Conditions: Attention Deficit Hyperactivity Disorder
Keywords: ADHD
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 13
Healthy volunteers: no

Brief summary:
With the pharmacokinetics (PK) of centanafadine currently being evaluated in adults. The PK of extended-release centanafadine may differ in children compared to adults due to physiological differences in the gastrointestinal tract. The information in this trial will support pediatric dose selection in future trials.

Detailed description:

Arms:
arm 1: Participants swallowed two capsules of centanafadine (one containing a 50-milligram \[mg\] dose as extended release beads and other containing a 5-mg dose as immediate-release \[IR\] beads), total dose of 55 mg, orally in the morning of Day 1 following a minimum 8-hour fast. arm 2: Participants were administered centanafadine 55 mg, contents of 2 capsules (one containing a 50-mg dose as beads and other containing a 5-mg dose as IR beads) sprinkled on a tablespoon of applesauce, orally in the morning of Day 1 following a minimum 8-hour fast.

Interventions: intervention 1: Centanafadine
Intervention descriptions: intervention 1: Extended-release and immediate-release capsules.

Protocol document:
Prot_000.pdf: 


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Table of Contents
Table of Contents...........................................................................................2
List of In-text Tables .....................................................................................7
List of In-text Figures....................................................................................8
1
Protocol Summary................................................................................9
1.1
Synopsis...............................................................................................................9
1.2
Schema ..............................................................................................................15
1.3
Schedule of Assessments...................................................................................16
2
Introduction ........................................................................................18
2.1
Trial Rationale...................................................................................................19
2.2
Background .......................................................................................................19
2.2.2
Clinical............................................................................................................20
2.3
Known and Potential Risks and Benefits ..........................................................21
3
Objectives and Endpoints..................................................................23
4
Trial Design.........................................................................................24
4.1
Type/Design of Trial .........................................................................................24
4.2
Scientific Rationale for Trial Design.................................................................24
4.3
Dosing Rationale...............................................................................................25
4.4
End of Trial Definition......................................................................................25
4.5
Definition of Completed Subjects.....................................................................25
5
Trial Population..................................................................................25
5.1
Subject Selection and Numbering.....................................................................25
5.2
Eligibility Criteria..............................................................................................26
5.2.1
Inclusion Criteria ............................................................................................26
5.2.2
Exclusion Criteria...........................................................................................27
5.3
Lifestyle Considerations....................................................................................29
5.3.2
Caffeine, Alcohol, and Tobacco .....................................................................30
5.3.3
Activity ...........................................................................................................30
5.4
Screen Failures ..................................................................................................30
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6
Trial Treatments.................................................................................31
6.1
Trial Treatments Administered .........................................................................31
6.1.1
Medical Devices .............................................................................................31
6.2
Management of Investigational Medicinal Product ..........................................31
6.2.1
Packaging and Labeling..................................................................................32
6.2.2
Storage ............................................................................................................32
6.2.3
Accountability.................................................................................................32
6.2.4
Returns and Destruction .................................................................................32
6.2.5
Reporting of Product Quality Complaints......................................................33
6.2.5.1
Eliciting and Reporting Product Quality Complaints .................................33
6.2.5.2
Information Required for Reporting Purposes............................................33
6.2.5.3
Return Process.............................................................................................34
6.2.5.4
Assessment/Evaluation ...............................................................................34
6.3
Measures to Minimize/Avoid Bias....................................................................34
6.4
Subject Compliance...........................................................................................34
6.5
Concomitant Medications or Therapies ............................................................34
6.5.2
Permitted Medications....................................................................................35
6.5.3
Rescue Medications........................................................................................35
6.6
Intervention after the End of the Trial...............................................................35
7
Stopping Rules, Withdrawal Criteria, and Procedures..................35
7.1
Entire Trial or Treatment...................................................................................35
7.2
Individual Site ...................................................................................................35
7.3
Individual Subject Discontinuation...................................................................35
7.3.1
Treatment Interruption....................................................................................35
7.3.2
Treatment Discontinuation .............................................................................36
7.3.3
Documenting Reasons for Treatment Interruption or Discontinuation..........36
7.3.4
Withdrawal of Consent or Assent...................................................................37
7.3.5
Procedures to Encourage Continued Trial Participation ................................38
7.4
Definition of Subjects Lost to Follow-up..........................................................38
8
Trial Procedures .................................................................................38
8.1
Efficacy Assessments........................................................................................38
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8.2.1
Pharmacokinetic Blood Samples....................................................................39
8.3
Pharmacodynamic Assessments........................................................................39
8.4
Pharmacogenomic Assessments........................................................................39
8.5
Biomarker Assessments ....................................................................................39
8.6
Future Biospecimen Research Samples ............................................................40
8.7
Safety Assessments ...........................................................................................40
8.7.1
Clinical Laboratory Assessments ...................................................................40
8.7.2
Physical Examination .....................................................................................40
8.7.3
Vital Signs ......................................................................................................41
8.7.4
Electrocardiogram...........................................................................................41
8.7.5
Suicidality Monitoring....................................................................................41
8.7.6
Other Safety Variables....................................................................................42
8.8
Adverse Events..................................................................................................42
8.8.1
Definitions ......................................................................................................42
8.8.2
Eliciting and Reporting Adverse Events.........................................................44
8.8.3
Immediately Reportable Events......................................................................45
8.8.4
Medical Device Incidents (Including Malfunctions)......................................45
8.8.5
Adverse Events of Special Interest.................................................................45
8.8.6
Potential Serious Hepatotoxicity ....................................................................45
8.8.7
Procedure for Breaking the Blind...................................................................45
8.8.8
Follow-up of Adverse Events .........................................................................46
8.8.8.1
Follow-up of Nonserious Adverse Events ..................................................46
8.8.8.2
Follow-up of Immediately Reportable Events ............................................46
8.8.8.3
Follow-up and Reporting of Immediately Reportable Events 
Occurring After Last Scheduled Contact....................................................47
8.9
Treatment of Overdose......................................................................................47
8.10
Subject Assessment Recording .........................................................................47
8.11
Other Assessments ............................................................................................47
8.11.1
Capsule Swallow Test.....................................................................................47
9
Statistical Considerations ..................................................................47
9.1
Sample Size.......................................................................................................47
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9.2
Datasets for Analysis.........................................................................................48
9.3
Handling of Missing Data for Primary and Other Endpoint Analysis ..............48
9.4
Statistical Analyses............................................................................................48
9.4.1
Efficacy Analyses ...........................................................................................48
9.4.2
Safety Analysis ...............................................................................................48
9.4.2.1
Adverse Events............................................................................................48
9.4.2.2
Clinical Laboratory Data.............................................................................48
9.4.2.3
Physical Examination and Vital Signs Data................................................49
9.4.2.4
Electrocardiogram Data ..............................................................................49
9.4.2.5
Other Safety Data........................................................................................49
9.4.2.5.1
Columbia-Suicide Severity Rating Scale ................................................49
9.4.3
Other Analyses................................................................................................49
9.4.3.1
Analysis of Demographic and Baseline Characteristics .............................49
9.4.3.2
Pharmacokinetic Analysis...........................................................................49
9.4.3.3
Pharmacodynamic Analysis........................................................................50
9.4.3.4
Pharmacokinetic/Pharmacodynamic Analysis............................................50
9.4.3.5
Pharmacogenomic Analysis........................................................................50
9.4.3.6
Exploratory Endpoint Analysis...................................................................50
9.4.3.7
Other Endpoint Analysis.............................................................................50
9.5
Interim Analysis and Adaptive Design .............................................................50
9.5.1
Data Monitoring Committee...........................................................................50
10
Supporting Documentation and Operational Considerations .......51
10.1
Appendix 1: Regulatory, Ethical, and Trial Oversight Considerations.............51
10.1.1
Ethics and Responsibility ...............................................................................51
10.1.2
Informed Consent ...........................................................................................51
10.1.3
Confidentiality................................................................................................53
10.1.4
Quality Control and Quality Assurance..........................................................53
10.1.4.1
Monitoring ..................................................................................................53
10.1.4.2
Auditing ......................................................................................................53
10.1.5
Protocol Deviations ........................................................................................54
10.1.6
Records Management .....................................................................................54
10.1.6.1
Source Documents ......................................................................................54
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10.1.6.2
Data Collection............................................................................................54
10.1.6.3
File Management at the Trial Site...............................................................56
10.1.6.4
Records Retention at the Trial Site .............................................................56
10.1.6.5
Publication Authorship Requirements ........................................................57
10.2
Appendix 2: Clinical Laboratory Tests .............................................................58
10.3
Appendix 3: Contraceptive Guidance and Collection of Pregnancy 
Information........................................................................................................59
10.4
Appendix 4: Abbreviations ...............................................................................61
10.5
Appendix 5: Criteria for Identifying Laboratory Values of Potential 
Clinical Relevance.............................................................................................63
10.6
Appendix 6: Criteria for Identifying Vital Signs of Potential Clinical 
Relevance ..........................................................................................................64
10.7
Appendix 7: Criteria for Identifying ECG Measurements of Potential 
Clinical Relevance.............................................................................................65
10.8
Appendix 8: Protocol Amendments ..................................................................66
11
References............................................................................................69
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List of In-text Tables
Table 1.3-1
Schedule of Assessments.............................................................. 16
Table 3-1
Trial Objectives and Endpoints..................................................... 23
Table 10.2-1
Clinical Laboratory Assessments.................................................. 58
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1
Protocol Summary
1.1
Synopsis
Name of Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.
Name of Investigational Medicinal Product: Centanafadine (EB-1020)
Protocol No.: 405-201-00037
IND No.: 119361
Protocol Title: A Pilot Phase 2a, Multicenter, Open-label, Single-dose Trial to Assess 
the Pharmacokinetics of Centanafadine Extended-release Capsules After Oral 
Administration in Pediatric Subjects (9 to 12 years, inclusive) With Attention-deficit 
Hyperactivity Disorder
Protocol Lay Person Short Title: Open-label, Single-dose Trial to Assess the 
Pharmacokinetics of Centanafadine Extended-release Capsules in Pediatric Subjects With 
Attention-deficit Hyperactivity Disorder
Clinical Phase: 2a
Treatment/Indication: Attention-deficit hyperactivity disorder (ADHD)
Objectives and Endpoints:
Objectives
Endpoints
Primary:
To characterize the single-dose 
concentration-time profile from 0 to 
12 hours of centanafadine in pediatric 
subjects (9 to 12 years, inclusive) 
with ADHD.
Primary:

Cmax of centanafadine

tmax of centanafadine

AUC0-12h of centanafadine
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Eligible subjects will check-in either on Day −1 or Day 1, based on the investigator’s 
decision. A single dose of centanafadine will be administered either as intact capsules or 
the capsule contents sprinkled on a tablespoon of applesauce on Day 1 in the morning. 
 
 Pharmacokinetic (PK) and safety assessments will be 
performed for approximately 24 hours postdose. Subjects may be released from the clinic 
after PK sample collection at 12 hours postdose to return the following morning or may 
remain in the clinic until 24 hours postdose, based on the investigator’s decision. Subjects 
released on Day 1 will return to the clinic on Day 2 between 22 to 26 hours postdose for 
an outpatient visit, which will include EoT assessments and one PK sample. In-clinic 
subjects may leave the clinic on Day 2 after EoT assessments and PK sampling are 
complete. 
Subjects and/or their caregivers will be contacted by telephone 7 days after dosing to 
assess any new or ongoing adverse events (AEs) and to record concomitant medications.
Trial Population:
The trial population will consist of males and females, aged 9 to 12 years (inclusive),
who have a documented history of ADHD and confirmation of an ADHD prescription 
medication. Up to 12 subjects may be treated in the trial.
Key Inclusion/Exclusion Criteria:
Key inclusion criteria are noted above, under Trial Population. In addition, subjects must 
be in good physical health, as determined by no clinically significant deviation from 
normal for all of the following, prior to enrollment in the trial:

Medical history

Clinical laboratory determination

Electrocardiograms (ECGs)

Physical examinations
Key exclusion criteria are as follows:

Subjects with a clinical presentation or history that is consistent with delirium, 
dementia, amnesia, or other cognitive disorders; subjects with psychiatric symptoms 
that are better accounted for by another general medical condition(s) or direct effect 
of a substance (ie, medication, illicit drug use, etc.).

Subjects with a history of intellectual disability as determined by at least 1 of the 
following: an intelligence quotient (IQ) < 70, or clinical evidence, or a social or 
school history that is suggestive of an intellectual disability.
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
Subjects who have any of the following:

A significant risk of committing suicide based on history and the principal 
investigator’s clinical judgment, or routine psychiatric status examination

Current suicidal behavior

Imminent risk of injury to self

Active suicidal ideation as it is evidenced by an answer of “yes” on Questions 4 
or 5 (over the last 6 months) on the suicidal ideation section of the 
“Baseline/Screening” version of the Columbia-Suicide Severity Rating Scale
(C-SSRS)

Any lifetime history of suicidal behavior detected by the “Baseline/Screening” 
version of the C-SSRS
The subject should not be enrolled (eg, dosed) if any active suicidal ideation is 
present prior to dosing (as evidenced by a clinical examination or an answer of “yes” 
on Questions 4 or 5 of the C-SSRS “Since Last Visit” version) or suicidal behavior is 
present in the C-SSRS “Since Last Visit” version.

Subjects who have supine or standing diastolic blood pressure, after resting for at 
least 5 minutes, ≥95 mmHg.

Subjects who participated in a clinical trial and were exposed to investigational 
medicinal product (IMP) within the last 30 days prior to screening or who 
participated in more than 2 interventional clinical trials within the past year.

Subjects with a history of true allergic response (ie, not intolerance) to a medication 
or a history of dermatologic adverse reactions or anaphylaxis secondary to drug 
exposure.

Subjects with a history of allergic reaction or a known or suspected sensitivity to any 
substance that is contained in the IMP formulation.
Trial Site(s):
This will be a multicenter trial (at approximately 3 trial sites) conducted in the 
United States.
Investigational Medicinal Product(s), Dose, Dosage Regimen, Treatment Duration, 
Formulation, Mode of Administration:
Centanafadine will be supplied as 1 capsule containing a 50-mg dose as extended-release 
with
beads and 1 capsule containing a 5-mg dose as IR beads 
for a total centanafadine dose of 55 mg. Both of the intact capsules or the capsule 
contents sprinkled on a tablespoon of applesauce will be taken orally in the morning 
 
following a minimum 8-hour fast. A 
snack will be provided approximately 2 hours after dosing and lunch will be provided 
approximately 4 hours after dosing. 
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Trial Duration:
Each subject in this trial is expected to participate in the following periods of the trial 
(approximate durations listed), for up to 29 (+ 2) days:

Eligibility screening period: 21 days (including optional check-in on Day −1)

Treatment period: 2 days (Day 1: dosing, Day 2: EoT)

Post-treatment follow-up: 7 (+ 2) days after the last dose of IMP
Overall, the trial duration from the first informed consent/assent to the final subject
assessment is expected to be 3 months.
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1.3
Schedule of Assessments
Table 1.3-1
Schedule of Assessments
Assessment
Screeninga
Check-inb
Treatment
Discharge
Follow-up 
Telephone Callc
Notes
Day −21 to Day −2
Day −1
Day 1
Day 2/EoT/ET
Day 8 (+ 2)
Screening
Informed consent/assent
X
Section 10.1.2
Inclusion/exclusion criteria check
X
Section 5.2
Demographic information
X
Medical history
X
Height
X
Section 8.7.2
Serology (HIV, HBsAg, anti-HCV)
X
Breath or urine alcohol test and urine drug 
screen
X
Section 10.2
Urine pregnancy test (for FOCBP)
X
X
Xd
X
Section 10.3
Trial Residency
Check-inb
X
X
Meals
X
Section 6.1
Discharge from clinic
Xe
Xe
IMP Administration
Centanafadine
X
Section 6.1
Safety and Tolerability
Record AEs
X
X
X
X
X
Section 8.8
Record concomitant medications
X
X
X
X
X
Section 6.5
Body weight
X
X
Xd
X
Section 8.7.2
Physical examination
X
X
Xd
X
Section 8.7.2
Vital signs
X
Xf
Xf
X
Section 8.7.3
12-lead ECG
X
X
Xd
X
Section 8.7.4
Serum chemistry, hematology, and urinalysis 
X
X
Xd
X
Section 8.7.1
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Table 1.3-1
Schedule of Assessments
Assessment
Screeninga
Check-inb
Treatment
Discharge
Follow-up 
Telephone Callc
Notes
Day −21 to Day −2
Day −1
Day 1
Day 2/EoT/ET
Day 8 (+ 2)
C-SSRS
X
X
Xd
X
Section 8.7.5
Pharmacokinetics
Centanafadine
) plasma 
concentrations
X
X
Section 8.2.1
Other Procedures
anti-HCV = hepatitis C antibodies; FOCBP = females of childbearing potential; HBsAg = hepatitis B surface antigen.
aThe screening period may be extended if additional time is needed to complete screening procedures, upon discussion with and approval by the medical 
monitor.
bEligible subjects will check-in either on Day −1 or Day 1, based on the investigator’s decision.
cA follow-up telephone call will be performed 7 (+ 2) days after dosing to assess AEs and record concomitant medications.
dDay 1 predose assessments will be performed only for those subjects who check-in on Day 1 (ie, subjects who check-in on Day −1 will have their predose 
assessments on Day −1).
eSubjects may be released from the clinic after PK sample collection at 12 hours postdose to return the following morning or may remain in the clinic until 
24 hours postdose, based on the investigator’s decision. Subjects released on Day 1 will return to the clinic on Day 2 between 22 to 26 hours postdose for 
an outpatient visit, which will include EoT assessments and one PK sample. In-clinic subjects may leave the clinic on Day 2 after the EoT assessments and 
PK sampling are complete.
fVital signs will be assessed for all subjects at check-in, predose (within 2 hours before dosing) on Day 1, and 3 hours postdose on Day 1.
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2
Introduction
Attention-deficit hyperactivity disorder (ADHD) is typically viewed as a 
childhood/adolescent disorder.1 ADHD frequently begins between 2 and 4 years of age2,3
and it is most commonly diagnosed between 7 and 10 years of age. The diagnosis and 
treatment of ADHD of a very young child represents a diagnostic challenge.4 Because 
inattention, impulsivity, and hyperactivity can all be normal behaviors for a young child, 
making a diagnosis of ADHD often requires the degree and impairment of these 
symptoms to be beyond what is developmentally appropriate.5
It is widely believed that the core symptoms in ADHD result from dysregulation in the 
balance of 2 neurotransmitter systems in the prefrontal cortex, ie, norepinephrine 
(noradrenaline) and dopamine.6,7,8
Centanafadine (EB-1020), which is an inhibitor of the uptake of norepinephrine, 
dopamine, and serotonin (5-hydroxytryptamine) in vitro and in vivo, is a novel drug
candidate that is being developed as a treatment for ADHD in adults (≥18 years) and in 
children (4 to 17 years, inclusive).
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Please refer to the centanafadine Investigator’s Brochure (IB) for more detailed 
information.9
2.1
Trial Rationale
Currently, the PK of centanafadine administered as IR/XR capsules is being evaluated in 
adults. It is possible that the PK (particularly absorption) of centanafadine following 
administration of the XR formulation may be different in children as compared to adults 
due to physiological differences in the gastrointestinal tract. Therefore, the primary 
purpose of this trial is to evaluate the PK of centanafadine
 following 
administration of centanafadine capsules in pediatric subjects (9 to 12 years, inclusive) 
with ADHD and determine if the XR formulation is appropriate for further evaluation. 
2.2
Background
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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2.2.2
Clinical
Centanafadine has been evaluated in 9 clinical trials (7 phase 1 trials and 2 phase 2 trials).
 
 
Refer to the IB for more information.9
 
 
 
 
 
 
 
 
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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 should be measured prior to initiation of therapy and 
periodically while on therapy. Subjects should 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).
Skin rashes ranging from mild pruritic rash, maculopapular rash to diffuse erythematous 
maculopapular rash have been observed in subjects who received multiple doses of 
centanafadine.
One subject experienced mild rash that was considered related to treatment after taking 
500 mg centanafadine SR TDD for 4 days. 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. Rashes resulted in discontinuation of dosing for 5 subjects 
and dose interruption and/or dose reduction for 3 subjects. The severity of the rash in 
subjects who discontinued investigational medicinal product (IMP) ranged from 
moderate to severe.
The majority of subjects who experienced rash were exposed to centanafadine doses 
greater than 400 mg/day (2 subjects received 800 mg/day, 4 subjects received 
600 mg/day, and 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 1 resolved within 12 days of treatment with IMP 
withdrawal or dose reduction. The 1 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 should be monitored 
closely for other symptoms of allergic reaction including shortness of breath, itching and 
swelling of the throat or mouth, or difficulty breathing.
The trial sites will receive updated versions of the IB, when available, and the trial sites 
should refer to the most current version as needed.
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4
Trial Design
4.1
Type/Design of Trial
This is a pilot phase 2a, multicenter, open-label, single-dose trial in pediatric subjects 
(9 to 12 years, inclusive) with a documented history of ADHD and confirmation of an
ADHD prescription medication. This trial consists of a screening period (Day −21 to 
Day −2), check-in (Day −1 or Day 1), 2-day treatment period (Day 1: dosing, Day 2: 
end-of-treatment [EoT]), and a safety follow-up telephone call 7 (+ 2) days after dosing
(Day 8). The screening period may be extended if additional time is needed to complete 
screening procedures, upon discussion with and approval by the medical monitor.
Written informed consent will be freely obtained from all subjects’ guardian(s) or legally 
acceptable representative(s), as applicable for local laws. Written informed assent will be 
freely obtained from all subjects. 
Eligible subjects will check-in either on Day −1 or Day 1, based on the investigator’s 
decision. A single dose of centanafadine will be administered either as intact capsules or 
the capsule contents sprinkled on a tablespoon of applesauce on Day 1 in the morning. 
 
 Pharmacokinetic 
and safety assessments will be performed for approximately 24 hours postdose. Subjects 
may be released from the clinic after PK sample collection at 12 hours postdose to return 
the following morning or may remain in the clinic until 24 hours postdose, based on the 
investigator’s decision. Subjects released on Day 1 will return to the clinic on Day 2 
between 22 to 26 hours postdose for an outpatient visit, which will include EoT 
assessments and one PK sample. In-clinic subjects may leave the clinic on Day 2 after 
EoT assessments and PK sampling are complete. 
Subjects and/or their caregivers will be contacted by telephone 7 days after dosing to 
assess any new or ongoing AEs and to record concomitant medications.
A schematic of the trial design is provided in Figure 1.2-1.
4.2
Scientific Rationale for Trial Design
A single dose is expected to be predictive of multiple dosing; therefore, this trial will 
evaluate a single dose of centanafadine. The focus is on the evaluation of the 
centanafadine concentration-time profile through 12 hours postdose and measuring 
centanafadine concentrations at 24 hours postdose to determine the potential for 
accumulation following multiple doses; therefore, PK sampling through 24 hours is 
sufficient.
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4.3
Dosing Rationale
In adults, dosing is started at a 200 mg TDD administered in divided doses, 5 hours apart,
using SR tablets; this regimen has been well tolerated. The 200 mg dose of
 
produced centanafadine concentrations approximately 75% of the 200 mg TDD of SR. 
In this trial, a dose of 5 mg of IR beads and 50 mg of 
 beads will be administered,
as the approximate median weight of 10- and 11-year-old pediatric subjects is 35 kg, 
based on the Centers for Disease Control and Prevention (CDC) growth charts.10 As 
75 kg is the approximate weight of adults from phase 1 and phase 2 trials, the 
expected centanafadine concentrations will be half of those observed in the PK 
Trial 405-201-00007. The same amount of dose will be administered to all subjects.
4.4
End of Trial Definition
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 electronic case report form (eCRF) page for 
the last subject completing or withdrawing from the trial.
4.5
Definition of Completed Subjects
The treatment period is defined as the time period during which subjects are evaluated for 
primary and/or secondary objectives of the trial irrespective of whether or not the subject 
actually consumed all doses of the IMP. Subjects who are evaluated at the last scheduled 
visit during the treatment period will be defined as trial completers. For purposes of this 
trial, subjects who complete Day 2 will be defined as trial completers.
5
Trial Population
The trial population will consist of males and females, aged 9 to 12 years (inclusive),
who have a documented history of ADHD and confirmation of an ADHD prescription 
medication.
Up to 12 subjects may be treated in the trial. Subjects who discontinue for a reason other 
than a safety-related event may be replaced at the discretion of the sponsor.
5.1
Subject Selection and Numbering
All subjects will be given a unique subject identifier
 
upon providing consent/assent. The site number will be 
designated by the sponsor. The subject number will be given sequentially from
 as 
the serial numbers in the trial sites.
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Demographic information (collection date, date of birth, sex, childbearing potential, race, 
ethnicity) and medical history will be recorded in the eCRF at the screening visit.
5.2
Eligibility Criteria
Exceptions for eligibility criteria will not be permitted during the trial, neither by the 
investigator nor by the medical monitor.
5.2.1
Inclusion Criteria
Subjects are required to meet the following inclusion criteria at the time points described 
in the schedule of assessments (Table 1.3-1).
1) Written informed consent obtained from a legally acceptable representative (eg, 
parent/guardian) and assent obtained from the subject prior to the initiation of any 
trial-related procedures. The subject must provide informed assent at screening 
and must be able to understand that he or she can withdraw from the trial at any 
time. All informed consent/assent procedures must be in accordance with the trial 
site’s institutional review board (IRB) and local regulatory requirements.
2) Ability, in the opinion of the investigator, of the subject and the subject’s legally 
acceptable representative (eg, parent/guardian) or caregiver(s) to understand the 
nature of the trial and follow protocol requirements, including the prescribed 
dosage regimens and discontinuation of prohibited concomitant medications, to 
reliably return for scheduled visits, and to be reliably rated on assessment scales.
3) Male or female subjects 9 to 12 years of age, inclusive, at the time of informed 
consent/assent.
4) Subjects with good physical health, as determined by no clinically significant 
deviation from normal for all of the following, prior to enrollment in the trial:

Medical history

Clinical laboratory determination

Electrocardiograms (ECGs)

Physical examinations
5) Subjects with documented history of ADHD and confirmation of an ADHD 
prescription medication.
6) For female subjects of childbearing potential (defined as post-menarche) who are 
also sexually active and male subjects who are sexually active, the ability to 
commit to remain fully abstinent (periodic abstinence [eg, calendar, ovulation, 
symptothermal, postovulation methods] or withdrawal are not acceptable methods 
of contraception) or use 2 approved methods of birth control during the trial and 
for 30 days following dosing.
7) Subject is judged by the investigator to be clinically stable and has not had any
psychiatric hospitalizations within the past 12 weeks.
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5.2.2
Exclusion Criteria
Subjects will be excluded if they meet any of the following exclusion criteria at the time 
points described in the schedule of assessments (Table 1.3-1).
1) Female subjects who are breast-feeding and/or have a positive pregnancy test 
result prior to receiving IMP.
2) Subjects with a clinical presentation or history that is consistent with delirium, 
dementia, amnesia, or other cognitive disorders; subjects with psychiatric 
symptoms that are better accounted for by another general medical condition(s) or 
direct effect of a substance (ie, medication, illicit drug use, etc.).
3) Subjects with a history of intellectual disability as determined by at least 1 of the 
following: an intelligence quotient (IQ) < 70, or clinical evidence, or a social or 
school history that is suggestive of an intellectual disability.
4) Subjects who have any of the following:

A significant risk of committing suicide based on history and the principal 
investigator’s clinical judgment, or routine psychiatric status examination

Current suicidal behavior

Imminent risk of injury to self

Active suicidal ideation as it is evidenced by an answer of “yes” on 
Questions 4 or 5 (over the last 6 months) on the suicidal ideation section of 
the “Baseline/Screening” version of the Columbia-Suicide Severity Rating 
Scale (C-SSRS)

Any lifetime history of suicidal behavior detected by the “Baseline/Screening”
version of the C-SSRS
The subject should not be enrolled (eg, dosed) if any active suicidal ideation is 
present prior to dosing (as evidenced by a clinical examination or an answer of 
“yes” on Questions 4 or 5 of the C-SSRS “Since Last Visit” version) or suicidal 
behavior is present in the C-SSRS “Since Last Visit” version.
5) Subjects with a lifetime history of a substance use disorder (as determined by the 
Diagnostic and Statistical Manual of Mental Disorders, 5th edition [DSM-5] 
criteria), or current substance misuse including alcohol and benzodiazepines, but 
excluding caffeine and nicotine.
6) Subjects with hypothyroidism or hyperthyroidism (unless the condition has been 
stabilized with medications for at least 90 days prior to dosing with the IMP) or 
an abnormal result for free thyroxine (T4) at screening. The eligibility of subjects 
excluded based on an abnormal free T4 result can be discussed with the medical 
monitor if, in the investigator’s judgment, the subject is a suitable candidate for 
the trial. (Note: free T4 is measured only if the result for thyroid-stimulating 
hormone [TSH] is abnormal.)
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7) Subjects who currently have clinically significant neurological, dermatological, 
hepatic, renal, metabolic, hematological, immunological, cardiovascular, 
pulmonary, or gastrointestinal disorders such as any history of myocardial 
infarction, congestive heart failure, human immunodeficiency virus (HIV)
seropositive status/acquired immunodeficiency syndrome (AIDS), or chronic 
hepatitis B or C. Medical conditions that are minor or well-controlled may be 
considered acceptable if the condition does not expose the subject to an undue 
risk of a significant AE or interfere with assessments during the course of the 
trial. The medical monitor should be contacted in any instance where the 
investigator is uncertain regarding the stability of a subject’s medical condition(s) 
and the potential impact of the condition(s) on trial participation.
8) Subjects with insulin-dependent diabetes mellitus (ie, any subjects using insulin).
9) Subjects with epilepsy or a history of seizures (except for a single seizure episode, 
for instance childhood febrile seizure or post traumatic) or a history of severe 
head trauma (eg, concussion with loss of consciousness) or cerebrovascular 
disease (eg, stroke, transient ischemic attack, etc.).
10) Any major surgery within 30 days prior to dosing with the IMP.
11) Any history of significant bleeding or hemorrhagic tendencies.
12) Blood transfusion within 30 days prior to dosing with the IMP.
13) Subjects with a positive drug screen for cocaine, marijuana (even if by 
prescription), or other illicit drugs, or alcohol, are excluded and may not be 
retested or rescreened. Subjects with a positive urine drug screen resulting from 
the confirmed use of prescription or over-the-counter medications or products that 
in the investigator’s documented opinion do not signal a clinical condition that 
would impact the safety of the subject or interpretation of the trial results may 
continue evaluation for the trial, following consultation and approval by the 
medical monitor.
14) The following laboratory test and ECG results are exclusionary:

Platelet count ≤ 130 × 103/μL

Hemoglobin ≤11.2 g/dL

Absolute neutrophil count ≤ 1.00 × 103/μL

White blood cell count (WBC) ≤ 4.35 × 103/μL

Aspartate aminotransferase (AST) > 2 × upper limit of normal (ULN)

Alanine aminotransferase (ALT) > 2 × ULN

Creatine phosphokinase (CPK) > 2 × ULN, unless discussed with and 
approved by the medical monitor

Creatinine ≥ 0.7 mg/dL

QT interval corrected for heart rate using Fridericia’s formula (QTcF)
≥450 msec for more than 1 of the 3 ECGs performed for subjects < 12 years 
old or QTcF ≥460 msec for more than 1 of the 3 ECGs performed for subjects 
≥12 years old.
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5.3.2
Caffeine, Alcohol, and Tobacco
The consumption of alcohol is prohibited within 72 hours prior to dosing and through the 
end of the 24-hour assessments. The use of tobacco following dosing through the end of 
the 24-hour assessments is prohibited.
5.3.3
Activity
Subjects will be asked to abstain from strenuous physical activity for 48 hours prior to 
check-in and for the duration of the dosing period and PK sampling period; subjects 
should also not start any new supplements during the trial.
5.4
Screen Failures
A screen failure is a subject from whom informed consent/assent is obtained and is 
documented in writing (ie, subject signs an informed consent form [ICF] or assent form), 
but who is not randomized or assigned trial treatment. Subjects who sign an ICF or assent 
form but who are not started on treatment are permitted to be rescreened. Subjects with a 
positive drug screen for cocaine, marijuana (even if by prescription), or other illicit drugs, 
or alcohol, may not be retested or rescreened; however, subjects excluded for other 
reasons may be rescreened at any time, at the discretion of the medical monitor, if the 
exclusion characteristic has changed or resolved. In the event that a subject is rescreened 
for trial participation, and the rescreening is not completed within the original 
protocol-specified screening period, a new ICF and assent form must be signed and 
screening procedures repeated.
If the subject meets the definition of a screen failure in this trial, the following 
information will be recorded in the eCRF:

Date of informed consent/assent

Visit date (screening visit)

Demographics (collection date, birth date, sex, race, ethnicity, country)

Result of eligibility assessment

Screen failure date

Reason for screen failure
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6
Trial Treatments
6.1
Trial Treatments Administered
Centanafadine will be supplied as 1 capsule containing a 50-mg dose as
beads 
and 1 capsule containing a 5-mg dose as IR beads for a total centanafadine dose of 
55 mg. Both of the intact capsules or the capsule contents sprinkled on a tablespoon of 
applesauce will be taken orally in the morning
 
following a minimum 8-hour fast.
 
 
 
The ability of a subject to swallow the intact capsules will be assessed during the 
screening period with empty capsules. Based on this assessment, subjects will either be 
instructed to take the centanafadine capsules intact or the capsule contents sprinkled on a 
tablespoon of applesauce. An attempt will be made to administer the intact capsules to 
approximately half of the subjects and approximately half of the subjects will be 
administered the capsule contents sprinkled on a tablespoon of applesauce.
 
 
 
For further information regarding the treatment period, including the follow-up period, 
see Section 4.1.
6.1.1
Medical Devices
Not applicable.
6.2
Management of Investigational Medicinal Product
For full details on IMP management, please refer to the centanafadine IB.9
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6.2.1
Packaging and Labeling
Investigational medicinal product will be provided to the investigators and the persons 
designated by the investigator(s) or institution(s) by the sponsor or designated agent. The 
 Each
will be labeled to clearly disclose the 
compound ID, trial number, sponsor’s name and address, instructions for use, route of 
administration, and appropriate precautionary statements.
6.2.2
Storage
The IMP will be stored in a securely locked cabinet or enclosure. Access will be limited 
to investigators and their designees. Neither investigators nor any designees may provide 
IMP to any subject not participating in this protocol.
The IMP will be stored according to the conditions indicated on the IMP label.
The clinical site staff will maintain a temperature log in the IMP storage area to record 
the temperature.
6.2.3
Accountability
The investigator or designee must maintain an inventory record of IMP (ie, 
centanafadine) received, dispensed, administered, and destroyed. Neither the investigator 
nor any designees may provide IMP to any subject not participating in this protocol.
6.2.4
Returns and Destruction
The IMP will be destroyed by the clinical trial site. The IMP may only be destroyed by 
the trial site(s), if approved by the sponsor and if the IMP destruction meets all local 
regulations. Accountability of the IMP must be completed and verified by the assigned 
trial monitor prior to destruction. The trial site(s) may utilize qualified third-party 
vendors for IMP destruction.
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
Pictures (if available)

Availability for return
6.2.5.3
Return Process
Indicate during the report of the PQC if the complaint sample is available for return. If 
the 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.
6.2.5.4
Assessment/Evaluation
Assessment and evaluation of PQCs will be handled by the sponsor.
6.3
Measures to Minimize/Avoid Bias
This is an open-label trial.
6.4
Subject Compliance
The time and dose of each IMP administration will be recorded on the eCRF. Information 
regarding any missed or inappropriately administered doses will also be documented on 
the eCRF. Compliance will be ensured by a mouth check during the oral dosing 
administration of IMP.
6.5
Concomitant Medications or Therapies
The investigator will record all medications and therapies taken by the subject from 
30 days prior to signing of informed consent/assent through the end of the evaluation 
period (defined as the time period during which subjects are evaluated for primary and/or 
secondary objectives) on the eCRF. The investigator will also 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.
For concomitant medications, the following will be recorded in the eCRF: medication, 
indication, dose, frequency, route, start date, and end date. For concomitant therapy, the 
following will be recorded in the eCRF: therapy, indication, start date, and end date.
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6.5.2
Permitted Medications
Not applicable.
6.5.3
Rescue Medications
Not applicable.
6.6
Intervention after the End of the Trial
Not applicable.
7
Stopping Rules, Withdrawal Criteria, and Procedures
7.1
Entire Trial or Treatment
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.
7.2
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 good clinical practice (GCP). The 
investigator will notify the sponsor promptly if the trial is terminated by the investigator 
or the IRB at the trial site.
7.3
Individual Subject Discontinuation
7.3.1
Treatment Interruption
Not applicable.
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7.3.2
Treatment Discontinuation
As this is a single-dose trial, treatment discontinuation is not applicable. Subjects who 
discontinue from the trial should be encouraged to complete all early termination (ET) 
and follow-up assessments with ET assessments conducted as soon as possible after the 
subject is withdrawn.
7.3.3
Documenting Reasons for Treatment Interruption or 
Discontinuation
A subject may discontinue from the trial for the reasons listed below:

Adverse event

Subject decides to discontinue because of annoyance or discomfort due to a 
nonserious AE which is not otherwise determined to be an undue hazard

SAE

Other potentially IMP-related safety concerns or AEs

Death

Lost to follow-up

Physician decision

Pregnancy (Section 10.3)

Protocol deviation

Protocol violation

Protocol-specific withdrawal criterion met

Recovery

Site terminated by sponsor

Trial terminated by sponsor

Technical problems

Withdrawal by parent/guardian

Withdrawal by subject

Other
If the subject discontinues from the trial 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 7.3.2 must be followed.
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7.3.4
Withdrawal of Consent or Assent
All subjects have the right to withdraw their consent/assent from further participation in 
the trial at any time without prejudice. Subjects cannot withdraw consent/assent 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 or the subject’s legally acceptable representative 
(eg, parent/guardian) provides their written withdrawal of consent/assent, 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/assent requires a subject’s or a subject’s legally 
acceptable representative’s (eg, parent/guardian) refusal of ALL of the following 
methods of follow-up:

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/assent 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/assent. 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 from the 
trial. As such, the investigator should follow the procedures outlined in Section 7.3.3 to 
determine if the subject can continue participation in the trial if modifications to his/her 
schedule of assessments can be accommodated. Only subjects who withdraw their 
permission for all of the above methods of follow-up are considered to have completely 
withdrawn their consent/assent to participate in the trial.
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7.3.5
Procedures to Encourage Continued Trial Participation
In all cases of impending trial discontinuation or withdrawal of consent/assent, 
investigators will be instructed to meet and discuss (without undue coercion) with the 
subject, and the subject’s legally acceptable representative (eg, parent/guardian), their 
options of continuing in the trial. The investigator should ensure understanding and 
documentation of the reasons for the subject’s desire to withdraw consent/assent.
7.4
Definition of Subjects Lost to Follow-up
Subjects who cannot be contacted on or before Day 8 (+ 2 days) or subjects who do not 
have a known reason for discontinuation (eg, withdrew consent/assent or AE) during the 
treatment period will be classified as “lost to follow-up”.
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.
If the subject was classified as “lost to follow-up”, “Were you able to contact the 
subject?”, “Date of contact/Date of final contact attempt”, and “Contact method” will be 
recorded in the source documents.
8
Trial Procedures
Each subject’s participation in the trial will be approximately 29 (+ 2) days in duration 
and will consist of a screening period (Day −21 to Day −2), check-in (Day −1 or Day 1), 
2-day treatment period (Day 1: dosing, Day 2: EoT), and a safety follow-up telephone 
call 7 (+ 2) days after dosing (Day 8).
The total duration of the trial is expected to be approximately 3 months.
The assessments to be conducted during the trial are summarized in Table 1.3-1.
8.1
Efficacy Assessments
Not applicable.
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8.2.1
Pharmacokinetic Blood Samples
Blood samples (4 mL, dipotassium ethylenediaminetetraacetic acid [K2EDTA]) will be 
collected on Day 1 (1, 2, 3, 4, 6, 8, 10 and 12 hours postdose) and on Day 2 (one PK 
sample between 22 to 26 hours postdose), and will be processed into plasma for the 
determination of centanafadine, EB-10601, 
 
 
 The actual date and time of the PK 
sample collection will be recorded in the eCRF. When vital signs or ECGs are scheduled 
at the same nominal time as PK sample collections, vital signs should be measured and 
ECGs should be performed before PK samples are collected.
After processing into plasma, aliquots will be placed into appropriately labeled tubes and 
will be placed in a freezer set at −70°C, unless otherwise instructed in the 
Operations/Laboratory Manual.
All plasma samples will be shipped to the bioanalytical laboratory for analysis.
Additional information will be provided in the Operations/Laboratory Manual.
8.3
Pharmacodynamic Assessments
Not applicable.
8.4
Pharmacogenomic Assessments
Not applicable.
8.5
Biomarker Assessments
Not applicable.
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8.6
Future Biospecimen Research Samples
Not applicable.
8.7
Safety Assessments
Safety assessments in this trial include AEs, clinical laboratory tests, physical 
examinations, vital signs, ECGs, and the C-SSRS.
Details pertaining to the definitions, collection, reporting, and follow-up of AEs are 
described in Section 8.8.
8.7.1
Clinical Laboratory Assessments
Clinical laboratory samples will be collected at the time points described in the schedule 
of assessments (Table 1.3-1) to perform the clinical laboratory assessments described in 
Section 10.2. Refer to Section 10.5 for criteria for identifying laboratory values of 
potential clinical relevance.
The total volume of blood to be collected during the trial will be documented in the ICF
and assent form. The central laboratory will be used for all laboratory testing required 
during the trial. 
Subjects should be fasting for a minimum of 8 hours prior to the blood draws, if possible. 
Vital sign measurements and ECG assessments should be completed before any blood 
samples are collected. See exclusion criteria in Section 5.2.2 based on screening 
laboratory tests. The results of these tests must be reviewed by the investigator prior to 
initiation of the administration of the IMP. Additional urine and blood samples may be 
collected for further evaluation of safety as warranted by the investigator’s judgment. 
Reports from the central laboratory will be assessed by the investigator or qualified 
designee for clinical significance within the eCRF.
8.7.2
Physical Examination
A complete physical examination will be performed at the time points described in the 
schedule of assessments (Table 1.3-1). The complete physical examination will include 
height (screening only), weight, and calculation of body mass index (BMI) as well as 
assessment of the head, eyes, ears, nose, and throat; thorax; abdomen; skin and mucosae;
neurological; and extremities. Directed physical examinations in response to reported 
AEs will be conducted as necessary.
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Whenever possible, the same individual should perform all physical examinations for any 
individual subject throughout the course of the trial. Individuals performing the physical 
examination must be permitted to do so by local regulations, must be listed on the Food 
and Drug Administration (FDA) Form 1572 as principal investigator or subinvestigator, 
and must be listed on the trial site delegation of authority form as performing this 
function.
Any post-screening abnormalities considered by the investigator to be clinically 
significant are to be recorded as AEs on the AE eCRF.
8.7.3
Vital Signs
Vital signs (include systolic and diastolic blood pressure and heart rate) will be collected 
at the time points described in the schedule of assessments (Table 1.3-1). Subjects should 
be monitored for potentially clinically significant vital signs values (Section 10.6).
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.
8.7.4
Electrocardiogram
Electrocardiograms will be performed at the time points described in the schedule of 
assessments (Table 1.3-1). Subjects should be monitored for potentially clinically 
significant ECG results (Section 10.7). Any abnormalities considered by the investigator 
to be clinically significant are to be recorded as AEs on the AE eCRF.
The 12-lead ECGs will be performed in the supine position. Predose 12-lead ECGs 
conducted at check-in (Day −1 or Day 1) will be performed in triplicate, taken at least 
1 minute apart following a 10-minute rest in the supine position. The average of the 
3 values will be the baseline value. Based on the QTcF, a subject will be excluded if the 
correction is ≥450 msec for more than 1 of the 3 time points of triplicate predose ECGs 
performed for subjects < 12 years old or ≥460 msec for more than 1 of the 3 time points 
of triplicate predose ECGs performed for subjects ≥12 years old.
A central ECG service will be utilized for reading all ECGs in order to standardize 
interpretations for the safety analysis. In addition, ECG results will be evaluated at the 
trial site to monitor safety during the trial.
8.7.5
Suicidality Monitoring
Suicidality monitoring will occur at the time points described in the schedule of 
assessments (Table 1.3-1).
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Suicidality will be monitored during the trial using the C-SSRS. The C-SSRS is a 
semi-structured interview that captures the occurrence, severity, and frequency of 
suicide-related thoughts and behaviors during the assessment period. The interview 
includes definitions and suggested questions to solicit the type of information needed to 
determine if a suicide-related thought or behavior has occurred. The interview and rating 
for the C-SSRS must be completed by a licensed clinician who has been successfully 
trained to rate this scale by the sponsor or a designee, and is medically responsible for the 
subject. Documentation of trial training should be maintained in the trial site’s files.
The “Baseline/Screening” version of the C-SSRS will be completed at the screening visit 
and the “Since Last Visit” version of the C-SSRS will be completed at check-in (Day −1
or Day 1) and EoT/ET. There are required items to be completed, potential additional 
items if there is a positive response to a required item, and 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.
8.7.6
Other Safety Variables
No other safety variables are applicable for this trial.
8.8
Adverse Events
8.8.1
Definitions
An AE is defined as any untoward medical occurrence in a clinical trial subject 
administered an IMP 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 pre-planned procedures for which the underlying condition was known and 
no worsening occurred. An adverse reaction is any untoward and unintended response to 
an IMP related to any dose administered.
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.
Treatment-emergent AEs (TEAEs) are defined as AEs with an onset date on or after the 
start of open-label treatment. In more detail, TEAEs are all AEs that started after the start 
of open-label IMP treatment; or if the event was continuous from baseline and was 
worsening, serious, IMP related, or resulted in death or discontinuation from the trial.
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An SAE includes any event that results in any of the following outcomes:

Death

Life-threatening; ie, the subject was, in the opinion of the investigator, at immediate
risk of death from the event as it occurred. It does not include an event that, had it
occurred in a more severe form, might have caused death.

Persistent or significant incapacity/disability or substantial disruption of the ability to
conduct normal life functions.

Requires inpatient hospitalization or prolongs hospitalization.

Hospitalization itself should not be reported as an SAE; whenever possible the
reason for the hospitalization should be reported.

Hospitalizations or prolonged hospitalizations for social admissions (ie, those
required for reasons of convenience or other nonmedical need) are not considered
SAEs.

Prescheduled hospitalization to address a condition that has existed prior to the
signing of the ICF and assent form should not be considered an SAE.

Congenital anomaly/birth defect.

Other medically significant events that, based upon appropriate medical judgment,
may jeopardize the subject and may require medical or surgical intervention to
prevent one of the outcomes listed above; eg, allergic bronchospasm requiring
intensive treatment in an emergency room or home, blood dyscrasias or convulsions
that do not result in hospitalization, or the development of drug dependency or drug
abuse.
Nonserious AEs are all AEs that do not meet the criteria for a "serious" AE.
Adverse Events of Special Interest (AESIs): A noteworthy event for the particular 
product/IMP or class of products that a sponsor may wish to monitor carefully. All AESIs 
are to be reported as immediately reportable events (IREs).
Immediately Reportable Event (IRE):

Any SAE

Any AE related to occupational exposure

Any AESIs (see Section 8.8.5)

Potential serious hepatotoxicity (see Section 8.8.6)

Pregnancies are also defined as IREs. Although normal pregnancy is not an AE, it
will mandate trial discontinuation and must be reported on an IRE form and the
Pregnancy Surveillance Form(s) to the sponsor. Pregnancy will only be documented
on the AE eCRF if there is an abnormality or complication. This includes pregnancy
of the subject or the partner of the subject.
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Clinical Laboratory Test Value Changes: It is the investigator’s responsibility to review 
the results of laboratory tests for each individual subject as they become available. This 
review will be documented by the investigator’s dated signature on the laboratory report.
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 (ie, clinically significant) by the investigator (subject is symptomatic, requiring 
corrective treatment or further evaluation), or if the laboratory value leads to 
discontinuation, and/or fulfills a seriousness criterion, this is considered an AE. 
Severity: Adverse events will be graded on a 3-point scale and reported as indicated on 
the eCRF. The severity 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.
8.8.2
Eliciting and Reporting Adverse Events
The investigator will regularly assess subjects for the occurrence of AEs. To avoid bias in 
eliciting AEs, subjects should be asked the nonleading question: “How have you felt 
since your last visit?” All AEs (serious and nonserious) reported by the subject must be 
recorded on the source documents and eCRF provided by the sponsor. Adverse event
collection will begin after a subject signs the ICF and assent form.
Medical terminology should be used for 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.
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An AE that undergoes a change in severity, seriousness, or toxicity should be reported as 
a new AE on the eCRF.
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 8.8.3. Special attention 
should be paid to recording hospitalization and concomitant medications.
The AE, start date (and start time, if possible), end date (and end time, if possible), 
seriousness, severity, relationship to trial treatment (IMP causality), action taken with 
trial treatment, and outcome will be recorded on the source documents and in the eCRF.
8.8.3
Immediately Reportable Events
The investigator must immediately report (within 24 hours), using an IRE form, after 
he/she or site personnel become aware of any IRE (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 (Please note that the IRE form is NOT the AE eCRF.).
8.8.4
Medical Device Incidents (Including Malfunctions)
Not applicable.
8.8.5
Adverse Events of Special Interest
Newly acquired skin eruptions that are nontraumatic will be considered AESIs. These 
may include, but are not limited to eruptions such as skin rashes, skin irritations, skin 
reactions, or acneiform lesions. This does not include localized contact irritation at ECG 
lead sites due to application/removal of lead adhesive.
Refer to the separate rash workup plan for complete details, including reporting forms, 
and extra measures that must be performed to characterize any skin AESI of a newly 
acquired skin eruption that is nontraumatic. 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 (see Section 8.8.3).
8.8.6
Potential Serious Hepatotoxicity
For a subject who experiences an elevation in AST or ALT that is ≥3 times the 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.
8.8.7
Procedure for Breaking the Blind
This trial does not use blinding procedures.
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8.8.8
Follow-up of Adverse Events
8.8.8.1
Follow-up of Nonserious Adverse Events
Nonserious AEs that are identified at any time during the trial must be recorded on the 
AE 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).
8.8.8.2
Follow-up of Immediately Reportable Events
This trial requires that subjects be actively monitored for IREs up to 7 (+ 2) days after 
dosing.
Immediately reportable events that are identified or ongoing at the last scheduled 
contact must be recorded as such on the AE eCRF page and the IRE form. If updated 
information (eg, resolved status) on IRE status becomes available after a subject’s last 
scheduled contact, this must be reported to the sponsor and recorded on the AE eCRF 
page and the IRE form, according to the appropriate reporting procedures described in 
Section 8.8.3.
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. The 
investigator will follow IREs until the events are:

Resolved,

Stabilized,

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.
Refer to Section 10.3 for additional information regarding the follow-up period for 
subjects that become pregnant or for pregnant partners of male subjects.
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8.8.8.3
Follow-up and Reporting of Immediately Reportable Events 
Occurring After Last Scheduled Contact
Any new 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 according to the procedures outlined in 
Section 8.8.3. This may include IREs that are captured on follow-up telephone contact or 
at any other time point 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.
8.9
Treatment of Overdose
For treatment of overdose, please refer to IB Section 6.4 (Overdose).
8.10
Subject Assessment Recording
Not applicable.
8.11
Other Assessments
8.11.1
Capsule Swallow Test
The ability of a subject to swallow the intact centanafadine XR capsule will be assessed 
during the screening period using a capsule swallow test. Based on this assessment, 
subjects will either be instructed to take the centanafadine capsules intact or the capsule 
contents sprinkled on a tablespoon of applesauce.
 
 
 
 
9
Statistical Considerations
9.1
Sample Size
Since this is an exploratory trial, no formal sample size calculations will be performed. 
Up to 12 subjects may be treated depending on the concentration data and the number of 
subjects completing through 24 hours.
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9.2
Datasets for Analysis
The PK dataset will include all subjects who receive the single dose of centanafadine and 
have at least 1 postdose evaluable plasma concentration.
The safety dataset will include all subjects who receive the single dose of centanafadine.
9.3
Handling of Missing Data for Primary and Other Endpoint Analysis
No data imputation will be performed for missing PK data in this trial. The handling of 
concentrations below the lower limit of quantitation will be according to the sponsor’s 
data handling processes.
9.4
Statistical Analyses
9.4.1
Efficacy Analyses
Not applicable.
9.4.2
Safety Analysis
The safety analysis will be conducted on the safety dataset. Safety variables to be 
analyzed include AEs, clinical laboratory tests, physical examinations, vital signs, ECGs, 
and the C-SSRS. In general, baseline measurements of safety variables are defined as the 
last measurement prior to the dosing of IMP.
9.4.2.1
Adverse Events
All AEs will be coded by system organ class and Medical Dictionary for Regulatory 
Activities (MedDRA) preferred term. The incidence of the following events will be 
summarized:

TEAEs

TEAEs by severity

TEAEs potentially causally related to the IMP

TEAEs with an outcome of death

Serious TEAEs

TEAEs leading to discontinuation from the trial
The TEAEs will also be presented in a listing.
9.4.2.2
Clinical Laboratory Data
Descriptive statistics will be used to summarize the change from baseline for laboratory 
tests. The incidence of potentially clinically relevant laboratory tests will be summarized 
by time point. 
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9.4.2.3
Physical Examination and Vital Signs Data
A listing of physical examination results will be provided.
Descriptive statistics will be used to summarize the change from baseline for vital signs. 
The incidence of potentially clinically relevant vital signs will be summarized by time 
point.
9.4.2.4
Electrocardiogram Data
Descriptive statistics will be used to summarize the change from baseline for ECGs. The 
incidence of potentially clinically relevant ECGs will be summarized by time point.
9.4.2.5
Other Safety Data
9.4.2.5.1
Columbia-Suicide Severity Rating Scale
Suicidality will be assessed based on the C-SSRS (“Baseline” Version and “Since Last 
Visit” Version). The incidence of suicidality, suicidal behavior, and suicidal ideation will 
be summarized descriptively by time point and presented in a listing.
9.4.3
Other Analyses
9.4.3.1
Analysis of Demographic and Baseline Characteristics
Baseline demographic characteristics including age, race, ethnicity, sex, weight, height, 
and BMI will be summarized by descriptive statistics for the enrolled subjects. 
Baseline disease characteristics and psychiatric history will be also summarized by 
descriptive statistics.
9.4.3.2
Pharmacokinetic Analysis
A noncompartmental analysis will be performed. Plasma concentrations of centanafadine
and metabolite(s) will be summarized by time point and mode of administration (intact 
capsules or capsule contents sprinkled on a tablespoon of applesauce). The PK 
parameters will be summarized by analyte and mode of administration using descriptive 
statistics.
No inferential statistical analysis will be conducted.
The following PK parameters will be summarized:

Maximum (peak) plasma concentration (Cmax) of centanafadine

Time to maximum concentration (tmax) of centanafadine

Area under the concentration-time curve from time 0 to 12 hours postdose (AUC0-12h)
of centanafadine
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10
Supporting Documentation and Operational Considerations
10.1
Appendix 1: Regulatory, Ethical, and Trial Oversight 
Considerations
10.1.1
Ethics and Responsibility
This trial must be conducted in compliance with the protocol, FDA regulations,
International Council for Harmonisation (ICH) GCP: Consolidated 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, 
subinvestigator, and their staff will take measures to ensure adequate care in protecting 
subject privacy. To this end, a subject ID will be used to identify each subject.
Financial aspects, subject insurance, and the publication policy for the trial will be 
documented in the agreement between the sponsor and the investigator.
10.1.2
Informed Consent
Informed consent will be freely obtained from the guardian or legally acceptable 
representative of all subjects, as applicable for local laws. The ICF will be approved by 
the same IRB that approves this protocol. Subjects will provide informed assent, as 
applicable for local laws, and subjects must be able to understand that he or she can 
withdraw from the trial at any time and for any reason.
Each ICF will comply with the ICH GCP: Consolidated Guideline E612 and local 
regulatory requirements. The investigator will ensure that the sponsor reviews and 
authorizes any written site-specific ICF used in the trial before submission to the IRB. In 
support of the site’s standard process for administering informed consent, this trial will 
also allow for electronic informed consent (eICF) as a tool within applicable regions and 
trial sites. The eICF utilizes the IRB-approved site-specific ICF to offer subjects an 
enhanced platform to review and understand their rights as a research subject as well as 
required trial procedures. When possible, trial sites will have subjects and their guardian 
or legally acceptable representative review and sign the eICF prior to starting any trial 
procedures; however, if local regulations do not allow for use of the electronic format, 
subjects may continue in the trial utilizing the standard paper and wet ink signature 
process.
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Investigators may discuss trial availability and the possibility for entry with potential 
subjects and their guardian or legally acceptable representative without first obtaining 
consent/assent. However, informed consent/assent 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 and their guardian or legally acceptable representative 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 subjects will be provided with controlled access to the eICF application 
by trial site staff. When the trial site staff, subject, and the subject’s guardian or legally 
acceptable representative agree that the subject and the guardian or legally acceptable 
representative has enough information to make an informed decision to participate, the 
subject’s guardian or legally acceptable representative will electronically sign in the eICF 
application and an electronic date and timestamp will be applied to the signature; the 
subject will sign the assent form in the eICF application and an electronic date and 
timestamp will be applied to the signature. The subject and the subject’s guardian or 
legally acceptable representative will be given a printed, signed copy of the ICF and 
assent. 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.
Once appropriate essential information has been provided and fully explained in 
layman’s language to the subject and the subject’s guardian or legally acceptable
representative by the investigator (or a qualified designee), and it has been documented 
that the subject and the subject’s guardian or legally acceptable representative has had the 
opportunity to ask questions, the IRB-approved written ICF and assent will be signed and 
dated by the subject’s guardian or legally acceptable representative and subject, 
respectively, and the person obtaining consent/assent (investigator or designee), as well 
as by any other parties required by the IRB. The subject the subject’s guardian or legally 
acceptable representative will receive a copy of the signed ICF and assent; the original 
shall be kept on file by the investigator.
Subjects and their guardian or legally acceptable representative may be asked to sign 
additional ICFs or give additional assent if the protocol is amended and the changes to 
the protocol result in additional information that needs to be provided to the subjects and 
their guardian or legally acceptable representative, so that they can make a 
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knowledgeable and voluntary decision on continued trial participation. Female partners 
of male subjects who become pregnant during the course of the trial may be asked to sign 
additional ICFs or give additional assent in order to collect additional information 
regarding the nonsubject partner and fetus.
10.1.3
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 IMP, subject bodily fluids, and/or other materials 
collected shall be used solely in accordance with this protocol, unless otherwise agreed to 
in writing by the sponsor.
Subjects will be identified only by unique subject ID in the eCRF. If further subject 
identification is required, subjects’ full names may be made known to a regulatory 
agency or other authorized officials if necessary, subject to local regulations.
10.1.4
Quality Control and Quality Assurance
10.1.4.1
Monitoring
The sponsor has ethical, legal, and scientific obligations to follow this trial in accordance 
with established research principles, the ICH GCP: Consolidated Guideline (E6), 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 trial 
site personnel will undergo initial and ongoing training for this particular trial, and this 
training will be clearly documented.
10.1.4.2
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/assent process, and a review of the eCRF with source documents, as 
applicable. 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.
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10.1.5
Protocol Deviations
In the event of a significant deviation from the protocol due to an emergency, accident, or 
mistake (eg, violation of the informed consent/assent 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 or via e-mail. The 
investigator and sponsor (or designee) 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 (or designee) and reviewed by the site monitor.
Any major protocol deviation will be recorded in the eCRF along with the start date and 
details of the deviation.
10.1.6
Records Management
10.1.6.1
Source Documents
Source documents are defined as the results of original observations and activities of a 
clinical investigation. Source documents will include but are not limited to medical 
records, electronic data, screening logs, and recorded data from automated instruments.
All source documents pertaining to this trial will be maintained by the 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 ICF. In all cases, subject confidentiality must be 
maintained in accordance with local regulatory requirements.
10.1.6.2
Data Collection
During each subject’s visit to the site, an investigator or their designee participating in the 
trial will record information to document all significant observations. At a minimum, 
these notes will contain:

Documentation of the informed consent/assent process, including any revised 
consents/assents;

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;
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
Any changes in concomitant medications or dosages;

A general reference to the procedures completed; 

The signature (or initials) and date of the investigator (or designee) who made an 
entry in the medical record.
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 (where permitted by 
local regulation) in this trial and will meet the same fundamental elements of data quality 
(eg, attributable, legible, contemporaneous, original, and accurate) as paper records. 
These data will be collected into a system that is fully validated according to 21 Code of 
Federal Regulations (CFR) Part 11. Changes to the data will be captured by an automatic 
audit trail.
Designated trial site staff will not be given access to the electronic source 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 per the monitoring 
plan 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 
investigator or their designee.
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.
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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.
10.1.6.3
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: Consolidated Guideline (E6) and as required by applicable 
local regulations. The investigator/institution will take measures to prevent accidental or 
premature destruction of these documents.
10.1.6.4
Records Retention at the Trial Site
The 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 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.
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10.1.6.5
Publication Authorship Requirements
Authorship for any Otsuka-sponsored publications resulting from the conduct of this trial 
will be based on International Committee of Medical Journal Editors (ICMJE) authorship 
criteria (http://www.icmje.org/recommendations). According to ICMJE guidelines, one 
may be considered an author only if the following criteria are met:
1) Substantial contributions to the conception or design of the work; or the 
acquisition, analysis, or interpretation of data for the work; AND
2) Drafting the work or revising it critically for important intellectual content; AND
3) Final approval of the version to be published; AND
4) Agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved.
All authors must meet the above criteria, and all who qualify for authorship based on the 
above criteria should be listed as authors.
Investigators or other trial subjects 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 subjects consent to such acknowledgement in any 
publications resulting from its conduct.
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10.2
Appendix 2: Clinical Laboratory Tests
The tests detailed in Table 10.2-1 will be performed.
Table 10.2-1
Clinical Laboratory Assessments
Hematology:
Hematocrit
Hemoglobin
Platelet count
Mean corpuscular hemoglobin
Mean corpuscular hemoglobin concentration
Mean corpuscular volume
RBC count
WBC count with differential
Microscopic urinalysis:
Appearance
Bilirubin
Color
Glucose
Ketones
Leukocyte esterase
Leukocytes
Nitrites
Occult blood
pH
Protein
Urobilinogen
Specific gravity
Microscopic analysis of RBC/WBC, per high 
powered field (casts, crystals, squamous cells)
Additional Tests:
TSH, with reflex to free T4 if TSH is abnormal
HBsAg
anti-HCV
HIV
Serum hCG/urine test pregnancy (for all female 
subjects ≥12 years of age and female subjects
< 12 years of age who have started menstruating)
Serum Chemistry:
Albumin
ALP
ALT
AST
Bicarbonate
Bilirubin, total
BUN
Calcium
Carbon dioxide
Chloride
Cholesterol (total, HDL, LDL)
CPK
Creatinine
GGT
Glucose
LDH
Magnesium
Phosphorus
Potassium
Protein, total
Sodium
Uric acid
Triglycerides
Drug Screen (all items in urine except where 
noted):
Alcohol (breath or urine)
Amphetamines
Barbiturates
Benzodiazepines
Cannabinoids
Cocaine
Cotinine (urine or serum)
Marijuana
Methadone
Opiates
Phencyclidine
Propoxyphene
ALP = alkaline phosphatase; anti-HCV = hepatitis C antibodies; BUN = blood urea nitrogen; 
GGT = gamma glutamyl transferase; HBsAg = hepatitis B surface antigen; hCG = human chorionic 
gonadotropin; HDL = high-density lipoprotein; LDH = lactic dehydrogenase; LDL = low-density 
lipoprotein; RBC = red blood cell count.
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10.3
Appendix 3: Contraceptive Guidance and Collection of Pregnancy 
Information
Females of childbearing potential (FOCBP) are females ≥12 years of age and females 
< 12 years of age whose menstruation has started and who are not documented as sterile 
(eg, have had a bilateral oophorectomy, or hysterectomy, or who have been 
postmenopausal for at least 12 months).
For males and FOCBP, who are sexually active, there must be a documented agreement 
that the subject and their partner will take effective measures (ie, 2 different approved 
methods of birth control or remains fully abstinent) to prevent pregnancy during the 
course of the trial and for 30 days after dosing. Periodic abstinence (eg, calendar, 
ovulation, symptothermal, postovulation methods) or withdrawal are not acceptable 
methods of contraception. Unless the subject is sterile (ie, females who have had a 
bilateral oophorectomy, have had a hysterectomy, or have been postmenopausal for at 
least 12 consecutive months; or males who have had a bilateral orchiectomy) or remains 
fully abstinent during the trial and for 30 days after dosing, 2 of the following approved 
methods of birth control must be used: vasectomy, tubal ligation, intrauterine device, 
birth control pills, birth control implant, birth control depot injection, condom with 
spermicide, sponge with spermicide, or occlusive cap (vaginal diaphragm or 
cervical/vault cap) with spermicide. Any single method of birth control, including 
vasectomy and tubal ligation, may fail, leading to pregnancy. The contraceptive method 
will be documented in the eCRF. Male subjects must also agree not to donate sperm from 
trial screening through 30 days after dosing.
Before enrolling males and females in this clinical trial, investigators must review the 
below information about trial participation as part of the ICF and assent process. The 
topics should generally include:

General information

Informed consent or assent form

Pregnancy prevention information

Drug interactions with hormonal contraceptives

Contraceptives in current use

Follow-up of a reported pregnancy
Before trial enrollment, males and FOCBP (and their guardian or legally acceptable 
representative) must be advised of the importance of avoiding pregnancy during trial 
participation and the potential risk factors for an unintentional pregnancy. Subjects and 
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their guardian or legally acceptable representative must sign the ICF and assent form
confirming that the above-mentioned risk factors and the consequences were discussed.
A urine or serum pregnancy test for human chorionic gonadotropin (hCG) will be 
performed at screening and check-in to the inpatient facility on all FOCBP (female 
subjects ≥12 years of age and all female subjects < 12 years of age, if menstruation has 
started). If a urine test is performed and is positive, the investigator will follow-up with a 
confirmatory serum test.
The investigator (or appropriate trial site staff) is advised to counsel subjects (and their 
guardian or legally acceptable representative) on the risk of pregnancy while participating 
in a clinical trial as well as ensuring that the subject understands how pregnancies occur 
and can be avoided. This should be documented in the source records.
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). Male subjects 
must be instructed to contact the investigator immediately, during the trial, if their partner
suspects that 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 after the subject has taken IMP, and the pregnancy is confirmed
with serum pregnancy test results, the subject will be withdrawn from the trial. 
Exceptions to trial discontinuation may be considered for life-threatening conditions only 
after consultations with the IRE contact (see the title page of this protocol for contact 
information).
The investigator must immediately notify the sponsor (within 24 hours) of any pregnancy 
associated with IMP exposure during the trial and for at least 30 days after dosing, and 
record the event on the IRE form and forward it to the sponsor. The sponsor will forward 
the Pregnancy Surveillance Form(s) to the investigator 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 the Pregnancy Surveillance Form(s), 
follow-up information regarding the course of the pregnancy, including perinatal and 
neonatal outcome. Infants will be followed for a minimum of 6 months from the date of 
birth.
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Abbreviation
Definition
PD
Pharmacodynamic
PK
Pharmacokinetic
PQC
Product Quality Complaint
QTc
Corrected QT interval
QTcF
QT interval corrected for heart rate using Fridericia’s formula
RBC
Red blood cell count
SAE
Serious adverse event
SR
Sustained-release
T4
Thyroxine
TDD
Total daily dose
TEAE
Treatment-emergent adverse event
tmax
Time to maximum concentration
TSH
Thyroid-stimulating hormone
ULN
Upper limit of normal
VAS
Visual analogue scale
WBC
White blood cell count
XR
Extended-release
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10.5
Appendix 5: Criteria for Identifying Laboratory Values of Potential 
Clinical Relevance
Laboratory Tests
Criteria (Normal Ranges) for Subjects 9 - 12 Years Olda,b
Chemistry
AST
≥2 × ULN
ALT
≥2 × ULN
ALP
≥2 × ULN
BUN
≥24 mg/dL (≤ 4 mg/dL or ≥24 mg/dL)
Creatinine
≥ 0.7 mg/dL (≤ 0.2 mg/dL or ≥ 0.7 mg/dL)
Uric acid
≥ 6.7 mg/dL (≤ 1.6 mg/dL or ≥ 6.7 mg/dL)
Bilirubin (total)
≥ 1.6 mg/dL (≤ 0.2 mg/dL or ≥ 1.6 mg/dL)
CPK
≥2 × ULN
Prolactin
≥ 21.00 ng/dL (≤ 2.63 ng/dL or ≥ 21.00 ng/dL)
Hematology
Hematocrit
≤ 33% (≤ 33% or ≥ 44%)
Hemoglobin
≤ 11.2 g/dL (≤ 11.2 g/dL or ≥ 15.5 g/dL)
White blood count
≤4.35 × 103/μL (≤4.35 × 103/μL or ≥13.65 × 103/μL)
Eosinophils
4.8%
Neutrophils
≤ 40.5% (≤ 40.5% or ≥ 75.0%)
Absolute neutrophil count
≤1.00 × 103/μL or ≥9.00 × 103/μL
Platelet count
≤130 × 103/μL (≤130 × 103/μL or ≥570 × 103/μL)
Urinalysis
Protein
Change from baseline
Glucose
Presence
Additional Criteria
Chloride
≤94 mEq/L or ≥112 mEq/L
Potassium
≤3.3 mEq/L or 5.2 mEq/L
Sodium
≤132 mEq/L or ≥148 mEq/L
Calcium
≤8.3 mg/dL or ≥10.9 mg/dL
Glucose
Fasting
≥100 mg/dL (≤70 mg/dL or ≥100 mg/dL)
Nonfasting
≥139 mg/dL (≤59 mg/dL or ≥139 mg/dL)
Total cholesterol, fasting
≥217 mg/dL (≤97 mg/dL or ≥217 mg/dL)
LDL cholesterol, fasting
≥130 mg/dL
HDL cholesterol, fasting
≤34 mg/dL (≤34 mg/dL or ≥75 mg/dL)
Triglycerides, fasting
≥131 mg/dL (≤30 mg/dL or ≥131 mg/dL)
aThe recommended criteria represented in this table are intended to identify on-treatment outside of 
normal values that could potentially be clinically relevant. Variations based on local laboratory 
ranges may need to be considered.
bInformation adapted from: 1. Soghier L, Pham K, Rooney S. Reference Range Values for Pediatric 
Care. The American Academy of Pediatrics. 2014; 2. Hughes HK, Kahl LK. The Johns Hopkins
Hospital: The Harriet Lane Handbook. 21st edition. 2015; 3. Covance central laboratory reference 
ranges, 2019.
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10.6
Appendix 6: Criteria for Identifying Vital Signs of Potential Clinical 
Relevance
Variable
Criterion Valuea
Change Relative to 
Baselinea
Heart rate at restb
< 60 bpm or > 110 bpm
Increase or decrease of 
≥15 bpm
Systolic blood pressurec
School-age (6 to 9 years old)
< 85 mmHg or > 115 mmHg
Increase or decrease of 
≥20 mmHg
Preadolescent (10 to 12 
years old)
< 90 mmHg or > 120 mmHg
Increase or decrease of 
≥15 mmHg
Diastolic blood pressurec
School-age (6 to 9 years old)
< 50 mmHg or > 80 mmHg
Increase or decrease of 
≥15 mmHg
Preadolescent (10 to 12 
years old)
< 60 mmHg or > 80 mmHg
Increase or decrease of 
≥15 mmHg
Orthostatic hypotension
≥30 mmHg decrease in systolic blood 
pressure and/or a decrease of 
≥20 mmHg in diastolic blood pressure 
after at least 3 minutes of standing 
compared to the previous supine blood 
pressure
Not applicable
(baseline status not 
considered)
Orthostatic tachycardia
≥25 bpm increase in heart rate from 
supine to standing
Not applicable
(baseline status not 
considered)
Weight
Not applicable
Increase or decrease of 
≥25%
bpm = beats per minute.
aThe criterion value and change relative to baseline represented in this table are intended to identify 
on-treatment values outside of normal changes and that could potentially be clinically relevant. In 
order to be identified as potentially clinically relevant, the 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. When evaluating these values, the 
emotional state of the subject must be taken into consideration (eg, crying, screaming) and 
documented as applicable.
bInformation adapted from: Hughes HK, Kahl LK. The Johns Hopkins Hospital: The Harriet Lane 
Handbook. 21st edition. 2015.
cInformation adapted from: Flynn JT, Kaelber DC, Baker-Smith CM, et al. Clinical Practice Guideline 
for Screening and Management of High Blood Pressure in Children and Adolescents: American 
Academy of Pediatrics Subcommittee on Screening and Management of High Blood Pressure in 
Children. Pediatrics. 2017;140(3):1-72.
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10.7
Appendix 7: Criteria for Identifying ECG Measurements of 
Potential Clinical Relevance13
Variable
Criterion Valuea
Change Relative to 
Baselinea
Rhythm
Sinus tachycardiab
≥110 bpm
increase of ≥15 bpm
Sinus bradycardiac
≤60 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
< 12 years old
≥ 12 years old
QTcF ≥450 msec
QTcF ≥460 msec
increase of 60 msec 
from baseline
QTc = corrected QT interval.
aThe criterion value and change relative to baseline represented in this table are intended to identify 
on-treatment values outside of normal changes and that could potentially be clinically relevant. In 
order to be identified as potentially clinically relevant, the 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. When evaluating these values, the 
emotional state of the subject must be taken into consideration (eg, crying, screaming) and 
documented as applicable.
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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10.8
Appendix 8: Protocol Amendments
The investigator will not make any changes to this protocol without the sponsor’s prior 
written consent and subsequent approval/favorable opinion by the IRB. Any permanent 
change to the protocol, whether an overall change or a change for specific trial site(s), 
must be handled as a protocol amendment. Any amendment will be written by the 
sponsor. Each amendment will be submitted to the IRB, as required by local regulations.
Except for “administrative” or “nonsubstantial” amendments, investigators will wait for 
IRB approval/favorable opinion of the amended protocol before implementing the 
change(s). Administrative amendments are defined as having no effect on the safety of 
subjects, conduct or management of the trial, trial design, or the quality or safety of 
IMP(s) used in the trial. A protocol change intended to eliminate an apparent immediate 
hazard to subjects should be implemented immediately after agreement by the sponsor 
and investigator, followed by IRB notification within local applicable timelines. The 
sponsor will submit protocol amendments to the applicable regulatory agencies within 
local applicable timelines.
When the IRB, investigators, and/or the sponsor conclude that the protocol amendment 
substantially alters the trial design and/or increases the potential risk to the subject, the 
currently approved written ICF and assent form will require similar modification. In such 
cases, after approval/favorable opinion of the new ICF and assent form by the IRB, repeat 
written informed consent/assent will be obtained from subjects enrolled in the trial and 
their guardian or legally acceptable representative before expecting continued 
participation and before the amendment-specified changes in the trial are implemented.
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11
References
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Sayal K, Prasad V, Daley D, Ford T, Coghill D. ADHD in children and young people: 
prevalence,care pathways, and service provision. Lancet Psychiatry. 2018;5: 175-186.
2
Connor DF. Preschool attention deficit hyperactivity disorder: a review of prevalence, 
diagnosis, neurobiology, and stimulant treatment. J Dev Behav Pediatr. 
2002;23:S1-S9.
3
Egger HL, Angold A. Common emotional and behavioral disorders in preschool 
children: presentation, nosology, and epidemiology. J Child Psychol Psychiatry. 
2006;47:313-337.
4
Rappley MD, Mullan PB, Alvarez FJ, Eneli IU, Wang J, Gardiner JC. Diagnosis of 
attention-deficit/hyperactivity disorder and use of psychotropic medication in very 
young children. Arch Pediatr Adolesc Med. 1999;153:1039-1045.
5
Biederman J, Kwon A, Aleardi M, Chouinard VA, Marino T, Cole H, et al. Absence 
of gender effects on attention deficit hyperactivity disorder: findings in nonreferred 
subjects. Am J Psychiatry. 2005;162:1083-1089. 
6
Arnsten AF. Fundamentals of attention-deficit/hyperactivity disorder: circuits and 
pathways. J Clin Psychiatry. 2006;67(Suppl 8):7-12.
7
Heal DJ, Smith SL, Findling RL. ADHD: current and future therapeutics. Curr Top 
Behav Neurosci. 2012;9:361-390.
8
Bolea-Alamañac B, Nutt DJ, Adamou M, Asherson P, Bazire S, Coghill D, et al. 
Evidence-based guidelines for the pharmacological management of attention deficit 
hyperactivity disorder: update on recommendations from the British Association for 
Psychopharmacology. J Psychopharmacol. 2014;28:179-203.
9
Otsuka Pharmaceutical Development and Commercialization. Centanafadine 
(EB-1020) Investigator’s Brochure, Edition 8. Otsuka Report, issued 12 Mar 2019.
10 Centers for Disease Control and Prevention. Weight-for-age charts, 2 to 20 years. 
Available at: https://www.cdc.gov/growthcharts/percentile_data_files.htm. Updated 
Aug 04, 2009. Accessed Mar 15, 2019.
11 Abdulla S, Amuri B, Kabanywanyi AM, Ubben D, Reynolds C, Pascoe S, et al. Early 
clinical development of artemether-lumefantrine dispersible tablet: palatability of 
three flavours and bioavailability in healthy subjects. Malar J. 2010;9:253. 
12 International Council for Harmonisation (ICH) [homepage on the Internet]. E6(R2): 
Good Clinical Practice: Integrated Addendum to ICH E6(R1) [finalized 2016 
November; cited 2019 Apr 11]. Available from: 
https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/
E6/E6_R2__Step_4_2016_1109.pdf.
13 Vink AS, Neumann B, Lieve KV, Sinner MF, Hofman N, Kadi S, et al. 
Determination and interpretation of the QT interval. Comprehensive analysis of a 
large cohort of long QT syndrome patients and controls. Circulation. 
2018;138:2345-2358.
Clinical Study Report 405-201-00037
16.1.1 Protocol and Protocol Amendments
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Protocol 405-201-00037
70
Confidential - Proprietary Information
Amendment 1 Approval: 23 Jul 2019
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, the concurrent 
medications, the efficacy and safety parameters and the conduct of the trial in general. I am aware that 
this protocol must be approved by the Institutional Review Board (IRB) responsible for such matters 
in the clinical trial facility where centanafadine will be tested prior to commencement of this trial. I 
agree to adhere strictly to the attached protocol (unless amended in the manner set forth in the 
sponsor's Clinical Trial Agreement, at which time I agree to adhere strictly to the protocol as 
amended).
I understand that this IRB-approved protocol will be submitted to the appropriate regulatory 
authority/ies by the sponsor. I agree that clinical data entered on eCRF by me and my staff will be 
utilized by the sponsor in various ways, such as for submission to governmental regulatory authorities 
and/or in combination with clinical data gathered from other research sites, whenever applicable. I 
agree to allow sponsor and designee monitors and auditors full access to all medical records at the 
research facility for subjects screened or enrolled in the trial.
I agree to await IRB approval before implementation of any substantial amendments to this protocol. 
If, however, there is an immediate hazard to subjects, I will implement the amendment immediately, 
and provide the information to the IRB within the required local applicable timelines. Administrative 
changes to the protocol will be transmitted to the IRB for informational purposes only, if required by 
local regulations.
I agree to provide all subjects with informed consent forms, as required by the applicable regulations 
and by ICH guidelines. I agree to report to the sponsor any adverse experiences in accordance with the 
terms of the sponsor's Clinical Trial Agreement and the relevant regional regulation(s) and 
guideline(s). I further agree to provide all required information regarding financial certification or 
disclosure to the sponsor for all investigators and subinvestigators in accordance with the terms of the 
relevant regional regulation(s). I understand that participation in the protocol involves a commitment 
to publish the data from this trial in a cooperative publication before publication of efficacy and safety 
results on an individual basis may occur, and I consent to be acknowledged in any such cooperative 
publications that result.
____________________________
_____________________________
___________
Principal Investigator Print Name
Signature
Date
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Document Name: 405-201-00037 Protocol Amendment 1
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yyyy hh:min) -
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Clinical Approval
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Biostatistics Approval
23-Jul-2019
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Clinical Pharmacology
Approval
23-Jul-2019
19:33:21
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16.1.1 Protocol and Protocol Amendments
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SAP_001.pdf: 
Otsuka Pharmaceutical
Development & Commercialization, Inc.
Investigational Medicinal Product 
Centanafadine (EB-1020)
Protocol No. 405-201-00037
IND No. 119,361
A Pilot Phase 2a, Multicenter, Open-label, Single-dose Trial to Assess the 
Pharmacokinetics of Centanafadine Extended-release Capsules After Oral Administration 
in Pediatric Subjects (9 to 12 years, inclusive) With Attention-deficit Hyperactivity 
Disorder
Statistical Analysis Plan
Phase 2a
Version: 1.0
Date: Jan 06, 2020
Protocol Version 3.0: Jul 23, 2019
Confidential
May not be used, divulged, published, or otherwise disclosed without the prior written
consent of Otsuka
Clinical Study Report 405-201-00037
16.1.9 Documentation of Statistical Methods
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
1


Protocol 405-201-00037
Statistical Analysis Plan                                        2 of 21
Version Date: 01/06/2020
Table of Contents
Table of Contents...........................................................................................2
List of In-text Figures....................................................................................4
List of Appendices..........................................................................................5
1
Introduction ..........................................................................................6
2
Trial Objectives.....................................................................................6
3
Trial Design...........................................................................................6
3.1
Type/Design of Trial ...........................................................................................6
3.2
Trial Treatments ..................................................................................................9
3.3
Trial Population...................................................................................................9
4
Sample Size............................................................................................9
5
Statistical Analysis Sample..................................................................9
5.1
Enrolled Analysis Set..........................................................................................9
5.2
Safety Analysis Set............................................................................................10
5.3
Pharmacokinetic (PK) Analysis Set ..................................................................10
5.4
Handling of Missing Data .................................................................................10
6
Primary and Secondary Outcome Variables...................................10
6.1
Primary Endpoints.............................................................................................10
6.2
Other Outcome Endpoints.................................................................................10
6.3
Other PK Endpoints...........................................................................................10
7
Disposition and Demographic Analysis............................................11
7.1
Subject Disposition............................................................................................11
7.2
Demographic and Baseline Disease Characteristics .........................................11
7.3
Medical History.................................................................................................11
7.4
Treatment Compliance ......................................................................................11
7.5
Concomitant Medication...................................................................................12
7.6
Protocol Deviations...........................................................................................12
8
Pharmacokinetic Analysis..................................................................12
10
Safety Analyses ...................................................................................13
Clinical Study Report 405-201-00037
16.1.9 Documentation of Statistical Methods
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Protocol 405-201-00037
Statistical Analysis Plan                                        3 of 21
Version Date: 01/06/2020
10.1
Extent of Exposure............................................................................................13
10.2
Adverse Events..................................................................................................13
10.3
Clinical Laboratory Data...................................................................................13
10.4
Vital Sign Data..................................................................................................14
10.5
Physical Examination Data ...............................................................................14
10.6
Electrocardiogram (ECG) Data.........................................................................15
10.7
Potential Serious Hepatotoxicity.......................................................................15
10.8
Other Safety Data..............................................................................................15
Clinical Study Report 405-201-00037
16.1.9 Documentation of Statistical Methods
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Protocol 405-201-00037
Statistical Analysis Plan                                        4 of 21
Version Date: 01/06/2020
List of In-text Figures
Figure 3.1-1
Trial Design Schematic................................................................... 8
Clinical Study Report 405-201-00037
16.1.9 Documentation of Statistical Methods
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Protocol 405-201-00037
Statistical Analysis Plan                                        5 of 21
Version Date: 01/06/2020
List of Appendices
Appendix 1
Criteria for Identifying Laboratory Values of Potential 
Clinical Relevance ........................................................................ 16
Appendix 2
Criteria for Potential Clinically Significant Vital Signs ............... 17
Appendix 3
Criteria for Identifying ECG Measurements of Potential 
Clinical Relevance ........................................................................ 18
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16.1.9 Documentation of Statistical Methods
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Protocol 405-201-00037
Statistical Analysis Plan                                        6 of 21
Version Date: 01/06/2020
1
Introduction
This statistical analysis plan (SAP) documents the statistical methodology and data 
analysis algorithms and conventions to be applied for the analysis of clinical trial data of 
trial 405-201-00037 for centanafadine. The current version of SAP is based on protocol 
version 3.0 dated on 23 Jul 2019 and final SAP will be consistent with the final version of 
the protocol. 
2
Trial Objectives
Primary Objectives: 
To characterize the single-dose concentration-time profile from 0 to 12 hours of 
centanafadine in pediatric subjects (9 to 12 years, inclusive) with attention-deficit 
hyperactivity disorder (ADHD).
Other Objectives: 

To assess the safety and tolerability of centanafadine XR in pediatric subjects.

To assess the ability of pediatric subjects to swallow the centanafadine XR capsule.

 

To assess centanafadine concentrations 24 hours postdose for evaluation of the 
potential for accumulation following multiple doses.

To compare the PK of centanafadine after administration of the intact capsules or the 
capsule contents sprinkled on to applesauce.
3
Trial Design
3.1
Type/Design of Trial
This is a pilot phase 2a, multicenter, open-label, single-dose trial in pediatric subjects (9 
to 12 years, inclusive) with a documented history of ADHD and confirmation of an 
ADHD prescription medication. This trial consists of a screening period (Day −21 to Day 
−2), check-in (Day −1 or Day 1), 2-day treatment period (Day 1: dosing, Day 2: end of-
treatment [EoT]), and a safety follow-up telephone call 7 (+ 2) days after dosing (Day 8). 
The screening period may be extended if additional time is needed to complete screening 
procedures, upon discussion with and approval by the medical monitor.
Written informed consent will be freely obtained from all subjects’ guardian(s) or legally 
acceptable representative(s), as applicable for local laws. Written informed assent will be 
freely obtained from all subjects. 
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Protocol 405-201-00037
Statistical Analysis Plan                                        7 of 21
Version Date: 01/06/2020
Eligible subjects will check-in either on Day −1 or Day 1, based on the investigator’s 
decision. A single dose of centanafadine will be administered either as intact capsules or 
the capsule contents sprinkled on a tablespoon of applesauce on Day 1 in the morning. 
 
 Pharmacokinetic 
and safety assessments will be performed for approximately 24 hours postdose. Subjects 
may be released from the clinic after PK sample collection at 12 hours postdose to return 
the following morning or may remain in the clinic until 24 hours postdose, based on the 
investigator’s decision. Subjects released on Day 1 will return to the clinic on Day 2 
between 22 to 26 hours postdose for an outpatient visit, which will include EoT 
assessments and one PK sample. In-clinic subjects may leave the clinic on Day 2 after 
EoT assessments and PK sampling are complete. 
Subjects and/or their caregivers will be contacted by telephone 7 days after dosing to 
assess any new or ongoing AEs and to record concomitant medications.
The trial design schematic is displayed in Figure 3.1-1.
 
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3.2
Trial Treatments
The ability of a subject to swallow the intact capsules will be assessed during the 
screening period with empty capsules. Based on this assessment, subjects will either be 
instructed to take the centanafadine capsules intact or the capsule contents sprinkled on a 
tablespoon of applesauce. An attempt will be made to administer the intact capsules to 
approximately half of the subjects and approximately half of the subjects will be 
administered the capsule contents sprinkled on a tablespoon of applesauce.
Centanafadine will be supplied as 1 capsule containing a 50-mg dose as
beads 
and 1 capsule containing a 5-mg dose as IR beads for a total centanafadine dose of 
55 mg. Both of the intact capsules or the capsule contents sprinkled on a tablespoon of 
applesauce will be taken orally in the morning
 
following a minimum 8-hour fast.
 
 
 
3.3
Trial Population
The trial population will consist of males and females, aged 9 to 12 years (inclusive), 
who have a documented history of ADHD and confirmation of an ADHD prescription 
medication.
Up to 12 subjects may be treated in the trial. Subjects who discontinue for a reason other 
than a safety-related event may be replaced at the discretion of the sponsor.
4
Sample Size
Since this is an exploratory trial, no formal sample size calculations will be performed. 
Up to 12 subjects may be treated depending on the concentration data and the number of 
subjects completing through 24 hours.
5
Statistical Analysis Sample
5.1
Enrolled Analysis Set
The enrolled analysis set includes all subjects who have eligibility to enroll in the trial 
based on screening process. 
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Protocol 405-201-00037
Statistical Analysis Plan                                        10 of 21
Version Date: 01/06/2020
5.2
Safety Analysis Set
The safety analysis set includes all subjects who receive the single dose of centanafadine.
5.3
Pharmacokinetic (PK) Analysis Set
The PK analysis set includes all subjects who receive the single dose of centanafadine 
and have at least 1 postdose evaluable plasma concentration.
5.4
Handling of Missing Data
No data imputation will be performed for missing PK data in this trial. The handling of 
concentrations below the lower limit of quantitation will be according to the sponsor’s 
data handling processes.
6
Primary and Secondary Outcome Variables
6.1
Primary Endpoints
The following primary endpoints will be evaluated:

Cmax of centanafadine

tmax of centanafadine

AUC0-12h of centanafadine
6.2
Other Outcome Endpoints
The following other endpoints will be evaluated:

Reported AEs, vital signs, body weight, ECGs, clinical laboratory tests, physical 
examinations, and the C-SSRS. 

Ability to swallow the centanafadine XR capsule.
 
 
 
 
6.3
Other PK Endpoints
The following PK endpoints will be evaluated:

Centanafadine concentrations at 24 hours postdose
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Protocol 405-201-00037
Statistical Analysis Plan                                        11 of 21
Version Date: 01/06/2020

PK parameters will be estimated (tmax, Cmax, and 
) for EB 10601 
(metabolite of centanafadine) 
.

 
7
Disposition and Demographic Analysis
7.1
Subject Disposition
The number of subjects who have been screened, the number of subjects who are treated, 
the number of subjects who discontinue from the trial, and the subjects who complete the 
trial will be tabulated for total subjects. In addition, the assignment based on capsule 
swallow test during screening period will also be presented by intact capsule and capsule 
contents sprinkled on applesauce. 
The number and percentage of subjects who discontinue are to be summarized by reason 
for discontinuation and mode of administration (intact capsules or capsule contents 
sprinkled on a tablespoon of applesauce) for the enrolled sample.
7.2
Demographic and Baseline Disease Characteristics
Baseline demographic characteristics include age, race, ethnicity, sex, weight, height, and 
BMI. Baseline disease characteristics include history of ADHD, history of allergy.
Summary statistics will consist of mean, median, minimum, maximum, and standard 
deviation (SD) for continuous variables and tabulations of frequency distributions for 
categorical variables. The summary will be based on the enrolled sample and by mode of 
administration (intact capsules or capsule contents sprinkled on a tablespoon of
applesauce).
7.3
Medical History
Listings for general medical history, surgical history, ADHD history, and psychiatric
history will be provided. The listings will be based on the safety sample and by mode of 
administration (intact capsules or capsule contents sprinkled on a tablespoon of
applesauce).
7.4
Treatment Compliance
The time and dose of each investigation medical product (IMP) administration will be 
recorded on the source documents and on the eCRF. Treatment compliance will be 
presented by mode of administration in a listing.
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Protocol 405-201-00037
Statistical Analysis Plan                                        13 of 21
Version Date: 01/06/2020
10
Safety Analyses
All the following safety analyses will be performed for the safety sample.  
10.1
Extent of Exposure
A table displaying the number of subjects who took 1 day of study medication will be 
presented by mode of administration (intact capsules or capsule contents sprinkled on a 
tablespoon of applesauce). The summary will be based on the Safety analysis Set. 
10.2
Adverse Events
All treatment-emergent adverse events (TEAEs) will be coded by Medical Dictionary for 
Regulatory Activities (MedDRA; Version 21 or later) system organ class and preferred 
term. Treatment-emergent adverse events are defined as those AEs that occur after 
administration of IMP or events that worsen relative to baseline.
Newly acquired skin eruptions that are nontraumatic will be considered AEs of special 
interest (AESIs). These may include but are not limited to eruptions such as skin rashes, 
skin irritations, skin reactions, or acneiform lesions. This does not include localized 
contact irritation at ECG lead sites due to application/removal of lead adhesive. Preferred 
terms from AE database will be reviewed by Otsuka medical team to determine the list to 
be included in AESIs table. 
The incidence of the following events will be summarized:

TEAEs

TEAEs by severity

TEAEs potentially causally related to the IMP

TEAEs with an outcome of death

Serious TEAEs

TEAEs leading to discontinuation of study

AESIs.
All TEAEs will be presented in a listing. The listing of death due to AEs, serious AEs, 
AEs leading to discontinuation, and AESIs will also be provided. 
10.3
Clinical Laboratory Data
Clinical hematology, chemistry, and urinalysis are tested at screening, check-in (Day -1 
or Day 1), and Day 2/ET. 
For clinical laboratory tests data, baseline is defined as the last non-missing value 
obtained before dosing. The predose assessment will be performed either on Day −1 or 
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Protocol 405-201-00037
Statistical Analysis Plan                                        14 of 21
Version Date: 01/06/2020
Day 1 depending on investigator’s decision. If the predose assessment is missing, the 
baseline value will be based on the screening visit. 
Clinical laboratory tests (observed and change from baseline data) will be summarized by 
time point and mode of administration (intact capsules or capsule contents sprinkled on a 
tablespoon of applesauce). The incidence of potentially clinically relevant clinical 
laboratory tests as defined in Appendix 1 will be summarized by mode of administration. 
Laboratory results that are potentially clinically relevant will also be listed out by 
subjects.
When laboratory test is repeated, the last repeat value will be used in the summary for 
that visit. Unscheduled laboratory data will not be summarized in the change from 
baseline table but will be included in incidence table.
10.4
Vital Sign Data 
Vital signs, including systolic and diastolic blood pressure and heart rate, will be assessed 
at check-in, predose (within 2 hours before dosing) on Day 1, and 3 hours postdose on 
Day 1.
The baseline of vital sign is defined as data collected within 2 hours before dosing on 
Day 1. If a parameter is missing on Day 1 then the screening data collected at check-in 
will be used.
Change from baseline in vital signs will be summarized for post-baseline assessment. The
incidence of potentially clinical relevant vital signs, as defined in Appendix 2 will be 
summarized by time point and mode of administration. Vital sign data that are potentially 
clinically relevant will also be listed out by subject.
When vital sign is repeated, the last repeat value will be used in the summary for that 
visit. Unscheduled vital sign data will not be summarized in the change from baseline 
table but will be included in incidence table.
10.5
Physical Examination Data
A complete physical examination will be performed at screening, check-in (Day -1 or
Day 1), and Day 2/ET. A complete physical examination will consist of measurement of 
height and weight and an assessment of the following body systems: head, eyes, ears, 
nose, and throat; thorax; abdomen; extremities; neurological; and skin and mucosae. Any 
abnormalities considered by the investigator to be clinically significant are to be recorded 
as AEs on the AE eCRF. 
Physical examination data will be presented in a listing.
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Protocol 405-201-00037
Statistical Analysis Plan                                        15 of 21
Version Date: 01/06/2020
10.6
Electrocardiogram (ECG) Data
Descriptive statistics of change from baseline in heart rate and ECG intervals of PR, 
QRS, QT, and QTcF, will be provided by time point and mode of administration. The 
incidence of potentially clinically relevant ECGs, as defined in Appendix 3 will be 
summarized by time point and mode of administration. ECG data that are potentially 
clinically relevant will also be listed out by subject.
When ECG assessment is repeated, the last repeat value will be used in the summary for 
that visit. Unscheduled ECG value will not be summarized in the change from baseline 
table but will be included in incidence table.
10.7
Potential Serious Hepatotoxicity
A listing will be provided to present the incidence of subjects who experience an 
elevation in AST or ALT that is ≥3 times the ULN.
10.8
Other Safety Data
The “Baseline/Screening” version of the C-SSRS will be completed at the screening visit 
and the “Since Last Visit” version of the C-SSRS will be completed at check-in (Day −1
or Day 1) and EoT/ET (Day 2).
The incidence of suicidal behavior and suicidal ideation will be summarized by time 
point and mode of administration.
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Protocol 405-201-00037
Statistical Analysis Plan                                        16 of 21
Version Date: 01/06/2020
Appendix 1
Criteria for Identifying Laboratory Values of Potential 
Clinical Relevance
Laboratory Tests
Criteria (Normal Ranges) for Subjects 9 - 12 Years Olda,b
Chemistry
AST
≥2 × ULN
ALT
≥2 × ULN
ALP
≥2 × ULN
BUN
≥24 mg/dL (≤ 4 mg/dL or ≥24 mg/dL)
Creatinine
≥ 0.7 mg/dL (≤ 0.2 mg/dL or ≥ 0.7 mg/dL)
Uric acid
≥ 6.7 mg/dL (≤ 1.6 mg/dL or ≥ 6.7 mg/dL)
Bilirubin (total)
≥ 1.6 mg/dL (≤ 0.2 mg/dL or ≥ 1.6 mg/dL)
CPK
≥2 × ULN
Prolactin
≥ 21.00 ng/dL (≤ 2.63 ng/dL or ≥ 21.00 ng/dL)
Hematology
Hematocrit
≤ 33% (≤ 33% or ≥ 44%)
Hemoglobin
≤ 11.2 g/dL (≤ 11.2 g/dL or ≥ 15.5 g/dL)
White blood count
≤4.35 × 103/μL (≤4.35 × 103/μL or ≥13.65 × 103/μL)
Eosinophils
4.8%
Neutrophils
≤ 40.5% (≤ 40.5% or ≥ 75.0%)
Absolute neutrophil count
≤1.00 × 103/μL or ≥9.00 × 103/μL
Platelet count
≤130 × 103/μL (≤130 × 103/μL or ≥570 × 103/μL)
Urinalysis
Protein
Change from baseline
Glucose
Presence
Additional Criteria
Chloride
≤94 mEq/L or ≥112 mEq/L
Potassium
≤3.3 mEq/L or 5.2 mEq/L
Sodium
≤132 mEq/L or ≥148 mEq/L
Calcium
≤8.3 mg/dL or ≥10.9 mg/dL
Glucose
Fasting
≥100 mg/dL (≤70 mg/dL or ≥100 mg/dL)
Nonfasting
≥139 mg/dL (≤59 mg/dL or ≥139 mg/dL)
Total cholesterol, fasting
≥217 mg/dL (≤97 mg/dL or ≥217 mg/dL)
LDL cholesterol, fasting
≥130 mg/dL
HDL cholesterol, fasting
≤34 mg/dL (≤34 mg/dL or ≥75 mg/dL)
Triglycerides, fasting
≥131 mg/dL (≤30 mg/dL or ≥131 mg/dL)
aThe recommended criteria represented in this table are intended to identify on-treatment outside of 
normal values that could potentially be clinically relevant. Variations based on local laboratory 
ranges may need to be considered.
bInformation adapted from: 1. Soghier L, Pham K, Rooney S. Reference Range Values for Pediatric 
Care. The American Academy of Pediatrics. 2014; 2. Hughes HK, Kahl LK. The Johns Hopkins
Hospital: The Harriet Lane Handbook. 21st edition. 2015; 3. Covance central laboratory reference 
ranges, 2019.
Clinical Study Report 405-201-00037
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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Protocol 405-201-00037
Statistical Analysis Plan                                        17 of 21
Version Date: 01/06/2020
Appendix 2
Criteria for Potential Clinically Significant Vital Signs
Variable
Criterion Valuea
Change Relative to 
Baselinea
Heart rate at restb
< 60 bpm or > 110 bpm
Increase or decrease of 
≥15 bpm
Systolic blood pressurec
School-age (6 to 9 years 
old)
< 85 mmHg or > 115 mmHg
Increase or decrease of 
≥20 mmHg
Preadolescent (10 to 12 
years old)
< 90 mmHg or > 120 mmHg
Increase or decrease of 
≥15 mmHg
Diastolic blood pressurec
School-age (6 to 9 years 
old)
< 50 mmHg or > 80 mmHg
Increase or decrease of 
≥15 mmHg
Preadolescent (10 to 12 
years old)
< 60 mmHg or > 80 mmHg
Increase or decrease of 
≥15 mmHg
Orthostatic hypotension
≥30 mmHg decrease in systolic blood 
pressure and/or a decrease of ≥20 mmHg 
in diastolic blood pressure after at least 
3 minutes of standing compared to the 
previous supine blood pressure
Not applicable
(baseline status not 
considered)
Orthostatic tachycardia
≥25 bpm increase in heart rate from 
supine to standing
Not applicable
(baseline status not 
considered)
Weight
Not applicable
Increase or decrease of 
≥25%
bpm = beats per minute.
aThe criterion value and change relative to baseline represented in this table are intended to identify 
on-treatment values outside of normal changes and that could potentially be clinically relevant. In 
order to be identified as potentially clinically relevant, the 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. When evaluating these values, the 
emotional state of the subject must be taken into consideration (eg, crying, screaming) and 
documented as applicable.
bInformation adapted from: Hughes HK, Kahl LK. The Johns Hopkins Hospital: The Harriet Lane 
Handbook. 21st edition. 2015.
cInformation adapted from: Flynn JT, Kaelber DC, Baker-Smith CM, et al. Clinical Practice Guideline 
for Screening and Management of High Blood Pressure in Children and Adolescents: American 
Academy of Pediatrics Subcommittee on Screening and Management of High Blood Pressure in 
Children. Pediatrics. 2017;140(3):1-72.
Clinical Study Report 405-201-00037
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
17


Protocol 405-201-00037
Statistical Analysis Plan                                        18 of 21
Version Date: 01/06/2020
Appendix 3
Criteria for Identifying ECG Measurements of Potential 
Clinical Relevance
Variable
Criterion Valuea
Change Relative to Baselinea
Rhythm
Sinus tachycardiab
≥110 bpm
increase of ≥15 bpm
Sinus bradycardiac
≤60 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
< 12 years old
≥ 12 years old
QTcF ≥450 msec
QTcF ≥460 msec
increase of 60 msec 
from baseline
QTc = corrected QT interval.
aThe criterion value and change relative to baseline represented in this table are intended to identify 
on-treatment values outside of normal changes and that could potentially be clinically relevant. In 
order to be identified as potentially clinically relevant, the 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. When evaluating these values, the 
emotional state of the subject must be taken into consideration (eg, crying, screaming) and 
documented as applicable.
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.
Clinical Study Report 405-201-00037
16.1.9 Documentation of Statistical Methods
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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Clinical Study Report 405-201-00037
16.1.9 Documentation of Statistical Methods
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