A Phase 3, Randomized, Double-blind, Multicenter, Placebo-controlled, Parallel-group Trial Evaluating the Efficacy, Safety, and Tolerability of Centanafadine Sustained-release Tablets in Adults With Attention-deficit/Hyperactivity Disorder
Phase: PHASE3
Conditions: Attention Deficit Disorder, Attention Deficit Hyperactivity Disorder
Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.

 
Official Title: 
A Phase 3, Randomized, Double-blind, Multicenter, Placebo-controlled, 
Parallel-group Trial Evaluating the Efficacy, Safety, and Tolerability of 
Centanafadine Sustained-release Tablets in Adults With Attention-
deficit/Hyperactivity Disorder 
NCT Number: 
NCT03605680 
 
Document Date: 
 
Protocol Version 4.0: 15 January 2020 
 
 
 
 
 
 
 
 

Protocol 405-201-00013
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Protocol Synopsis
Name of Sponsor: Otsuka Pharmaceutical
Development & Commercialization, Inc.
Name of Investigational Medicinal Product: 
Centanafadine (EB-1020)
Protocol No.: 405-201-00013
IND No.: 119361
Protocol Title:
A Phase 3, Randomized, Double-blind, Multicenter, 
Placebo-controlled, Parallel-group Trial Evaluating the 
Efficacy, Safety, and Tolerability of Centanafadine 
Sustained-release Tablets in Adults with 
Attention-deficit/Hyperactivity Disorder
(Trial 405-201-00013)
Clinical Phase/Trial 
Type:
3
Treatment Indication: 
Adult Attention-deficit/Hyperactivity Disorder (ADHD)
Objective(s):
Primary: To confirm the efficacy of centanafadine 
sustained-release (SR) tablets administered twice-daily (BID; 
200 mg or 400 mg total daily doses [TDDs]) compared to 
placebo in the treatment of adults with ADHD
Secondary: To confirm the safety and tolerability of 
centanafadine SR tablets administered BID (200 mg or 
400 mg TDDs) compared to placebo in the treatment of adults 
with ADHD
Trial Design:
This trial is a phase 3, randomized, double-blind, multicenter, 
placebo-controlled, parallel-group trial to confirm the efficacy, 
safety, and tolerability of centanafadine SR (200 mg TDD or 
400 mg TDD) compared to placebo for the treatment of adults 
with ADHD.
The trial will have 4 periods: (1) screening and washout; 
(2) 1-week single-blind placebo run-in; (3) 6-week 
double-blind treatment; and (4) 7-day follow-up period 
(follow-up telephone calls at 1, 3, and 5 days after the last 
dose of investigational medicinal product (IMP), and in-clinic 
visits 2 and 7 days after the last dose of IMP) for subjects who 
complete the trial, and decide to enroll in 
Trial 405-201-00015. For subjects who terminate early, decide 
to not enroll in Trial 405-201-00015, or who are not eligible to 
enroll in Trial 405-201-00015, they will be required to 
participate in the 7-day follow-up period as well as participate 
in an additional follow-up telephone call 10 days after the last 
dose of IMP. Subjects randomized to receive a TDD of 
200 mg centanafadine SR will start at their target dose at the 
start of the double-blind treatment period.
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Subjects randomized to receive 400 mg TDD centanafadine 
SR will start the double-blind treatment period at the TDD of 
200 mg centanafadine SR for 7 days, before they are escalated 
to their target TDD of 400 mg for a total of approximately 
42 days of treatment. Subjects will be required to visit the site 
up to 12 times over the trial.
Subjects who complete both the 6-week double-blind 
treatment period and the 7-day follow up (follow-up telephone 
calls at 1, 3, and 5 days after the last dose of IMP, and 
in-clinic visits 2 and 7 days after the last dose of IMP), and 
refrain from using prohibited medications after the IMP is 
stopped may be eligible to enroll into Trial 405-201-00015, 
which is a 12-month, observational, open-label trial to 
evaluate the long term safety and tolerability of subjects with 
ADHD who previously participated in Trials 405-201-00013 
or 405-201-00014. Subjects who terminate early, decide to not 
enroll in Trial 405-201-00015, or who are not eligible to enroll 
in Trial 405-201-00015, will be required to participate in the 
7-day follow-up period as well as participate in an additional 
follow-up telephone call 10 days after the last dose of IMP. 
For subjects who early terminate or decline participation in the 
open-label trial, they will be instructed to refrain from utilizing 
prohibited concomitant medications (Section 4.1), including 
ADHD treatments, until after the follow-up telephone call 
10 days after the last dose of IMP.
Subject Population:
A total of up to 1150 male and female subjects with current 
diagnosis ADHD and between the ages of 18 and 55 years, 
inclusive, are planned to be screened in order to randomize 
approximately 450 subjects to yield 292+ completers.
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.
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Subjects who were not receiving any pharmacological 
treatment for ADHD must have an Adult ADHD Investigator 
Symptom Rating Scale (AISRS) score of ≥ 28 at screening and 
baseline. Subjects who were receiving pharmacological 
treatment for ADHD at screening must have a minimum 
AISRS score of ≥ 22 at screening, and a score of ≥ 28 at 
baseline.
All subjects must be willing to discontinue all prohibited 
psychotropic medications (Section 4) starting from the time of 
signing the informed consent through the 7-day follow-up 
period. Subjects that do not rollover into Trial 405-201-00015 
must be willing to discontinue all prohibited psychotropic 
medications starting from the time of signing the informed 
consent until after the follow-up telephone call 10 days after 
the last dose of IMP.
Subjects must have a Clinical Global Impression-Severity of 
Illness Scale (CGI-S) score of ≥ 4 (≥ moderate impairment) at 
baseline.
Inclusion/Exclusion 
Criteria:
Key inclusion criteria are described under Subject Population 
in this synopsis. Key exclusion criteria include the following:
Screening:

Subject has a DSM-5 diagnosis of Other Specified or 
Unspecified Attention Deficit/Hyperactivity Disorder.

Subject has a 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.

In the opinion of the investigator, subject has not derived 
significant therapeutic benefit from 2 or more ADHD 
therapies of 2 different classes (eg, amphetamine and 
methylphenidate, or amphetamine and atomoxetine) given 
with an acceptable dose and duration during adulthood 
(aged 18 or older). NOTE: If subject has not derived 
significant therapeutic benefit due to an inability to tolerate 
side effects, eligibility can be discussed on case-by-case 
basis with the medical monitor.
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
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.
Single-blind placebo run-in:

Subjects who have a positive alcohol test (via breathalyzer 
or blood), a positive drug screen assessed prior to Visit 2 
for cocaine, other illicit drugs (including marijuana), or 
prescription or OTC ADHD medications will be screen 
failed. This includes medications such as opioids or 
benzodiazepines taken without prescription.

Subjects with a ≥ 30% improvement in the (18 item) 
ADHD Symptoms score of the Adult ADHD Self Report 
Scale (ASRS) compared with the score at screening will be 
screen failed, and not eligible for rescreening.
Baseline:

Subjects who have a positive alcohol test (via breathalyzer 
or blood), a positive drug screen assessed prior to the 
baseline visit for cocaine, other illicit drugs (including 
marijuana), or prescription or OTC ADHD medications 
will be early terminated. This includes medications such as 
opioids or benzodiazepines taken without prescription.

Subjects with a ≥ 30% improvement in the (18 item) 
ADHD Symptoms score of the ASRS compared with the 
score at the start of single-blind placebo run-in will be 
early terminated.

In the opinion of the investigator, the subject is unable to 
adhere to the treatment regimen or other requirements 
outlined in the protocol.
Trial Site(s):
The trial is expected to enroll subjects at approximately 
40 sites in the United States.
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Investigational 
Medicinal Product(s), 
Dose, Dosage 
regimen, Treatment 
period, Formulation, 
Mode of 
Administration:
The IMP will be supplied as weekly blister cards. All subjects 
will begin oral BID dosing with single-blind matching placebo 
on Visit 2 (Day −7) and continue through Visit 3 (baseline).
Trial assignments for the double-blind treatment period will be 
made once eligibility is confirmed. Eligible subjects will be 
randomized in a 1:1:1 ratio at baseline (Visit 3) to one of the 
following 3 treatment groups:

Centanafadine SR 200 mg

Centanafadine SR 400 mg

Matching placebo
Subjects randomized to receive the target TDD of 200 mg 
centanafadine SR will start at the target dose on Day 1 of the 
double-blind treatment period and remain there for the 
duration of the trial. Subjects randomized to receive a TDD of 
400 mg centanafadine SR will receive a TDD of 200 mg 
centanafadine SR on Day 1 of the double-blind treatment 
period for 7 days before they are escalated to their target TDD 
of 400 mg on Day 8 for the duration of the trial.
Day(s)
Time
Total Daily Dose
200 mg Target
400 mg Target
1 through 
7
2 tablets orally in 
morning
1 × 100 mg +
1 × PBO tablet
1 × 100 mg +
1 × PBO tablet
2 tablets orally 
4-6 hr later
1 × 100 mg +
1 × PBO tablet
1 × 100 mg +
1 × PBO tablet
8 and
thereafter
2 tablets orally in 
morning
1 × 100 mg +
1 × PBO tablet
2 ×100 mg
2 tablets orally 
4-6 hr later
1 × 100 mg +
1 × PBO tablet
2 ×100 mg
PBO = placebo.
Neither the investigator nor the subject will be aware of the 
treatment assignment after randomization. All doses of 
centanafadine SR and matching placebo should be taken orally 
BID and can be administered without regard to meals, and 
should be taken at approximately the same time each day, with 
the first dose taken in the morning. The second dose should be 
taken 4 to 6 hours after the morning dose is administered.
The total duration of the double-blind treatment period will be 
6 weeks for all randomized subjects.
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Trial Assessments:
Efficacy: AISRS, CGI-S, Clinical Global Impression (CGI) 
Change from Baseline
Pharmacokinetic: Sparse pharmacokinetic (PK) samples will 
be taken for determination of concentrations of centanafadine 
and metabolite(s) in plasma on Days 7, 14, 28, 42/end of 
treatment/early termination (ET), and 49/7-day follow-up. 
Samples collected at Day 14 and Day 42/ET should be taken 
concurrently with the serum chemistry sample.
Safety: Adverse event (AE) reporting (including evaluations 
for rash, AEs related to abuse potential, and AEs involving 
medication handling irregularities), clinical laboratory tests, 
physical examinations, vital sign measurements, 
electrocardiograms (ECGs), assessments of withdrawal (Study 
Medication Withdrawal Questionnaire [SMWQ]), and 
suicidality (Columbia-Suicide Severity Rating Scale 
[C-SSRS]).
Screening/Other: ADHD Impact Module - Adult (AIM-A) and 
ASRS. A whole blood sample to extract deoxyribonucleic acid 
(DNA) for genotyping and a future biospecimen research
sample will be collected at baseline.
Criteria for 
Evaluation:
Primary Efficacy Endpoint:
The primary efficacy endpoint is the change from baseline at 
Day 42 in the AISRS total score.
Key Secondary Efficacy Endpoint:
The key secondary efficacy endpoint is change from baseline 
at Day 42 on the CGI-S.
Other Efficacy Endpoints:

Change from baseline in AISRS total score for every 
scheduled visit;

Change from baseline in the Inattentive subscale and 
Hyperactivity-Impulsive subscale scores of the AISRS for 
every scheduled visit;

Change from baseline in CGI-S score for every scheduled 
visit;

CGI Change from Baseline score at each scheduled visit;

Percentage of responders at each post-baseline visit, where 
a responder is defined as a subject with a CGI Change 
from Baseline score of 1 or 2 OR a ≥ 30% improvement in 
ADHD symptoms compared with baseline as measured by 
the AISRS total score.
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Exploratory Efficacy Endpoints:
The exploratory endpoints are the change from baseline to 
Day 28 and Day 42 in the AIM-A and the ASRS total score 
and subscale scores.
Safety Endpoints:
Standard safety variables will include AEs (including 
evaluations for rash, AEs related to abuse potential, and AEs 
involving medication handling irregularities), clinical 
laboratory tests (hematology, serum chemistry, and 
urinalysis), physical examinations, vital sign measurements, 
ECGs, assessments of withdrawal (SMWQ), and suicidality 
(C-SSRS).
Abuse-related AEs and AEs involving medication 
irregularities will be recorded verbatim on source 
documentation with detailed narratives.
Statistical Methods:
A sufficient number of subjects will be enrolled and 
randomized to achieve approximately 405 evaluable subjects 
in the double-blind treatment period (ie, subjects with an 
AISRS total score at baseline and at least 1 subsequent AISRS 
total score in the double-blind treatment period). After 
allowance of 10% nonevaluable subjects in the double-blind 
treatment period, the total number of subjects to be 
randomized is 450 subjects (150 subjects in each treatment 
arm). In order to ensure 405 evaluable subjects, the number of 
nonevaluable subjects will be monitored in a blinded manner 
on an ongoing basis during the trial. The power and sample 
size were obtained using the PASS 14 (2015) statistical 
computing software.
The primary efficacy endpoint is the change from baseline to 
Day 42 in AISRS total score. The estimand for the primary 
efficacy analysis is the difference in outcome improvement if 
all subjects tolerated and adhered to their treatment. This
approach is Estimand #3, recommended by the 2010 National 
Academy of Sciences’ National Research Council report on 
prevention and treatment of missing data and International 
Council for Harmonisation E9 (R1) “Addendum to Statistical 
Principles for Clinical Trials on Choosing Appropriate 
Estimands and Defining Sensitivity Analyses in Clinical 
Trials”. This estimand focuses on the efficacy of 
centanafadine (SR 200mg TDD or SR 400mg TDD) in change 
from the baseline in AISRS total score. The objective of this 
trial is consistent with the election of an efficacy rather than 
effectiveness estimand.
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The primary efficacy analysis will be performed by fitting a 
mixed-effect model repeated measures analysis with an 
unstructured variance covariance structure in which the 
change from baseline in AISRS total score at the scheduled 
double-blind treatment period visits will be the dependent 
variable based on the observed-case data set. The model will 
include fixed class effect terms for treatment, trial center, visit 
day, and an interaction term of treatment by visit day. The 
model will also include baseline values of AISRS total score 
and the interaction term of baseline values of AISRS total 
score by visit day as covariates. The primary comparison 
between the centanafadine (200 mg TDD or 400 mg TDD 
group) and the placebo group at Day 42 in the double-blind 
treatment phase will be estimated as the difference between 
Least Squares means utilizing the computing software SAS 
procedure PROC MIXED.
The comparison between centanafadine 200 mg TDD or 
400 mg TDD group and placebo group will be tested at a 
significance level of 0.05 (2-sided) in the order of 1) 400 mg 
versus placebo, and 2) 200 mg versus placebo. Additional 
details will be provided in the statistical analysis plan (SAP). 
Based on the results at various dose strengths from phase 2 
centanafadine trials, it is reasonable to expect a treatment 
difference of 5 points with a standard deviation (SD) of 12.5 in 
the mean change from baseline to Day 42 on AISRS total 
score in either the 200 mg TDD or 400 mg TDD arms. The 
planned sample size of 405 evaluable subjects (135 in each 
treatment arm) will yield at least 90% power to detect the 
treatment effects at a 2-tailed significance level of 0.05. The 2-
sided alpha level for the final analysis is 0.05.
Descriptive statistics will be provided for all efficacy and 
safety variables in general. Continuous variables will be 
summarized by tabulations of mean, median, range, and SD. 
Tabulations of frequency distributions will be provided for 
categorical variables.
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Trial Duration:
A total of up to 1150 male and female subjects are planned to 
be screened in order to randomize approximately 450 subjects 
to yield approximately 292 completers. Individual 
participation for all subjects in the trial is 12 to 13 weeks, 
consisting of an up to 28-day screening period, a 1-week 
single-blind placebo run-in period, a 6-week double-blind 
treatment period, and a 7-day follow-up period (follow-up 
telephone calls at 1, 3, and 5 days after the last dose of IMP, 
and in-clinic visits 2 and 7 days after the last dose of IMP) for 
all subjects. For subjects who early terminate or decline 
participation in the open-label trial, they will be required to 
participate in an additional follow-up telephone call 10 days 
after the last dose of IMP.
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Table of Contents
Protocol Synopsis...........................................................................................2
Table of Contents.........................................................................................11
List of In-text Tables ...................................................................................16
List of In-text Figures..................................................................................17
List of Appendices........................................................................................18
List of Abbreviations and Definitions of Terms .......................................19
1
Introduction ........................................................................................21
1.1
Nonclinical Data................................................................................................22
1.2
Clinical Data......................................................................................................23
1.3
Known and Potential Risks and Benefits ..........................................................23
2
Trial Rationale and Objectives..........................................................25
2.1
Trial Rationale...................................................................................................25
2.2
Dosing Rationale...............................................................................................25
2.3
Trial Objectives.................................................................................................26
3
Trial Design.........................................................................................26
3.1
Type/Design of Trial .........................................................................................26
3.2
Trial Treatments ................................................................................................29
3.2.1
Single-blind Placebo Run-in Period ...............................................................29
3.2.2
Double-blind Treatment Period......................................................................29
3.3
Trial Population.................................................................................................30
3.3.1
Number of Subjects and Description of Population .......................................30
3.3.2
Subject Selection and Numbering ..................................................................30
3.4
Eligibility Criteria..............................................................................................31
3.4.1
Informed Consent ...........................................................................................31
3.4.2
Inclusion Criteria ............................................................................................32
3.4.3
Exclusion Criteria...........................................................................................33
3.5
Endpoints...........................................................................................................36
3.5.1
Primary Endpoint............................................................................................36
3.5.1.1
Primary Efficacy Endpoint..........................................................................36
3.5.2
Secondary Endpoints ......................................................................................36
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3.5.2.1
Key Secondary Efficacy Endpoint..............................................................36
3.5.2.2
Other Efficacy Endpoints............................................................................36
3.5.3
Exploratory Endpoints....................................................................................36
3.5.4
Safety Endpoints.............................................................................................36
3.6
Measures to Minimize/Avoid Bias....................................................................37
3.6.1
Randomization................................................................................................37
3.7
Trial Procedures ................................................................................................37
3.7.1
Schedule of Assessments................................................................................41
3.7.1.1
Visit 1 (Screening) ......................................................................................41
3.7.1.2
Visit 2 (Single-blind Placebo Run-in).........................................................42
3.7.1.3
Visit 3 (Baseline).........................................................................................42
3.7.1.4
Double-Blind Treatment Period..................................................................43
3.7.1.4.1
Visits 4 through 8 ....................................................................................43
3.7.1.4.2
Visit 9/End of Treatment/Early Termination ..........................................43
3.7.1.5
Visits 10 Through 14 (Follow-up) ..............................................................44
3.7.1.6
Visit 15 (Follow-up)....................................................................................45
3.7.2
Efficacy Assessments .....................................................................................45
3.7.2.1
Adult Attention-deficit/Hyperactivity Disorder Investigator Symptom 
Rating Scale ................................................................................................45
3.7.2.2
Clinical Global Impression-Severity of Illness Scale - Modified for 
Attention-deficit/Hyperactivity Disorder....................................................45
3.7.2.3
Clinical Global Impression Change from Baseline.....................................46
3.7.3
Other Assessments..........................................................................................46
3.7.3.1
Mini International Neuropsychiatric Interview...........................................46
3.7.3.2
Adult ADHD Clinical Diagnostic Scale .....................................................46
3.7.3.3
Attention-deficit/Hyperactivity Disorder Impact Module - Adult..............46
3.7.3.4
Adult Attention-deficit/Hyperactivity Disorder Self-Report Scale, 
Expanded Version.......................................................................................47
3.7.4
Prior and Concomitant Medications...............................................................47
3.7.5
Safety Assessments.........................................................................................47
3.7.5.1
Adverse Events............................................................................................47
3.7.5.2
Clinical Laboratory Assessments................................................................47
3.7.5.3
Physical Examination and Vital Signs........................................................49
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3.7.5.3.1
Physical Examination..............................................................................49
3.7.5.3.2
Vital Signs ...............................................................................................50
3.7.5.4
Electrocardiogram Assessments..................................................................50
3.7.5.5
Other Safety Assessments...........................................................................50
3.7.5.5.1
Study Medication Withdrawal Questionnaire .........................................50
3.7.5.5.2
Columbia-Suicide Severity Rating Scale ................................................50
3.7.6
Pharmacokinetic and Pharmacogenomic Assessments ..................................51
3.7.6.1
Pharmacokinetic Assessments ....................................................................51
3.7.6.1.1
Pharmacokinetic Blood Samples.............................................................51
3.7.6.2
DNA Blood Samples for Pharmacogenomic Testing .................................52
3.7.6.3
Future Biospecimen Research.....................................................................52
3.7.7
End of Trial.....................................................................................................52
3.8
Stopping Rules, Withdrawal Criteria, and Procedures......................................53
3.8.1
Entire Trial or Treatment Arm(s) ...................................................................53
3.8.2
Individual Site.................................................................................................53
3.8.3
Individual Subject Discontinuation ................................................................53
3.8.3.1
Treatment Discontinuation..........................................................................53
3.8.3.2
Documenting Reasons for Treatment Discontinuation...............................54
3.8.3.3
Withdrawal of Consent ...............................................................................55
3.8.3.4
Procedures to Encourage Continued Trial Participation.............................56
3.9
Screen Failures ..................................................................................................56
3.10
Definition of Completed Subjects.....................................................................57
3.11
Definition of Subjects Lost to Follow-up..........................................................57
3.12
Subject Compliance...........................................................................................57
3.12.1
AiCure Investigational Medicinal Product Adherence and Reminder 
System.............................................................................................................58
3.12.2
AiCure Subject Risk .......................................................................................59
3.12.3
AiCure Subject Confidentiality ......................................................................59
3.13
Protocol Deviations...........................................................................................60
4
Restrictions..........................................................................................60
4.1
Prohibited Medications......................................................................................60
4.2
Other Restrictions..............................................................................................62
4.2.1
Restricted Therapies and Precautions.............................................................62
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4.2.2
Non-therapy Precautions and Restrictions......................................................62
4.2.2.1
Precautions..................................................................................................62
4.2.2.2
Restrictions..................................................................................................62
5
Reporting of Adverse Events.............................................................63
5.1
Definitions.........................................................................................................63
5.2
Eliciting and Reporting Adverse Events ...........................................................65
5.3
Immediately Reportable Events ........................................................................65
5.4
Adverse Events of Special Interest....................................................................65
5.5
Abuse Potential Monitoring Plan, Events Subject to Additional 
Monitoring, and Medication Handling Irregularities ........................................66
5.6
Potential Serious Hepatotoxicity.......................................................................66
5.7
Pregnancy..........................................................................................................67
5.8
Procedure for Breaking the Blind......................................................................68
5.9
Follow-up of Adverse Events............................................................................69
5.9.1
Follow-up of Nonserious Adverse Events......................................................69
5.9.2
Follow-up of Serious Adverse Events and Immediately Reportable 
Events .............................................................................................................69
5.9.3
Follow-up and Reporting of Serious Adverse Events and Immediately 
Reportable Events Occurring after Last Scheduled Contact ..........................70
6
Pharmacokinetic/pharmacogenomic Analysis.................................70
7
Statistical Analysis..............................................................................70
7.1
Sample Size.......................................................................................................70
7.1.1
Datasets for Analysis ......................................................................................71
7.2
Handling of Missing Data .................................................................................71
7.3
Primary, Secondary, and Exploratory Endpoint Analyses................................72
7.3.1
Primary Efficacy Endpoint Analysis ..............................................................72
7.3.1.1
Sensitivity Analyses....................................................................................74
7.3.1.1.1
Sensitivity Analyses for Missing at Random Assumption......................74
7.3.1.1.2
Sensitivity Analyses for Violation of Normality Assumption ................76
7.3.2
Secondary Efficacy Endpoint Analyses..........................................................76
7.3.2.1
Key Secondary Efficacy Endpoint Analysis...............................................76
7.3.2.2
Other Efficacy Endpoint Analyses..............................................................77
7.3.3
Exploratory Efficacy Endpoint Analyses .......................................................77
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7.4
Analysis of Demographic and Baseline Characteristics....................................77
7.5
Safety Analysis..................................................................................................78
7.5.1
Adverse Events ...............................................................................................78
7.5.2
Clinical Laboratory Data ................................................................................78
7.5.3
Physical Examination and Vital Signs Data ...................................................78
7.5.4
Electrocardiogram Data..................................................................................79
7.5.5
Other Safety Data ...........................................................................................79
7.5.6
Abuse Liability Analysis ................................................................................79
8
Management of Investigational Medicinal Product........................79
8.1
Packaging and Labeling ....................................................................................79
8.2
Storage...............................................................................................................80
8.3
Accountability ...................................................................................................80
8.4
Returns and Destruction....................................................................................80
8.5
Reporting of Product Quality Complaints.........................................................80
8.5.1
Eliciting and Reporting Product Quality Complaints.....................................81
8.5.2
Information Required for Reporting Purposes ...............................................81
8.5.3
Return Process ................................................................................................81
8.5.4
Assessment/Evaluation...................................................................................82
9
Records Management.........................................................................82
9.1
Source Documents.............................................................................................82
9.2
Data Collection..................................................................................................82
9.3
File Management at the Trial Site.....................................................................84
9.4
Records Retention at the Trial Site....................................................................84
10
Quality Control and Quality Assurance...........................................84
10.1
Monitoring.........................................................................................................84
10.2
Auditing.............................................................................................................85
11
Ethics and Responsibility...................................................................85
12
Confidentiality ....................................................................................85
13
Amendment Policy..............................................................................86
14
Publication Authorship Requirements.............................................86
15
References............................................................................................88
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List of In-text Tables
Table 3.2.2-1
Dosing Schedule for Centanafadine SR Tablets............................30
Table 3.4.2-1
Inclusion Criteria ...........................................................................32
Table 3.4.3-1
Exclusion Criteria ..........................................................................33
Table 3.7-1
Schedule of Assessments - Screening Through 
End of Treatment ...........................................................................38
Table 3.7-2
Schedule of Assessments - Follow-up...........................................40
Table 3.7.5.2-1
Clinical Laboratory Assessments...................................................48
Table 4.1-1
List of Medications Prohibited Before the Trial............................61
Table 4.1-2
List of Medications Prohibited During the Trial............................61
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List of In-text Figures
Figure 3.1-1
Trial Design Schematic..................................................................28
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List of Appendices
Appendix 1
Collection, Handling, and Shipment of Bioanalytical Samples.....92
Appendix 2
Criteria for Identifying Laboratory Values of Potential 
Clinical Relevance .........................................................................94
Appendix 3
Criteria for Identifying Vital Signs of Potential 
Clinical Relevance .........................................................................95
Appendix 4
Criteria for Identifying Electrocardiogram Measurements of 
Potential Clinical Relevance..........................................................96
Appendix 5
Protocol Amendment(s)/Administrative Change(s) ......................97
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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
ASRS
Adult ADHD Self Report Scale
AST
Aspartate aminotransferase
BID
Twice daily
BMI
Body mass index
CGI
Clinical Global Impression
CGI-S
Clinical Global Impression-Severity of Illness Scale
CMH
Cochran Mantel Haenszel
CPK
Creatine phosphokinase
CRO
Clinical research organization
C-SSRS
Columbia-Suicide Severity Rating Scale
CST
Clinical Surveillance & Training
CTN SR
Centanafadine sustained release
DNA
Deoxyribonucleic acid
DSM
Diagnostic and Statistical Manual of Mental Disorders
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
DSM-IV
Diagnostic and Statistical Manual of Mental Disorders, Fourth 
Edition
ECG
Electrocardiogram
eCRF
Electronic case report form
eICF
Electronic informed consent form
ESAM
Events Subject to Additional Monitoring
ET
Early termination
FAS
Full Analysis Set
FBR
Future biospecimen research
FDA
Food and Drug Administration
FOCBP
Females of childbearing potential
GCP
Good Clinical Practice 
GEE
Generalized estimating equations
HbA1c
Glycosylated hemoglobin
HBsAg
Hepatitis B surface antigen
HDL
High-density lipoprotein
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human immunodeficiency virus
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IB
Investigator’s Brochure
ICH
International Council for Harmonisation
ICMJE
International Committee of Medical Journal Editors
ID
Identification
IMP
Investigational medicinal product
INR
International normalized ratio
IRB
Institutional review board
IRE
Immediately reportable event
ITT
Intent-to-treat
LOCF
Last-observation-carried-forward
LDL
Low-density lipoprotein
LOE
Lack of efficacy
MAR
Missing at random
MCAR
Missing completely at random
MedDRA
Medical Dictionary for Regulatory Activities
MHI
Medication handling irregularities
MI
Multiple Imputation
MINI
Mini International Neuropsychiatric Interview
MMRM
Mixed-effect model repeated measures
MNAR
Missing not at random
OC
Observed-case
OPDC
Otsuka Pharmaceutical Development & Commercialization, Inc
OTC
Over-the-counter
PBO
Placebo
PK
Pharmacokinetic
PQC
Product Quality Complaint
PT
Prothrombin time
QTcB
QT interval corrected for heart rate by the Bazett formula
QTcF
QT interval corrected for heart rate by the Fridericia formula
QTcN
QT interval corrected for heart rate by the FDA Neuropharm 
Division formula
RBC
Red blood cell
RNA
Ribonucleic acid
SAE
Serious adverse event
SAP
Statistical analysis plan
SD
Standard deviation
SMWQ
Study Medication Withdrawal Questionnaire
SR
Sustained release
T4
Thyroxine
TDD
Total daily dose
TEAE
Treatment-emergent adverse event
TSH
Thyroid-stimulating hormone
UDS
urine drug screen
ULN
Upper limit of normal
US
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 86.5% 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 (2006) 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. In the 
current trial a 200 mg and a 400 mg total daily dose (TDD) of centanafadine SR will be 
evaluated against placebo.
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 1 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 five phase 1 trials and 120 subjects with ADHD received 
centanafadine in two 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 subjects with ADHD.
Please 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. Preliminary data suggest centanafadine may 
also confer an improved safety profile and a 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 healthy adult subjects and adult subjects with ADHD have 
been conducted with centanafadine. A total of 140 healthy adult subjects received 
centanafadine in 5 phase 1 trials and 120 adult 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. To date, 1 serious AE (SAE) (ischemic cardiovascular accident) occurred in 
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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 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/day). 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 
one 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
This phase 3 registrational trial, in conjunction with other registrational trials, is part of 
the centanafadine clinical development program that has been designed to confirm the 
efficacy and safety of centanafadine for the treatment of adults experiencing ADHD 
symptoms. As efficacy is dependent on both treatment duration and dose, a fixed-dose, 
parallel-group approach represents the optimal trial design to evaluate efficacy.
This trial is being conducted to obtain information on the efficacy, safety, and tolerability 
of TDDs of 200 mg and 400 mg centanafadine SR compared to placebo in adults with 
ADHD. A double-blind, randomized design will be used to minimize bias while 
collecting data and when interpreting the results. A single-blind placebo run-in will also 
be used to exclude likely placebo responders before randomization to minimize the 
impact of a placebo-effect on determining the efficacy of centanafadine SR on ADHD 
symptoms during the double-blind treatment period.
2.2
Dosing Rationale
In the current trial, centanafadine will be administered twice daily (BID) as multiple 
100 mg SR tablets to achieve TDDs of 200 mg or 400 mg.
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-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 centanafadine will be included in this 
trial to further confirm the efficacy, safety, and tolerability of the previously-established 
maximum tolerated dose.
During the NVI-EB-1020-202 trial, subjects that received 100 to 200 mg/day while 
titrating up to the maximum dose of centanafadine exhibited a statistically significant 
separation from placebo at Day 7 (p < 0.001), suggesting a TDD of 200 mg centanafadine 
may also be effective for the treatment of ADHD symptoms. A TDD of 200 mg 
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centanafadine will be included in this trial to further explore the efficacy, safety, and 
tolerability of a minimum effective dose of centanafadine.
Please refer to the IB for additional information about the IMP.25
2.3
Trial Objectives
Primary:
To confirm the efficacy of centanafadine SR tablets administered BID
(200 mg or 400 mg TDDs) compared to placebo in the treatment of adults 
with ADHD
Secondary:
To confirm the safety and tolerability of centanafadine SR tablets 
administered BID (200 mg or 400 mg TDDs) compared to placebo in the 
treatment of adults with ADHD
3
Trial Design
3.1
Type/Design of Trial
This trial is a phase 3, randomized, double-blind, multicenter, placebo-controlled, 
parallel-group trial to confirm the efficacy, safety, and tolerability of centanafadine SR 
(200 mg TDD or 400 mg TDD) compared to placebo for the treatment of adults with 
ADHD. The trial population will include male and female subjects 18 to 55 years of age 
(inclusive) with a current diagnosis of ADHD as confirmed by the Adult ADHD Clinical 
Diagnostic Scale (ACDS) Version 1.2 at screening.
The trial will have 4 periods: (1) screening and washout; (2) 1 week single-blind placebo 
run-in; (3) 6-week double blind treatment; and (4) 7-day follow-up period (follow-up 
telephone calls at 1, 3, and 5 days after the last dose of IMP, and in-clinic visits 2 and 
7 days after the last dose of IMP) for subjects who complete the trial, and decide to enroll 
in Trial 405-201-00015. For subjects who terminate early, decide to not enroll in 
Trial 405-201-00015, or who are not eligible to enroll in Trial 405-201-00015, they will 
be required to participate in the 7-day follow-up period as well as participate in an 
additional follow-up telephone call 10 days after the last dose of IMP. Subjects 
randomized to receive a TDD of 200 mg centanafadine SR will start at their target dose at 
the start of the double-blind treatment period. Subjects randomized to receive a TDD of 
400 mg centanafadine SR will start the double-blind treatment period at the TDD of 
200 mg centanafadine SR for 7 days, before they are escalated to their target TDD of 
400 mg for a total of approximately 42 days of treatment. Subjects will be required to 
visit the site up to 12 times over the trial. See Figure 3.1-1 for a schematic of the trial 
design.
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Subjects who complete both the 6-week double-blind treatment period and the 7-day 
safety follow-up period (follow-up telephone calls at 1, 3, and 5 days after the last dose of 
IMP, and in-clinic visits 2 and 7 days after the last dose of IMP), and refrain from using 
prohibited medications (Section 4.1) after the IMP is stopped may be eligible to enroll 
into Trial 405-201-00015, which is a 12-month, observational, open-label trial to evaluate 
the long-term safety and tolerability of subjects with ADHD who previously participated 
in Trials 405-201-00013 or 405-201-00014. Subjects who terminate early, decide to not 
enroll in Trial 405-201-00015, or who are not eligible to enroll in Trial 405-201-00015, 
will be required to participate in the 7-day follow-up period as well as participate in an 
additional follow-up telephone call 10 days after the last dose of IMP. For subjects who 
early terminate or decline participation in the open-label trial, they will be instructed to 
refrain from utilizing prohibited concomitant medications (Section 4.1), including ADHD 
treatments, until after the follow-up telephone call 10 days after the last dose of IMP.
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Figure 3.1-1
Trial Design Schematic
ASRS = Adult ADHD Self Report Scale; CTN SR = centanafadine sustained release; ET = early termination; P = placebo administration; R = randomization.
aAll subjects will be required to participate in the 7-day follow-up period (follow-up telephone calls at 1, 3, and 5 days after the last dose of IMP, and in-clinic 
follow-up visits at 2 and 7 days after the last dose of IMP). Subjects who terminate early, decide to not enroll in Trial 405-201-00015, or who are not 
eligible to enroll in Trial 405-201-00015, will be required to participate in an additional follow-up telephone call 10 days after the last dose of IMP.
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3.2
Trial Treatments
3.2.1
Single-blind Placebo Run-in Period
All subjects will begin BID dosing with single-blind matching placebo on Visit 2 
(Day −7) and continue through Visit 3 (baseline) (Section 3.7.1.2). Two tablets of 
matching placebo should be taken orally in the morning followed by an additional 
2 tablets 4 to 6 hours later. The morning and subsequent dose of matching placebo should 
be taken at approximately the same time each day. All subjects must be unaware of the 
single-blind placebo run-in period so that it is indistinguishable from the double-blind 
treatment period.
3.2.2
Double-blind Treatment Period
Trial assignments for the double-blind treatment period will be made once eligibility is 
confirmed. Eligible subjects will be randomized in a 1:1:1 ratio at baseline (Visit 3) to 
one of the following 3 treatment groups:

Centanafadine SR 200 mg TDD

Centanafadine SR 400 mg TDD

Matching placebo
Neither the investigator nor the subject will be aware of the treatment assignment after 
randomization. All doses of centanafadine SR and matching placebo should be taken 
orally BID and can be administered without regard to meals, and should be taken at 
approximately the same time each day, with the first dose taken in the morning. The 
second dose should be taken 4 to 6 hours after the morning dose is administered.
Subjects randomized to receive the target TDD of 200 mg centanafadine SR will start at 
the target dose on Day 1 of the double-blind treatment period and remain at that dose for 
the duration of the trial (Table 3.2.2-1). Subjects randomized to receive a TDD of 400 mg 
centanafadine SR will receive a TDD of 200 mg centanafadine SR on Day 1 of the 
double-blind treatment period for 7 days before they are escalated to their target TDD of 
400 mg on Day 8 for the duration of the trial (Table 3.2.2-1).
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Table 3.2.2-1
Dosing Schedule for Centanafadine SR Tablets
Total Daily Dose
Day(s)
Time
200 mg Target
400 mg Target
1 
through 
7
2 tablets orally in 
morning
1 × 100 mg + 1 × PBO tablet
1 × 100 mg + 1 × PBO tablet
2 tablets orally 4-6 hr 
later
1 × 100 mg + 1 × PBO tablet
1 × 100 mg + 1 × PBO tablet
8 and
thereafter
2 tablets orally in 
morning
1 × 100 mg + 1 × PBO tablet
2 ×100 mg
2 tablets orally 4-6 hr 
later
1 × 100 mg + 1 × PBO tablet
2 ×100 mg
PBO = placebo.
For subjects randomized to placebo, they will take 2 placebo tablets in the morning and 
2 tablets in the afternoon for the duration of treatment.
Once the subject is at the target dose, further dose modification is not permitted. Dose 
modification is not allowed at any time during the trial.
3.3
Trial Population
3.3.1
Number of Subjects and Description of Population
A total of up to 1150 male and female subjects with current diagnosis ADHD and 
between the ages of 18 and 55 years, inclusive, are planned to be screened in order to 
randomize approximately 450 subjects to yield 292+ completers.
Subjects must meet the DSM Fifth Edition (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.
Subjects who are not receiving any pharmacological treatment for ADHD must have an 
Adult ADHD Investigator Symptom Rating Scale (AISRS) score of ≥28 at screening and 
baseline. Subjects who are receiving pharmacological treatment for ADHD at screening 
must have a minimum AISRS score of ≥ 22 at screening, and a score of ≥ 28 at baseline 
(Section 3.4.2). Subjects must washout of their current ADHD therapy, if applicable, and 
any prohibited medications prior to baseline (Table 4.1-1).
3.3.2
Subject Selection and Numbering
At screening, subjects will be assigned a unique subject identification (ID) number upon 
signing the electronic informed consent form (eICF) based on sequential enrollment in 
the trial. Subjects will be assigned a randomization number upon randomization 
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(Section 3.6.1), at the baseline visit (Day −1). The clinical site will maintain a list 
identifying all subjects by their subject ID number and initials.
3.4
Eligibility Criteria
3.4.1
Informed Consent
Informed consent will be freely obtained from all subjects (or their guardian or legally 
acceptable representative, as applicable for local laws). 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) Guideline26 and local regulatory requirements. The investigator 
will ensure that the sponsor reviews and authorizes any 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.
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.
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3.4.2
Inclusion Criteria
Subjects are required to meet the inclusion criteria presented in Table 3.4.2-1.
Table 3.4.2-1 Inclusion Criteria
Screening
1.
Subjects with a current primary DSM-5 diagnosis of ADHD (including predominantly inattentive 
presentation, hyperactive presentation, or combined presentations) as confirmed by the ACDS
Version 1.2.
2.
Subjects who are not receiving any pharmacological treatment for ADHD must have an AISRS 
score of ≥ 28 at screening. Subjects who are receiving pharmacological treatment for ADHD at 
screening must have a minimum AISRS score of ≥ 22 at screening.
3.
Subject is 18 to 55 years of age, inclusive, at the time of consent.
4.
Subject has a BMI of 18 to 40, inclusive.
5.
Subject is able to swallow multiple tablets.
6.
Subject is willing and able to comply with all testing and requirements as defined in this protocol.
7.
Subject is 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.
8.
Subject is willing to discontinue all prohibited psychotropic medications (Section 4) starting from 
the time of signing the informed consent and up to the 7-day follow-up period. Subjects that do not 
rollover into Trial 405-201-00015 must be willing to discontinue all prohibited psychotropic 
medications starting from the time of signing the informed consent until after the follow-up 
telephone call 10 days after the last dose of IMP.
9.
Subject is 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.
Inclusion Criteria Assessed at Baseline
10.
Subjects who were not receiving any pharmacological treatment for ADHD at screening must have 
an AISRS score of ≥ 28 at baseline. Subjects who were receiving pharmacological treatment for 
ADHD at screening must also have a minimum AISRS score of ≥ 28 at baseline.
11.
Subject must have a CGI-S score of ≥ 4 (≥ moderate impairment) at baseline.
BMI = body mass index; CGI-S = Clinical Global Impression-Severity of Illness Scale.
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3.4.3
Exclusion Criteria
Subjects will be excluded if they meet any of the exclusion criteria in Table 3.4.3-1.
Table 3.4.3-1 Exclusion Criteria
Screening
1.
Females who are breast-feeding 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, women who have had a bilateral oophorectomy or 
hysterectomy or who have been postmenopausal for at least 12 consecutive months; or men who 
have had a bilateral orchidectomy) or remains abstinent, 2 of the following precautions must be 
used: vasectomy, tubal ligation, vaginal diaphragm, intrauterine device, birth control pills, birth 
control 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.
Subject has a DSM-5 diagnosis of Other Specified or Unspecified Attention Deficit/Hyperactivity 
Disorder.
4.
Subject has initiated, changed, or discontinued receiving psychological (eg, supportive 
psychotherapy, cognitive behavior therapy, interpersonal therapy) interventions for ADHD within 
the 60 days before the screening visit, or are anticipated to start new treatment during the trial. 
Subjects who are receiving psychotherapy that was initiated > 60 days before the screening visit 
will be allowed to continue to receive their psychotherapy during the trial only if they agree to not 
make any changes in the frequency or nature of their psychotherapy during the course of this trial.
5.
Subject has a lifetime history of electroconvulsive therapy, or a lifetime history of vagal nerve 
stimulation or deep brain stimulation for the treatment of depression.
6.
Subject has a 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.
7.
Subjects with a clinically significant current DSM-5 diagnosis of borderline, antisocial, paranoid, 
schizoid, schizotypal, histrionic, narcissistic, avoidant, or dependent personality disorders.
8.
Subjects who meet criteria for C-SSRS Suicidal Ideation Items 4 or 5 within the last 6 months 
prior to screening or subjects who meet criteria for any of the 5 C-SSRS Suicidal Behavior Items 
(actual attempt, interrupted attempt, aborted attempt, preparatory acts, or behavior) and whose 
most recent episode meeting criteria for any of these 5 C-SSRS Suicidal Behavior Items occurred 
within the last 2 years prior to screening,
OR
Subjects who, in the opinion of the investigator, present a serious risk of suicide.
9.
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. This would also 
include most bariatric surgeries, with the only exception being those where there has been no 
breach of the gastrointestinal wall (ie, uncomplicated lap band surgery) AND no sign of 
malabsorption.
10.
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.
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Table 3.4.3-1 Exclusion Criteria
11.
Subject has a life-time history of a pattern of abuse or diversion of stimulants.
12.
Subject has any current or suspected drug or alcohol use disorder. Subject has met the DSM-5 
criteria for a substance use disorder in the past 6 months. Nicotine use disorder is not 
exclusionary.
13.
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.
14.
Subjects with a known intellectual disability or clinical evidence of intellectual disability based on 
the opinion of the investigator.
15.
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.
16.
Subjects presenting with, or having a history of, uncontrolled hypertension (systolic blood 
pressure > 140 mmHg 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 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.
17.
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.
18.
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) QTcF 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.
19.
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 3.4.3-1 Exclusion Criteria
20.
Subjects receiving any of the prohibited medications within the specified period prior to the start 
of the single-blind placebo run-in period, or who would be likely to require prohibited 
concomitant therapy during the trial (Section 4).
21.
Subject has a history of prior exposure to centanafadine.
22.
Subject has a history of dermatologic adverse reactions secondary to any drug exposure or 
anaphylaxis (or some type of systemic allergic reaction) to any substance.
23.
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.
24.
Subject has previously been randomized in this trial and subsequently withdrawn. 
25.
In the opinion of the investigator, subject has not derived significant therapeutic benefit from 2 or
more ADHD therapies of 2 different classes (eg, amphetamine and methylphenidate, or 
amphetamine and atomoxetine) given with an acceptable dose and duration during adulthood 
(aged 18 or older).
NOTE: If subject has not derived significant therapeutic benefit due to an inability to tolerate side 
effects, eligibility can be discussed on case-by-case basis with the medical monitor.
26.
Any subject who, in the opinion of the investigator, should not participate in the trial.
27.
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).
Exclusion Criteria Assessed Prior to Start of the Single-blind Placebo Run-in
28.
Subjects who have a positive alcohol test (via breathalyzer or blood), a positive drug screen 
assessed prior to Visit 2 for cocaine, other illicit drugs (including marijuana), or prescription or 
OTC ADHD medications will be screen failed. This includes medications such as opioids or 
benzodiazepines taken without prescription.
29.
Subjects with a ≥ 30% improvement in the (18 item) ADHD Symptoms score of the ASRS 
compared to the score at screening will be screen failed, and not eligible for rescreening.
Exclusion Criteria Assessed at Baseline
30.
Subjects who have a positive alcohol test (via breathalyzer or blood), a positive drug screen 
assessed prior to the baseline visit for cocaine, other illicit drugs (including marijuana), or
prescription or OTC ADHD medications will be early terminated. This includes medications such 
as opioids or benzodiazepines taken without prescription.
31.
Subjects with a ≥ 30% improvement in the (18 item) ADHD Symptoms score of the ASRS 
compared to the score at the start of single-blind placebo run-in will be early terminated.
32.
In the opinion of the investigator, the subject is unable to adhere to the treatment regimen or other 
requirements outlined in the protocol.
ALT = alanine aminotransferase; anti-HCV = hepatitis C antibodies; ASRS = Adult ADHD Self Report 
Scale; AST = aspartate aminotransferase; C-SSRS = Columbia-Suicide Severity Rating Scale; 
ECG = electrocardiogram; FOCBP = females of childbearing potential; HbA1c = glycosylated 
hemoglobin; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; HIV = human 
immunodeficiency virus; OTC = over-the-counter; QTcB = QT interval corrected for heart rate by the 
Bazett formula; QTcF = QT interval corrected for heart rate by the Fridericia formula; RNA = 
ribonucleic acid; T4 = thyroxine; TSH = thyroid-stimulating hormone.
Please refer to Section 3.9 for details regarding screen failures.
Subjects must agree to restrictions to medications and lifestyle as described in Section 4.
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3.5
Endpoints
3.5.1
Primary Endpoint
3.5.1.1
Primary Efficacy Endpoint
The primary efficacy endpoint is the change from baseline at Day 42 in the AISRS total 
score.
3.5.2
Secondary Endpoints
3.5.2.1
Key Secondary Efficacy Endpoint
The key secondary efficacy endpoint is change from baseline at Day 42 on the Clinical 
Global Impression-Severity of Illness Scale (CGI-S).
3.5.2.2
Other Efficacy Endpoints

Change from baseline in AISRS total score for every scheduled visit;

Change from baseline in the Inattentive subscale and Hyperactivity-Impulsive 
subscale scores of the AISRS for every scheduled visit;

Change from baseline in CGI-S score for every scheduled visit;

Clinical Global Impression (CGI) Change from Baseline score at each scheduled 
visit;

Percentage of responders at each post-baseline visit, where a responder is defined as a 
subject with a CGI Change from Baseline score of 1 or 2 OR a ≥ 30% improvement 
in ADHD symptoms compared with baseline as measured by the AISRS total score;
3.5.3
Exploratory Endpoints
The exploratory endpoints are the change from baseline to Day 28 and Day 42 in the 
ADHD Impact Module - Adult (AIM-A) and the Adult ADHD Self Report Scale (ASRS)
total score and subscale scores.
3.5.4
Safety Endpoints
Standard safety variables will include AEs (including evaluations for rash, an AE of 
special interest [AESI]), clinical laboratory tests (hematology, serum chemistry, and 
urinalysis), physical examinations, vital sign measurements, electrocardiograms (ECGs), 
assessments of withdrawal (Study Medication Withdrawal Questionnaire [SMWQ]), and 
suicidality (Columbia-Suicide Severity Rating Scale [C-SSRS]).
Abuse-related AEs and AEs involving medication irregularities will be recorded verbatim 
on source documentation with detailed narratives (see Section 5.5).
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3.6
Measures to Minimize/Avoid Bias
3.6.1
Randomization
During the trial, administration of the IMP will be double-blind. In other words, neither 
the investigator nor the subject will have knowledge of the treatment assignment 
(eg, centanafadine SR 200 mg, 400 mg, or placebo). Treatment assignments will be based 
on a computer-generated randomization code provided by the Otsuka Pharmaceutical 
Development & Commercialization, Inc (OPDC) Biometrics Department. Sponsor 
personnel, including those involved in monitoring, data management, and data analysis, 
will not have access to the treatment code during the trial. The bioanalytical laboratory 
will also be sent the randomization code. Access to the treatment codes will be restricted 
to personnel charged with generating and maintaining randomization files, packaging 
trial medication, operating electronic case report form (eCRF), and reporting SAEs to 
regulatory agencies. The randomization will be stratified by trial site and designed to 
allocate subjects in a 1:1:1 ratio to centanafadine SR 200 mg/day or 400 mg/day or 
placebo.
3.7
Trial Procedures
The time from enrollment of the first subject to the last subject’s last trial visit will be 
approximately 12 months. Individual participation for subjects who complete the trial 
will be approximately 12 weeks, consisting of a 28-day screening and washout period, a 
1-week single-blind placebo run-in period, a baseline day, a 6-week double-blind 
treatment period, and a 7-day follow-up period (follow-up telephone calls at 1, 3, and 
5 days after the last dose of IMP, and in-clinic visits 2 and 7 days after the last dose of 
IMP). For subjects who terminate early, decide to not enroll in Trial 405-201-00015, or 
who are not eligible to enroll in Trial 405-201-00015, they will be required to participate 
in the 7-day follow-up period as well as participate in an additional follow-up telephone 
call 10 days after the last dose of IMP.
When Trial 405-201-00013 reaches its conclusion, all subjects participating in the trial, 
regardless of trial period, may be eligible to enroll into Trial 405-201-00015, which is a 
12-month, observational, open-label trial (Section 3.1). All subjects will be required to 
comply with the appropriate follow-up procedures described in Section 3.7.1.5 and 
Section 3.7.1.6. 
Trial assessment time points are summarized in Table 3.7-1 and Table 3.7-2.
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Table 3.7-1
Schedule of Assessments - Screening Through End of Treatment
Period
Screeninga
PBO
Run-inb
Double-blind Treatment
NOTES
Days
−35 to −8
Day
−7
Baseline
Day
−1
Day
7
+1
Day
Day
14
±2
Days
Day
21
±2
Days
Day
28
±2
Days
Day
35
±2
Days
Day
42/ET
±2
Days
Visit
1
2
3
4
5
6
7
8
9
ENTRANCE/HISTORY
Informed consent
X
Section 3.4.1
Inclusion/exclusion criteria
X
X
X
Section 3.4
Demography
X
Concomitant medication(s)
X
X
X
X
X
X
X
X
X
Medical history
X
X
X
ACDS
X
Identification of comorbidities using 
MINI
X
Psychiatric evaluation
X
HIV/HBsAg/anti-HCV
X
Section 3.7.5.2
Randomization
X
Section 3.6.1
Urine pregnancy test
X
X
X
X
X
X
X
X
X
Section 3.7.5.2
Section 5.7
EFFICACY
AISRS
X
X
X
X
X
X
X
X
X
Section 3.7.2.1
CGI-S
X
X
X
X
X
X
X
Section 3.7.2.2
CGI Change from Baseline
X
X
X
X
X
X
Section 3.7.2.3
SAFETY
Adverse events
X
X
X
X
X
X
X
X
X
Section 5.2
Physical examination
X
X
X
Section 3.7.5.3.1
Vital signs
X
X
X
X
X
X
X
X
X
Section 3.7.5.3.2
12-lead ECG
X
X
X
X
X
X
X
Section 3.7.5.4
Clinical laboratory tests
X
X
X
X
X
Section 3.7.5.2
SMWQ
X
X
Section 3.7.5.5.1
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Table 3.7-1
Schedule of Assessments - Screening Through End of Treatment
Period
Screeninga
PBO
Run-inb
Double-blind Treatment
NOTES
Days
−35 to −8
Day
−7
Baseline
Day
−1
Day
7
+1
Day
Day
14
±2
Days
Day
21
±2
Days
Day
28
±2
Days
Day
35
±2
Days
Day
42/ET
±2
Days
Visit
1
2
3
4
5
6
7
8
9
UDS/alcohol testing via breathalyzer or 
blood
X
X
X
X
X
X
X
X
X
Section 3.7.5.2
C-SSRS
X
X
X
X
X
X
X
X
X
Section 3.7.5.5.2
PHARMACOKINETIC/PHARMACOGENOMIC
PK blood sample
X
X
X
X
Section 3.7.6.1
Pharmacogenomic and FBR samples
X
Section 3.7.6.2
Section 3.7.6.3
EXPLORATORY
AIM-A
X
X
X
X
Section 3.7.3.1
ASRS
X
X
X
X
X
Section 3.7.3.4
OTHER
IMP/placebo dispensing
X
X
X
X
X
X
X
IMP/placebo return and accountability
X
X
X
X
X
X
X
Section 8.4
Section 3.12
anti-HCV = hepatitis C antibodies; FBR = future biospecimen research; HBsAg = hepatitis B surface antigen; HIV = human immunodeficiency virus; 
UDS = urine drug screen.
aScreening will include a washout period that can range from 7 to 28 days
bSee Section 3.7.1.2
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Table 3.7-2
Schedule of Assessments - Follow-up
Period
Follow-upa
NOTES
1 (+1) day 
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
10
11
12
13
14
15
ENTRANCE/HISTORY
Concomitant medication(s)
X
X
X
X
X
X
EFFICACY
AISRS
X
X
Section 3.7.2.1
SAFETY
Adverse events
X
X
X
X
X
X
Section 5.2
Vital signs
X
X
Section 3.7.5.3.2
SMWQ
X
X
X
X
X
X
Section 3.7.5.5.1
UDS/alcohol testing via breathalyzer or blood
X
X
Section 3.7.5.2
C-SSRS
X
X
Section 3.7.5.5.2
PHARMACOKINETIC/PHARMACOGENOMIC
PK blood sample
X
Section 3.7.6.1
aAll subjects will be required to participate in the 7-day follow-up period (follow-up telephone calls at 1, 3, and 5 days after the last dose of IMP, and in-clinic 
follow-up visits at 2 and 7 days after the last dose of IMP). Subjects who terminate early, decide to not enroll in Trial 405-201-00015, or who are not 
eligible to enroll in Trial 405-201-00015, will be required to participate in an additional follow-up telephone call 10 days after the last dose of IMP.
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3.7.1
Schedule of Assessments
3.7.1.1
Visit 1 (Screening)
The screening period begins after consent is obtained and will take place between 
Day −35 and Day −8 prior to the initiation of the single-blind placebo run-in period. 
Completion of screening activities may require more than 1 visit. All procedures outlined 
for screening in the Schedule of Assessments (Table 3.7-1) will be performed. The 
following should also be noted:

The investigator or his/her designee must obtain informed consent from the subject 
prior to any trial-related procedures being performed.

A urine drug screen will be collected and sent to the central lab for evaluation. 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 7 days off stimulants and 21 days off nonstimulants will be 
required before the single-blind placebo run-in period. A complete washout schedule, 
including common excluded medications and herbal preparations, is provided in 
Section 4.1. A subject who tested positive for any prohibited medications at the 
screening visit must have a repeat urine drug screen that is confirmed as negative 
prior to performing Visit 2.

An assessment of all inclusion and exclusion criteria will be made to determine the 
subject’s eligibility for the trial.

Medical and psychiatric history will be recorded, including the DSM-5 diagnosis of 
ADHD using the ACDS Version 1.2.

Subjects will be administered the ASRS.

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 
a serum pregnancy test. Subjects with a positive serum test result will be excluded 
from the trial.
External quality oversight methods will be used by Clinical Surveillance & Training 
(CST) to promote appropriate subject enrollment. Such methods will require sites to 
communicate certain aspects of subject data during the screening period to CST as 
detailed in the Operations Manual. Subjects cannot be randomized until approval from 
CST has been received. The investigator is responsible for ensuring that subjects are 
eligible for enrollment into the trial and for assessing subject safety throughout the trial.
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3.7.1.2
Visit 2 (Single-blind Placebo Run-in)
After the subject has completed the medication washout period (if applicable), the Visit 2 
(Day −7) assessments described in the Schedule of Assessments (Table 3.7-1) will be 
performed. The following should also be noted:

Urine drug screen results from the previous visit will be reviewed. If the subject is 
positive for any prohibited medications at screening (including medications for the 
treatment of ADHD, see Section 4.1), and has not had a negative repeat urine drug 
screen confirmed since, the subject will be screen failed.

Subjects will be administered the ASRS prior to the start of the single-blind placebo 
run-in period, and those with a ≥ 30% improvement in the (18-item) ADHD 
Symptoms score compared to the score at screening will be screen failed, and not 
eligible for rescreening.

All subjects must be unaware of the single-blind placebo run-in period so that it is 
indistinguishable from the double-blind treatment period. All subjects must be under 
the impression that they are starting to receive randomized treatment at the time of 
Visit 2 (Day −7).

Placebo will be dispensed for the single-blind placebo run-in period, and subjects will 
be instructed to take their first dose from the dosing card in the clinic. Subjects will 
be instructed to take their doses at approximately the same time every day.

The subject will download the AiCure Platform (Section 3.12) or receive a 
provisioned device with the AiCure Platform predownloaded, and will be trained on 
IMP compliance using this application.
Subjects who discontinue the trial during the single-blind placebo run-in period 
should be considered early termination subjects, and should proceed with the early 
termination visit (Section 3.7.1.4.2) and follow-up procedures (Section 3.7.1.5 and 
Section 3.7.1.6).
3.7.1.3
Visit 3 (Baseline)
After the subject has completed the single-blind placebo run-in period, the Visit 3 
(Day −1) assessments described in the Schedule of Assessments (Table 3.7-1) will be 
completed.
The following should also be noted:

Urine drug screen results from the previous visit will be reviewed. If the subject is 
positive for any prohibited medications (including medications for the treatment of 
ADHD, see Section 4.1), the subject will be early terminated, and the procedures 
outlined in Section 3.7.1.4.2 will be completed.

Subjects will be administered the ASRS, and those with a ≥ 30% improvement in the 
(18-item) ADHD Symptoms score compared to the score at the start of single-blind 
placebo run-in will be early terminated.
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
Subjects who do not meet eligibility (see Exclusion Criteria #30, #31, and #32) at the 
baseline visit are considered early termination subjects, and should proceed with the 
early termination visit (Section 3.7.1.4.2) and follow-up procedures (Section 3.7.1.5
and Section 3.7.1.6).

Dosing cards from the single-blind run-in period will be returned; accountability and 
compliance will be verified.

Blood samples for genotyping and for future biospecimen research (FBR) will be 
collected.

Subjects entering the double-blind treatment period will be randomized (1:1:1) to 
receive centanafadine SR 200 mg TDD, 400 mg TDD, or placebo.

Subjects will receive a dosing card for dosing on Days 1 to 7, and will be instructed to 
start dosing from the new card on the following day (Day 1), and to take their doses at 
approximately the same time every day.
3.7.1.4
Double-Blind Treatment Period
3.7.1.4.1
Visits 4 through 8
The assessments described for Visits 4 through 8 (Days 7-35) in the Schedule of 
Assessments (Table 3.7-1) will be completed. The following should also be noted:

Urine drug screen results from the previous visit will be reviewed. If the subject is 
positive for any prohibited medications (including medications for the treatment of 
ADHD, see Section 4.1), the subject will be early terminated, and the procedures 
outlined in Section 3.7.1.4.2 will be completed.

At each visit dosing cards from the prior week will be returned; accountability and 
compliance will be verified.

Sparse PK samples will be collected at Visits 4 (Day 7), 5 (Day 14), and 7 (Day 28).

Subjects will receive a dosing card for dosing at each visit for the next week, and will 
be instructed to start dosing from the new card on the following day, and to take their 
doses at approximately the same time every day.
3.7.1.4.2
Visit 9/End of Treatment/Early Termination
The assessments described for Visit 9 (Day 42/early termination [ET]) in the Schedule of 
Assessments (Table 3.7-1) will be completed. If a subject discontinues early before 
Day 42, procedures noted for Day 42 must be completed at the ET visit. Attempts should 
be made to complete ALL evaluations, particularly efficacy assessments (ie, AISRS, CGI 
Change from Baseline, CGI-S, ASRS, and AIM-A), for the Day 42/ET visit prior to the 
administration of any new ADHD medications. However, if the subject receives a new 
ADHD medication or has a urine drug screen positive for any new ADHD medication 
prior to the conduct of ET procedures, no efficacy assessments should be performed.
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The following should also be noted:

Urine drug screen results from the previous visit will be reviewed. If the subject is 
positive for any new ADHD medication, no efficacy assessments should be 
conducted.

Subjects will return their dosing card from the prior week, accountability, and 
compliance will be verified.

Sparse PK sample will be collected.

For all subjects who complete the trial (Section 3.10) and are considering entry into 
the open-label rollover trial, they will be instructed to refrain from utilizing prohibited 
concomitant medications (Section 4.1), including ADHD treatments, during the 7-day 
safety follow-up period. For subjects who early terminate or decline participation in 
the open-label trial, they will be instructed to refrain from utilizing prohibited 
concomitant medications (Section 4.1), including ADHD treatments, until after the 
follow-up telephone call 10 days after the last dose of IMP.

For subjects who early terminate or decline participation in the open-label trial, future 
treatment options will be discussed, and subjects will complete follow-up visits and 
procedures described in Section 3.7.1.5 and Section 3.7.1.6.
3.7.1.5
Visits 10 Through 14 (Follow-up)
All subjects, whether they complete the trial or are withdrawn prematurely for any 
reason, will be followed up for a safety evaluation for 7 days (follow-up telephone calls 
at 1, 3, and 5 days after the last dose of IMP, and in-clinic visits 2 and 7 days after the last 
dose of IMP). The assessments described in the Follow-up Schedule of Assessments 
(Table 3.7-2) will be completed. The following should also be noted:
Subjects who complete both the 6-week double-blind treatment period, the 7-day
follow-up period (follow-up telephone calls at 1, 3, and 5 days after the last dose of IMP, 
and in-clinic visits 2 and 7 days after the last dose of IMP), and who refrain from using 
prohibited medications (Section 4.1) after the IMP is stopped, may be eligible to enroll 
into Trial 405-201-00015, which is a 12-month, observational, open-label trial to evaluate 
the long-term safety and tolerability of subjects with ADHD who previously participated 
in Trials 405-201-00013 or 405-201-00014. For subjects who early terminate or decline 
participation in the open-label trial, they will be instructed to refrain from utilizing 
prohibited concomitant medications (Section 4.1), including ADHD treatments, until 
after the follow-up telephone call 10 days after the last dose of IMP (Section 3.7.1.6).
Subjects who will be rolling over into the open-label trial will need to sign the 
Trial 405-201-00015 informed consent form prior to activities performed at the 7-day 
follow-up visit of Trial 405-201-00013.
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3.7.1.6
Visit 15 (Follow-up)
Subjects who terminate early, decide to not enroll in Trial 405-201-00015, or who are not 
eligible to enroll in Trial 405-201-00015, will be required to participate in an additional 
follow-up via telephone call 10 days after the last dose of IMP. For subjects who early 
terminate or decline participation in the open-label trial, they will be instructed to refrain 
from utilizing prohibited concomitant medications (Section 4.1), including ADHD 
treatments, until after the follow-up telephone call 10 days after the last dose of IMP. The 
assessments described in the Follow-up Schedule of Assessments (Table 3.7-2) will be 
completed.
3.7.2
Efficacy Assessments
It is required that adequately trained and experienced clinicians administer the ACDS, 
MINI, AISRS, CGI-S, and CGI Change from Baseline. 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 reflects the impact and 
severity of ADHD among adults, and will be administered as described in the Schedule 
of Assessments (Table 3.7-1 and Table 3.7-2). 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.27
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) is an observer-rated scale that will be used to measure 
symptom severity.28 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.29
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3.7.2.3
Clinical Global Impression Change from Baseline
The CGI Change from Baseline (Table 3.7-1) is an observer-rated scale that will be used 
to measure the subject's total improvement compared to before trial drug treatment was 
initiated.28 The rater or investigator will rate the subject’s total improvement relative to 
baseline. Response choices include: 1 = very much improved, 2 = much improved, 
3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 
7 = very much worse.29
3.7.3
Other Assessments
3.7.3.1
Mini International Neuropsychiatric Interview
The MINI30,31,32 will be conducted as outlined in the Schedule of Assessments 
(Table 3.7-1) to rule out exclusionary comorbid psychiatric diagnoses. Detailed 
instructions for administration of this structured interview will be provided.
3.7.3.2
Adult ADHD Clinical Diagnostic Scale
The ACDS Version 1.2 (Table 3.7-1) 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 symptoms believed to be relevant to adult ADHD.33
3.7.3.3
Attention-deficit/Hyperactivity Disorder Impact Module - Adult
The AIM-A (Table 3.7-1) 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.34
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3.7.3.4
Adult Attention-deficit/Hyperactivity Disorder Self-Report Scale, 
Expanded Version
The ASRS Version 1.1, (Table 3.7-1) is a self-report questionnaire developed by the
WHO. The subject will answer 31 questions. Of those 31, 18 of the questions pertain to 
the 18 DSM-5 ADHD symptoms (ADHD Symptoms). The expanded version includes 
9 additional items that assess Executive Function Deficits, and 4 items that assess 
Emotional Dyscontrol.35
3.7.4
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 
secondary objectives) on the 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 for treatment of an AE or which caused an AE until the end of the trial 
(defined as the last date of contact or date of final contact attempt) on the eCRF.
3.7.5
Safety Assessments
3.7.5.1
Adverse Events
Refer to Section 5.
3.7.5.2
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 during screening 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 at screening, nonfasting blood 
samples may be obtained initially for determining eligibility for the trial. 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. Clinical 
laboratory tests at other visits should be drawn fasting, if possible, but must be drawn 
after a minimum 8-hour fast at Day 42/ET. All blood collections must occur after the 
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administration of efficacy assessments and safety assessments (eg, AE monitoring, 
physical examination, vital sign measurements, ECGs, medication withdrawal scales, and 
suicidality) at any given visit. See exclusion criteria (Section 3.4.3) based on screening 
laboratory tests. 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 laboratory vendor's online portal and 
assessed by the investigator or qualified designee for clinical significance within the 
eCRF.
Table 3.7.5.2-1
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
Alcohol testing via breathalyzer or blood
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 (FOCBP), serum test will 
confirm positive urine test results
PT and INR (screening, baseline, and Day 42/ET)
CPK reflex for isoenzymes if CPK > 3 × ULN; 
serum and urine myogloblin collected if 
CPK > 5 × ULN
Additional Tests (Screening Only)
HBsAg
Anti-HCV
HIV
TSH, with reflex to free T4 if TSH is abnormal
HbA1c
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CPK = creatine phosphokinase; HDL = high-density lipoprotein; INR = international normalized ratio; 
LDL = low-density lipoprotein; PT = prothrombin time; RBC = red blood cell; ULN = upper limit of 
normal; 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. If the 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. 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 will be performed in FOCBP at each visit during the trial. An additional 
pregnancy test will be conducted in FOCBP at the Day 42/ET visit.
3.7.5.3
Physical Examination and Vital Signs
3.7.5.3.1
Physical Examination
A complete physical examination will be performed at screening, 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). A complete physical examination will 
include height (screening only), weight, waist circumference, and calculation of body 
mass index (BMI) (screening and Day 42/ET only); and assessment of the head, eyes, 
ears, nose, throat, thorax, abdomen, urogenital, skin and mucosae, neurological, and 
extremities. Examinations 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.
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3.7.5.3.2
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). 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.
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).
3.7.5.4
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).
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.
3.7.5.5
Other Safety Assessments
3.7.5.5.1
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). 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.
3.7.5.5.2
Columbia-Suicide Severity Rating Scale
Suicidality will be monitored during the trial (Table 3.7-1 and Table 3.7-2) 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. 
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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.
The C-SSRS has a “Screening/Baseline” version, which will be completed at screening 
and a ”Since Last Visit” version that will be completed at all other visits (including the 
ET visit, if applicable). There are a maximum of 19 items to be completed: 7 required, 
10 potential additional items if there is a positive response to a required item, and 2 items 
for suicide/suicide behavior present during the interview. The C-SSRS uses dichotomous 
scales (ie, yes or no), Likert scales, and text or narrative to further describe the thoughts 
or behaviors.
3.7.6
Pharmacokinetic and Pharmacogenomic Assessments
All blood collections must occur after the administration of efficacy assessments and 
safety assessments (eg, AE monitoring, physical examination, vital sign measurements, 
ECGs, medication withdrawal scales, and suicidality) at any given visit.
3.7.6.1
Pharmacokinetic Assessments
3.7.6.1.1
Pharmacokinetic Blood Samples
Five sparse PK samples will be taken for determination of concentrations of 
centanafadine and metabolite(s) in plasma. Blood samples will be collected by trial 
centers that have appropriate facilities. A 2-mL sample will be collected at the time 
points presented in the Schedule of Assessments (Table 3.7-1). Samples collected at 
Day 14 and Day 42/ET should be taken concurrently with the serum chemistry sample. 
The actual date and time of the PK sample collection must be recorded on the eCRF. The 
exact timing of sampling relative to previous dose is not critical and can vary as much as 
is operationally practical. Preferentially, 3 of the 4 PK samples taken during the treatment 
period per subject should be taken as follows:

At least 1 sample should be taken prior to the first morning dose (trough 
concentration) at either Day 7, Day 14, or Day 28

At least 1 sample should be taken at least 1 hour after the morning dose

At least 1 sample should be taken after the afternoon dose
All plasma samples will be shipped to the central laboratory. Detailed handling and 
shipping instructions are in Appendix 1.
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3.7.6.2
DNA Blood Samples for Pharmacogenomic Testing
A blood sample will be collected at the time point presented in the Schedule of 
Assessments (Table 3.7-1) in order to extract deoxyribonucleic acid (DNA) and 
determine the genotypes related to drug metabolizing enzymes and transporters to 
determine the genotypes of genes related to absorption, distribution, metabolism, and 
excretion. Genotypes and estimated phenotypes may be included as part of a population 
PK analysis to be reported separately. All samples will be shipped to the central 
laboratory. Detailed handling and shipping instructions are provided in Appendix 1.
3.7.6.3
Future Biospecimen Research
A blood sample will be collected at the time point presented in the Schedule of 
Assessments (Table 3.7-1) only from those subjects that provided consent for FBR 
sample collection. Research performed on this sample may include genetic analyses 
(DNA), gene expression profiling (ribonucleic acid [RNA]), proteomics, metabolomics or 
the measurement of other analytes. Such research is for biomarker testing to address 
emergent questions not described elsewhere in the protocol (as part of the main trial) and 
will only be conducted on specimens from appropriately consented subjects. The 
objective of collecting specimens for future biomedical research is to explore and identify 
biomarkers that inform the scientific understanding of diseases and their therapeutic 
treatments. Processing, storage, and shipping instructions for FBR samples are provided 
in Appendix 1.
3.7.7
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.
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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. Subjects who remain in the trial when the trial reaches its conclusion may 
be eligible to enter an open-label rollover trial (Trial 405-201-00015) if they meet all of 
the inclusion/exclusion criteria for that trial.
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 Discontinuation
After randomization, a subject may stop treatment permanently for a variety of reasons. 
Treatment discontinuations may be initiated by a subject who is not satisfied with 
treatment or may become medically necessary due to AEs, required treatment with a 
disallowed medication or therapy, or other issues, as determined by the investigator. 
However, each investigator must comprehensively review the circumstances and offer the 
subject options for continued treatment to the degree possible as described in 
Section 3.8.3.4. Refer to Table 3.7-2 for a description of follow-up procedures.
A urine drug screen will be collected and sent to the central lab at the time points 
described Table 3.7-1 and Table 3.7-2. At the start of the single-blind placebo run-in 
period through the Day 42/ET visit, if the subject is tests positive for any prohibited 
medications (including medications for the treatment of ADHD, see Section 4.1), the 
subject will be early terminated, and the procedures outlined in Section 3.7.1.4.2 will be 
completed.
At the baseline visit only, if subjects have a ≥ 30% improvement in the ASRS (18 item) 
ADHD Symptoms score compared to the score at the start of the single-blind placebo 
run-in, they will be early terminated.
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3.8.3.2
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

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 (LOE)
Subjects withdrawn prior to Day 42 must complete the Day 42/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 and 
7 days after the last dose of the IMP, and 10 days via telephone 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 post-randomization 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.
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3.8.3.3
Withdrawal of Consent
All subjects have the right to withdraw their consent from further participation in the trial 
at any time without prejudice. Subjects cannot withdraw consent for use of data already 
collected as part of the trial, but only for future participation. The investigator 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 discontinue IMP administration, which is 
not equivalent to a complete withdrawal of consent for further participation (see 
Section 3.8.3.1). 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 3.8.3.4 to determine if the subject can continue 
participation in the trial if modifications to his/her treatment or schedule of assessments 
can be accommodated. Only subjects who withdraw their permission for all of the above 
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degrees of follow-up are considered to have completely withdrawn their consent to 
participate in the trial.
3.8.3.4
Procedures to Encourage Continued Trial Participation
In all cases of impending IMP discontinuation or consent withdrawal, investigators will 
meet and discuss with the subject their options of continuing in the trial, preferably on 
therapy. The investigator should ensure understanding and documentation of the reasons 
for the subject’s desire to withdraw consent.
3.9
Screen Failures
A screen failure subject is one from whom informed consent is obtained and is 
documented in writing (ie, subject signs an eICF), but who is not randomized or assigned 
to trial treatment.
For this trial, treatment begins with the first dose of the IMP in the single-blind placebo 
run-in period. Subjects that have a positive alcohol test (via breathalyzer or blood), or 
positive drug screen for cocaine, or other illicit drugs (excluding marijuana) are not 
eligible to be retested or rescreened, and will be considered screen failures. 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 after the allotted washout period, a subject tests positive for ADHD 
medications prior to the start of the single blind placebo run-in period, subjects will be 
screen failed, and not permitted to rescreen. Screen failures previously excluded for a 
positive urine drug screen due to use of prescription or over-the-counter (OTC) 
medications or products not used for the treatment of ADHD, may be retested or 
rescreened for participation in the trial only with the explicit consent of the medical 
monitor. Subjects will be administered the ASRS prior to the start of the single-blind 
placebo run-in period, and those with a ≥ 30% improvement in the (18-item) ADHD 
Symptoms score compared to the score at screening will be screen failed, and not eligible 
for rescreening. Screen failures excluded for any other reasons may be rescreened at any 
time if the exclusion characteristic has changed. In the event that a screen failure is 
rescreened a new eICF must be signed, a new screening number assigned, and all 
screening procedures repeated.
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3.10
Definition of Completed Subjects
The treatment period is defined as the time period during which subjects are evaluated for 
primary and secondary objectives of the trial irrespective of whether or not the subject 
actually consumed all doses of the IMP. Subjects who are evaluated at the last scheduled 
visit during the treatment period will be defined as trial completers. For purposes of this 
trial, subjects who complete the Day 42/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 Day 42/ET 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). Accountability and compliance verification will 
be monitored with a medication adherence monitoring platform, and results should be 
documented in the subject’s trial records. Subjects must be counseled on the importance 
of taking the IMP as directed at all trial visits. If poor compliance continues (eg, multiple 
missed doses resulting in less than 80% overall compliance), discontinuation of the 
subject from the trial should be considered.
Details on the AiCure technology to be used in this trial to assess IMP compliance are 
provided below.
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3.12.1
AiCure Investigational Medicinal Product Adherence and 
Reminder System
This trial will employ an IMP adherence monitoring platform (“AiCure Platform”) for all 
subjects in the trial. The AiCure Platform uses artificial intelligence on smartphones to 
confirm IMP ingestion. In addition, built-in reminders and a communication system 
allow real time intervention in case of IMP interruptions.
Use of this AiCure Platform will in no way supersede or replace the physician or 
prescribed IMP protocol of the subjects. Because the AiCure Platform does not change 
the IMP protocol of the subjects, but rather encourages adherence to the predefined 
protocol, use of this AiCure Platform presents minimal risk to the subjects. Use of the 
AiCure Platform will be required for all subjects in the trial.
The monitoring AiCure Platform requires that all subjects take each dose of the IMP 
while using a smartphone. The AiCure Platform will be provided to subjects preloaded on 
a smartphone, or subjects will download the AiCure Platform onto their own mobile 
device at the start of the single-blind placebo run-in period (Day −7).
When at home, subjects will receive an IMP reminder at a time within a predefined 
window. This notification reminds subjects to take their IMP dose while using the AiCure 
Platform. Subjects will follow a series of prescribed steps in front of the front facing 
webcam to visually confirm their ingestion of the IMP. The application on the 
smartphone will make an automated determination of whether the subject has properly 
taken their IMP at the prescribed time. There is no need for the trial site staff to review 
the administration, nor would the trial site staff need to be available at the time the 
subject takes their IMP. The amount of guidance that the device provides to the subjects 
is automatically reduced as the subject becomes more proficient at using the application.
After the device confirms proper IMP ingestion, video recordings will be encrypted and 
transmitted to a secure centralized location for further analysis, including testing for 
duplicate enrollment. The captured data and video are reviewable through a roles and 
rules restricted system ensuring privacy of the information. The system is compliant with 
the Health Insurance Portability and Accountability Act (HIPAA), which protects the 
privacy and security of healthcare information.
Phone numbers of the subjects may also be collected and stored in an encrypted manner. 
Storing the phone numbers will allow for direct communication with subjects, including 
automated messaging from the AiCure Platform device and contact by the trial site staff 
or other monitoring personnel. At no time is the phone number visible to the trial site 
staff or monitoring personnel on the AiCure Platform. Individuals outside the trial site 
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will not be provided with subject names, nor will they be given access to subject medical 
records.
3.12.2
AiCure Subject Risk
The AiCure Platform provides no more than minimal risk to subjects. This protocol only 
introduces a smartphone-based monitoring application that prompts the user to take their 
IMP, verifies ingestion, and stores encrypted data securely for analysis. When 
functioning properly, use of the AiCure Platform does not affect titration, dosage, route 
of administration, or treatment duration, conforming to any trial requirements as noted by 
trial site staff. 
It is possible, though very unlikely, that the AiCure application can fail to remind 
subjects to take the IMP or tell them to take their IMP when not required. To date, 
AiCure has not encountered such a malfunction.
All trial data, including any identifiable subject information, will be obtained and 
encrypted by the application. Subjects will be coded according to the protocol and their 
identity will not be stored with the trial data obtained. After the subject has taken the IMP 
and confirmation of proper ingestion has been completed, the encrypted data will be 
automatically forwarded to a secure server. The server is compliant with the HIPAA, 
which protects the privacy and security of healthcare information. The data will be 
securely stored and only accessible to the trial site staff and other authorized personnel 
through two-way authentication.
The data may also be retained in a secure manner beyond the term of the trial and utilized 
to improve the operation of the AiCure Platform, categorize adherence activity by disease 
state or other useful categories, or for regulatory filings by the AiCure Platform Provider 
to support future applications for the AiCure Platform Provider’s product. Individuals 
who are not associated with the care and treatment of subjects will not have access to 
subject identity or any medical records.
3.12.3
AiCure Subject Confidentiality
The AiCure Platform Provider will protect subjects’ personal information to the full 
extent required by law. However, information from this trial, including de-identified 
video recording(s) of subject performance of various actions, may be submitted to the 
trial site, and potentially to the FDA. Both information obtained by the application, and 
information in the subject Informed Consent, may be examined by the trial site or the trial 
site’s representatives, and may also be reviewed by the FDA and other regulatory 
agencies, IRBs, or Ethics Committee(s). All of these parties are bound to safeguard the 
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rights, safety, and well-being of all clinical trial subjects, and to maintain all information 
in confidence, with special consideration given to trials that may include vulnerable 
subjects.
The results of this trial may be presented at meetings or in publications; however, specific 
subjects will not be identified by name in these presentations or publications. Information 
from this trial may also be retained by the AiCure Platform Provider for the purpose of 
improving the AiCure Platform, to allow for future analysis of various facial and other 
parameters, the reporting of high level statistical analysis of the AiCure Platform, to 
improve the internal workings of the system running on the smartphone device, or for 
regulatory filings by the AiCure Platform Provider to support future applications for the 
Provider’s product.
3.13
Protocol Deviations
In the event of a significant deviation from the protocol due to an emergency, accident, or 
mistake (eg, violation of informed consent process, IMP dispensing or subject dosing 
error, treatment assignment error, subject enrolled in violation of eligibility criteria or 
concomitant medication criteria), the investigator or designee will contact the sponsor or 
designee 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
Subjects who are currently taking any therapy for ADHD at screening will washout from 
their current ADHD therapy (see Table 4.1-1) before the start of the single-blind placebo 
run-in period (Day −7). All subjects must agree to discontinue all prohibited medications 
during the screening period. Table 4.1-1 provides the required duration of washout for 
selected prohibited medications. All other prohibited medications must be discontinued at 
least 24 hours before Day −7.
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Table 4.1-1
List of Medications Prohibited Before the Trial
Medication
Required Washout Prior to Start of 
Placebo Run-in Period
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)
7 days
6.
Antihypertensives
Clonidine
Propranolol
Guanfacine
21 days
7.
Anorexics (weight loss supplements)
7 days
8.
Investigational compounds
7 days
Table 4.1-2 lists all medications prohibited during the trial, including exceptions, where 
appropriate.
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)
Sedating antihistamines (eg, diphenhydramine, hydroxyzine, chlorpheniramine)
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)
aNon-benzodiazepine sleep aids (ie, zolpidem, zaleplon, zopiclone, and eszopiclone only) are permitted 
for the treatment of insomnia AEs.
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4.2
Other Restrictions
4.2.1
Restricted Therapies and Precautions
St. John’s Wort (Hypericum perforatum) is prohibited for 14 days prior to IMP 
administration and during the trial. Investigators should inform subjects that normal 
consumption of caffeine is permitted.
The subject’s best medical interests should guide the investigator in the management of 
conditions that are pre-existing or that develop during the trial (intercurrent illness or 
AEs). The investigator should examine the acceptability of all concomitant medications 
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 may only receive psychotherapy for ADHD (eg, supportive psychotherapy, 
cognitive behavior therapy, interpersonal therapy) if they have been participating in the 
therapy regularly (ie, at consistent intervals) for at least 60 days prior to screening and 
commit to maintain their participation during the course of the trial with no changes 
unless permission is obtained from the medical monitor.
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 at any time during the trial if there is a suspicion of illicit 
drug use.
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5
Reporting of Adverse Events
5.1
Definitions
An AE is defined as any untoward medical occurrence in a patient or clinical trial subject 
administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. Adverse events would not include information recorded 
as 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.
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.
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Immediately Reportable Event (IRE):

Any SAE.

Any AESI (see Section 5.4).

Any AE related to occupational exposure.

Potential serious hepatotoxicity (see Section 5.6).

Pregnancies are also defined as IREs. Although normal pregnancy is not an AE, it 
will mandate IMP discontinuation and must be reported on an IRE form to the 
sponsor. Pregnancy will only be documented on the AE 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 
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, 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.
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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.
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 or 
designee 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 or 
designee. (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 or designee.
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 or removal of lead adhesive.
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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.
All AESIs 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 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.
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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 
or hysterectomy or who have been postmenopausal for at least 12 consecutive months).
For FOCBP and for males who are sexually active, there must be a documented 
agreement that the subject and 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, 
women who have had a bilateral oophorectomy or hysterectomy or who have been 
postmenopausal for at least 12 consecutive months; or men who have had a bilateral 
orchidectomy) or remains abstinent, 2 of the following precautions must be used: 
vasectomy, tubal ligation, vaginal diaphragm, intrauterine device, birth control pills, birth 
control 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 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 or serum pregnancy test for human chorionic gonadotropin will be performed at 
screening on all subjects that are FOCBP. If a urine test is performed and is positive, the 
investigator will follow up with a confirmatory serum test.
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During the trial, all 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.
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
The investigator is encouraged to contact the sponsor/clinical research organization 
(CRO) medical monitor to discuss their rationale for unblinding. However, to prevent 
delays to the investigator or medical personnel responding to a potentially emergent 
situation, unblinding of IMP will not be dependent upon the investigator receiving 
approval from the sponsor/CRO medical advisor (ie, the investigator will be able to 
obtain the code break information independent of the sponsor/CRO medical advisor). The 
investigator must contact the sponsor/CRO medical advisor by telephone or e-mail with 
an explanation of the need for opening the treatment assignment code within 24 hours of 
opening the code. If the blind is broken, the Clinical Safety and Pharmacovigilance 
department must be notified immediately (see the cover page of this protocol for contact 
information). Documentation of breaking the blind should be recorded in the subject’s 
medical record with the date and time the blind was broken and the names of the 
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personnel involved. Once the blind is broken for a subject, that subject may not reinitiate 
treatment with the IMP.
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 that complete the trial be actively monitored for SAEs and 
IREs up to 7 days after the last dose of IMP is administered. Subjects that decide to not 
enroll in Trial 405-201-00015, or for subjects that do not complete Trial 405-201-00013, 
will 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
The PK samples will be analyzed for centanafadine (EB-1020) and its metabolite(s)
concentrations. Times postdose will be determined from the date and time of first pill 
captured by AiCure for the dose prior to the PK sample and the sampling date and time 
captured in the eCRF; for the sample taken 7 days after the last dose of IMP (Day 49 for 
completers), the date and time of the first pill from last dose taken (on Day 42 for 
completers) will be used as the date and time of the dose prior to the sample. No formal 
statistical comparisons are planned. A separate population or PK/pharmacogenomic 
modeling may be performed using the data from this trial and other trials.
7
Statistical Analysis
7.1
Sample Size
The primary efficacy endpoint is the change from baseline at Day 42 in AISRS total 
score. The trial will compare the placebo arm to the centanafadine dose arms, randomized 
at a ratio of 1:1:1, with an overall alpha of 0.05 for the primary endpoint.
Based on the results at various dose strengths from phase 2 centanafadine trials, it is 
reasonable to expect a treatment difference of 5 points with a standard deviation (SD) of 
12.5 in the mean change from baseline to Day 42 on AISRS total score in either the 
200 mg TDD or 400 mg TDD arms. The planned sample size of 405 evaluable subjects 
(135 in each treatment arm) will yield at least 90% power to detect the treatment effects 
at a 2-tailed significance level of 0.05. The 2-sided alpha level for the final analysis is 
0.05.
A sufficient number of subjects will be enrolled and randomized to achieve 
approximately 405 evaluable subjects in the double-blind treatment period (ie, subjects 
with an AISRS total score at baseline and at least 1 subsequent AISRS total score in the 
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double-blind treatment period). After allowance of 10% nonevaluable subjects in the 
double-blind treatment period, the total number of subjects to be randomized is 
450 subjects (150 subjects in each treatment arm). In order to ensure 405 evaluable 
subjects, the number of nonevaluable subjects will be monitored in a blinded manner on 
an ongoing basis during the trial. The power and sample size were obtained using the 
PASS 14 (2015) statistical computing software.
7.1.1
Datasets for Analysis
The following samples are defined for this trial:

Enrolled Sample: comprises all subjects who signed an eICF for the trial and enrolled 
into the single-blind placebo run-in period

Randomized Sample: comprises of all subjects who were randomized in the 
double-blind treatment period. Subjects are considered randomized when they are 
assigned a treatment group by eCRF at the end of the single-blind placebo run-in 
period. A subject receiving IMP outside of the eCRF will not be considered 
randomized, but safety will be reported.

Safety Sample: comprises those randomized subjects in the double-blind treatment 
period who receive at least 1 dose of double-blind IMP as indicated on the dosing 
record. Subjects will only be excluded from this population if there is documented 
evidence (ie, drug dispensed = drug returned or no IMP dispensed) that the subject 
did not take IMP. If a subject is dispensed IMP and is lost to follow-up, he/she will be 
considered exposed.

Efficacy Sample: the Full Analysis Set (FAS) comprises all subjects in the Safety 
Sample who have a baseline value and at least 1 valid post-randomization efficacy 
evaluation for AISRS total score in the double-blind treatment period.
The core dataset for all efficacy analyses is the FAS, which is created based on the 
intent-to-treat (ITT) principle. However, as will be described below, in order to handle 
missing data and restrictions imposed by different types of analyses (eg, change from 
baseline analysis), datasets derived from the FAS dataset will be used for the efficacy 
analysis.
7.2
Handling of Missing Data
The AISRS is utilized as the primary efficacy assessment of a subject’s level of ADHD 
symptoms. This 18-item scale directly corresponds to the 18 DSM-5 symptoms of ADHD 
where 9 Inattentiveness items alternate with 9 Hyperactivity/Impulsivity items. Each item 
is scored as follows: 0 (none), 1 (mild), 2 (moderate), 3 (severe). For all items, 0 is the 
“best” rating and 3 is the “worst” rating. The maximum total score for the scale is 
54 points, with 27 points for each subscale. The AISRS total score is the sum of the 
Inattentiveness and Hyperactivity/Impulsivity subscale scores. The range of the AISRS 
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total score is from 0 to 54. The AISRS Inattentive subscale score and 
Hyperactivity/Impulsivity 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 Inattentiveness subscale or 
Hyperactivity/Impulsivity subscale, separately. If one item is missing for a given subscale 
(Inattentiveness or Hyperactivity/Impulsivity), then the subscale score will be derived as 
the mean of scores for non-missing items multiplied by 9. All imputed scores are rounded 
to the first decimal place.
The mixed-effect model repeated measures (MMRM) assumes data are missing at 
random (MAR), which is a reasonable assumption in longitudinal clinical trials in 
ADHD. However, the possibility of “missing not at random” (MNAR) data can never be 
ruled out. As sensitivity analyses, either selection model41 pattern-mixture 
model42,43,44,45 or shared parameter model46 will be used to explore data missing 
mechanisms of MNAR and investigate the response profile of dropout reason. Pattern 
Mixture Models based on Multiple Imputation (MI) with mixed missing data mechanisms 
will be used to investigate the response profile of dropout subjects by last dropout reason 
under MNAR mechanism for the following 3 scenarios: 1) Dropout reasons due to either 
AE or lack of efficacy as MNAR, 2) Dropout reasons due to either AE or lack of efficacy 
or subject withdrew consent as MNAR, 3) All dropouts as MNAR using both 1) Delta 
adjustment imputation method which is to departure from MAR assumption by 
progressively increasing the delta until conclusion from the primary analysis is 
overturned, and 2) Placebo based imputation methods in which missing data for both 
placebo and drug group are imputed based on the imputation model derived from placebo 
data. If drug improved outcomes prior to dropout, this benefit is carried into subsequent 
imputed values, but will diminish over time in accordance with the correlation structure. 
Details of these exploratory analyses will be provided in the statistical analysis plan 
(SAP).
7.3
Primary, Secondary, and Exploratory Endpoint Analyses
7.3.1
Primary Efficacy Endpoint Analysis
The objective of the primary efficacy analysis is to compare the efficacy between 
centanafadine (SR 200 mg TDD or SR 400 mg TDD) and placebo. The primary efficacy 
endpoint is the change from baseline to Day 42 in AISRS total score. For analysis of the 
double-blind treatment period data, baseline is defined as the last available measurement 
prior to the first dose of double-blind IMP in the double-blind treatment period.
The estimand for the primary efficacy analysis is the difference in outcome improvement 
if all subjects tolerated and adhered to their treatment. This approach is Estimand #3,
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recommended by the 2010 National Academy of Sciences’ National Research Council 
report on prevention and treatment of missing data and ICH E9 (R1) “Addendum to 
Statistical Principles for Clinical Trials on Choosing Appropriate Estimands and Defining 
Sensitivity Analyses in Clinical Trials”.
This estimand focuses on the efficacy of centanafadine (SR 200 mg TDD or SR 400 mg 
TDD) in change from the baseline in AISRS total score. The objective of this trial is 
consistent with the election of an efficacy rather than effectiveness estimand.
The primary analysis will be performed on the Efficacy Sample which includes all 
randomized subjects who took at least 1 dose of IMP in the double-blind treatment period 
and who have both baseline and at least 1 post-randomization AISRS total score during 
the double-blind treatment period. The primary efficacy analysis will be performed by 
fitting a MMRM analysis with an unstructured variance covariance structure in which the 
change from baseline in AISRS total score at the scheduled double-blind treatment period 
visits will be the dependent variable based on the observed cases (OC) data set. The 
model will include fixed class effect terms for treatment, trial center, visit day, and an 
interaction term of treatment by visit day. The model will also include baseline values for 
the double-blind treatment period of AISRS total score and the interaction term of 
baseline values of AISRS total score by visit day as covariates. The primary comparison 
between the centanafadine (400 mg TDD group or 200 mg TDD group) and the placebo 
group at Day 42 in the double-blind treatment phase will be estimated as the difference 
between Least Squares means utilizing the computing software SAS procedure PROC 
MIXED. The comparison between the centanafadine (400 mg TDD group or the 200 mg 
TDD group) and the placebo group will be tested at a significance level of 0.05 (2-sided)
in the order of 1) 400 mg versus placebo, and 2) 200 mg versus placebo. If there is a 
convergence problem with the unstructured variance covariance matrix of the MMRM 
model, the following structures other than unstructured will be used in order of 
1) heterogeneous toeplitz, 2) heterogeneous autoregressive of order 1, and 
3) heterogeneous compound symmetry and the first (co)variance structure converging to 
the best fit will be used as the primary analysis. If a structured covariance has to be used, 
the “sandwich” estimator of the standard error of the fixed effects parameters will be used 
in order to deal with possible model misspecification of the covariance matrix. Details of 
this analysis will be provided in the SAP.
Small centers will be defined as centers that do not have at least 1 evaluable subject 
(evaluable with regard to the primary efficacy variable) in each treatment arm in the 
double-blind treatment period. All small centers will be pooled to form “pseudo centers” 
for the purpose of analysis according to the following algorithm. Small centers will be 
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ordered from the largest to the smallest based on the number of evaluable subjects (ie, 
subjects who have baseline and at least 1 post-baseline value for the primary endpoint in 
the double-blind treatment period). The process will start by pooling the largest of the 
small centers with the smallest of the small centers until a non-small center is formed. 
This process will be repeated using the centers left out of the previous pass. In case of ties 
in center size, the center with the smallest center code will be selected. If any centers are 
left out at the end of this process, they will be pooled with the smallest pseudo centers, or 
if no pseudo centers exist, they will be pooled with the smallest non-small center.
In the case of gross violations of the linear model assumptions, nonparametric van 
Elteren test will be performed to compare the treatment effect at Day 42 in the 
double-blind treatment period on both last-observation-carried-forward (LOCF) and MI 
data. Details will be provided in the SAP.
7.3.1.1
Sensitivity Analyses
7.3.1.1.1
Sensitivity Analyses for Missing at Random Assumption
Traditionally the dropout mechanisms are divided into 3 types43: (1) missing completely 
at random (MCAR), in which the probability of dropout doesn’t depend on the observed 
data and the missing data; (2) MAR, in which the probability of dropout depends on the 
observed data, and (3) MNAR, where the probability of dropout depends on the missing 
data and possibly the observed data.
Most of MNAR methods41 have treated all observations with dropout as if they fall 
within the same dropout type. In practice, we would find that different dropout reasons 
may be related to the outcomes in different ways, for example, detailed dropout reasons 
for this trial are: AE, LOE, death, reasons unrelated to medical condition, withdrawal of 
informed consent, lost to follow-up, rash, pregnancy, and termination of all or part of the 
trial by sponsor. Dropout due to an AE, rash, and LOE may lead to MNAR dropout. 
Subjects that withdrew consent may also lead to MNAR dropout. However, it is 
debatable whether a dropout caused by subjects that withdrew consent are MAR or 
MNAR. Except AE, rash, LOE, and subjects that withdrew consent, all the other dropout 
reasons may be assumed as either MCAR or MAR dropout.
As sensitivity analyses for MAR assumptions, analyses for MNAR will be carried out. 
Pattern Mixture Models based on MI with mixed missing data mechanisms will be used 
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to investigate the response profile of dropout subjects by last dropout reason under the 
MNAR mechanism for the following 3 scenarios:
1) Dropout reasons due to either AE, rash, or LOE as MNAR
2) Dropout reasons due to either AE, rash, or LOE or subject withdrew consent as 
MNAR
3) All dropouts as MNAR
Delta Adjustment Imputation Methods
This MNAR sensitivity analysis will be performed to address a departure from the MAR 
assumptions by progressively increasing the delta until the conclusion from the primary 
analysis is overturned. The delta is 0%, 10%, 20%, 30%, .., 100% of the expected 
treatment difference of 5 points and/or the observed treatment difference between 
centanafadine and placebo from the primary analysis of MMRM model until the 
conclusion of the primary analysis is overturned. When delta=0 it is MAR. When delta 
> 0 it is MNAR.
1) Using Monte Carlo Markov Chain methodology from PROC MI to impute the 
intermittent missing data to a monotone missing pattern;
2) Using a standard MAR-based multiple imputation approach from PROC MI to 
impute the monotone missingness data
3) For subjects in the treated group and with a dropout reason of AE or LOE or 
subject withdrew consent, a delta will be added for all the values after the dropout 
time. 
4) Using MMRM model in the primary analysis to analyzed the completed data 
using PROC MIXED on the multiple imputed data
5) Obtaining the overall results using PROC MIANALYZE
Placebo Based Imputation Methods
The placebo-based imputation methods will be similar to the “Standard” multiple 
imputations method, except the parameters for the imputation model will only be 
obtained from the placebo (control) group. Missing data for both the placebo and drug
groups are imputed based on the imputation model derived from placebo data. If drug 
improved the outcomes prior to dropout, this benefit is carried into subsequent imputed 
values, but will diminish over time in accordance with the correlation structure.
In addition, model based MNAR methods such as the shared parameter model46 and 
random coefficient pattern mixture model44 will be also performed.
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7.3.1.1.2
Sensitivity Analyses for Violation of Normality Assumption
The primary endpoint MMRM analysis is a maximum likelihood method that relies on 
the normality assumption. Residual analyses will be carried out to examine model 
assumption.
In the case of gross violations of the normality assumptions, nonparametric van Elteren 
test47 will be performed to compare treatment effect at Day 42 on both LOCF dataset and 
MI data. The van Elteren test is a generalized Cochran Mantel Haenszel (CMH)
procedure useful for stratified continuous data in non-normal setting. It belongs to a 
general family of Mantel-Haenszel mean score tests. The test is performed via SAS 
procedure PROC FREQ, by including CMH2 and SCORES=MODRIDIT options in the 
TABLE statement. The stratification factor is trial center.
In addition, other methods that are robust to distributional assumption will also be 
performed to provide different views on the primary efficacy result, these include 
generalized estimating equations (GEE), weighted GEE, and MI-robust regression.48
For MI-van Elteren test and MI-robust regression, imputation datasets will be generated 
with SAS MI procedure, each dataset will be analyzed, and then an overall estimate is 
derived with SAS MIANALYZE procedure.
7.3.2
Secondary Efficacy Endpoint Analyses
7.3.2.1
Key Secondary Efficacy Endpoint Analysis
The key secondary efficacy endpoint is the change from baseline to Day 42 between 
treatment groups using the CGI-S. The estimand for the key secondary efficacy analysis 
is also the difference in outcome improvement if all subjects tolerated and adhered to 
their treatment. This approach is Estimand #3 recommended by the 2010 National 
Academy of Sciences’ National Research Council report on prevention and treatment of 
missing data and ICH E9 (R1) Addendum. This key secondary efficacy endpoint will be 
analyzed by fitting the same MMRM model described in the primary analysis.
To control the overall experiment-wise type I error at 0.05 level, a fixed-sequence testing 
approach will be applied. 
The statistical test will be performed in the following order:
1) Change from baseline to Day 42 in the double-blind treatment period in AISRS total 
score between centanafadine 400 mg TDD and placebo;
2) Change from baseline to Day 42 in CGI-S score between centanafadine 400 mg TDD
and placebo;
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3) Change from baseline to Day 42 in the double-blind treatment period in AISRS total 
score between centanafadine 200 mg TDD and placebo;
4) Change from baseline to Day 42 in CGI-S score between centanafadine 200 mg TDD
and placebo.
7.3.2.2
Other Efficacy Endpoint Analyses
Other efficacy analyses are listed below. All other efficacy variables will be evaluated at 
a nominal 0.05 level (2-sided) without adjusting for multiplicity.
1) Change from baseline in AISRS total score for every scheduled visit during the 
double-blind treatment period other than the Day 42 visit;
2) Change from baseline for the Inattentive subscale and Hyperactive-Impulsive 
subscale of the AISRS for scheduled visits during the double-blind treatment period, 
separately at every visit
3) Change from baseline in CGI-S for every scheduled visit during the double-blind 
treatment period other than the Day 42 visit
4) CGI Change from Baseline at each scheduled visit
5) Percentage of responders at each post-baseline visit, where a responder is defined as a 
subject with a CGI Change from Baseline score of 1 or 2 OR a ≥ 30% improvement 
in ADHD symptoms compared with baseline as measured by the AISRS total score
Variable (1) through variable (3) will be evaluated using the same MMRM model 
described in the primary analysis. Variable (4) will be evaluated by the CMH Row Mean 
Score Differ Test controlling, in LOCF analysis, for trial center. Variable (5) will be 
evaluated by the CMH General Association Test controlling, in LOCF analysis, for trial
center. An OC analysis will also be conducted for variables (4) and (5), but will not 
control for trial center. Statistical significance for analysis of all other efficacy variables 
will be evaluated at a nominal 0.05 level (2-sided).
7.3.3
Exploratory Efficacy Endpoint Analyses
Statistical analysis of the exploratory endpoints will be further described in the SAP.
7.4
Analysis of Demographic and Baseline Characteristics
Baseline demographic characteristics including age, race, ethnicity, gender, weight, 
height, and BMI for the randomized subjects will be summarized by descriptive statistics 
(frequency, mean, median, SD, maximum, minimum, and percentage when applicable).
Baseline disease severity and medical history will be also be summarized by descriptive 
statistics for the Safety Sample to identify any potential lack of balance between the 
treatment groups.
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7.5
Safety Analysis
Safety analysis regarding safety and tolerability in the double-blind treatment period will 
be conducted based on the Safety Sample defined in Section 7.1.1. 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 laboratory tests, vital 
signs, ECGs, and body weight. Details of safety analysis will be provided in the SAP.
7.5.1
Adverse Events
All AEs will be coded by system organ class and MedDRA preferred term. The incidence 
of the following events will be summarized by treatment group:

Treatment-emergent AEs (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 MHIs
The above summaries will also be prepared for TEAEs potentially causally related to the 
IMP.
7.5.2
Clinical Laboratory Data
Summary statistics for changes from baseline in the routine clinical laboratory 
measurements will be provided. In addition, potentially clinically significant laboratory 
results will be identified using criteria prospectively defined in the SAP, and will be 
summarized.
7.5.3
Physical Examination and Vital Signs Data
By-subject listings will be provided for physical examination findings. Summary 
statistics for changes from baseline in vital signs and body weight will be provided. 
Potentially clinically significant results in vital signs and body weight will also be 
summarized. The SAP will define other information to be analyzed for physical 
examination data.
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7.5.4
Electrocardiogram Data
Mean change from baseline and incidence of clinically significant changes will be 
calculated for ECG parameters.
For the analysis of QT and QTc, data from 3 consecutive complexes (representing 
3 consecutive heart beats) will be measured to determine average values. The following 
QT corrections will be used for reporting purposes in the clinical trial report:
1) QTcB is the length of the QT interval corrected for heart rate by the Bazett formula:
QTcB = QT / (RR)0.5
2) QTcF is the length of the QT interval corrected for heart rate by the Fridericia 
formula: QTcF = QT / (RR)0.33
3) QTcN is the length of the QT interval corrected for heart rate by the FDA 
Neuropharm Division formula: QTcN = QT / (RR)0.37
7.5.5
Other Safety Data
Medication withdrawal symptoms assessed by SMWQ total scores at the scheduled 
visit(s) will be summarized by treatment group by descriptive statistics. Details will be 
described in the SAP.
Suicidality monitored during the trial using the C-SSRS will be summarized by treatment 
group by descriptive statistics. Details will be described in the SAP.
7.5.6
Abuse Liability Analysis
Abuse potential will be assessed through the active monitoring of ESAMs (eg, AEs 
related to abuse potential and AEs involving MHI).
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. The IMP will be 
supplied as weekly blister cards. Each blister card used in the dosing period 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.
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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 received, 
dispensed, administered, and returned.
8.4
Returns and Destruction
Upon completion or termination of the trial, all used IMP containers, unused IMP, and 
partially used IMP must be returned to the sponsor or a designated agent, or destroyed at 
the trial site. The IMP may only be destroyed by the trial site, 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 (PQC) is any written, electronic, or verbal communication 
by a healthcare professional, consumer, subject, medical representative, Competent 
Authority, regulatory agency, partner, affiliate or other third party that alleges 
deficiencies or dissatisfaction related to identity, quality, labeling, packaging, reliability, 
safety, durability, tampering, counterfeiting, theft, effectiveness or performance of a drug 
product or medical device after it is released for distribution. Examples include, but are 
not limited to, communications involving:

Failure/malfunction of a product to meet any of its specifications

Incorrect or missing labeling

Packaging issues (eg, damaged, dirty, crushed, missing product)
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
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
8.5.1
Eliciting and Reporting Product Quality Complaints
The investigator or designee must record all PQCs identified through any means from the 
receipt of the IMP from the sponsor, or sponsor’s designee, through and including 
reconciliation and up to destruction, including subject dosing. The investigator or 
designee must notify the sponsor (or sponsor’s designee) by e-mail or telephone within 
24 hours of becoming aware of the PQC according to the procedure outlined below.

Online: Send information required for reporting purposes (listed below) to 

Phone:
at
Identification of a PQC by the subject should be reported to the site investigator, who 
should then follow one of the reporting mechanisms above.
8.5.2
Information Required for Reporting Purposes

Description of compliant

Reporter identification (eg, subject, investigator, site, etc)

Reporter contact information (eg, address, phone number, e-mail address)

ID of material (product/compound name, coding)

Clinical protocol reference (number 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.
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8.5.4
Assessment/Evaluation
Assessment and evaluation of PQCs will be handled by the sponsor.
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, 
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contemporaneous, original, and accurate) as paper records. These data will be collected 
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 E626 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 (FDA) 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 the 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 the 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 (CIOMS) guidelines, and 
applicable local laws and regulations. Each trial site will seek approval/favorable opinion 
by an IRB according to regional requirements, and the investigator will provide that 
documentation to the sponsor. The IRB will evaluate the ethical, scientific and medical 
appropriateness of the trial. Further, in preparing and handling the 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, or other materials 
collected shall be used solely in accordance with this protocol, unless otherwise agreed to 
in writing by the sponsor.
Subjects will be identified only by unique subject numbers in 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.
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13
Amendment Policy
The investigator will not make any changes to this protocol without the sponsor’s prior 
written consent and subsequent approval/favorable opinion by the IRB. Any permanent 
change to the protocol, whether an overall change or a change for specific trial site(s), 
must be handled as a protocol amendment. Any amendment will be written by the 
sponsor. Each amendment will be submitted to the IRB, as required by local regulations. 
Except for “administrative” or “non-substantial” amendments, investigators will wait for 
IRB approval/favorable opinion of the amended protocol before implementing the 
change(s). Administrative amendments are defined as having no effect on the safety of 
subjects, conduct or management of the trial, trial design, or the quality or safety of 
IMP(s) used in the trial. A protocol change intended to eliminate an apparent immediate 
hazard to subjects should be implemented immediately after agreement by the sponsor 
and investigator, followed by IRB notification within local applicable timelines. The 
sponsor will submit protocol amendments to the applicable regulatory agencies within 
local applicable timelines.
When the IRB, investigators, or the sponsor conclude that the protocol amendment 
substantially alters the trial design 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.
14
Publication Authorship Requirements
Authorship for any Otsuka-sponsored publications resulting from the conduct of this trial 
will be based on International Committee of Medical Journal Editors (ICMJE) authorship 
criteria (http://www.icmje.org/recommendations). According to ICMJE guidelines, one 
may be considered an author only if the following criteria are met:
1. Substantial contributions to the conception or design of the work; or the 
acquisition, analysis, or interpretation of data for the work; AND
2. Drafting the work or revising it critically for important intellectual content; AND
3. Final approval of the version to be published; AND
4. Agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved.
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All authors must meet the above criteria, and all who qualify for authorship based on the 
above criteria should be listed as authors.
Investigators or other trial participants who do not qualify for authorship may be 
acknowledged in publications resulting from the trial. By agreeing to participate in the 
trial, investigators or other trial participants consent to such acknowledgement in any 
publications resulting from its conduct.
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15
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14 Weiss M, Murray C. Assessment and management of attention-deficit hyperactivity 
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28 Guy W. ECDEU Assessment Manual for Psychopharmacology. US Department of 
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Health Organization Adult Attention-Deficit/Hyperactivity Disorder Self-Report
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34 Landgraf JM. Monitoring quality of life in adults with ADHD: reliability and validity 
of a new measure. J of Att Dis. 2007;11(3):351–362.
35 Silverstein MJ, Faraone SV, Alperin S, Leon TL, Biederman J, Spencer TJ, et al. 
Validation of the expanded versions of the adult ADHD self-report scale v1.1 
symptom checklist and the adult ADHD investigator symptom rating scale. J Atten 
Disord. 2018:1087054718756198.
36 Srisurapanont M, Jarusuraisin N, Jittiwutikan J. Amphetamine withdrawal: I. 
Reliability, validity and factor structure of a measure. Aust N Z J Psychiatry. 
1999;33(1):89-93.
37 Hendricks EJ, Srisurapanont M, Schmidt SL, Haggard M, Souter S, Mitchell CL, et 
al. Addiction potential of phentermine prescribed during long-term treatment of 
obesity. Int J Obes (Lond). 2014;38(2):292-298.
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The nature, time course and severity of methamphetamine withdrawal. Addiction. 
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39 Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification 
Algorithm of Suicide Assessment (C-CASA): classification of suicidal events in the 
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Centre for Drug Evaluation and Research. Assessment of Abuse Potential of Drugs. 
Guidance for Industry. Jan 2017.
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41 Diggle P, Kenward MG. Informative drop-out in longitudinal data analysis. Applied 
Statistics. 1994;43:49-93.
42 Little RJA. Pattern-mixture models for multivariate incomplete data. J Am Stat 
Assoc. 1993;88:125-134.
43 Little RJA. Modeling the drop-out mechanism in repeated measures studies. J Am 
Stat Assoc. 1995;90:1112-1121.
44 Hedeker D, Gibbons RD. Application of random effects pattern-mixture models for 
missing data in longitudinal studies. Psychological Methods. 1997;2:64-78.
45 Ali MW, Siddiqui O. Multiple imputation compared with some information dropout 
procedures in the estimation and comparison of rates of change in longitudinal 
clinical trials with dropouts. J Biopharmaceutical Stats. 2000;10(2):165-181.
46 Wu MC, Bailey KR. Estimation and comparison of changes in the presence of 
informative right censoring: conditional linear model. Biometrics. 1989;45(3):939-
955.
47 van Elteren PH. On the combination of independent two sample tests of Wilcoxon. 
Bull Int Stat Inst. 1960;37:351-361.
48 Mehrotra D, Li X, Liu J, Lu K. Analysis of Longitudinal Clinical Trials with Missing 
Data Using Multiple Imputation in Conjunction with Robust Regression. Biometrics. 
2012;68(4):1250-1259.
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Appendix 1
Collection, Handling, and Shipment of Bioanalytical Samples
Pharmacokinetic Sample Collection
Blood (2 mL) will be collected for the determination of plasma concentrations of 
centanafadine (EB-1020) and its metabolite(s).
The PK samples will be collected into 2-mL Vacutainer® tubes containing potassium 
ethylenediaminetetraacetic acid (K2EDTA). Each tube must be gently inverted at least 
8 times. Within 60 minutes of collection, the blood tubes must be centrifuged at 2000 to 
3000 rpm for 10 to 15 minutes at 4°C (± 3°C). The rpm, time and temperature should
remain the same throughout the trial. Within 90 minutes of collection, the separated 
plasma from the tube should then be transferred to the bar-code labeled transfer or plasma
tube.
All tubes must be labeled using the labels provided by the sponsor or sponsor designee. If 
information needs to be written on the tube label, then the pen will need to use 
waterproof ink and the label must be covered with transparent tape, or other means, in 
order to prevent damage to the label during freeze/thaw cycles. An electronic manifest 
must be provided with all sample shipments and must be approved by the sponsor prior to 
sample shipment.
The sample must be stored at −70°C (± 10°C). If a −70°C freezer is not available, the PK
samples must be shipped on dry ice to the central laboratory on the day of collection, 
otherwise samples should be shipped on dry ice within 1 month of collection.
Pharmacogenomic Sample Collection
A 4-mL whole blood sample for the pharmacogenomic determination of drug 
metabolizing enzymes and transporters will be collected by venipuncture into one 4-mL 
K2EDTA Vacutainer tube. Each tube should be gently inverted 10 times to ensure proper 
mixing with the anticoagulant. Refrigerate the whole blood samples at 4C (± 3°C) for at 
least 1 day (but no longer than 4 days). Then, the samples should be stored upright at 
−20C (± 10°C) or below. If refrigerating is not possible, samples can be frozen directly 
from ambient. The tube will be shipped on dry ice to the central laboratory.
Blood Samples for Future Biospecimen Research
Blood (approximately 10 mL) will be collected into an evacuated collection tube(s). The 
trial site is expected to follow the instructions for collection, processing, storage, and 
shipment of blood samples. The FBR samples will be shipped to the central laboratory.
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The FBR samples will be stored for potential analysis for up to 20 years from acquisition. 
The specimens will be stored under strict supervision in a limited access facility which 
operates to ensure the integrity of the specimens.
Sample Shipment
Plasma samples must be neatly packed in a Styrofoam container which should be 
completely filled with dry ice to avoid air spaces that allow evaporation of the dry ice. 
The Styrofoam container should be sealed with tape and placed in a cardboard box. The 
recipient of the samples must be alerted of sample shipment. Packages will be shipped 
via an overnight carrier and must not be shipped on Thursdays, Fridays, Saturdays, or any 
day prior to a holiday without the expressed consent of the sponsor. The names and 
addresses of the laboratories for shipping purposes will be provided in the Operations 
Manual.
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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 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 Electrocardiogram 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 405-201-00013, issued 08 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 for all subjects enrolled in Trial 405-201-00013.

Revised the last day of subject contact from Day +14 to Day +10 for subjects that 
do not complete Trial 405-201-00013, are not eligible for, or do not rollover to 
Trial 405-201-00015.

Added criteria excluding 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).

Clarified that pregnancy testing at screening should only be performed on 
FOCBP.

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).

Revised exclusion language regarding participating in other prior clinical trials.

Added statistical language to address new requirements set forth by the 
ICH E9(R1) Addendum.

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.
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
Clarified that SMWQ will be completed by the subject at the site and completed 
remotely for non-site visits.

Removed CYP2D6 inhibitors and substrates from the List of Medications 
Prohibited Before the Trial 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 405-201-00013, originally issued on 08 Mar 2018 
and amended on 18 May 2018, were made to address administrative changes and correct 
minor errors.
MODIFICATIONS TO PROTOCOL:
General Revisions:

Updated the email address for reporting IREs.

Changed the FBR blood volume collection from “up to 10 mL” to “approximately 
10 mL”.

Changed “birth control depot injection” to “birth control injection”.

Clarified that some clinical laboratory assessments (alcohol testing) are not 
performed at screening only.

Added clarification that subjects who will be rolling over into the open-label trial 
will need to sign the Trial 405-201-00015 informed consent form prior to 
activities performed at the 7-day follow-up visit of Trial 405-201-00013.
ADDITIONAL RISK TO THE SUBJECT:
There is no additional risk to the subjects.
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Amendment Number:
2
Issue Date:
15 Jan 2020
PURPOSE:
The purpose of this protocol amendment is to remove the mention of the interim analysis
and provide revisions and clarifications to exclusion criteria. In addition, there are 
revisions to a number of planned screen subjects and clarifications around the drug 
screening. 
BACKGROUND:
These changes to clinical trial protocol 405-201-00013, originally issued on 08 Mar 2018,
amended on 18 May 2018, and an administrative change on 30 Aug 2018, were made to 
remove the interim analysis based on FDA comments received, and to address other 
administrative changes.
MODIFICATIONS TO PROTOCOL:
General Revisions:

Number of planned screened subjects revised from 900 to 1150 in Section 3.3.1. 

The statement added to exclusion criteria 9 “This would also include most 
bariatric surgeries, with the only exception being those where there has been no 
breach of the gastrointestinal wall (ie, uncomplicated lap band surgery) AND no 
sign of malabsorption”.

Exclusion criteria 22 revised to provide clarity to the text.

Exclusion criteria 28 and 30 revised to clarify that a drug screen will be assessed 
prior to Visit 2 and baseline visit, respectively, and clarification added that the 
criteria include medications such as opioids or benzodiazepines taken without 
prescription.

Interim analysis was removed from the following:

Section 3.7 Trial Procedures

Section 3.7.8 Interim Analysis Review Committee

Section 3.8.1 Entire Trial or Treatment Arm(s)

Section 7.1 Sample Size

Section 7.3.2.1 Key Secondary Efficacy Endpoint Analysis

Section 7.3.4 Interim Analysis

Clarification around positive drug screenings and negative repeat screens added to 
Section 3.7.1.1, Visit 1 (Screening) and Section 3.7.1.2, Visit 2 (Single-blind
Placebo Run-in).

Statement added in Section 3.7.1.1, Visit 1 (Screening) “a urine drug screen will 
be collected and sent to the central lab for evaluation” for clarity. 
Clinical Study Report 405-201-00013
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.
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Protocol 405-201-00013
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Version 4.0, 15 Jan 2020

Removed language that urine drug screen should be performed prior to the start of 
any other screening procedures added to Section 3.7.1.1.1, Visit 1 (Screening).

Removed language that urine drug screen should be performed prior to the start of 
any other screening procedures and added a clarifier that urine drug screen results 
from the previous visit will be reviewed. Revisions were made in the following 
sections:

Section 3.7.1.2, Visit 2 (Single-blind Placebo Run-in)

Section 3.7.1.3, Visit 3 (Baseline)

Section 3.7.1.4.1, Visits 4 through 8

Section 3.7.1.4.2, Visit 9/End of Treatment/Early Termination

Revisions for clarification around blood samples for genotyping made to 
Section 3.7.6.2, DNA Blood Samples for Pharmacogenomic Testing and 
Section 3.7.1.3, Visit 3 (Baseline).

Corrected various typographical errors.
ADDITIONAL RISK TO THE SUBJECT:
There is no additional risk to the subjects.
Clinical Study Report 405-201-00013
16.1.1 Protocol and Protocol Amendments
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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Protocol 405-201-00013
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Version 4.0, 15 Jan 2020
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
Clinical Study Report 405-201-00013
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.
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This page is a manifestation of an electronically captured signature
SIGNATURE PAGE
Document Name: 405-201-00013 Protocol Amendment 2
Document Number: 0001281022
Document Version: 5.0
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:min) -
UTC timezone
Clinical Pharmacology
Approval
15-Jan-2020
21:01:06
Clinical Approval
15-Jan-2020
19:45:13
Biostatistics Approval
15-Jan-2020
20:18:59
Clinical Study Report 405-201-00013
16.1.1 Protocol and Protocol Amendments
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.
103