a change for specific trial site(s), 
must be handled as a protocol amendment. Any amendment will be written by the 
sponsor. Each amendment will be submitted to the IRB, as required by local regulations. 
Except for “administrative” or “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 written informed consent 
will be obtained from subjects enrolled in the trial before expecting continued 
participation and before the amendment-specified changes in the trial are implemented.


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


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15
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14 Weiss M, Murray C. Assessment and management of attention-deficit hyperactivity 
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Reliability, validity and factor structure of a measure. Aust N Z J Psychiatry. 
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The nature, time course and severity of methamphetamine withdrawal. Addiction. 
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Guidance for Industry. Jan 2017.


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CCI


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Appendix 2
Criteria for Identifying Laboratory Values of Potential 
Clinical Relevance
Laboratory Tests
Criteria
Chemistry
AST
3 × ULN
ALT
3 × ULN
Alkaline phosphatase
3 × ULN
Blood urea nitrogen
30 mg/dL
Creatinine
2.0 mg/dL
Uric acid
Men
10.5 mg/dL
Women
8.5 mg/dL
Bilirubin (total)
2.0 mg/dL
Creatine phosphokinase
> 3 × ULN
Hematology
Hematocrit
Men
37 % and decrease of 3 percentage points from baseline
Women
32 % and decrease of 3 percentage points from baseline
Hemoglobin
Men
11.5 g/dL
Women
9.5 g/dL
WBC count
2,800 mm3 or 16,000 mm3
Eosinophils
10%
Neutrophils
15%
Absolute neutrophil count
1,500/mm3
Platelet count
75,000/mm3 or 700,000/mm3
Urinalysis
Protein
Increase of 2 units
Glucose
Increase of 2 units
Additional Criteria
Chloride
90 mEq/L or 118 mEq/L
Potassium
2.5 mEq/L or 6.5 mEq/L
Sodium
126 mEq/L or 156 mEq/L
Calcium
8.2 mg/dL or 12 mg/dL
Glucose
Fasting
100 mg/dL
Nonfasting
200 mg/dL
Total cholesterol, fasting
240 mg/dL
LDL cholesterol, fasting
160 mg/dL
HDL cholesterol, fasting
Men
< 40 mg/dL
Women
< 50 mg/dL
Triglycerides, fasting
150 mg/dL


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Appendix 3
Criteria for Identifying Vital Signs of Potential 
Clinical Relevance
Variable
Criterion Valuea
Change Relative to 
Baselinea
Heart rateb
> 100 bpm
< 50 bpm
10 bpm increase
10 bpm decrease
Systolic blood pressureb
≥140 mmHg Supine
< 90 mmHg
20 mmHg increase
20 mmHg decrease
Diastolic blood pressureb
≥90 mmHg Supine
< 60 mmHg
10 mmHg increase
10 mmHg decrease
Orthostatic hypotension
30 mmHg decrease in systolic blood 
pressure and/or a decrease of ≥ 20 
mmHg in diastolic blood pressure after 
at least 3 minutes of standing compared 
to the previous supine blood pressure
Not applicable
(baseline status not 
considered)
Orthostatic tachycardia
25 bpm increase in heart rate from 
supine to standing
Not applicable
(baseline status not 
considered)
Weight
−
7% increase
7% decrease
aIn order to be identified as potentially clinically relevant, an on-treatment value must meet the 
“Criterion Value” and also represent a change from the subject’s baseline value of at least the 
magnitude shown in the “Change Relative to Baseline” column.
bAs defined in “Supplementary Suggestions for Preparing an Integrated Summary of Safety Information
in an Original New Drug Application Submission and for Organizing Information in Periodic Safety 
Updates,” FDA Division of Neuropharmacological Drug Products draft (2/27/87).


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Appendix 4
Criteria for Identifying ECG Measurements of Potential 
Clinical Relevance
Variable
Criterion Valuea
Change Relative to 
Baselinea
Rate
Tachycardia
120 bpm
increase of 15 bpm
Bradycardia
50 bpm
decrease of 15 bpm
Rhythm
Sinus tachycardiab
120 bpm
increase of 15 bpm
Sinus bradycardiac
50 bpm
decrease of 15 bpm
Supraventricular premature beat
all
not present present
Ventricular premature beat
all
not present present
Supraventricular tachycardia
all
not present present
Ventricular tachycardia
all
not present present
Atrial fibrillation
all
not present present
Atrial flutter
all
not present present
Conduction
1atrioventricular block
PR 200 msec
increase of 50 msec
2atrioventricular block
all
not present present
3atrioventricular block
all
not present present
Left bundle-branch block
all
not present present
Right bundle-branch block
all
not present present
Pre-excitation syndrome
all
not present present
Other intraventricular conduction blockd
QRS 120 msec
increase of 20 msec
Infarction
Acute or subacute
all
not present present
Old
all
not present present
12 weeks post trial entry
ST/T Morphological
Myocardial ischemia
all
not present present
Symmetrical T-wave inversion
all
not present present
Increase in QTc
QTcF > 450 msec
(men)
QTcF > 470 msec
(women)
aIn order to be identified as potentially clinically relevant, an on-treatment value must meet the 
“Criterion Value” and also represent a change from the subject’s baseline value of at least the 
magnitude shown in the “Change Relative to Baseline” column.
bNo current diagnosis of supraventricular tachycardia, ventricular tachycardia, atrial fibrillation, atrial 
flutter, or other rhythm abnormality.
cNo current diagnosis of atrial fibrillation, atrial flutter, or other rhythm abnormality.
dNo current diagnosis of left bundle-branch block or right bundle-branch block.


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Appendix 5
Protocol Amendment(s)/Administrative Change(s)
Amendment Number:
1
Issue Date:
18 May 2018
PURPOSE:
This amendment serves to provide clarifications, additions, and subtractions to trial 
procedures intended to gather additional safety data during the follow-up period. In 
addition, administrative clarifications were made, including corrections to typographical, 
punctuation, and formatting errors. These changes were minor and do not change the 
design or content of the protocol, and therefore, are not summarized in this appendix.
BACKGROUND:
These changes to clinical trial protocol 405-201-00015, issued 7 Mar 2018, were made to 
address preliminary FDA comments received on 27 Apr 2018 in regards to the Type C 
briefing package, and to address other minor administrative changes.
MODIFICATIONS TO PROTOCOL:
General Revisions:

Added additional follow-up contacts to be conducted via telephone on 1, 3, and 
5 days after the last dose of IMP.

Revised the last day of subject contact from Day +14 to Day +10 after the last 
dose of IMP.

Added criteria excluding de novo subjects only with HIV seropositive 
status/acquired immunodeficiency syndrome, seropositive status for hepatitis B 
(ie, HBsAg positive), or hepatitis C (ie, anti-HCV positive and HCV RNA 
positive).

Added wording in the clinical laboratory table indicating that a CPK reflex for 
isoenzymes if CPK > 3 × ULN; serum and urine myogloblin collected if 
CPK > 5 × ULN, and that the urine drug screen should include methylphenidate 
(ritalinic acid) and not “stimulants (including those for the treatment of ADHD).”

Revised exclusion language regarding participating in other prior clinical trials for 
de novo subjects only.

Removed Appendices 5-8 from the protocol and replaced in-text references to 
these appendices with reference to external documentation.

Revised postmenopausal criteria to be aligned with template text.

Updated assignment of subject ID numbers for de novo and rollover subjects.

Clarified that SMWQ will be completed by the subject at the site and completed
remotely for non-site visits.


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
Removed CYP2D6 inhibitors and substrates from the Washout of Prohibited 
Medications Required Before the Trial - De Novo Subjects table and the List of 
Medications Prohibited During the Trial table.

Corrected various typographical errors and provided clarifications to text.
ADDITIONAL RISK TO THE SUBJECT:
There is no additional risk to the subjects.


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Administrative Change Number:
1
Issue Date:
30 Aug 2018
PURPOSE:
The purpose of this administrative change is to provide clarifications to trial procedures.
This administrative change will not affect the safety of subjects, the scope of the 
investigation, or the scientific quality of the trial.
BACKGROUND:
These changes to clinical trial protocol 405-201-00015, originally issued on 07 Mar 2018
and amended on 18 May 2018, were made to address administrative changes and correct 
minor errors.
MODIFICATIONS TO PROTOCOL:
General Revisions:

Changed the FBR blood volume collection from “up to 10 mL” to “approximately 
10 mL”.

Changed “birth control depot injection” to “birth control injection”.

Removed the medication adherence platform for IMP accountability and 
compliance, as that will not be used in this trial.

Clarified that vital signs will be performed in the supine and standing positions 
only, and not the sitting position, consistent with Trials 405-201-00013 and 
405-201-00014.

Clarified that the fasting blood sample test results for rollover subjects do not 
need to be reviewed by the investigator prior to the administration of IMP, 
because the results will not be available until after the subject has started IMP.

Added footnotes to the Schedule of Assessments to clarify that the following
assessments may be conducted at the 7-day follow-up visits of 
Trials 405-201-00013 or 405-201-00014, and the information can be carried over 
into Trial 405-201-00015 for the baseline visit: concomitant medications, AEs, 
vital signs, urine drug screen, alcohol testing, C-SSRS, and AISRS.

Updated the email address for reporting IREs.
ADDITIONAL RISK TO THE SUBJECT:
There is no additional risk to the subjects.


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Amendment Number:
2
Issue Date:
02 Jun 2020
PURPOSE:
The purpose of this protocol amendment is to introduce a COVID-19 Addendum for any 
protocol-specified activities that are not able to be performed or cannot be performed due 
to COVID-19 considerations. Refer to the COVID-19 Addendum for the appropriate 
measures to be followed.
BACKGROUND:
These changes to clinical trial protocol 405-201-00015, originally issued on 07 Mar 2018 
and amended on 18 May 2018 and 30 Aug 2018, were made to introduce a COVID-19 
Addendum. No other changes were made.
ADDITIONAL RISK TO THE SUBJECT:
There is no additional risk to the subjects.


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Agreement
I, the undersigned principal investigator, have read and understand the protocol (including the 
Investigator's Brochure) and agree that it contains all the ethical, legal and scientific information 
necessary to conduct this trial in accordance with the principles of Good Clinical Practices and as 
described herein and in the sponsor's (or designee's) Clinical Trial Agreement.
I will provide copies of the protocol to all physicians, nurses, and other professional personnel to 
whom I delegate trial responsibilities. I will discuss the protocol with them to ensure that they are 
sufficiently informed regarding the investigational new drug, centanafadine (EB-1020), 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) or receive 
a favorable opinion by the Independent Ethics Committee (IEC) responsible for such matters in 
the clinical trial facility where centanafadine (EB-1020) 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- or IEC-approved protocol will be submitted to the appropriate 
regulatory authority/ies by the sponsor. I agree that clinical data entered on case report forms by 
me and my staff will be utilized by the sponsor in various ways, such as for submission to 
governmental regulatory authorities and/or in combination with clinical data gathered from other 
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/IEC 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/IEC within the required local applicable 
timelines. Administrative changes to the protocol will be transmitted to the IRB/IEC 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 sub-investigators 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


Cli nic al St u d y Re p ort 4 0 5- 2 0 1- 0 0 0 1 5
1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
U ntil t he i nf or m ati o n herei n is rele ase d b y Ots u k a t o t he p u blic d o m ai n, t he c o nte nts of t his d oc u me nt are Ots u k a
c o nfi de nti al i nf or m ati o n a n d s h o ul d n ot be d u plic ate d or re- distri b ute d wit h o ut pri or writte n c o nse nt of Ots u k a.
1 0 8
T hi s p a g e i s a m a nif e st ati o n of a n el e ctr o ni c all y c a pt ur e d si g n at ur e
SI G N A T U R E P A G E
D o c u m e nt N a m e: 4 0 5- 2 0 1- 0 0 0 1 5 Pr ot o c ol A m e n d m e nt 2
D o c u m e nt N u m b er: 
D o c u m e nt V er si o n: 5. 0
Si g n e d b y
M e a ni n g of Si g n at ur e
S er v er D at e
( d d- M M M-
y y y y h h: mi n) -
U T C ti m e z o n e
Cli ni c al A p pr o v al
0 2- J u n- 2 0 2 0
1 8: 0 8: 3 3
Bi o st ati sti c s A p pr o v al
0 2- J u n- 2 0 2 0
1 9: 5 2: 3 0
Cli ni c al P h ar m a c ol o g y
A p pr o v al
0 2- J u n- 2 0 2 0
1 9: 5 5: 3 2
S af et y A p pr o v al
0 3- J u n- 2 0 2 0
0 3: 0 6: 3 3
P P D
P P D
P P D
P P D
C CI


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
Otsuka Pharmaceutical Development & Commercialization, Inc
Investigational Medicinal Product
Centanafadine (EB-1020)
ADDENDUM FOR CLINICAL PROTOCOL FOR TRIAL 405-201-00015
An Open-label, 52-Week, Multicenter Trial Evaluating the Long-term Safety and 
Tolerability of Centanafadine Sustained-Release Tablets in Adults with 
Attention-Deficit/Hyperactivity Disorder 
Protocol No. 405-201-00015
IND No. 119,361
CONFIDENTIAL – PROPRIETARY INFORMATION
Clinical Development Phase:
3
Sponsor:
Otsuka Pharmaceutical Development & 
Commercialization, Inc
2440 Research Boulevard
Rockville, Maryland 20850
Immediately Reportable Event 
Syneos Health Pharmacovigilance & Drug 
Safety
Fax: 
E-mail:
Issue Date:
02 Jun 2020
Version No.:
1.0
CCI
CCI


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Trial Conduct for COVID-19
All procedures and assessments in the protocol are to be followed to the fullest 
extent possible. The sponsor, in coordination with the site, investigator(s), and 
medical monitor, will continuously monitor and evaluate the benefits and risks to 
subject participation in the clinical trial as it relates to COVID-19. If any 
protocol-specified activities were not able to be performed, or cannot be performed 
due to COVID-19 considerations, the appropriate measures to be followed will be 
provided in this document.


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Table of Contents 
Trial Conduct for COVID-19.......................................................................2
Table of Contents...........................................................................................3
List of In-text Tables .....................................................................................4
List of In-text Figures....................................................................................5
List of Abbreviations and Definitions of Terms .........................................6
1
Trial 405-201-00015 COVID-19 Protocol Summary.........................7
1.1
Trial Design Schematic .......................................................................................7
1.2
Schedule of Assessments.....................................................................................8
2
General Considerations......................................................................12
2.1
Telemedicine .....................................................................................................12
2.2
Reconsent ..........................................................................................................12
2.3
Protocol Deviations...........................................................................................12
2.4
Guidance to Record Adverse Events and Discontinuations Due to 
COVID-19.........................................................................................................12
2.5
Statistical Analyses............................................................................................13
3
Trial Population..................................................................................13
3.1
Inclusion Criteria...............................................................................................13
3.2
Exclusion Criteria..............................................................................................14
4
Trial Procedures .................................................................................15
4.1
Safety Assessments ...........................................................................................16
4.1.1
Vital Signs ......................................................................................................16
4.1.2
Pregnancy .......................................................................................................16
4.2
Clinical Outcomes.............................................................................................17
4.2.1
General Considerations...................................................................................17
4.2.2
Semi-Structured Interviews ............................................................................17
4.2.3
Subject or Caregiver Reported Outcomes ......................................................18
4.2.4
Global Assessments of Severity and Subject Status.......................................18
4.2.5
Suicidal Behavior and Suicidal Ideation.........................................................18
5
Investigational Medicinal Product....................................................19


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List of In-text Tables
Table 1.2-1
COVID-19 Impact Schedule of Assessments (Baseline 
Through End of Treatment) .............................................................8
Table 1.2-2
COVID-19 Impact Schedule of Assessments (Follow-up)............11
Table 3.1-1
Inclusion Criteria for Late Rollover Subjects From 
Trial 405-201-00013 or Trial 405-201-00014 ...............................13
Table 3.2-1
Exclusion Criteria for Late Rollover Subjects From 
Trial 405-201-00013 or Trial 405-201-00014 ...............................14


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List of In-text Figures
Figure 1.1-1
COVID-19 Impact Trial Design Schematic.....................................7


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List of Abbreviations and Definitions of Terms
Abbreviation
Definition
ACDS
Adult ADHD Clinical Diagnostic Scale
ADHD
Attention-deficit hyperactivity disorder
AE
Adverse event
AIM-A
ADHD Impact Module - Adult
AISRS
Adult ADHD Investigator Symptom Rating Scale
ALT
Alanine aminotransferase
Anti-HCV
Hepatitis C antibodies
AST
Aspartate aminotransferase
CGI-S
Clinical Global Impression-Severity of Illness Scale
CRO
Contract research organization
C-SSRS
Columbia-Suicide Severity Rating Scale
ECG
Electrocardiogram
ET
Early termination
FOCBP
Females of childbearing potential
HbA1c
Glycosylated hemoglobin
HBsAg
Hepatitis B surface antigen
HIV
Human immunodeficiency virus
IMP
Investigational medicinal product
INR
International normalized ratio
IRB
Institutional review board
MINI
Mini International Neuropsychiatric Interview
PRO
Patient-reported outcome
PT
Prothrombin time
QTcB
QT interval corrected for heart rate by Bazett’s formula
QTcF
QT interval corrected for heart rate by Fridericia’s formula
SAE
Serious adverse event
SMWQ
Study Medication Withdrawal Questionnaire
SR
Sustained-release
T4
Free thyroxine
TDD
Total daily dose
TSH
Thyroid-stimulating hormone
CCI


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1
Trial 405-201-00015 COVID-19 Protocol Summary
1.1
Trial Design Schematic
ADHD = attention deficit hyperactivity disorder; ET = early termination; IMP = investigational medicinal product; SR = sustained release;
TDD = total daily dose.
Figure 1.1-1
COVID-19 Impact Trial Design Schematic


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1.2
Schedule of Assessments
Table 1.2-1
COVID-19 Impact Schedule of Assessments (Baseline Through End of Treatment)
Screening
Baselinea
52-Week Open-label Treatment Period
W 1 & 2
(3 days)
W 4, 8, 12, 
& 16
(3 days)
W 20
(3 
days)
W 26
(3 
days)
W 32
(3 
days)
W 38
(3 
days)
W 44
(3 
days)
W 48b
(3 
days)
End of 
Treatment
W 52/ET
(3 days)
Visit
1
2
3 & 4
5, 6, 7, & 8
9
10
11
12
13
14
15
ENTRANCE/HISTORY
Informed consent
X
Inclusion/exclusion criteria
X
X
Demography
X
Concomitant medication(s)
X
X
X
X
X
X
X
X
X
X
X
Medical history
X
ACDS
X
Identification of
comorbidities using MINI
X
Psychiatric history
X
HIV/HBsAg/anti-HCV
X
Urine pregnancy testc
X
X
X
X
X
X
X
X
X
X
SAFETY
Adverse events
X
X
X
X
X
X
X
X
X
X
X
Physical examination
Xd
X
Xe,f
Xf
Xf
Vital signs
X
X
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
12-lead ECG
X
X
Xf
Xf,h
Xf
Xf
Xf
Clinical laboratory tests
(hematology, serum 
chemistry [including 
HbA1c and TSH], and 
urinalysis)
X
X
Xe,f
Xf
Xf
Xf


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Protocol 405-201-00015
Confidential - Proprietary Information
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Version 1.0, 02 Jun 2020
Table 1.2-1
COVID-19 Impact Schedule of Assessments (Baseline Through End of Treatment)
Screening
Baselinea
52-Week Open-label Treatment Period
W 1 & 2
(! 3 days)
W 4, 8, 12, 
& 16
(! 3 days)
W 20
(! 3 
days)
W 26
(! 3 
days)
W 32
(! 3 
days)
W 38
(! 3 
days)
W 44
(! 3 
days)
W 48b
(! 3 
days)
End of 
Treatment
W 52/ET
(! 3 days)
Visit
1
2
3 & 4
5, 6, 7, & 8
9
10
11
12
13
14
15
PT/INR
X
Xf
Xf
SMWQ
X
Urine drug screen
X
X
Xf,i
Xf
Xf
Alcohol testingj
X
X
Xf,i
Xf
Xf
C-SSRS
X
X
X
X
X
X
X
X
X
X
EFFICACY
AISRS
X
X
X
X
X
X
X
X
X
CGI-S
X
X
X
X
X
X
X
X
X
AIM-A
X
X
X
OTHER
IMP dispensing
X
X
X
X
X
X
X
X
IMP return and 
accountability
X
X
X
X
X
X
X
X
ACDS = Adult ADHD Clinical Diagnostic Scale; AIM-A = ADHD Impact Module - Adult; AISRS = Adult ADHD Investigator Symptom Rating Scale;
anti-HCV = hepatitis C antibodies; 
; CGI-S = Clinical Global Impression-Severity of 
Illness Scale; C-SSRS = Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; HbA1c = glycosylated hemoglobin; HBsAg = hepatitis B 
surface antigen; HIV = human immunodeficiency virus; INR = international normalized ratio; MINI = Mini International Neuropsychiatric Interview; 
PT = prothrombin time; SMWQ = Study Medication Withdrawal Questionnaire; TSH = thyroid-stimulating hormone.
Note: If an in-person screening and baseline visit cannot be performed, then the subject cannot continue or be enrolled in the trial. The postbaseline visits 
should also be conducted in person; however, they may be conducted remotely due to COVID-19 restrictions. Subjects may miss up to 2 consecutive 
in-person assessments due to COVID-19 restrictions. The medical monitor must be consulted if the subject will miss more than 2 consecutive visits and 
determine whether or not the subject can continue on IMP. During the trial, if efficacy/safety assessments are unable to be obtained, the subject may 
CCI
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continue in the trial; however, if a subject is unable to collect a urine pregnancy test, the medical monitor must be contacted. At all postbaseline visits
conducted remotely, the assessments will be done by telephone or video chat.
aDosing will commence the day after the baseline visit.
bTelephone or video chat.
cIf the urine pregnancy test is positive, see Section 4.1.2 for additional details.
dPhysical examination at screening will include height measurements.
eWeek 8 only.
fThese assessments will be conducted at in-person visits only and will not be conducted remotely.
gAt all postbaseline visits, subjects may collect their own vital signs using an appropriate device at home, if available; see Section 4.1.1 for additional details. 
For subjects who cannot obtain vital signs, a maximum of 2 consecutive months of missed vital sign assessments are permitted. If a subject cannot be seen 
in the clinic or cannot obtain vital signs remotely through available collection devices after that point, the medical monitor must be consulted to ascertain 
whether the subject should be discontinued from the trial.
hWeeks 4, 8, and 16 only.
iWeeks 4 and 12 only.
jAlcohol testing may be conducted via a blood test or using a breathalyzer.
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Table 1.2-2
COVID-19 Impact Schedule of Assessments (Follow-up)
Follow-upa
1 (+1) days 
after the last 
dose of IMP
2 (+1) days 
after the last 
dose of IMP
3 (+ 1) days 
after the last 
dose of IMP
5 (+ 1) days 
after the last 
dose of IMP
7 (+ 2) days 
after the last 
dose of IMP
10 (+ 2) days 
after the last 
dose of IMP
Visit
16
17
18
19
20
21
ENTRANCE/HISTORY
Concomitant medication(s)
X
X
X
X
X
X
EFFICACY
AISRS
X
X
SAFETY
Adverse events
X
X
X
X
X
X
Vital signs
Xb
Xb
SMWQ
X
X
X
X
X
X
Urine drug screen
Xc
Xc
Alcohol testingd
Xc
Xc
C-SSRS
X
X
aFollow-up telephone calls will be conducted at 1, 3, and 5 days after the last dose of IMP, and a follow-up telephone call or video chat will be conducted
10 days after the last dose of IMP. At 2 and 7 days after the last dose of IMP, subjects should be seen in person; however, if a clinic visit is not possible, 
these visits may be conducted remotely (telephone or video chat).
bSubjects may collect their own vital signs using an appropriate device at home, if available; see Section 4.1.1 for additional details.
cThese assessments will be conducted at in-person visits only and will not be conducted remotely.
dAlcohol testing may be conducted via a blood test or using a breathalyzer.


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2
General Considerations
2.1
Telemedicine
Guidance will be provided to sites on whether use of telephone is acceptable, or if video 
is required. Sites will be instructed to attempt to standardize collection via telephone or 
video depending on the requirements of the trial to minimize confusion and risk of errors 
of utilizing varying collection strategies. All applicable country-by-country guidances 
and local regulations will be followed when implementing telemedicine options.
2.2
Reconsent
If there is an immediate need to reconsent subjects during the period of COVID-19 
restrictions, a paper reconsent process will be followed and sites are encouraged to 
contact the contract research organization (CRO) and sponsor with questions. In regions 
where remote capacity exists to collect remote eConsent, the necessary information will 
be provided by the CRO and sponsor.
2.3
Protocol Deviations
Protocol deviations that occur as a direct result of the COVID-19 pandemic must be 
recorded in eSource separately from other protocol deviations as soon as they are 
identified and will be recorded as “Major” in eSource for data capture purposes. 
Examples of the types of COVID-19 related deviations to be reported may include: 
missed visits, missed assessments, assessments performed remotely (completed outside 
of protocol procedure), missed investigational medicinal product (IMP) dose, IMP 
dispensed/returned via courier, IMP not returned to site, site unable to verify IMP
compliance, out of window visits, and prohibited concomitant medications. A “direct 
result” is defined as being due to actual illness, or as a result of quarantine, social 
distancing, or site closures. All other deviations will follow the normal deviation process 
described in the protocol and should not be entered proactively by sites.
2.4
Guidance to Record Adverse Events and Discontinuations Due to 
COVID-19
If a subject tests positive OR is presumed positive with COVID-19, the subject must be 
discontinued from the trial and an adverse event (AE) of “Coronavirus Infection” OR 
“Coronavirus Positive Test Result” should be recorded on the AE page of the electronic 
case report form. A positive test result or a presumed positive subject is not automatically 
a serious adverse event (SAE), unless an SAE criterion is met (eg, hospitalization).


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If a subject discontinues due to COVID-19 either because the subject tests positive OR is 
presumed positive with COVID-19, then the primary reason for discontinuation should be 
reported as “Adverse Event” and indicate the AE number in the “Specify the reason for 
discontinuation” space that corresponds with the AE of “Coronavirus Infection” OR 
“Coronavirus Positive Test Result.” Be sure to remember to enter an AE in the AE form 
for the “Coronavirus Infection” OR “Coronavirus Positive Test Result.”
If a subject discontinues due to COVID-19 other than the subject testing positive OR 
being presumed positive with COVID-19, then the primary reason for discontinuation 
should be reported as “Other.” Be sure to specify the reason as “COVID-19” followed by 
the reason ensuring that the prefix of the description includes “COVID-19.” Do note that 
the reason “Other” should be selected even if the subject decides to withdraw consent or 
if the investigator decides to withdraw the subject due to COVID-19 concerns.
2.5
Statistical Analyses
Any impact of COVID-19 on the planned statistical analyses for the trial will be 
described in the final statistical analysis plan.
3
Trial Population
3.1
Inclusion Criteria
Late rollover subjects (ie, those who were unable to rollover from Trial 405-201-00013 
or Trial 405-201-00014 due to the inability of an in-person baseline visit in 
Trial 405-201-00015) are required to meet the inclusion criteria presented in Table 3.1-1.
Table 3.1-1
Inclusion Criteria for Late Rollover Subjects From 
Trial 405-201-00013 or Trial 405-201-00014
1.
Subjects who completed or were administratively early terminated from the double-blind phase 3 
trial (ie, Trial 405-201-00013 or Trial 405-201-00014) within the period restricting rollover due 
to the COVID-19 pandemic and who, in the opinion of the investigator, could potentially benefit 
from centanafadine for ADHD.
2.
Subjects who are able to complete the consent process and/or consent obtained from a legally 
acceptable representative (as required by the IRB) prior to the initiation of any protocol-required 
procedures.
3.
Subjects who, during the double-blind trials, demonstrated adequate compliance with medication 
and protocol requirements, per the investigator’s judgment.
4.
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 ingestion, and 
discontinuation of prohibited medications, and to read and understand the written word in order 
to be reliably rated on assessment scales.
5.
Subjects who are willing to discontinue all prohibited psychotropic medications (refer to 
Section 4.1 of the protocol) starting from the time of signing the informed consent and up to the 
10-day safety follow-up period.
IRB = institutional review board.


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3.2
Exclusion Criteria
Late rollover subjects (ie, those who were unable to rollover from Trial 405-201-00013 
or Trial 405-201-00014 due to the inability of an in-person baseline visit in 
Trial 405-201-00015) will be excluded if they meet any of the exclusion criteria 
presented in Table 3.2-1.
Table 3.2-1
Exclusion Criteria for Late Rollover Subjects From 
Trial 405-201-00013 or Trial 405-201-00014
1.
Subjects who, during the double-blind phase 3 trial (ie, Trial 405-201-00013 or 
Trial 405-201-00014), experienced, in the opinion of the investigator, poor tolerability to the 
IMP or whose safety assessments resulted in new concerns that would suggest the subject may 
not be appropriate for a 52-week treatment with IMP.
2.
Subjects who have demonstrated noncompliance, based on the investigator’s judgment, to follow 
trial procedures during the course of their participation in the double-blind phase 3 trial (ie, 
Trial 405-201-00013 or Trial 405-201-00014). The medical monitor should be contacted if the 
investigator is unsure of a subject’s eligibility.
3.
Females who have a positive pregnancy test result prior to receiving IMP.
4.
Sexually active males or FOCBP who do not agree to practice 2 different methods of birth 
control or remain abstinent during the course of the trial and for 30 days after the last dose of 
IMP for female subjects, and 90 days after the last dose of IMP for male subjects and their 
partners who are FOCBP. Unless the subject is sterile (ie, females who have had a bilateral 
oophorectomy or hysterectomy or who have been postmenopausal for at least 12 consecutive 
months; or males who have had a bilateral orchiectomy) or remains abstinent, 2 of the following 
precautions must be used: vasectomy, tubal ligation, vaginal diaphragm, intrauterine device, 
birth control pills, birth control injection, birth control implant, birth control patch, condom with 
spermicide, or sponge with spermicide. Male subjects who do not agree to refrain from donating 
sperm from screening through 90 days after the last dose of IMP will also be excluded.
5.
Following responses from the “Since Last Visit” version of the C-SSRS (subjects should 
reference their last visit on Trial 405-201-00013 or Trial 405-201-00014):

Subjects with a response of “Yes” on the C-SSRS Suicidal Ideation Item 4 (Active Suicidal 
Ideation with Some Intent to Act, Without Specific Plan) at entry, OR

Subjects with a response of “Yes” on the C-SSRS Suicidal Ideation Item 5 (Active Suicidal 
Ideation with Specific Plan and Intent) at entry, OR

Subjects with a response of “Yes” on any of the 5 C-SSRS Suicidal Behavior Items (actual 
attempt, interrupted attempt, aborted attempt, preparatory acts, or behavior) at entry, 
OR
Subjects who, in the opinion of the investigator (including consideration of responses on the 
C-SSRS throughout Trial 405-201-00013 or Trial 405-201-00014), present a serious risk of 
suicide.
6.
Subjects with a newly developed psychiatric or medical condition that would be exclusionary 
under the criteria listed for Trial 405-201-00013 or Trial 405-201-00014.
7.
Subjects that have a positive alcohol test (via breathalyzer or blood), or a positive drug screen 
for cocaine or other illicit drugs (excluding marijuana). Subjects with a positive drug screen for 
confirmed prescription medications at baseline will not be permitted to continue participation in 
Trial 405-201-00015.
NOTE: Subjects that test positive for marijuana may be permitted to be enrolled if they have no 
evidence of a substance use disorder, and if they agree to refrain from use for the duration of the 
trial. Allowance for subjects testing positive for marijuana at screening requires explicit approval 
from the medical monitor.
8.
Any new or developing safety concerns related to vital signs in the opinion of the investigator 
during the baseline visit.


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Table 3.2-1
Exclusion Criteria for Late Rollover Subjects From 
Trial 405-201-00013 or Trial 405-201-00014
9.
The following laboratory test and ECG results are exclusionary:
1) Platelets ≤ 75000/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 for males or > 470 msec for females
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 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. The medical monitor should be 
contacted if the investigator is unsure of a subject’s eligibility.
10.
Subjects receiving any of the prohibited medications within the specified period prior to the first 
dose of IMP or who would be likely to require prohibited concomitant therapy during the trial 
(refer to Section 4.1 of the protocol).
11.
Subjects who have previously been enrolled in this trial and subsequently withdrawn.
12.
Any subject who, in the opinion of the investigator, should not participate in the trial.
ALT = alanine aminotransferase; AST = aspartate aminotransferase; FOCBP = females of childbearing 
potential; QTcB = QT interval corrected for heart rate by Bazett's formula; QTcF = QT interval 
corrected for heart rate by Fridericia's formula; T4 = free thyroxine.
4
Trial Procedures
If an in-person screening and baseline visit cannot be performed, then the subject cannot 
continue or be enrolled in the trial. The postbaseline visits should also be conducted in 
person; however, they may be conducted remotely due to COVID-19 restrictions. 
Subjects may miss up to 2 consecutive in-person assessments due to COVID-19
restrictions. The medical monitor must be consulted if the subject will miss more than 
2 consecutive visits and determine whether or not the subject can continue on IMP. 
During the trial, if efficacy/safety assessments are unable to be obtained, the subject may 
continue in the trial; however, if a subject is unable to collect a urine pregnancy test, the 
medical monitor must be contacted. At all postbaseline visits conducted remotely, the 
assessments will be done by telephone or video chat.


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4.1
Safety Assessments
4.1.1
Vital Signs
Blood pressure, heart rate, weight, and temperature may be measured as described in the 
protocol at the time points defined in this COVID-19 Addendum Schedule of 
Assessments (Table 1.2-1 and Table 1.2-2) with the following changes:

Subjects will be asked to use their own collection device, if available. (Device(s) may 
be provided to subjects).

Subjects will be instructed to be as consistent as possible regarding the time of day 
the measurement is taken, and to notify the site staff of the measurement results via 
telephone, or other means, on the appropriate visits.

Site staff will be instructed to record the measurement in eSource, and if there are 
believed to be any errors, inconsistencies, or safety concerns with the reported home 
measurement, the medical monitor should be notified.
For subjects who cannot obtain vital signs, a maximum of 2 consecutive months of 
missed vital sign assessments are permitted. If a subject cannot be seen in the clinic or 
cannot obtain vital signs remotely through available collection devices after that point, 
the medical monitor must be consulted to ascertain whether the subject should be 
discontinued from the trial.
4.1.2
Pregnancy
Pregnancy tests will be performed as described in the protocol at the time points defined 
in this COVID-19 Addendum Schedule of Assessments (Table 1.2-1) with the following 
changes: 

For planned visits that require a pregnancy test for females of childbearing potential 
(FOCBP), the site will provide the necessary tests and instructions so the test may be 
performed at home.

Applicable subjects will perform a pregnancy test prior to dosing with IMP, ensuring 
a date and time-stamped picture or video of the result is taken. The subject will notify 
the site staff of the test results by telephone and send the time-stamped picture or 
video to the site staff by email.

If negative, site to inform the subject to proceed with dosing.

If positive, the site must instruct the subject to immediately stop taking IMP, and 
the site will refer to the Pregnancy section of the protocol for appropriate 
immediately reportable event reporting.

Further instruction must be agreed upon in consultation with the sponsor.


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4.2
Clinical Outcomes
4.2.1
General Considerations
Attempt to standardize the method of administration for a scale across subjects (eg, video 
chat or telephone) to decrease variability, and consult trial-specific guidance for 
recommendations on preferred methods for a given outcome. Prior to starting the remote 
visit, the subject should be informed of the estimated amount of time the visit is expected 
to take, and confirm subject access to a sufficient mobile or Wi-Fi signal and that the 
subject’s device has an adequate charge. Any potential distractions should be addressed 
proactively to ensure the subject is not distracted during the remote visit. Assessments 
should be administered by the same qualified/trained rater who rated the subject 
previously; if this is not possible due to staff availability and/or technological limitations, 
discuss relevant information with previous raters to obtain clinical context (note that per 
protocol, raters must be trained/qualified to conduct assessments in all cases). Do your 
best to conduct all assessments during the same call/video chat, on the same day. Video 
chat is the preferred method for the Adult ADHD Investigator Symptom Rating Scale 
(AISRS), while other assessments can be completed by telephone or video chat.
All site staff will adhere to all Good Clinical Practice Guidelines, including Good 
Documenting Practices. Any factors that may potentially affect the subject’s report (eg, 
unavoidable distractions, rater assessment of subject’s level of engagement, any 
unexpected modifications to procedures) should be documented in eSource, along with 
how an assessment was completed (eg, via video, telephone, etc) and any modifications 
or accommodations performed. All assessment start times should be documented 
(including those that are interview based). If any AE-related information is reported, 
standard procedures for remote AE assessments with evaluation and follow-up with the 
medical monitor, as necessary, should be followed and documented accordingly.
4.2.2
Semi-Structured Interviews
Those administering scales must follow scale administration, training guidelines, and 
rating conventions as much as possible as provided by the sponsor, and ensure they 
maintain neutrality/research rapport as usual. Careful attention must be provided to 
subject engagement to try to ascertain whether the subject is distracted or minimizing, 
and efforts must be made to redirect the subject and ask additional questioning, if needed. 
Things to pay attention to are, but not limited to, the following: tone of voice, cadence, 
volume, and rate of speech if visual cues are not available (ie, if administered by 
telephone). Assessment start-stop times will be documented in eSource. The interviewer 
will be asked to “Rate what you see” and “Rate what you hear”, and should not discount 


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symptoms on the assumption that they are caused or exacerbated by COVID-19 or 
changes in life circumstances.
4.2.3
Subject or Caregiver Reported Outcomes
Patient-reported outcomes (PROs) are to be completed by subjects on paper rather than 
be administered by raters over the telephone or teleconference platform. The subject 
should complete the paper scale during the telephonic/video conference assessment visit 
to ensure the correct date and time for PRO completion. It is recommended to use the 
video conference platform to observe the subject completing the paper PROs in a manner 
that does not allow the site staff to see the subject’s responses but rather to ensure that the 
ratings are completed by the subject themselves. If this is not feasible, before ending the 
assessment visit, ask the subject to check if they have completed the PRO forms and to 
check again for completeness. Documentation must clearly detail the mode of 
administration and data entry. All assessments, including paper reports, should be 
completed during the telephonic/video conference visit.
4.2.4
Global Assessments of Severity and Subject Status
Sites will use all available sources of information to complete global assessments of 
severity, change/improvement, or subject status (eg, subject report, informant report, 
medical records if available, other assessment data if allowed per protocol). Site staff will 
be asked to conduct a general relatively unstructured evaluation and utilize informants as 
needed, ensuring that informants are also in a quiet and private place during evaluation. 
Attempt to complete global assessments after other assessments have been completed so 
all information from the visit is available, if allowed per protocol and per sponsor team 
instruction. The raters will be asked to “Rate what you see” and “Rate what you hear”,
and not rate according to what might be reasonable/expected due to COVID-19 as the 
rater must make a clinical assessment of subject status regardless of cause.
4.2.5
Suicidal Behavior and Suicidal Ideation
Evaluations of suicidality should be completed similar to how it is described in the 
protocol.
If suicidal ideation or behavior is reported, conduct further risk evaluation as per typical 
procedures and follow site processes and utilize emergency services or crisis lines, as 
needed. The medical monitor should be contacted for immediate guidance and support.


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5
Investigational Medicinal Product
Given the ongoing COVID-19 restrictions, clinical sites are permitted to ship IMP 
directly to subjects.


Cli nic al St u d y Re p ort 4 0 5- 2 0 1- 0 0 0 1 5
1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
U ntil t he i nf or m ati o n herei n is rele ase d b y Ots u k a t o t he p u blic d o m ai n, t he c o nte nts of t his d oc u me nt are Ots u k a
c o nfi de nti al i nf or m ati o n a n d s h o ul d n ot be d u plic ate d or re- distri b ute d wit h o ut pri or writte n c o nse nt of Ots u k a.
1 2 8
T hi s p a g e i s a m a nif e st ati o n of a n el e ctr o ni c all y c a pt ur e d si g n at ur e
SI G N A T U R E P A G E
D o c u m e nt N a m e: 4 0 5- 2 0 1- 0 0 0 1 5 Pr ot o c ol A d d e n d u m
D o c u m e nt N u m b er: 
D o c u m e nt V er si o n: 2. 0
Si g n e d b y
M e a ni n g of Si g n at ur e
S er v er D at e
( d d- M M M-
y y y y h h: mi n) -
U T C ti m e z o n e
Cli ni c al P h ar m a c ol o g y
A p pr o v al
0 2- J u n- 2 0 2 0
1 9: 5 5: 5 8
Bi o st ati sti c s A p pr o v al
0 2- J u n- 2 0 2 0
1 9: 5 5: 5 6
Cli ni c al A p pr o v al
0 2- J u n- 2 0 2 0
1 8: 0 8: 0 0
S af et y A p pr o v al
0 3- J u n- 2 0 2 0
0 3: 0 5: 5 8
P P D
P P D
P P D
P P D
C CI

SAP_001.pdf: 
NCT Number: 
Document Date: 
An Open-label, 52-Week, Multicenter Trial Evaluating the 
Long-term Safety and Tolerability of Centanafadine 
Sustained-Release Tablets in Adults with Attention-Deficit/
Hyperactivity Disorder
NCT03605849
Statistical Analysis Plan Final Version: 15 September 2021
Official Title: 


SAP 405-201-00015 
Confidential - Proprietary Information  
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15 September 2021
Otsuka Pharmaceutical Development & Commercialization, Inc.
Investigational Medicinal Product
Centanafadine (EB-1020)
An Open-label, 52-Week, Multicenter Trial Evaluating the Long-term Safety and Tolerability 
of Centanafadine Sustained-Release Tablets in Adults with Attention-Deficit/Hyperactivity 
Disorder
Protocol No. 405-201-00015
IND No. 119,361
Statistical Analysis Plan
Version: Final
Date: September 15, 2021
CONFIDENTIAL – PROPRIETARY INFORMATION
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Otsuka Pharmaceutical Development & Commercialization, Inc.
Clinical Study Report 405-201-00015
16.1.9 Documentation of Statistical Methods
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
1


SAP 405-201-00015 
Confidential - Proprietary Information  
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15 September 2021
Table of Contents
Table of Contents ..........................................................................................2
1
Introduction..........................................................................................4
2
Study Objectives...................................................................................4
3
Study Design .........................................................................................4
4
Sample Size and Power Justification................................................10
5
Data Sets for Analysis and Missing Data .........................................10
5.1
Data Sets for Analysis.......................................................................................10
5.2
Handling of Missing Data .................................................................................10
6
Study Conduct ....................................................................................11
6.1
Subject Disposition, Completion Rate and Reasons for Discontinuation.........11
6.2
Treatment Compliance ......................................................................................11
6.3
Protocol Deviation.............................................................................................11
7
Baseline Characteristics.....................................................................11
7.1
Baseline Definition............................................................................................11
7.2
Demographic Characteristics ............................................................................11
7.3
Medical and Psychiatric History .......................................................................12
7.4
Baseline Psychiatric Evaluation........................................................................12
8
Efficacy Analysis ................................................................................12
8.1
COVID-19 Related Supplementary Analyses...................................................14
9
Safety Analysis....................................................................................14
9.1
Adverse Events..................................................................................................15
9.2
Clinical Laboratory Tests..................................................................................16
9.2.1
Drug Induced Liver Injury (DILI)..................................................................16
9.3
Physical Examination and Vital Signs ..............................................................16
9.4
Electrocardiogram (ECG) Data.........................................................................17
9.5
Suicidality Data.................................................................................................18
9.6
SMWQ ..............................................................................................................18
9.7
Medication Handling Irregularities (MHIs) and Events Subject to Additional 
Monitoring (ESAMs) ........................................................................................18
9.8
Concomitant Medications .................................................................................18
Clinical Study Report 405-201-00015
16.1.9 Documentation of Statistical Methods
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9.9
Extent of Exposure............................................................................................19
10
Conventions.........................................................................................19
10.1
Study Visit Windows ........................................................................................19
10.2
Scales: Rules for Scoring and Handling of Missing Data.................................20
10.2.1
Adult ADHD Investigator Symptom Rating Scale (AISRS)..........................20
10.2.2
Clinical Global Impression Severity of Illness Scale – Modified for 
Attention-Deficit Hyperactivity Disorder.......................................................21
10.2.3
Attention-Deficit Hyperactivity Disorder Impact Module – Adult (AIM-A) 21
10.2.4
Study Medication Withdrawal Questionnaire (SMWQ) ................................21
10.2.5
Columbia-Suicide Severity Rating Scale (C-SSRS).......................................21
11
Potential Clinical Relevance Criteria from Protocol ......................23
12
Proposed List of Summary Tables....................................................26
29
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9.9
Extent of Exposure............................................................................................19
10
Conventions.........................................................................................19
10.1
Study Visit Windows ........................................................................................19
10.2
Scales: Rules for Scoring and Handling of Missing Data.................................20
10.2.1
Adult ADHD Investigator Symptom Rating Scale (AISRS)..........................20
10.2.2
Clinical Global Impression Severity of Illness Scale – Modified for 
Attention-Deficit Hyperactivity Disorder.......................................................21
10.2.3
Attention-Deficit Hyperactivity Disorder Impact Module – Adult (AIM-A) 21
10.2.4
Study Medication Withdrawal Questionnaire (SMWQ) ................................21
10.2.5
Columbia-Suicide Severity Rating Scale (C-SSRS).......................................21
11
Potential Clinical Relevance Criteria from Protocol ......................23
12
Proposed List of Summary Tables....................................................26
29
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1
Introduction
This statistical analysis plan (SAP) documents the statistical methodology and data analysis 
algorithms and conventions to be applied for statistical analysis and reporting of efficacy and 
safety data of study 405-201-00015. All amendments to the protocol are taken into 
consideration in developing this SAP. 
2
Study Objectives
The primary objective of this trial is to assess the safety and tolerability of centanafadine SR 
tablets administered BID (400 mg TDD) in the treatment of adults with ADHD.
3
  Study Design
This is a phase 3, 52-week, open-label, multicenter trial to assess the long-term safety and 
tolerability of centanafadine SR tablets (400 mg TDD) for the treatment of adults with 
ADHD. The trial population will include male and female subjects 18 to 55 years of age 
(inclusive) who meet Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
(DSM-5) criteria for ADHD (including predominantly inattentive presentation, hyperactive 
presentation, and combined presentations) as confirmed by the Adult ADHD Clinical 
Diagnostic Scale (ACDS) Version 1.2. Subjects who rollover from the double-blind phase 3 
trial (i.e., Trial 405-201-00013 or Trial 405-201-00014) and de novo subjects from selected 
sites are permitted to enroll in this trial. 
This trial will have 3 periods for rollover subjects:
1. Baseline;
2. Open-label treatment; and
3. Follow-up.
The trial will have 4 periods for de novo subjects: 
1. Screening and washout;
2. Baseline;
3. Open-label treatment; and
4. Follow-up.
The trial will be organized as follows: 
Clinical Study Report 405-201-00015
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Rollover Subjects from Double-blind Phase 3 Trial (i.e., Trial 405-201-00013 or 
Trial 405-201-00014)
Open-label Screening/Baseline: Subjects who completed one of the double-blind phase 3 
trials may be eligible to enroll in this trial; subjects who discontinued will not be eligible. 
Subjects who complete both the 6-week double-blind treatment period and the 7-day follow-
up visit are eligible to enroll into this trial. Subjects will be evaluated for eligibility at the 7-
day follow-up visit of the double-blind phase 3 trial, and informed consent will be obtained 
before any procedures for the open-label trial are conducted. Therefore the assessments from 
the 7-day follow-up visit of the double-blind phase 3 trial may serve as the baseline 
assessments for the open-label trial. 
 
 
Open-label Treatment: Eligible subjects from the double-blind phase 3 trial will receive daily 
treatment with open-label centanafadine SR tablets as described in Section 3.2 of the protocol.
During the open-label treatment period, subjects will return to the clinic for evaluations at the 
end of Weeks 1, 2, 4, 8, 12, 16, 20, 26, 32, 38, 44, and 52/ET. A Week 48 visit will be 
conducted via telephone, web, or other acceptable means of contact.
Follow-up: If any subject discontinues the trial early, every effort should be made to complete 
the early termination (ET) evaluations as soon as possible and, whenever possible, prior to 
starting any new medication or treatment. All subjects (completers and early withdrawals) 
will be evaluated for safety during a 10-day follow up (follow-up telephone calls at 1, 3, and 5 
days after the last dose of IMP, in-clinic visits 2 and 7 days after the last dose of IMP, and a 
follow-up telephone call [or web, or other acceptable means of contact] 10 days after the last 
dose of IMP).
De Novo Subjects
Screening and Washout: De novo subjects must meet the DSM-5 criteria for ADHD 
(including predominantly inattentive presentation, hyperactive presentation, and combined 
presentations) as confirmed by the ACDS Version 1.2. To confirm that ADHD is the primary 
diagnosis, the Mini International Neuropsychiatric Interview (MINI) will be used to identify 
and exclude other psychiatric conditions. 
Subjects will be screened to establish eligibility for trial participation. The length of screening 
(Day –28 to Day –2) will include a washout period (if needed), which will range from 7 to 28 
days. The investigator or his/her designee must obtain informed consent from the subject prior 
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to any trial-related procedures being performed. An identification (ID) number will be 
assigned for each subject with documented consent. Those subjects who meet eligibility 
requirements will undergo ADHD medication washout, if applicable. If subjects are taking 
disallowed medications and are able to taper appropriately and safely, they will do so during 
the screening period. If medication taken is for ADHD, a minimum of 7 days off stimulants 
and 21 days off nonstimulants will be required before baseline. A complete washout schedule, 
including common excluded medications and herbal preparations, is provided in Table 4.1-1 
of the protocol. The screening visit may take place over multiple days to accommodate the 
subject’s schedule, if needed.
Baseline: Following medication washout, subjects will return to the clinic for reassessment of 
eligibility criteria and establishment of baseline measurements. The interval between the first 
day of the screening visit (informed consent date) and the baseline visit (Day –1) must not 
exceed 28 days. Subjects who meet relevant entry criteria by the time they leave the clinic on 
the day of the baseline visit will be dispensed the trial medication. 
 
 
Open-Label Treatment: After completing the baseline assessments, eligible subjects will 
receive daily treatment with open-label centanafadine SR tablets during the open-label 
treatment period, as described in Section 3.2 of the protocol.
During the open-label treatment period, subjects will return to the clinic for evaluations at the 
end of Weeks 1, 2, 4, 8, 12, 16, 20, 26, 32, 38, 44, and 52/ET. A Week 48 visit will be 
conducted via telephone, the web, or other acceptable means of contact.
Follow-up: If any subject discontinues the trial early, every effort should be made to complete 
the Week 52/ET evaluations as soon as possible and whenever possible prior to starting any 
new medication or treatment. All subjects (completers and early withdrawals) will be 
evaluated for safety during a 10-day follow up (follow-up telephone calls at 1, 3, and 5 days 
after the last dose of IMP, in-clinic visits 2 and 7 days after the last dose of IMP, and a 
follow-up telephone call [or web, or other acceptable means of contact] 10 days after the last 
dose of IMP).
Late rollover subjects (i.e., those who were unable to rollover from Trial 405-201-00013
or Trial 405-201-00014 due to the inability of an in-person baseline visit in
Trial 405-201-00015) will follow the de novo path (see details in the protocol addendum).
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
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See Figure 3-1 and Figure 3-2 for schematics of the trial design for rollover and de novo 
subjects, respectively.
Clinical Study Report 405-201-00015
16.1.9 Documentation of Statistical Methods
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Figure 5.1
Trial Design Schematic - Rollover Subjects from Trial 405-201-00013 or Trial 405-201-00014
Eligible rollover subjects 
who completed one of the 
double-blind phase 3 trials 
(ie, Trial 405-201-000013 or 
Trial 405-201-00014) and 
would potentially benefit 
from treatment with 
centanafadine SR for adult 
ADHD per investigator
Baseline
(7-day follow-up visit for 
Trial 405-201-00013 or 
Trial 405-201-00014)
Open-label Treatment Period
Follow-up Period
Open-label Centanafadine SR 400 mg (TDD)
Weeks 1, 2, 4, 8, 12, 16, 20, 26, 32, 38, and 44: clinic visits
Week 48: telephone, web, or other means of contact
(unscheduled visits as necessary)
Safety follow-up on 1, 2, 3, 5, 
7, and 10 days after the last 
dose of IMP
•
1-day, 3-day, and 5-day 
follow-up: telephone
•
2-day and 7-day 
follow-up: clinic visits
•
10-day follow-up: 
telephone, web, or other 
means of contact
Day -1
Baseline
Week 52/ET  
Screening/baseline values 
will be derived from the  
double-blind phase 3 trials 
(ie, Trial 405-201-000013 
or Trial 405-201-00014), 
as required
Day 1
First dose  
Clinical Study Report 405-201-00015
16.1.9 Documentation of Statistical Methods
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Figure 5.1
Trial Design Schematic - De Novo Subjects
Eligible de novo 
subjects who could 
potentially benefit from 
treatment with 
centanafadine SR for 
ADHD per investigator
One or more visits 
as needed
(Days -28 to -2)
Day -1
Baseline
Screening Period
Week 52/ET  
Weeks 1, 2, 4, 8, 12, 16, 20, 26, 32, 38, and 44: clinic visits
Week 48: telephone, web, or other means of contact
(unscheduled visits as necessary)
Open-label Treatment Period
Follow-up Period
Open-label Centanafadine SR 400 mg/day (TDD)
Safety follow-up on 1, 2, 3, 5, 
7, and 10 days after the last 
dose of IMP
•
1-day, 3-day, and 5-day 
follow-up: telephone
•
2-day and 7-day 
follow-up: clinic visits
•
10-day follow-up: 
telephone, web, or other 
means of contact
Day 1
First dose  
Clinical Study Report 405-201-00015
16.1.9 Documentation of Statistical Methods
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4
Sample Size and Power Justification
The sample size is not based on statistical power considerations but on ICH/GCP 
requirements. The trial population will be derived from eligible subjects from the double-
blind phase 3 trial (i.e., Trial 405-201-00013 or Trial 405-201-00014) and de novo subjects 
from selected sites. It is expected that approximately 560 completing rollover subjects from 
double-blind phase 3 trial (Trial 405-201-00013 or Trial 405-201-00014) and approximately 
145 de novo subjects will be enrolled into this trial.
5
Data Sets for Analysis and Missing Data 
5.1
Data Sets for Analysis
The following samples are defined for this trial:

Enrolled Sample, which comprises all subjects who sign an eICF for the trial;

Safety Sample, which comprises all subjects that will receive at least 1 dose of IMP;

Efficacy Sample, which comprises those subjects in the Safety Sample who have at least 1 
post baseline efficacy evaluation of AISRS Total Score
The observed case (OC) dataset will consist of the actual observations recorded at each visit 
and will be used to present summaries per trial week.
The last-observation-carried-forward (LOCF) data set will include data recorded at a given 
visit in the Treatment Phase or, if no observation is recorded at that visit, data carried forward 
from the previous visit in the Treatment Phase.  Data collected prior to or on the first day of 
Treatment Phase dosing will not be carried forward or averaged with Treatment Phase data to 
impute missing values for the LOCF data set.
5.2
Handling of Missing Data
In order to assess the sensitivity of results due to missing data, 2 types of analyses will be 
performed:  last observation carried forward (LOCF) and observed cases (OC). The OC 
dataset will consist of the actual observations recorded at each visit.  The LOCF dataset will 
include data recorded at a scheduled visit, i.e., all OC data, or, if no observation is recorded at 
that visit, data will be carried forward from the previously scheduled visit.  Baseline data will 
not be carried forward to impute missing values for the LOCF dataset. The OC dataset will be 
used for analyses at each trial visit and the LOCF dataset will be used for analyses at the last 
visit. 
Clinical Study Report 405-201-00015
16.1.9 Documentation of Statistical Methods
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6
Study Conduct
Late rollover subjects will contribute as de novo subjects in the analyses as they could not 
rollover to 405-201-00015 due to the COVID-19 pandemic and they will follow the de novo 
path as described in the protocol addendum.
6.1
Subject Disposition, Completion Rate and Reasons for Discontinuation
Subject disposition will be summarized for the Enrolled Sample by parent study treatment 
group for rollover subjects, de novo subjects and overall. 
Subject completion rate and reasons for discontinuation will be summarized for the Enrolled 
Sample by parent study treatment group for rollover subjects, de novo subjects and overall. 
6.2
Treatment Compliance
For each subject, compliance in taking IMP is calculated by dividing the number of tablets 
taken by the total number of tablets the patients were scheduled to take during the study period. 
Compliance is calculated on the IMP for the study period. For lost-to-follow up patients, the 
last IMP end date record will be used as the treatment end date.  
6.3
Protocol Deviation
Protocol deviations are summarized by center and type of deviation for enrolled subjects by 
parent treatment group. Listing of protocol deviation will list the treatment phases during which 
the deviations occurred.
7
Baseline Characteristics
7.1
Baseline Definition 
Baseline is defined as the last available measurement prior to the first dose of open-label IMP 
in the open-label treatment period.
7.2
Demographic Characteristics
Baseline demographic characteristics including age, race, ethnicity, gender, weight, height, and 
body mass index (BMI) will be summarized by descriptive statistics (frequency, mean, median, 
standard deviation, maximum, minimum, and percentage when applicable) for the Enrolled 
Sample by parent study treatment group for rollover subjects, de novo subjects and overall.
Clinical Study Report 405-201-00015
16.1.9 Documentation of Statistical Methods
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7.3
Medical and Psychiatric History
A summary of medical and psychiatric history will be presented for the Enrolled Sample by 
parent study treatment group for rollover subjects, de novo subjects and overall.  
A summary of the Adult ADHD Clinical Diagnostic Scale (ACDS) at screening will also be 
presented for the Enrolled Sample (by parent study treatment group for rollover subjects, de 
novo subjects and overall). The number and percentage of patients with each response to items 
A23-A41 from Section A (Childhood ADHD Symptoms Summary), B22-B39 from Section B 
(Adult ADHD Symptoms Summary), and C1-C5 will be presented.
7.4
Baseline Psychiatric Evaluation
Baseline psychiatric scale evaluation for the open-label treatment period will be summarized 
for the Enrolled Sample by parent study treatment group for rollover subjects, de novo 
subjects and overall. The mean, median, range and standard deviation will be used to 
summarize the assessments of: AISRS total score, CGI - Severity of Illness Score (CGI-S), 
and ADHD Impact Module – Adult (AIM-A).
8
Efficacy Analysis
Exploratory (efficacy) endpoints for the open-label trial are:
•
Change from baseline in AISRS Total Score, by trial visit and at the last visit (i.e., Week 
52/ET);
•
Change from baseline in CGI-S, by trial visit and at the last visit (i.e., Week 52/ET); 
•
Change from baseline in AIM-A Score by trial visit and at the last visit;
Descriptive statistics will be provided for each endpoint and will be summarized at each trial 
visit based on the Efficacy Sample using the OC dataset and at the last visit using the LOCF 
dataset. These summaries will be presented by parent study treatment group for rollover 
subjects, de novo subjects and overall. Baseline is defined as the last available measurement 
prior to the first dose of open-label IMP in the open-label treatment period.
For AIM-A, the following will be provided:
1) Change from baseline for Question 1 (Global Quality of Life) and Questions 9Aa – 
9Ai and 9Ba – 9Bi (Impact of Symptoms) of AIM-A at scheduled visits during the 
open-label treatment period, separately at every visit
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2) Proportion of subjects in each response for the following questions of AIM-A at 
scheduled visits during the open-label treatment period, separately at every visit  
a.
Questions 2-4 (Global Quality of Life) 
b. Questions 5a-5j (Living with ADHD)
c.
Questions 6a-6k (General Well-Being)
d. Questions 7a-7j (Work, Home and School Performance and Daily Functioning)
e.
Questions 8a-8h (Relationships and Communication)
f.
Economic impact (5 items)
g. Questions 17-23 (Demographics/Medication Status)
The key outcome measures from the CANTAB assessments include the following:
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8.1
COVID-19 Related Supplementary Analyses 
Summary statistics for mean and mean change from baseline in AISRS Total Score, by trial 
visit and at the last visit (i.e., Week 52/ET) and by visit type (face-to-face vs. virtual) based on 
the Efficacy Sample will be provided by parent study treatment group for rollover subjects, de 
novo subjects and overall. 
9
Safety Analysis
The primary safety endpoint analysis is the frequency and severity of AEs in the open-label 
treatment period (see Section 9.1). Other standard safety variables to be analyzed include 
clinical laboratory tests, vital signs, body weight, waist circumference, BMI, 12-lead 
electrocardiograms (ECGs), and physical examinations. In addition, data from the following 
safety scales will be evaluated: C-SSRS and Study Medication Withdrawal Questionnaire 
(SMWQ).
Safety analyses will be conducted based on the Safety Sample, and summary statistics will be 
provided by parent study treatment group for rollover subjects, de novo subjects and overall, 
unless otherwise indicated. 
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
Section 9.1
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Unless otherwise specified, in general, analysis of safety data will be performed on observed 
case and for last visit.
9.1
Adverse Events 
All adverse events will be coded by System Organ Class (SOC) and Preferred Term (PT) 
according to the Medical Dictionary for Regulatory Activities (MedDRA). AEs that are sex-
specific, e.g., ovarian cancer, will have their incidence rates evaluated for the specific sex.
Treatment-emergent AEs (TEAEs) are defined as AEs with an onset date on or after the first 
dose of IMP. In more detail, TEAEs are all adverse events which started after start of IMP; or 
if the event was continuous from baseline and was worsening, serious, study drug related, or 
resulted in death, discontinuation, interruption or reduction of study therapy. Adverse events 
occurring up to 30 days after the last day of IMP will be included in the summary tables. 
The incidence of the following events in the open-label treatment phase will be summarized 
using the Safety Sample:
a)
Treatment-emergent AEs (TEAEs)
b)
TEAEs by severity
c)
TEAEs potentially causally related to the IMP
d)
TEAEs with an outcome of death
e)
Serious TEAEs
f)
TEAEs leading to discontinuation of the IMP 
g)
Treatment-emergent Adverse Events of Special Interest (AESI)
h)
Abuse-related TEAEs and TEAEs involving MHIs (Medication handling irregularities) 
AEs will be classified by Primary SOC and PT according to the MedDRA. AEs that are 
gender-specific, e.g., ovarian cancer, will have their incidence rates evaluated for the specific 
gender. 
Incidence of TEAEs will be summarized for the open-label treatment period. Incidence of 
TEAEs by SOC and MedDRA PT will be summarized for sex and race.
Adverse Events of Special Interest
Newly acquired skin eruptions that are non-traumatic will be considered AESIs. These may 
include but are not limited to eruptions such as skin rashes, skin irritations, skin reactions, or 
acneiform lesions. This does not include localized contact irritation at ECG lead sites due to 
application or removal of lead adhesive.
Clinical Study Report 405-201-00015
16.1.9 Documentation of Statistical Methods
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Refer to the separate rash workup plan for complete details, including reporting forms, and 
extra measures that must be performed to characterize any skin AESI of a newly acquired skin 
eruption that is non-traumatic. The trial site will have a local designated dermatologist 
available for immediate consultation during the trial for these AESIs. 
9.2
Clinical Laboratory Tests
Summary statistics for mean and mean change from baseline in the routine clinical laboratory 
measurements, HbA1c, TSH, and PT/INR will be provided. Potentially clinically relevant 
results in laboratory tests will also be summarized.
Potentially clinically relevant laboratory measurement test results in the open-label treatment 
period will be identified, summarized, and listed. Criteria for identifying laboratory values of 
potential clinical relevance are provided in  Appendix 2.
9.2.1
Drug Induced Liver Injury (DILI)
Total bilirubin level should be checked for any subject with increased ALT or AST levels  
three times the upper normal limits (ULN) or baseline. 

Reporting all DILI as SAE to the FDA based on Hy's Law: 
AST or ALT > 3 x ULN or baseline and 
T_Bili  > 2 x ULN or baseline
A separate incidence table will be provided for DILI cases, and the corresponding listing will 
be provided for Safety Sample during the open-label treatment period.
9.3
Physical Examination and Vital Signs
Summary statistics for changes from baseline in vital signs will be provided for the Safety 
Sample. By-patient listings will be provided for physical examination.
Potentially clinically relevant vital signs measurements identified in the open-label treatment 
phase for the Safety Sample will be listed and summarized. Criteria for identifying vital signs 
of potential clinical relevance are provided in Appendix 1.
In addition, the change from baseline in weight, BMI, and waist circumference, and 
potentially clinically relevant abnormalities in weight, will also be summarized.
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9.4
Electrocardiogram (ECG) Data
Summary statistics and incidence of potentially clinically relevant changes will be provided 
for ECG parameters.
For the analysis of QT and QTc, data from three consecutive complexes (representing three 
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 and
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 
Potentially clinically relevant changes in the 12-lead ECG identified in the open-label 
treatment phase for the Safety Sample will be listed and summarized. Criteria for identifying 
ECG measurements of potential clinical relevance are provided in Appendix 3.
Categorical changes in ECG parameters during the open-label treatment period will be 
summarized based on the following criteria:
Categorical Change Criteria in QT/QTc Parameters
Classification
Category
Criteria 
QT
New Onset (> 450 Msec)
New onset (>450 msec) in QT means a subject who 
attains a value > 450 msec during treatment period 
but not at baseline.
QTc *
New Onset (> 450 Msec)
New onset (> 450 msec) in QTc means a subject 
who attains a value > 450 msec during treatment 
period but not at baseline.
New Onset (> 450 Msec) 
And > 10% Increase
New onset (> 450 msec) and 
> 10% increase in QTc means a subject who attains 
a value > 450 msec and > 10% increase during 
treatment period but not at baseline
New Onset (> 500 Msec)
New onset (> 500 msec) in QTc means a subject 
who attains a value > 500 msec during treatment 
period but not at baseline.
Increase 30 - 60 Msec
Increase from baseline value > 30 and  60 msec in 
QTc
Increase > 60 Msec
Increase from baseline value > 60 msec in QTc
* QTc categorical change criteria apply to QTcB, QTcF and QTcN.
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9.5
Suicidality Data
Suicidality will be monitored during the study using the C-SSRS and will be summarized as 
number and percentage of subjects reporting any suicidal behavior, ideation, behavior by type 
(4 types), ideation by type (5 types) and treatment emergent suicidal behavior and ideation. 
Summary will be provided for the open-label treatment period for the Safety Sample.
Suicidality is defined as report of at least one occurrence of any type of suicidal ideation or at 
least one occurrence of any type of suicidal behavior during assessment period (count each 
person only once).
Treatment emergent suicidal behavior and ideation is summarized by four types: Emergence 
of suicidal ideation, Emergence of serious suicidal ideation, Worsening of suicidal ideation, 
Emergence of suicidal behavior. 
Emergence of suicidal behavior/ideation is defined as report of any type of suicidal 
behavior/ideation during treatment when there was no baseline suicidal behavior/ideation.
Emergence of serious suicidal ideation is defined as observation of suicidal ideation severity 
rating of 4 or 5 during treatment when there was no baseline suicidal ideation.                                                   
Worsening of suicidal ideation is defined as a suicidal ideation severity rating that is more 
severe than it was at baseline.
For the open-label treatment period analyses, the last available measurement prior to the first 
dose of open-label IMP is being used as “Baseline”.
9.6
SMWQ
Medication withdrawal symptoms assessed by SMWQ total scores at the scheduled visits 
during the open-label treatment period and follow-up period will be summarized for the 
Safety Sample by parent study treatment group for rollover subjects, de novo subjects and 
overall. The number of patients, mean, median, range and standard deviation will be 
presented.
9.7
Medication Handling Irregularities (MHIs) and Events Subject to 
Additional Monitoring (ESAMs)
MHIs and ESAMs will be summarized for the Safety Sample by treatment group and overall. 
By-patient listings will be provided. 
9.8
Concomitant Medications
Number and proportion of patients taking concomitant medications prior to the open-label 
treatment phase, during the open-label treatment phase, and after study therapy are tabulated by 
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drug classification using the World Health Organization (WHO) drug dictionary for the Safety 
Sample.
9.9
Extent of Exposure
The start date of the open-label study therapy - centanafadine - will be the first day of dosing 
during the open-label treatment phase. The number and percentage of patients who receive 
study medication during the open-label treatment phase, will be presented by week. Each 
dosing week will be based on the actual week; i.e., Day 1-7 in Week 1, Day 8-14 in Week 2, 
etc. This summary will be performed on the Safety Sample. 
The mean daily dosage will be summarized by week using descriptive statistics. The mean 
daily dosage per patient per week will be determined for each week of the study. This will be 
calculated by dividing the sum of individual total doses by the number of days in the week 
interval. The summary will contain the number of patients receiving study medication during 
the open-label treatment phase, and the mean and range of the mean daily dose for each week
10 Conventions
10.1 Study Visit Windows
Study visit windows will be used to map visits using study day intervals. This visit window 
convention applies to tables and listings for all efficacy and safety scales (AISRS, CGI-S, 
AIM-A, CGI Change from Baseline, 
). This 
derived study window variable will be named as WEEK and will be footnoted. In listings it 
will be listed along with the eCRF study visit.
Table 10-1 shows classifications for study day intervals in the open-label treatment period. 
The variable “target day” is defined using the number of days since the start of open-label 
dosing in the open-label treatment period. The first day of open-label dosing is defined as 
“Day 1”. 
If more than one observation falls within a particular study day interval, then the last
observation within that interval is used. Evaluations occurring more than three days after the 
last open-label dosing date and evaluations occurring during the follow-up period will not be 
mapped into study visit windows and will be excluded from the open-label treatment period
analysis.
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Table 10-1: Study Day and Visit Windows in the Open-label Treatment Period
Week
Target Day a
Study Day Interval a
1
7
2-10
2
14
11-21
4
28
22-42
8
56
43-70
12
84
71-98
16
112
99-126
20
140
127-161
26
182
162-203
32 c
224
204-245
38 c
266
246-287
44 c
308
288-336
52 c
364
337-385 b
a Relative to the first day of open-label IMP in the open-label treatment period.
b Evaluations occurring more than three days after the last open-label dosing date and evaluations occurring 
during the follow-up period will be excluded from the open-label treatment period analyses.  
10.2 Scales: Rules for Scoring and Handling of Missing Data
10.2.1
Adult ADHD Investigator Symptom Rating Scale (AISRS)
The AISRS is a modified version of the ADHD Rating Scale that reflects the impact and 
severity of ADHD among adults and will be administered at each scheduled visit in the open-
label treatment period, and at 2 and 7 days after the last dose of IMP in the follow-up period. 
It is a clinician-administered scale that measures the 18 symptoms of adult ADHD using a 
Likert scale: 0 (none); 1 (mild); 2 (moderate); and 3 (severe) and uses a semi-structured 
interview methodology with suggested prompts for each item to improve interrater reliability. 
The scale's 18 items directly correspond to the 18 DSM-5 symptoms of ADHD where 9 
inattentive items alternate with 9 hyperactive impulsive items. The maximum total score for 
the scale is 54 points, with 27 points for each subscale. The total score is the sum of both the 
Inattentive and Hyperactive Impulsive subscales. 
The AISRS inattentive subscale score and hyperactive-impulsive subscale score, as well as 
the AISRS total score is set to be missing if more than one item of a subscale is missing for 
inattentive subscale or hyperactive-impulsive subscale, separately. If one item is missing for a 
given subscale (inattentive or hyperactive-impulsive), then the subscale score is derived as the 
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mean of scores from the 8 non-missing items multiplied by 9. All imputed scores are rounded 
to the first decimal place. The 9 inattentive items consist of the 9 odd numbered items and the 
9 hyperactive impulsive items consist of the 9 even numbered items. 
10.2.2
Clinical Global Impression Severity of Illness Scale – Modified for 
Attention-Deficit Hyperactivity Disorder
The CGI-S modified is an observer-rated scale that will be used to measure symptom severity. 
To perform this assessment, the investigator or rater will respond to the following question: 
“Considering your total clinical experience with adult ADHD, how mentally ill is the patient 
at this time?” Response choices include: 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. CGI-S is assessed at each scheduled visit in the open-label treatment 
period. 
10.2.3
Attention-Deficit Hyperactivity Disorder Impact Module – Adult (AIM-
A)
The AIM-A is a subject self-report questionnaire which assesses quality of life in adults with 
ADHD. The questionnaire has 4 global quality of life items, 5 economic impact items, and 
5 multi-item scales that assess the following key concepts: Living with ADHD, General Well-
Being, Work, Home and School Performance and Daily Functioning. Additionally, 
Relationships and Communication, and Impact of Symptoms are also included. 
10.2.4
Study Medication Withdrawal Questionnaire (SMWQ)
The SMWQ is a questionnaire to assess withdrawal symptoms. The SMWQ is a modification 
of the Amphetamine Withdrawal Questionnaire in which the terms “amphetamines and 
methamphetamine” are replaced with the term “the study medication.” The SMWQ is 
assessed at Week 52/ET in the open-label treatment period and at 1, 2, 3, 5, 7, and 10 days 
after the last dose of IMP in the follow-up period.
10.2.5
Columbia-Suicide Severity Rating Scale (C-SSRS)
Suicidality will be monitored during the trial using the C-SSRS. The C-SSRS is a semi-
structured interview that captures the occurrence, severity, and frequency of suicide-related 
thoughts and behaviors during the assessment period. The interview includes definitions and 
suggested questions to solicit the type of information needed to determine if a suicide-related 
thought or behavior has occurred. The interview and rating for the C-SSRS must be 
completed by a licensed clinician who has been successfully trained to rate this scale by the 
sponsor or a designee and is medically responsible for the subject. Documentation of trial 
training should be maintained in the investigational site’s files.
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This trial will use the “Baseline/Screening” and “Since Last Visit” versions of the scale. The 
“Baseline/Screening” version, which assesses the life-time experience of the subject with 
suicide events and suicidal ideation and the occurrence of suicide events or ideation within a 
specified time period prior to entry into the trial, will be completed for all de novo subjects at 
the screening visit to determine the eligibility. Any subject with active suicidal ideation within 
the last 30 days, suicidal behaviors within the last year, or who in the clinical judgment of the 
investigator presents a serious risk of suicide should be excluded from the trial. The “Since 
Last Visit” C-SSRS form will be completed at all other in-clinic visits for all subjects 
(rollover and de novo).
The C-SSRS is assessed at each scheduled visit in the screening period (for de novo subjects), 
the open-label treatment period and at 2 and 7 days after the last dose of IMP in the follow-up 
period.
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11 Potential Clinical Relevance Criteria from Protocol
Appendix 1
Criteria for Identifying Vital Signs of Potential Clinical Relevance
Variable
Criterion Valuea
Change Relative to Baselinea
Heart Rateb
> 100 bpm
< 50 bpm
 10 bpm increase
 10 bpm decrease
Systolic Blood Pressureb
 140 mmHg
< 90 mmHg
 20 mmHg increase
 20 mmHg decrease
Diastolic Blood Pressureb
 90 mmHg
< 60 mmHg
 10 mmHg increase
 10 mmHg decrease
Orthostatic Hypotension
 30 mmHg decrease in systolic blood 
pressure and/or a  20 mmHg
in diastolic blood pressure after at least
3 minutes of standing compared to the
previous supine blood pressure.
Not Applicable
(baseline status not considered)
Orthostatic Tachycardia
 25 bpm increase in heart rate from
supine to standing
Not Applicable
(baseline status not considered)
Weight
-
 7% increase
 7% decrease
a In order to be identified as potentially clinically relevant, an on-treatment value must meet the “Criterion 
Value” and also represent a change from the subject’s baseline value of at least the magnitude shown in the 
“Change Relative to Baseline” column.
b As defined in “Supplementary Suggestions for Preparing an Integrated Summary of Safety Information in 
an Original NDA Submission and for Organizing Information in Periodic Safety Updates,” FDA Division 
of Neuropharmacological Drug Products draft (2/27/87).
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Appendix 2
Criteria for Identifying Laboratory Values of Potential Clinical 
Relevance
Laboratory Tests
Criteria
Chemistry
AST (SGOT)
 3 x upper limit of normal (ULN)
ALT (SGPT)
 3 x ULN
Alkaline phosphatase
 3 x ULN
BUN
 30 mg/dL
Creatinine
 2.0 mg/dL
Uric Acid
Men
 10.5 mg/dL
Women
 8.5 mg/dL
Bilirubin (total)
 2.0 mg/dL
Creatine Phosphokinase (CPK)
> 3 x ULN
Hematology
Hematocrit
Men
 37 % and decrease of  3 percentage points from Baseline
Women
 32 % and decrease of  3 percentage points from Baseline
Hemoglobin
Men
 11.5 g/dL
Women
 9.5 g/dL
White blood count
 2,800/ mm3 or  16,000/ mm3
Eosinophils
 10%
Neutrophils
 15%
Absolute neutrophil count
 1,500/ mm3
Platelet count
 75,000/ mm3 or  700,000/ mm3
Urinalysis
Protein
Increase of  2 units
Glucose
Increase of  2 units
Additional Criteria
Chloride
 90 mEq/L or  118 mEq/L
Potassium
 2.5 mEq/L or  6.5 mEq/L
Sodium
 126 mEq/L or  156 mEq/L
Calcium
 8.2 mg/dL or  12 mg/dL
Glucose
Fasting
 100 mg/dL 
Non-Fasting
 200 mg/dL
Total Cholesterol, Fasting
 240 mg/dL 
LDL Cholesterol, Fasting
 160 mg/dL 
HDL Cholesterol, Fasting
Men
< 40 mg/dL
Women
< 50 mg/dL
Triglycerides, Fasting
 150 mg/dL
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Appendix 3
Criteria for Identifying ECG Measurements of Potential Clinical 
Relevance
Variable
Criterion Valuea
Change Relative to Baselinea
Rate
Tachycardia
 120 bpm
increase of   15 bpm
Bradycardia
 50 bpm
decrease of  15 bpm
Rhythm
Sinus tachycardiab
 120 bpm
increase of  15 bpm
Sinus bradycardiac
 50 bpm
decrease of  15 bpm
Supraventricular premature beat
all
not present  present
Ventricular premature beat
all
not present  present
Supraventricular tachycardia
all
not present  present
Ventricular tachycardia
all
not present  present
Atrial fibrillation
all
not present  present
Atrial flutter
all
not present  present
Conduction
1 atrioventricular block
PR  200 msec
increase of   50 msec
2 atrioventricular block
all
not present  present
3 atrioventricular block
all
not present  present
Left bundle-branch block
all
not present  present
Right bundle-branch block
all
not present  present
Pre-excitation syndrome
all
not present  present
Other intraventricular conduction blockd
QRS  120 msec
increase of  20 msec
Infarction
Acute or subacute
all
not present  present
Old
all
not present  present
 12 weeks post study entry
ST/T Morphological
Myocardial Ischemia
all
not present  present
Symmetrical T-wave inversion
all
not present  present
Increase in QTc
QTcF  450 msec 
(men) 
QTcF  470 msec 
(women)
a In order to be identified as potentially clinically relevant, an on-treatment value must meet the “Criterion 
Value” and also represent a change from the subject’s baseline value of at least the magnitude shown in the 
“Change Relative to Baseline” column.
b No current diagnosis of supraventricular tachycardia, ventricular tachycardia, atrial fibrillation, atrial flutter, 
or other rhythm abnormality.
c No current diagnosis of atrial fibrillation, atrial flutter, or other rhythm abnormality.
d No current diagnosis of left bundle branch block or right bundle branch block.
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12
Proposed List of Summary Tables
CT-1.1   Subject Disposition (Enrolled Sample)
CT-1.2   Subject Disposition by Center (Enrolled Sample)  
CT-1.3   Subject Completion Rates by Week (Enrolled Sample)
CT-1.4.1   Subject Enrollment by Country (Enrolled Sample)
CT-1.4.2   Subject Enrollment by Country by Age Group (Enrolled Sample)
CT-1.5   Summary of Proportion of Face-to-Face and Virtual Visits by Study Week (Enrolled Sample)
CT-2   Reasons for Discontinuation (Enrolled Sample)
CT-3.1   Demographic Characteristics (Enrolled Sample)
CT-3.2.1   Medical History (Enrolled Sample)
CT-3.2.2   Psychiatric History (Enrolled Sample)
CT-3.2.3   Summary of Adult ADHD Clinical Diagnostic Scale (ACDS) (Enrolled Sample)
CT-3.3   MINI International Neuropsychiatric Interview (M.I.N.I.)   (Enrolled Sample)
CT-3.4.1   Baseline Psychiatric Scale Evaluations (Enrolled Sample)
CT-4.1.1   Concomitant Medications: Medications Taken Prior to Start of Study Therapy (Safety Sample)
CT-4.1.2   Concomitant Medications: Medications Taken During Study Therapy (Safety Sample)
CT-4.1.3   Concomitant Medications: Medications Taken Post Study Period (Safety Sample)
CT-5.1.1   Summary of Mean Change from Baseline in Adult ADHD Investigator Symptom Rating Scale 
(AISRS) Total Score (Efficacy Sample)
CT-5.1.2   Summary of Mean Change from Baseline in Adult ADHD Investigator Symptom Rating Scale 
(AISRS) Total Score by Visit Type (Efficacy Sample)
CT-5.2   Summary of Mean Change from Baseline in AISRS Inattentive Subscale (Efficacy Sample)
CT-5.3   Summary of Mean Change from Baseline in AISRS Hyperactive-Impulsive Subscale (Efficacy Sample)
CT-5.4   Summary of Mean Change from Baseline in Clinical Global Impression - Severity of Illness Modified 
for ADHD (CGI-S) Scale (Efficacy Sample)
CT-5.5.1   Summary of Mean Change in Attention-Deficit Hyperactivity Disorder Impact Module - Adult (AIM-
A) Scale (Efficacy Sample)
CT-5.5.2   Summary of Proportion of Subjects in Each Category in Attention-Deficit Hyperactivity Disorder 
Impact Module - Adult (AIM-A) Scale (Efficacy Sample)
 
CT-6.1   Columbia-Suicide Severity Rating Scale(C-SSRS), Suicidality (Safety Sample)
CT-6.2   Columbia-Suicide Severity Rating Scale(C-SSRS), Suicidal Behavior by Type (Safety Sample)
CT-6.3   Columbia-Suicide Severity Rating Scale(C-SSRS), Suicidal Ideation by Type (Safety Sample)
CT-6.4   Columbia-Suicide Severity Rating Scale(C-SSRS), Treatment Emergent Suicidal Behavior and Ideation 
(Safety Sample) 
CT-6.5   Columbia-Suicide Severity Rating Scale (C-SSRS) – Listing of Treatment Emergent Suicidal Ideation 
(Safety Sample)
CT-6.6   Columbia-Suicide Severity Rating Scale (C-SSRS) – Listing of Treatment Emergent Suicidal Behavior 
(Safety Sample)
CT-6.7   Columbia-Suicide Severity Rating Scale (C-SSRS) – Listing of Treatment Emergent Serious Suicidal 
Ideation (Safety Sample)
CT-6.8   Columbia-Suicide Severity Rating Scale (C-SSRS) – Listing of Worsening Suicidal Ideation (Safety 
Sample) 
CT-7.1   Extent of Exposure to Study Medication (Safety Sample)
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CT-7.2   Number and Percentage of Subjects Receiving Study Medication and Mean and Range of Average 
Daily Dose (Safety Sample)
CT-8.1   Adverse Events (All Causalities) (Safety Sample)
CT-8.2.1   Incidence of TEAEs by System Organ Class and MedDRA Preferred Term (Safety Sample)
CT-8.2.2   Incidence of TEAEs B by System Organ Class, MedDRA Preferred Term and Severity (Safety 
Sample)
CT-8.2.3 Incidence of TEAE of at Least 5% by System Organ Class and MedDRA Preferred Term (Safety 
Sample)
CT-8.2.4   Incidence of TEAEs by System Organ Class and MedDRA Preferred Term, by Sex (Safety Sample)
CT-8.2.5   Incidence of TEAEs by System Organ Class and MedDRA Preferred Term, by Race (Safety Sample)
CT-8.2.6   Incidence of Non-Serious TEAE of at Least 5% by System Organ Class and MedDRA Preferred 
Term (Safety Sample)
CT-8.2.7   Incidence of TEAE of at Least 2% by System Organ Class and MedDRA Preferred Term (Safety 
Sample) 
CT-8.2.8   Incidence and Occurrence (Number of Events) of Serious Treatment-Emergent Adverse Events by 
System Organ Class and MedDRA Preferred Term
CT-8.2.9   Incidence and Occurrence (Number of Events) of Potentially Drug-Related Serious Treatment-
Emergent Adverse Events by System Organ Class and MedDRA Preferred Term
CT-8.2.10   Incidence and Occurrence (Number of Events) of Non-Serious Treatment-Emergent Adverse Events 
by System Organ Class and MedDRA Preferred Term
CT-8.3.1   Incidence of Potentially Drug-Related TEAEs by System Organ Class and MedDRA Preferred Term 
(Safety Sample)
CT-8.3.2   Incidence of Potentially Drug-Related TEAEs by System Organ Class, MedDRA Preferred Term and 
Severity (Safety Sample)
CT-8.4   Incidence of Deaths Due to TEAEs by System Organ Class and MedDRA Preferred Term (Safety 
Sample)
CT-8.5.1   Incidence of Serious TEAEs by System Organ Class and MedDRA Preferred Term (Safety Sample)
CT-8.5.2   Incidence of Serious TEAEs by System Organ Class, MedDRA Preferred Term and Severity (Safety 
Sample) 
CT-8.6.1   Incidence of TEAEs Resulting in Discontinuation from Study by System Organ Class and MedDRA 
Preferred Term (Safety Sample)
CT-8.6.2   Incidence of TEAEs Resulting in Discontinuation from Study by System Organ Class, MedDRA 
Preferred Term and Severity (Safety Sample)
CT-8.7.1   Incidence of Treatment-Emergent Adverse Events of Special Interests (AESIs) by System Organ 
Class and MedDRA Preferred Term (Safety Sample)
CT-8.7.2   Incidence of Treatment-Emergent Adverse Events of Special Interests (AESIs) by System Organ 
Class and MedDRA Preferred Term and Severity (Safety Sample)
CT-8.8.1   Incidence of Treatment-Emergent Abuse Potential-Related Adverse Events by System Organ Class 
and MedDRA Preferred Term (Safety Sample)
CT-8.8.2   Incidence of Treatment-Emergent Abuse Potential-Related Adverse Events by System Organ Class 
and MedDRA Preferred Term and Severity (Safety Sample)
CT-9.1   Listing of Deaths 
CT-9.2   Listing of Serious Adverse Events 
CT-9.3   Listing of Discontinuations of Study Medications Due to Adverse Events  
CT-10.1   Criteria for Laboratory Test Values with Potential Clinical Relevance
CT-10.2.1   Listing of Laboratory Test Values with Potential Clinical Relevance by Subject (Safety Sample)
CT-10.2.2   Listing of Laboratory Test Values with Potential Clinical Relevance by Test (Safety Sample)
CT-10.2.3   Incidence of Laboratory Test Values with Potential Clinical Relevance (Safety Sample) 
Clinical Study Report 405-201-00015
16.1.9 Documentation of Statistical Methods
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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CT-10.3.1   Mean Change from Baseline in Clinical Laboratory Test Results - Serum Chemistry (Safety Sample)
CT-10.3.2   Mean Change from Baseline in Clinical Laboratory Test Results - Hematology (Safety Sample)
CT-10.3.3   Mean Change from Baseline in Clinical Laboratory Test Results - Urinalysis (Safety Sample)
CT-10.3.4   Mean Change from Baseline in Clinical Laboratory Test Results – Other Tests (Safety Sample)
CT-10.4.1   Incidence of Potentially Liver Injury Related Laboratory Test Abnormalities (Safety Sample) 
CT-10.4.2   Listing of Potentially Liver Injury Related Laboratory Test Abnormalities (Safety Sample) 
CT-11.1   Criteria for Potentially Clinically Relevant Abnormalities in Vital Signs
CT-11.2.1   Listing of Potentially Clinically Relevant Abnormalities in Vital Signs (Safety Sample)
CT-11.2.2   Incidence of Potentially Clinically Relevant Abnormalities in Vital Signs (Safety Sample)
CT-11.2.3   Mean Change from Baseline in Vital Signs (Safety Sample) 
CT-11.3   Mean Change from Baseline in Body Weight (kg) (Safety Sample)
CT-11.4   Mean Change from Baseline in Waist Circumference (cm) (Safety Sample) 
CT-11.5   Mean Change from Baseline in BMI (kg/m2) (Safety Sample) 
CT-12.1.1   Criteria for Potentially Clinically Relevant Abnormalities in ECG Evaluations
CT-12.2.1   Listing of Potentially Clinically Relevant Abnormalities in ECG Evaluations (Safety Sample)
CT-12.2.2   Incidence of Potentially Clinically Relevant Changes in ECG Evaluations (Safety Sample)
CT-12.2.3   Mean Change from Baseline in Electrocardiogram Results (Safety Sample)
CT-12.3.1   Listing of Categorical Changes in QT/QTc (Safety Sample)
CT-12.3.2   Incidence of Categorical Changes in QT/QTc (Safety Sample) 
CT-13   Summary of Mean Study Medication Withdrawal Questionnaire (SMWQ) Total Score During the Open-
Label Treatment Period and Follow-up Period (Safety Sample)
CT-14   Summary of Medication Handling Irregularity (Safety Sample)
CT-15.1   Summary of ESAMs Reported as Abuse Potential AEs by System Organ Class and MedDRA 
Preferred Term (Safety Sample)
CT-15.2   Summary of Non-Adverse Events Reported as Findings (ESAM) (Safety Sample)
Clinical Study Report 405-201-00015
16.1.9 Documentation of Statistical Methods
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.
28


SAP 405-201-00015 
Confidential - Proprietary Information  
29
15 September 2021
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31
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T hi s p a g e i s a m a nif e st ati o n of a n el e ctr o ni c all y c a pt ur e d si g n at ur e
SI G N A T U R E P A G E
D o c u m e nt N a m e: 4 0 5- 2 0 1- 0 0 0 1 5 _ St ati sti c al _ A n al y si s _ Pl a n
D o c u m e nt N u m b er: 
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U ntil t he i nf or m ati o n herei n is rele ase d b y Ots u k a t o t he p u blic d o m ai n, t he c o nte nts of t his d oc u me nt are Ots u k a
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