A Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled Trial to Assess the Efficacy, Safety, and Tolerability of Centanafadine Sustained-release Tablets After Oral Administration in Adult Subjects With Binge Eating Disorder
Phase: PHASE2
Conditions: Binge-Eating Disorder
Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.

Otsuka Pharmaceutical Development & Commercialization, Inc.
Investigational Medicinal Product
Centanafadine (EB-1020) 
REVISED CLINICAL PROTOCOL
A Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled Trial to Assess 
the Efficacy, Safety, and Tolerability of Centanafadine Sustained-release Tablets After 
Oral Administration in Adult Subjects with Binge Eating Disorder
A Trial of Centanafadine Efficacy, Safety, and Tolerability in Adult Subjects with Binge 
Eating Disorder
Protocol No. 405-201-00056
IND No. 155,243
CONFIDENTIAL  PROPRIETARY INFORMATION
Drug Development Phase:
2
Sponsor:
Otsuka Pharmaceutical
Development & Commercialization, Inc.
2440 Research Boulevard
Rockville, Maryland 20850, United States
Immediately Reportable Event 
Global Pharmacovigilance
Fax: +1 301-212-8626
Email: global_intake@otsuka-us.com
Amendment 2 Approval:
24 Jan 2022
Amendment 1 Approval:
28 Oct 2021
Approval:
07 Jul 2021
Synopsis Clinical Study Report 405-201-00056
4.1 Protocol and Protocol Amendments
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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Table of Contents
Table of Contents ..........................................................................................2
List of In-text Tables.....................................................................................7
List of In-text Figures ...................................................................................8
List of Abbreviations.....................................................................................9
1
Protocol Summary..............................................................................11
1.1
Synopsis ............................................................................................................11
1.2
Schema ..............................................................................................................15
1.3
Schedule of Assessments ..................................................................................16
2
Introduction........................................................................................19
2.1
Trial Rationale...................................................................................................19
2.2
Background .......................................................................................................19
2.3
Known and Potential Risks and Benefits ..........................................................20
3
Objectives, Endpoints, and Estimands.............................................20
4
Trial Design.........................................................................................22
4.1
Type/Design of Trial .........................................................................................22
4.2
Scientific Rationale for Trial Design.................................................................23
4.3
Dosing Rationale...............................................................................................24
4.4
End of Trial Definition......................................................................................24
4.5
Definition of Completed Subjects.....................................................................24
5
Trial Population..................................................................................24
5.1
Subject Selection and Numbering.....................................................................25
5.2
Eligibility Criteria .............................................................................................25
5.2.1
Inclusion Criteria ............................................................................................25
5.2.2
Exclusion Criteria...........................................................................................26
5.3
Lifestyle Considerations....................................................................................27
5.3.1
Meals and Dietary Restrictions.......................................................................27
5.3.2
Caffeine, Alcohol, Tobacco, and Other Substances .......................................27
5.3.3
Activity ...........................................................................................................28
5.4
Screen Failures ..................................................................................................28
6
Trial Treatments ................................................................................29
Synopsis Clinical Study Report 405-201-00056
4.1 Protocol and Protocol Amendments
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6.1
Trial Treatments Administered .........................................................................29
6.1.1
Medical Devices .............................................................................................30
6.2
Management of Investigational Medicinal Product ..........................................30
6.2.1
Packaging and Labeling..................................................................................30
6.2.2
Storage............................................................................................................30
6.2.3
Accountability.................................................................................................31
6.2.4
Returns and Destruction .................................................................................31
6.2.5
Reporting of Product Quality Complaints......................................................31
6.2.5.1
Eliciting and Reporting Product Quality Complaints .................................31
6.2.5.2
Information Required for Reporting Purposes............................................32
6.2.5.3
Return Process.............................................................................................32
6.2.5.4
Assessment/Evaluation ...............................................................................32
6.3
Measures to Minimize/Avoid Bias....................................................................32
6.4
Subject Compliance...........................................................................................33
6.5
Concomitant Medications or Therapies ............................................................33
6.5.1
Prohibited Medications or Therapies..............................................................33
6.5.2
Permitted Medications or Therapies...............................................................34
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...................................................................36
7.3.1
Treatment Interruption....................................................................................36
7.3.2
Treatment Discontinuation .............................................................................36
7.3.3
Documenting Reasons for Treatment Interruption or Discontinuation ..........36
7.3.4
Withdrawal of Consent...................................................................................37
7.3.5
Procedures to Encourage Continued Trial Participation ................................38
7.4
Definition of Subjects Lost to Follow-up..........................................................38
8
Trial Procedures.................................................................................39
8.1
Efficacy Assessments........................................................................................39
8.1.1
Patient-Reported Outcomes............................................................................39
Synopsis Clinical Study Report 405-201-00056
4.1 Protocol and Protocol Amendments
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8.1.1.1
Binge Eating Diary......................................................................................39
8.1.1.2
Eating Disorder Examination Questionnaire and Eating Disorder 
Examination Questionnaire - 7-Item Version .............................................40
8.1.1.3
Patient Global Impression - Severity ..........................................................40
8.1.1.4
Patient Global Impression - Change ...........................................................40
8.1.1.5
36-Item Short-Form Health Survey ............................................................40
8.1.2
Clinician Rating Scales...................................................................................41
8.1.2.1
Clinical Global Impression - Severity.........................................................41
8.1.2.2
Clinical Global Impression - Change..........................................................41
8.1.2.3
Yale-Brown Obsessive-Compulsive Scale Modified for Binge Eating......41
8.2
Pharmacokinetic Assessments...........................................................................41
8.2.1
Pharmacokinetic Blood Samples....................................................................41
8.3
Pharmacodynamic Assessments........................................................................42
8.4
Pharmacogenomic Assessments........................................................................42
8.5
Biomarker Assessments ....................................................................................42
8.7
Safety Assessments ...........................................................................................43
8.7.1
Clinical Laboratory Assessments ...................................................................43
8.7.2
Physical Examination .....................................................................................44
8.7.3
Vital Signs ......................................................................................................45
8.7.4
Electrocardiogram...........................................................................................45
8.7.5
Suicidality Monitoring....................................................................................45
8.7.6
Other Safety Variables....................................................................................46
8.7.6.1
Study Medication Withdrawal Questionnaire.............................................46
8.7.6.2
Hamilton Anxiety Rating Scale ..................................................................46
8.7.6.3
Montgomery-Asberg Depression Rating Scale...........................................46
8.8
Adverse Events..................................................................................................46
8.8.1
Definitions ......................................................................................................46
8.8.2
Eliciting and Reporting Adverse Events.........................................................49
8.8.3
Immediately Reportable Events......................................................................49
8.8.4
Medical Device Incidents (Including Malfunctions)......................................49
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8.8.5
Adverse Events of Special Interest.................................................................50
8.8.6
Abuse Potential Monitoring Process, Events Subject to Additional 
Monitoring, and Medication Handling Irregularities......................................50
8.8.7
Potential Serious Hepatotoxicity ....................................................................51
8.8.8
Procedure for Breaking the Blind...................................................................51
8.8.9
Follow-up of Adverse Events.........................................................................51
8.8.9.1
Follow-up of Nonserious Adverse Events ..................................................51
8.8.9.2
Follow-up of Immediately Reportable Events............................................51
8.8.9.3
Follow-up and Reporting of Immediately Reportable Events 
Occurring After Last Scheduled Contact....................................................52
8.9
Treatment of Overdose......................................................................................52
8.10
Subject Assessment Recording .........................................................................53
8.10.1
Diagnostic Criteria for Binge Eating Disorder...............................................53
8.10.2
Structured Clinical Interview for DSM-5.......................................................53
8.11
Other Assessments ............................................................................................53
9
Statistical Considerations ..................................................................53
9.1
Sample Size.......................................................................................................53
9.2
Datasets for Analysis.........................................................................................53
9.3
Handling of Missing Data for Primary and Key Secondary Endpoint 
Analysis.............................................................................................................54
9.4
Statistical Analyses ...........................................................................................54
9.4.1
Efficacy Analyses...........................................................................................54
9.4.1.1
Primary Efficacy Endpoint Analysis...........................................................54
9.4.1.3
Key Secondary Efficacy Endpoint Analysis...............................................56
9.4.1.4
Other Efficacy Endpoint Analysis ..............................................................56
9.4.1.5
Control of Experiment-wise Type 1 Error ..................................................57
9.4.1.6
Other Efficacy Endpoint Analysis ..............................................................57
9.4.2
Safety Analysis...............................................................................................57
9.4.2.1
Adverse Events ...........................................................................................57
9.4.2.2
Clinical Laboratory Data.............................................................................57
9.4.2.3
Physical Examination and Vital Signs Data ...............................................58
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9.4.2.4
Electrocardiogram Data ..............................................................................58
9.4.2.5
Other Safety Data........................................................................................58
9.4.3
Other Analyses................................................................................................58
9.4.3.1
Analysis of Demographic and Baseline Characteristics .............................58
9.4.3.2
Pharmacokinetic Analysis...........................................................................59
9.4.3.3
Pharmacodynamic Analysis........................................................................59
9.4.3.4
Pharmacokinetic/Pharmacodynamic Analysis............................................59
9.4.3.5
Pharmacogenomic Analysis........................................................................59
59
9.5
Interim Analysis and Adaptive Design .............................................................59
9.5.1
Data Monitoring Committee...........................................................................59
10
Supporting Documentation and Operational Considerations .......60
10.1
Appendix 1: Regulatory, Ethical, and Trial Oversight Considerations.............60
10.1.1
Ethics and Responsibility ...............................................................................60
10.1.2
Informed Consent ...........................................................................................60
10.1.3
Confidentiality................................................................................................61
10.1.4
Quality Control and Quality Assurance..........................................................62
10.1.4.1
Monitoring ..................................................................................................62
10.1.4.2
Auditing ......................................................................................................62
10.1.5
Protocol Deviations ........................................................................................62
10.1.6
Records Management .....................................................................................63
10.1.6.1
Source Documents ......................................................................................63
10.1.6.2
Data Collection ...........................................................................................63
10.1.6.3
File Management at the Trial Site...............................................................65
10.1.6.4
Records Retention at the Trial Site .............................................................65
10.1.6.5
Publication Authorship Requirements ........................................................65
10.2
Appendix 2: Clinical Laboratory Tests .............................................................67
10.3
Appendix 3: Contraceptive Guidance and Collection of Pregnancy 
Information........................................................................................................68
10.4
Appendix 10: Protocol Amendments ................................................................70
10.4.1
Protocol Amendment(s)/Administrative Change(s) .......................................71
10.4.1.1
Protocol Amendment 1 ...............................................................................71
10.4.1.2
Protocol Amendment 2 ...............................................................................73
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11
References ...........................................................................................74
List of In-text Tables
Table 1.3-1
Schedule of Assessments...............................................................16
Table 3-1
Trial Objectives and Endpoints .....................................................20
Table 5.2.1-1
Inclusion Criteria ...........................................................................25
Table 5.2.2-1
Exclusion Criteria ..........................................................................26
Table 6.5.1-1
List of Medications or Therapies Prohibited/Restricted from 
the Screening Visit through the end of Safety Follow-Up ............34
Table 6.5.2-1
List of Medications Permitted During the Trial ............................34
Synopsis Clinical Study Report 405-201-00056
4.1 Protocol and Protocol Amendments
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List of In-text Figures
Figure 1.2-1
Trial Design Schematic..................................................................15
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4.1 Protocol and Protocol Amendments
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List of Abbreviations
Abbreviation
Definition
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine aminotransferase
aPTT
Activated partial thromboplastin time
AST 
Aspartate aminotransferase
BID
Twice daily (or 2 times a day)
BMI
Body mass index
bpm
Beats per minute
BUN
Blood urea nitrogen
CBP
Childbearing potential
CFR
Code of Federal Regulations
CIOMS
Council for International Organizations of Medical Science
CMH
Cochran-Mantel-Haenszel
COVID-19
Coronavirus disease 2019
CPK
Creatine phosphokinase
CRF
Case report form
CRO
Contract research organization
C-SSRS
Columbia-Suicide Severity Rating Scale
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
eCRF
Electronic case report form
eICF
Electronic informed consent form
EDE
Eating Disorder Examination
EDE-Q
Eating Disorder Examination Questionnaire
EDE-Q7
Eating Disorder Examination Questionnaire - 7-Item Version
ESAM
Events subject to additional monitoring
ET
Early termination
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GGT
Gamma glutamyl transferase
HAM-A
Hamilton Anxiety Rating Scale
HbA1c
Glycosylated hemoglobin
hCG
Human chorionic gonadotropin
HDL
High-density lipoprotein
IB
Investigator’s Brochure
ICH
International Council for Harmonisation
ICMJE
International Committee of Medical Journal Editors
ID
Identifier
IMP
Investigational medicinal product
INR
International normalized ratio
IRB
Institutional review board
IRE
Immediately reportable event
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Abbreviation
Definition
K2EDTA
Dipotassium ethylenediaminetetraacetic acid
LDH
Lactic dehydrogenase
LOE
Lack of efficacy
MADRS
Montgomery-Asberg Depression Rating Scale
MAR
Missing at random
MCH
Mean corpuscular hemoglobin
MCS
Mental Component Summary score
MedDRA
Medical Dictionary for Regulatory Activities
MHI
Medication handling irregularity
MMRM
Mixed-effect model repeated measures
MNAR
Missing not at random
OC
Observed cases
OPDC
Otsuka Pharmaceutical Development & Commercialization, Inc
PCS
Physical Component Summary score
PK
Pharmacokinetic
PQC
Product quality complaint
PT
Prothrombin time
QTc
Corrected QT interval
QTcF
QT interval corrected for heart rate using Fridericia’s formula
RBC
Red blood cell count
RDW
Red cell distribution width
RNA
Ribonucleic acid
SAE
Serious adverse event
SAP
Statistical analysis plan
SCID-5-CT
Structured Clinical Interview for DSM-5 Disorders, Clinical Trials 
Version
SF-36v2
36-item Short-Form Health Survey Version 2
SMWQ
Study Medication Withdrawal Questionnaire
T4
Thyroxine
TDD
Total daily dose
TEAE
Treatment-emergent adverse event
TSH
Thyroid stimulating hormone
ULN
Upper limit of normal
WBC
White blood cell count
Synopsis Clinical Study Report 405-201-00056
4.1 Protocol and Protocol Amendments
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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.: 405-201-00056
IND No.: 155,243
Protocol Title: A Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled 
Trial to Assess the Efficacy, Safety, and Tolerability of Centanafadine Sustained-release 
Tablets After Oral Administration in Adult Subjects with Binge Eating Disorder
Protocol Lay Person Short Title: A Trial of Centanafadine Efficacy, Safety, and 
Tolerability in Adult Subjects with Binge Eating Disorder
Clinical Phase: 2
Treatment/Indication: Binge eating disorder (BED)
Objectives and Endpoints:
Objectives
Endpoints
Primary: To assess the efficacy of 2 doses of 
centanafadine SR (200 and 400 mg TDD) compared 
with placebo in adults with moderate to severe BED.
Primary Efficacy: Change from baseline in 
binge eating days per week at Weeks 7-8, 
having binge eating day defined as a day with at 
least one binge eating episode
Key Secondary Efficacy: 

Change from baseline in CGI-S score at 
Week 8
Other Efficacy: 

Change from baseline in CGI-S score at 
Weeks 1, 2, 3, 4, and 6

CGI-C score

Change from baseline in Y-BOCS-BE score

Proportion of subjects with four-week 
cessation from binging at Week 8/ET

Change from baseline in number of binge 
episodes per week

Change from baseline in PGI-S score

PGI-C score

Change from baseline in SF-36v2 PCS and 
MCS scores 

Change from baseline in EDE-Q7 total 
score
Synopsis Clinical Study Report 405-201-00056
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Objectives
Endpoints
Secondary: 

To assess the safety and tolerability of 
centanafadine SR tablets administered daily (200 
and 400 mg TDD) in the treatment of subjects 
with BED.
Safety: AEs (including AESIs [rash], 
abuse-related AEs, and AEs involving MHIs), 
clinical laboratory tests (hematology, serum 
chemistry [including change from baseline in 
total cholesterol and triglycerides], and 
urinalysis), vital sign measurements (including 
change from baseline in body weight and 
percent change from baseline in body weight), 
12-lead ECGs, SMWQ, HAM-A, MADRS, and 
C-SSRS
AE = adverse event; AESI = adverse event of special interest; CGI-C = Clinical Global Impression - 
Change; CGI-S = Clinical Global Impression - Severity; C-SSRS = Columbia-Suicide Severity 
Rating Scale; ECG = electrocardiogram; EDE-Q7 = Eating Disorder Examination Questionnaire - 
7-Item Version; ET = early termination; HAM-A = Hamilton Anxiety Rating Scale; MADRS = 
Montgomery-Asberg Depression Rating Scale; MCS = Mental Component Summary score; 
MHI = medication handling irregularity; PCS = Physical Component Summary score; 
PGI-C = Patient Global Impression - Change; PGI-S = Patient Global Impression - Severity; 
SF-36v2 = 36-item Short-Form Health Survey Version 2; SMWQ = Study Medication Withdrawal 
Questionnaire; TDD = total daily dose; Y-BOCS-BE = Yale-Brown Obsessive-Compulsive Scale 
Modified for Binge Eating.
Trial Design: This will be a phase 2, multicenter, randomized, double-blind, 
placebo-controlled trial to assess the efficacy, safety, and tolerability of centanafadine SR 
tablets for the treatment of adult subjects with BED. The trial will consist of a 28-day 
screening period that includes completion of a binge eating diary for at least 14 days, a 
baseline visit, an 8-week (56-day) double-blind treatment period, and a 7-day safety 
follow-up period. All baseline assessments will be conducted prior to first dose of IMP.
Trial Population: Approximately 228 adult subjects with BED are anticipated to be 
screened with the expectation that approximately 126 subjects will be randomized 
(42 subjects per treatment arm).
Key Inclusion/Exclusion Criteria: Subjects will be 18 to 65 years of age (inclusive), 
with a primary diagnosis of BED of at least moderate severity, with a history of at least 
2 binge eating days per week for 6 months prior to screening and at least 3 binge eating 
days in each week during the previous 14 days of a subject’s screening period as 
reviewed at baseline (minimum screening period is 2 weeks), a rating of 4 or higher on 
the Clinical Global Impression - Severity (CGI-S) at screening and baseline, and a BMI 
of 18 to 45 kg/m2, inclusive. Subjects with a lifetime history or current diagnosis of 
bulimia nervosa or anorexia nervosa will be excluded.
Trial Site(s): This is a multicenter trial in the United States. 
Investigational Medicinal Product(s), Dose, Dosage Regimen, Treatment Duration, 
Formulation, Mode of Administration: IMP consisting of high dose centanafadine 
(400 mg total daily dose [TDD]), low dose centanafadine (200 mg TDD), or placebo will 
Synopsis Clinical Study Report 405-201-00056
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be administered orally as 100 mg sustained-release (SR) tablets or matching placebo 
taken twice daily, approximately 4 to 6 hours apart.
Trial Assessments:
Assessments for Efficacy: Binge eating diary, CGI-S, Clinical Global Impression - 
Change (CGI-C), Yale-Brown Obsessive-Compulsive Scale Modified for Binge Eating 
(Y-BOCS-BE), Eating Disorder Examination Questionnaire (EDE-Q), Eating Disorder 
Examination Questionnaire - 7-Item Version (EDE-Q7), Patient Global Impression - 
Severity (PGI-S), Patient Global Impression - Change (PGI-C), 36-item Short-Form 
Health Survey Version 2 (SF-36v2)
Assessments for Pharmacokinetics and 
 
 
 
 
 
Assessments for Safety: AEs (including AESI evaluations [rash], abuse-related AEs, and 
AEs involving medication handling irregularities [MHIs]), clinical laboratory tests 
(hematology, serum chemistry [including total cholesterol and triglycerides], and 
urinalysis), physical examinations, vital sign measurements (including body weight), 
electrocardiograms (ECGs), and assessments of suicidality (Columbia-Suicide Severity 
Rating Scale [C-SSRS]), withdrawal (Study Medication Withdrawal Questionnaire 
[SMWQ]), anxiety (Hamilton Anxiety Rating Scale [HAM-A]), and depression 
(Montgomery-Asberg Depression Rating Scale [MADRS]).
Screening/Other: pregnancy test, urine drug screen/alcohol testing via breathalyzer, 
blood, or urine, and psychiatric evaluation
Data Monitoring Committee: No
Statistical Methods: Assuming a treatment difference of 1.1 points with a standard 
deviation of 1.7 in the mean change from baseline in binge eating days per week at 
Weeks 7-8 in either centanafadine dose group (high dose centanafadine or low dose 
centanafadine) compared to the placebo group (effect size = 0.65), a sample size of 
114 evaluable subjects (38 in each treatment arm) will yield at least 80% power to detect 
the treatment effects at a 2-tailed significance level of 0.05. Approximately 126 subjects 
will be randomized (42 in each treatment arm) to ensure 114 evaluable subjects in the 
study. The primary efficacy analysis will be performed by fitting a mixed-effect model 
repeated measures (MMRM) analysis with an unstructured variance covariance structure, 
in which change from baseline in binge eating days per week at the scheduled visits will 
be the dependent variable based on the observed cases (OC) data set. The model will 
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include fixed effect terms for treatment, trial center, visit week, and an interaction term of 
treatment by visit week. The model will also include the interaction term of baseline 
values of binge eating days per week by visit week as covariates. The primary 
comparison between centanafadine groups and the placebo group at Weeks 7-8 will be 
estimated as the difference between Least Squares means utilizing the computing 
software SAS procedure PROC MIXED. If there is a convergence problem with the 
unstructured variance covariance matrix of the MMRM model, the following structures 
other than unstructured will be used in order of 1) heterogeneous toeplitz, 
2) heterogeneous autoregressive of order 1, and 3) heterogeneous compound symmetry 
and the first (co)variance structure converging to the best fit will be used as the primary 
analysis. If a structured covariance has to be used, the “sandwich” estimator of the 
standard error of the fixed effects parameters will be used in order to deal with possible 
model misspecification of the covariance matrix.
Trial Duration:
The anticipated duration for each participant to complete the trial is up to 13 weeks, 
which will include the following periods:

Screening period: up to 4 weeks (28 days)

Double-blind treatment period: 8 weeks

Follow-up period: 7 (+ 2) days 
Overall, the trial duration from signing of the first informed consent form to the final 
subject assessment is expected to be approximately 10 months.
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1.2
Schema
N = number of subjects; R = randomization; T = telephone visit.
aExtension of screening may be requested and discussed with the medical monitor prior to the expiration of the screening period.
Figure 1.2-1
Trial Design Schematic
Visit 2
Day -1 
(Baseline)
Visit 4
Week 1
(± 2 days)
Visit 5
Week 2 
(± 2 days)
Visit 6
Week 3
(± 2 days)
Visit 7
Week 4 
(± 2 days)
Visit 9
Week 6 
(± 2 days)
Centanafadine SR 400 mg TDD
(n = 42)
Centanafadine SR 200 mg TDD
(n = 42)
Placebo
(n = 42)
N = ~126
N = 228
Visit 1
Visit 12 (T)
7 (+ 2) 
days
post last 
dose
R
Day 1
First dose
Subjects will be randomly assigned (1:1:1) to 
one of the following treatments:
Screening 
Perioda
8-Week Double-blind Treatment Period
Safety Follow-up Period
Up to 28 days 
prior to Day −2
One visit 
between 
Day -28 and 
Day -2
Visit 11
 Week 8 
(± 2 days)
7-day safety follow-up period, 
with last visit 7 (+ 2) days post 
last dose
(telephone contact only)
Visit 3 (T)
Visit 8 (T)
Visit 10 (T)
Week 7 
(± 2 days
Week 5 
(± 2 days)
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1.3
Schedule of Assessments
Table 1.3-1
Schedule of Assessments
Screeninga
Baseline
Double-Blind Treatment Period
Safety 
Follow-
up
Days 
−28 to −2
Day −1
First 
Dose 
Day 
1
WK 
1
(± 2 
days)
WK 
2
(± 2 
days)
WK 
3
(± 2 
days)
WK 
4
(± 2 
days)
WK 
5 
(± 2 
days)
WK 
6
(± 2 
days)
WK 
7
(± 2 
days)
WK 
8/ET
(± 2 
days)
7 (+ 2) 
days post 
last dose
Notes:
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
Visit Type
O
O
T
O
O
O
O
T
O
T
O
T
ENTRANCE CRITERIA
Informed consent
X
Section 10.1.2
Inclusion/exclusion 
criteria
X
X
Section 5.2
Demographics
X
Section 5.1
Concomitant 
medication(s)
X
X
X
X
X
X
X
X
X
X
X
X
Section 6.5
Medical history
X
Section 5.1
SCID-5-CT
X
Section 8.10.2
Urine pregnancy test
X
X
X
X
Section 10.3
UDS/alcohol testingb
X
X
Section 5.3.2 
and 
Section 10.2
EFFICACYc 
Binge Eating Diary
<---------------------------------------------- daily completion by subject ---------------------------------------->
(severity criteria must be confirmed at baseline on previous 14 days of binge eating diary data)
Section 8.1.1
CGI-S
X
X
X
X
X
X
X
X
Section 8.1.2
CGI-C
X
X
X
X
X
X
Section 8.1.2.2
Y-BOCS-BE
X
X
X
X
X
X
X
X
Section 8.1.2.3
EDE-Q (full scale)
X
Section 8.1.1.2
EDE-Q7 
X
X
Section 8.1.1.2
PGI-S
X
X
X
X
X
X
X
X
Section 8.1.1.3
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Table 1.3-1
Schedule of Assessments
Screeninga
Baseline
Double-Blind Treatment Period
Safety 
Follow-
up
Days 
−28 to −2
Day −1
First 
Dose 
Day 
1
WK 
1
(± 2 
days)
WK 
2
(± 2 
days)
WK 
3
(± 2 
days)
WK 
4
(± 2 
days)
WK 
5 
(± 2 
days)
WK 
6
(± 2 
days)
WK 
7
(± 2 
days)
WK 
8/ET
(± 2 
days)
7 (+ 2) 
days post 
last dose
Notes:
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
Visit Type
O
O
T
O
O
O
O
T
O
T
O
T
PGI-C
X
X
X
X
X
X
Section 8.1.1.4
SF-36v2 
X
X
X
Section 8.1.1.5
SAFETYc
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
Section 8.8
Clinical laboratory 
assessmentsd,e
X
Section 8.7.1
Clinical laboratory 
assessments, fastingd
X
X
X
Section 8.7.1
Urinalysisd
X
X
X
X
Section 8.7.1
Physical examination
X
Section 8.7.2
Height (screening 
only) and weight
X
X
X
X
X
X
X
X
Section 8.7.2
Vital signsc
X
X
X
X
X
X
X
X
Section 8.7.3
12-lead ECGc,d
X
X
X
X
Section 8.7.4
C-SSRS
X
X
X
X
X
X
X
X
Section 8.7.5
SMWQ
X
X
Section 8.7.6.1
HAM-A
X
X
Section 8.7.6.2
MADRS
Xf
X
Section 8.7.6.3
PHARMACOKINETIC/
 
PK blood draws
X
X
Section 8.2.1
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Table 1.3-1
Schedule of Assessments
Screeninga
Baseline
Double-Blind Treatment Period
Safety 
Follow-
up
Days 
−28 to −2
Day −1
First 
Dose 
Day 
1
WK 
1
(± 2 
days)
WK 
2
(± 2 
days)
WK 
3
(± 2 
days)
WK 
4
(± 2 
days)
WK 
5 
(± 2 
days)
WK 
6
(± 2 
days)
WK 
7
(± 2 
days)
WK 
8/ET
(± 2 
days)
7 (+ 2) 
days post 
last dose
Notes:
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
Visit Type
O
O
T
O
O
O
O
T
O
T
O
T
OTHER
IMP dispensing
X
X
X
X
X
X
Section 6.2.3
IMP administration
X
X
X
X
X
X
X
X
X
Section 6.1
IMP return and 
accountability
X
X
X
X
X
X
Section 6.2.3 
and 
Section 6.2.4
ET = early termination; O = office; SCID-5-CT = Structured Clinical Interview for DSM-5 Disorders, Clinical Trials Version; T = telephone; UDS = urine 
drug screen; WK = week.
aExtension of screening may be requested and discussed with the medical monitor prior to the expiration of the screening period.
bUDS is to be done on-site initially, with a confirmatory urine sample collected if needed for processing through the central lab. Alcohol test is to be 
conducted initially via breathalyzer, with confirmation via blood or urine sample through central lab processing. Additional UDS/alcohol testing can be 
performed during the double-blind treatment period at the investigator’s discretion.
cEfficacy assessments should be completed prior to safety assessments and PK 
 blood draws. Vital signs and ECGs should be completed prior to any 
blood draws.
dOnly if results are exclusionary at screening will a repeat test be performed prior to the baseline visit.  Results must be available and inclusionary prior to 
randomization.
eSubjects are not required to be fasting for screening laboratory assessments.
fTo be completed at the beginning of the baseline visit for confirmation of eligibility criteria.
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2
Introduction
Centanafadine (EB-1020) is a triple monoamine reuptake inhibitor being developed for 
attention-deficit/hyperactivity disorder (ADHD). The current trial is designed to assess its 
efficacy as treatment of binge eating disorder (BED) in adults. This trial is intended to 
evaluate the efficacy and safety of centanafadine sustained release (SR) tablets compared 
to placebo for the treatment of BED in adult subjects who have a clinical diagnosis of 
moderate to severe BED based on the DSM-5 diagnosis criteria and confirmed by the 
Structured Clinical Interview for DSM-5 Disorders, Clinical Trials Version 
(SCID-5-CT). 
2.1
Trial Rationale
Centanafadine is a new molecular entity with inhibitory activity at the norepinepherine 
(NE), dopamine (DA), and serotonin (5-HT)-reuptake transporters and has demonstrated 
safety and efficacy as a treatment of ADHD in adults. As positive results from phase 3 
trials support the notion that DA and NE transmission plays in the etiology of both 
ADHD and BED, centanafadine is being evaluated for the treatment of BED (see 
Section 4.2). This Phase 2 proof-of-concept trial is designed to assess initial efficacy in 
reducing symptoms of BED in adults.
2.2
Background
Binge eating disorder is defined by the Diagnostic and Statistical Manual of Mental 
Disorders - 5th Edition (DSM-5) as a condition marked by recurrent episodes of eating 
large quantities of food that is accompanied by a sense of loss of control and followed by 
guilt, shame, or distress; and without common use of compensatory measures such as 
purging, restricting, or excessive exercising to counter binge episodes. According to the 
National Comorbidity Survey, the lifetime prevalence of BED is up to 3.5% in women 
and 2.0% in men in the United States, making it more common than anorexia and bulimia 
combined. Onset begins in late adolescence and occurs more frequently in women than in 
men.1 A recent report suggests BED and other specified feeding or eating disorders are 
unrepresented in global estimates of disease burden.2 Various behavioral therapies are 
utilized and off-label use of antidepressants or anticonvulsants are sometimes utilized.3 
Currently, only Vyvanse® (lisdexamfetamine) is approved for the treatment of BED.4 
Less than half of individuals with BED receive treatment specifically for this condition.1 
There are likely various reasons for this,  including under-reporting of symptoms by 
patients who may feel shame, under-diagnosis of the condition which was only recently 
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identified as a distinct condition in the DSM-5, and evidence-based treatment options 
being limited to specialized psychotherapy and only a single approved medication.
The correlation between impulsivity in ADHD and BED has long been hypothesized and 
is supported by findings of numerous studies5 including those showing shared neural 
circuitry.6 The efficacy of lisdexamfetamine for both ADHD and BED further suggests 
treatments effective for one indication could provide efficacy for the other.
This trial is intended to evaluate the efficacy and safety of 2 oral doses of centanafadine 
SR tablets compared to placebo for the treatment of BED in adult subjects who have a 
clinical diagnosis of moderate to severe BED. 
Please refer to the centanafadine Investigator’s Brochure (IB) for more detailed 
information.
2.3
Known and Potential Risks and Benefits
The anticipated risks of centanafadine are described in detail in the currently approved 
version of the Investigator’s Brochure. There are no unique risks anticipated in the BED 
population.
Trial sites will receive updated versions of the IB when available, and should refer to the 
most current version as needed.
3
Objectives, Endpoints, and Estimands
Table 3-1
Trial Objectives and Endpoints
Objectives
Endpoints
Primary: To assess the efficacy of 
2 doses of centanafadine SR (200 
and 400 mg TDD) compared with 
placebo in adults with moderate to 
severe BED.
Primary Efficacy: Change from baseline in binge 
eating days per week at Weeks 7-8, having binge 
eating day defined as a day with at least one 
binge eating episode
Key Secondary Efficacy: 

Change from baseline in CGI-S score at 
Week 8
Other Efficacy: 

Change from baseline in CGI-S score at 
Weeks 1, 2, 3, 4, and 6

CGI-C score

Change from baseline in Y-BOCS-BE score

Proportion of subjects with four-week 
cessation from binging at Week 8/ET
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Table 3-1
Trial Objectives and Endpoints
Objectives
Endpoints

Change from baseline in number of binge 
episodes per week

Change from baseline in PGI-S score

PGI-C score

Change from baseline in SF-36v2 PCS and 
MCS scores 

Change from baseline in EDE-Q7 total score
Secondary: 

To assess the safety and 
tolerability of centanafadine 
SR tablets administered daily 
(200 and 400 mg TDD) in the 
treatment of subjects with 
BED.
Safety: AEs (including AESIs [rash], abuse-
related AEs, and AEs involving MHIs), clinical 
laboratory tests (hematology, serum chemistry 
[including change from baseline in total 
cholesterol and triglycerides], and urinalysis), 
vital sign measurements (including change from 
baseline in body weight and percent change from 
baseline in body weight), 12-lead ECGs, SMWQ, 
HAM-A, MADRS, and C-SSRS
AE = adverse event; AESI = adverse event of special interest; CGI-C = Clinical Global Impression - 
Change; CGI-S = Clinical Global Impression - Severity; C-SSRS = Columbia-Suicide Severity 
Rating Scale; ECG = electrocardiogram; EDE-Q7 = Eating Disorder Examination Questionnaire - 
7-Item Version; HAM-A = Hamilton Anxiety Rating Scale; MADRS = Montgomery-Asberg 
Depression Rating Scale; MCS = Mental Component Summary score; MHI = medication handling 
irregularity; PCS = Physical Component Summary score; PGI-C = Patient Global Impression - 
Change; PGI-S = Patient Global Impression - Severity; SF-36v2 = 36-item Short-Form Health Survey 
Version 2; SMWQ = Study Medication Withdrawal Questionnaire; TDD = total daily dose; 
Y-BOCS-BE = Yale-Brown Obsessive-Compulsive Scale Modified for Binge Eating.
Section 9.4 describes the statistical analysis of the endpoints.
Primary Estimand
The primary clinical question of interest is: what is the treatment difference in binge 
eating days per week after 8 weeks of centanafadine treatment compared to placebo 
treatment in adult subjects with moderate to severe BED, where no subject would 
discontinue treatment due to any reason?
The primary estimand has the following attributes:

Population: adult subjects with moderate to severe BED who meet the 
inclusion/exclusion criteria. Details are specified in Section 5.

Endpoint: change from baseline in binge eating days per week at Weeks 7-8.

Intercurrent events: premature treatment discontinuation.
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
Treatment condition: one of the randomized treatment groups of the following per 
protocol: high dose centanafadine 400 mg TDD, low dose centanafadine 200 mg 
TDD, or placebo. Details can be found in Section 6.

Population-level summary: difference in mean of endpoint between treatment 
conditions.

Rationale for estimand: the hypothetical estimand is to evaluate the pharmacological 
effect if no withdrawals had occurred. It is justifiable since the focus is on the 
pharmacological effect of the drug additional to non-specific effects. Subjects who 
withdraw from a symptomatic IMP treatment either could have lost the treatment 
effect if the subjects had not taken any other symptomatic medication after 
withdrawal or could have the treatment effect masked if the subjects had taken other 
symptomatic medication after withdrawal. In those cases, any observations taken after 
subjects stop IMP will most likely not contribute to relevant information about the 
pharmacological effect of the drug. Therefore, the last collected efficacy assessment 
after premature trial discontinuation will be performed only once at the ET Visit.
Secondary and Other Estimands
The clinical question of interest for the key secondary estimand is: what is the treatment 
difference in CGI-S Score after 8 weeks of centanafadine treatment compared to placebo 
treatment in adult subjects with moderate to severe BED, where no subject would 
discontinue treatment due to any reason?
The key secondary estimand has similar attibutes to the primary estimand except that key 
secondary endpoint is change from baseline in CGI-S score at Week 8. Other estimands 
have similar attributes to the primary and key secondary estimands. 
4
Trial Design
4.1
Type/Design of Trial
This will be a phase 2, multicenter, randomized, double-blind, placebo-controlled trial to 
assess the efficacy, safety, and tolerability of centanafadine SR tablets for the treatment 
of adult subjects with BED. Subjects with a primary clinical diagnosis of moderate to 
severe BED based on the DSM-57 diagnosis criteria and confirmed by the SCID-5-CT 
will be eligible for enrollment. The trial will consist of a screening period of up to 
28 days that includes completion of a binge eating diary for at least 14 days (that shows 
at least 3 binge eating days in each week during the previous 14 days of a subject’s 
screening period as reviewed at baseline [minimum screening period is 2 weeks]), a 
baseline visit, an 8-week (56-day) double-blind treatment period, and a 7-day safety 
follow-up period. All baseline assessments will be conducted prior to first dose of IMP.
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Eligible subjects will be randomized 1:1:1 at baseline to receive 1 of 2 doses of 
centanafadine SR or placebo daily for 8 weeks. The doses of centanafadine SR that will 
be assessed in adult subjects during this trial were selected based on the efficacious and 
safe doses in the adult ADHD phase 2 and 3 trials.
Sparse pharmacokinetic (PK) blood samples will be taken. 
 
 
 
 
 (Table 1.3-1). 
All subjects who terminate early will be required to participate in a 7-day safety 
follow-up period, which will consist of telephone contact 7 (+ 2) days after the last dose 
of investigational medicinal product (IMP). For subjects who early terminate, they will be 
instructed to refrain from using prohibited concomitant medications, including BED 
treatments, until after the safety follow-up visit.
4.2
Scientific Rationale for Trial Design
Centanafadine, a new molecular entity with inhibitory activity at the NE, DA, and 
5-HT-reuptake transporters, is being evaluated for the treatment of BED. In vivo studies 
have demonstrated that centanafadine is a monoamine reuptake inhibitor that 
differentially increases NE, DA, and 5-HT extracellular concentrations in the prefrontal 
cortex and DA in the striatum,8 areas known to play a role in executive function, and 
impulsivity and reward in BED, respectively.9
Centanafadine has demonstrated efficacy in adult ADHD (Trial 405-201-00013 and 
Trial 405-201-00014) through increased neurotransmission of DA and NE 
(Trial 405-201-00022). Non-clinical studies10,11,12,13,14 and clinical trial data (Trial 
405-201-00019) suggests centanafadine may have a lower abuse potential compared to 
stimulants, which may support less restrictive scheduling, if any. The combined result 
may mean a safe and tolerable treatment option for this most common of eating disorders.
Lisdexamfetamine and dasotraline are 2 drugs that have positive results from large phase 
3 trials in BED, as well as positive results from large phase 3 trials in adult ADHD, 
which supports the role that DA and NE transmission plays in the etiology of both 
disorders. Lisdexamfetamine remains the only Food and Drug Administration (FDA) 
approved drug for the treatment of BED and is limited by its restrictive scheduling and 
high side effect burden.4 
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Centanafadine sustained-release (SR) tablets administered orally as either 200 or 400 mg 
total daily doses (TDDs) have demonstrated efficacy in treating impulsive symptoms in 
adults with ADHD and was also reported to be generally safe and well tolerated as 
demonstrated by the low rate of reported treatment-emergent adverse events (TEAEs) 
that were dose-dependent, a low incidence of adverse events (AEs) of special interest 
(AESIs) (newly acquired, non-traumatic skin eruptions), and a low incidence of abuse 
potential-related AEs.15 Its unique pharmacology, high tolerability, and the fact that it 
does not require titration could offer general psychiatrists or primary care physicians a 
distinct and potentially preferable alternative treatment option to the only currently 
approved medication. Having an accessible, approved treatment could go far to fill the 
unmet need of undertreated individuals struggling with BED. This Phase 2 proof-of-
concept trial is designed to assess initial efficacy in reducing symptoms of BED in adults.
4.3
Dosing Rationale
The 2 doses of centanafadine SR that will be evaluated in this trial will be 200 mg and 
400 mg TDD, administered as 100 mg BID (4 - 6 hours apart) and 200 mg BID 
(4 - 6 hours apart), respectively. These doses have demonstrated efficacy in phase 2 as 
well as in two phase 3 trials in adult ADHD. Dose-dependent increases in side effects 
were experienced in phase 2 trials at higher doses. While not considered dose-limiting, 
the efficacy at lower doses in ADHD supports assessing 200 mg and 400 mg before 
considering whether a higher dose is warranted.
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 consumes all doses of the IMP. Subjects who are evaluated at the last scheduled 
visit during the double-blind treatment period (Week 8) will be defined as trial 
completers.
5
Trial Population
The trial population will include adult subjects between 18 and 65 years of age, inclusive, 
at the time of informed consent with a clinical diagnosis of BED according to DSM-5 
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criteria and confirmed by the SCID-5-CT. Subjects may have a historical diagnosis or 
may be diagnosed at screening.
Approximately 228 subjects are anticipated to be screened with the expectation that 
approximately 126 subjects will be randomized (42 subjects per treatment arm).
5.1
Subject Selection and Numbering
All subjects will be given a unique subject identifier (ID; site number [3 digits] + subject 
number [‘S’ + 5 digits] upon providing consent). The site number will be designated by 
the sponsor.
Demographic information (collection date, date of birth, sex at birth, childbearing 
potential, race, ethnicity) and medical history will be recorded in the eCRF at the 
screening visit.
Eligible subjects who are enrolled in the trial will be assigned a unique subject 
randomization number for treatment assignment. Subjects who discontinue from the trial 
will not be replaced.
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 when assessed:
Table 5.2.1-1
Inclusion Criteria
1.
Adult subjects 18 to 65 years of age (inclusive) at the time of informed consent.
2.
A primary diagnosis of BED, or is diagnosed at screening, according to DSM-5 criteria and 
confirmed by the SCID-5-CT.
3.
BED with a history of at least 2 binge eating days per week for 6 months prior to screening.
4.
BED of at least moderate severity with at least 3 binge eating days in each week during the 
previous 14 days of a subject’s screening period according to the subject’s binge diary as 
reviewed at baseline (minimum screening period is 2 weeks).
5.
A rating of 4 or higher on the CGI-S at screening and baseline.
6.
BMI of 18 to 45 kg/m2, inclusive.
BMI = body mass index
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5.2.2
Exclusion Criteria
Subjects will be excluded if they meet any of the following exclusion criteria when 
assessed:
Table 5.2.2-1
Exclusion Criteria
1.
Subjects of CBP who are breast-feeding and/or have a positive pregnancy test result prior to 
receiving IMP.
2.
Sexually active subjects or subjects of CBP who do not agree to practice 2 different methods of 
birth control or remain abstinent during the course of the trial and for 30 days after the last dose 
of IMP for subjects of CBP, and 30 days after the last dose of IMP for subjects and their partners 
who are subjects of CBP. Unless the subject is sterile (ie, subjects who have had a bilateral 
oophorectomy or hysterectomy or who have been postmenopausal for at least 12 consecutive 
months; or subjects who have had a bilateral orchidectomy) or remains abstinent, 2 of the 
following precautions must be used: vasectomy, tubal ligation, vaginal diaphragm, intrauterine 
device, birth control pills, birth control injection, birth control implant, birth control patch, 
condom with spermicide, or sponge with spermicide. Subjects who do not agree to refrain from 
donating sperm from screening through 30 days after the last dose of IMP.
3.
Lifetime history of bulimia nervosa or anorexia nervosa.
4.
Started psychotherapy for BED within 3 months of screening.
5.
Participation in a formal weight loss program within 3 months of screening or planning to start a 
weight loss program during the trial.
6.
Lifetime history of major bariatric surgery, including gastro-jejunal bypass, roux-en-y gastric 
bypass, sleeve, and duodenal switch for weight loss at any time.
7.
Minor bariatric surgery, including lap band, in the past 2 years.
8.
Use of psychostimulant or mood stabilizer within 3 months of screening.
9.
Use of any other medications for treatment of BED, other eating disorder, or obesity; anorexics 
(weight loss supplements), or other weight management medications within the last 3 months, or 
started or changed dose of any other medication that can result in weight gain or weight loss 
within 3 months prior to screening.
10.
Lifetime history of psychotic disorder, bipolar disorder, hypomania, dementia, or ADHD 
according to DSM-5 criteria.
11.
Initiation of treatment for depression within 3 months prior to screening.
12.
MADRS score ≥ 18.
13.
Substance use disorder (as determined by DSM-5 criteria) within 12 months prior to screening.
14.
A positive alcohol test (via breathalyzer, blood, or urine), a positive drug screen for illicit drugs 
(excluding marijuana) at screening or baseline.
NOTE: Subjects who test positive for marijuana at screening may be enrolled if they have no 
evidence of a substance use disorder, if they agree to refrain from use for the duration of the trial, 
and if they test negative prior to the baseline visit.
15.
Any of the following:

A significant risk of committing suicide based on history and the 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 
C-SSRS

Any lifetime history of suicidal behavior detected by the Baseline/Screening version of the 
C-SSRS.
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Table 5.2.2-1
Exclusion Criteria
16.
Any other medical or physical condition(s) that, in the opinion of the investigator, may prevent 
the subject from completing the trial or would go against the subject’s best interest with 
participation in the trial. This would include any significant illness or unstable medical condition 
that could lead to difficulty complying with the protocol.
17.
The following laboratory test and ECG results are exclusionary:
1) Platelets ≤ 75,000/mm3
2) Hemoglobin ≤ 9 g/dL
3) Neutrophils, absolute ≤ 1000/mm3
4) AST > 2 × upper limit of normal
5) ALT > 2 × upper limit of normal
6) Creatinine ≥ 2 mg/dL
7) HbA1c ≥ 7%
8) QTcF > 450 msec for males or > 470 msec for females
NOTE: In addition, subjects should be excluded if they have any other abnormal laboratory tests, 
vital sign results, or ECG findings which in the investigator’s judgment are medically significant 
and that would impact the safety of the subject or the interpretation of the trial results. Tests with 
abnormal results should be repeated to ensure reproducibility of the abnormality before 
excluding a subject based on the criteria noted above.
18.
A history of dermatologic adverse reactions secondary to any drug exposure or anaphylaxis (or 
some type of systemic allergic reaction) to any substance.
19.
A history of allergic reaction or a known or suspected sensitivity to any substance that is 
contained in the IMP formulation.
20.
A history of prior exposure to centanafadine.
21.
Participation in a clinical trial and exposure to interventional trial medication within the last 30 
days prior to screening or participation in more than 2 interventional clinical trials within the past 
year.
ALT = alanine aminotransferase; AST = aspartate aminotransferase; CBP = childbearing potential; 
HbA1c = glycosylated hemoglobin; QTcF = QT interval corrected for heart rate by the Fridericia 
formula.
A definition of childbearing potential (CBP) can be found in Section 10.3.
Subjects must agree to restrictions to medications and lifestyle described in Section 6.5.1 
and Section 5.3, respectively.
5.3
Lifestyle Considerations
Not applicable.
5.3.1
Meals and Dietary Restrictions
Not applicable.
5.3.2
Caffeine, Alcohol, Tobacco, and Other Substances
Investigators should inform subjects that normal consumption of caffeine is permitted.
Instruction will be given to subjects to refrain from drinking alcoholic beverages or using 
illicit drugs (including marijuana) during participation in the trial.
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Should the subject test positive for illicit drugs (including marijuana), the site will 
provide counseling to the subject on not using illicit drugs. A urine drug screen is 
required at the times designated in the Schedule of Assessments (Table 1.3-1), but the 
investigator may request a blood or urine drug screen at any time during the trial if there 
is a suspicion of illicit drug use in subjects. The UDS is to be done on-site initially, with a 
confirmatory urine sample collected if needed for processing through the central lab. 
Alcohol testing will be performed at screening and baseline via urine, blood, or 
breathalyzer test and is to be conducted initially via breathalyzer, with confirmation via 
blood or urine sample through central lab processing. Additional alcohol tests may be 
performed at the discretion of the investigator. Refer to Section 5.4 for additional details 
regarding positive alcohol or drug test results.
No restrictions for tobacco apply.
5.3.3
Activity
Subjects should not significantly alter their current activity levels or exercise routines. 
They should be encouraged to maintain their usual levels of physical activity throughout 
the trial.
Subjects should not undergo any elective medical procedure without prior consultation 
with the investigator. An elective procedure (minor surgery, dental surgery, orthopedic 
surgery, etc.) that might require hospitalization or general anesthesia should be deferred 
until after the trial whenever clinically appropriate.
5.4
Screen Failures
A screen failure is a subject from whom informed consent is obtained and is documented 
in writing (ie, subject signs an ICF), but who is not randomized or assigned trial 
treatment. All AEs must be reported after subject informed consent has been obtained, 
including screening failures due to AEs, irrespectively of IMP administration.
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

Visit date (screening visit)

Demographics (collection date, birth date, sex at birth, race, ethnicity)

Result of eligibility assessment

Screen failure date

Reason for screen failure
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In the event that a subject cannot be randomized prior to the expiration of the 28-day 
screening period, additional extension of screening may be requested and discussed with 
the medical monitor. Any extension should be requested prior to the expiration of the 
screening period, as applicable. If no extension is granted, and the subject meets criteria 
for rescreening after the screening period has expired, a new ICF must be signed, a new 
screening number assigned, and all screening procedures repeated.
In the case that subjects sign a consent form but have not started on treatment, subjects 
are permitted to be rescreened if exclusion criteria have changed and following 
consultation with the Medical Monitor. In the event that the subject is rescreened for trial 
participation, including after the 28-day screening period expires, a new consent form 
must be signed, a new screening number assigned, and all screening procedures repeated.
Subjects that have a positive alcohol test (via urine, blood, or breathalyzer), or positive 
drug screen for illicit drugs (excluding marijuana) are not eligible to be retested or 
rescreened, and will be considered screen failures. Subjects that test positive for 
marijuana at screening may be permitted to be enrolled if they have no evidence of a 
substance use disorder, agree to refrain from use for the duration of the trial, and test 
negative prior to baseline. Subjects that test positive for use of prohibited medications at 
screening will be required to undergo a washout period (Section 6.5.1). After the allotted 
washout period, if a subject tests positive for prohibited medications, the subject will be 
screen failed and not permitted to rescreen. Screen failures previously excluded for a 
positive urine drug screen due to use of prescription or over-the-counter medications or 
products not used for the treatment of BED, may be rescreened for participation in the 
trial only with the explicit consent of the medical monitor. Screen failures excluded for 
any other reasons may be rescreened at any time if the exclusion characteristic has 
changed.
6
Trial Treatments
6.1
Trial Treatments Administered
Eligible subjects will be randomized 1:1:1 at baseline to receive 1 of 2 doses of 
centanafadine SR or placebo daily for 8 weeks:

High dose centanafadine: 400 mg centanafadine SR oral tablets TDD (2 × 100 mg 
BID, approximately 4 - 6 hours apart)

Low dose centanafadine: 200 mg centanafadine SR oral tablets TDD (1 × 100 mg) + 
1 placebo oral tablet (BID, approximately 4 - 6 hours apart)

Placebo: 2 placebo oral tablets (BID, approximately 4 - 6 hours apart)
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Neither the investigator nor the subject will be aware of the treatment assignment after 
randomization. IMP will be dispensed at the baseline visit and the first dose of IMP will 
be taken on the morning of Day 1, when the subjects will be home. A telephone call will 
be placed from site to subject to confirm dosing. The date and time of the first dose will 
be recorded.
All doses of centanafadine SR and matching placebo should be taken orally BID (with up 
to 240 mL of water). Doses should be taken at approximately the same time each day, 
with the first dose taken in the morning and the second dose taken 4 to 6 hours after the 
morning dose is administered. All doses can be administered without regard to meals.
If a subject forgets to take their morning dose at their normal dosing time, the subject 
should take the dose as soon as they remember that same day. If a subject forgets to take 
their second dose and 6 hours have elapsed since the time of the morning dose, they 
should skip the dose and resume dosing the next day. If a subject does not remember to 
take a missed dose on the same day it is missed, the subject should skip that dose and 
resume the normal dosing schedule for the following dose. Subjects should not take more 
than 2 doses in one day.
For information regarding the dose regimen and treatment period(s), including any 
follow-up period(s) for each treatment group/arm of the trial, 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.15
6.2.1
Packaging and Labeling
Investigational medicinal product will be provided by the sponsor or designated agent to 
the investigators and the persons designated by the investigator(s) or institution(s). The 
IMP will be supplied as blister cards. Each blister card used in the dosing period will be 
labeled to clearly disclose the trial number, sponsor’s name and address, instructions for 
use, route of administration, and appropriate precautionary statements and other 
information required by local regulatory authorities.
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.
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The IMP will be stored according to the conditions indicated on the IMP label. The trial 
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 (including 
investigational or placebo) received, dispensed, administered, and returned. 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 may only be destroyed by the trial site(s), if approved by the sponsor and if the 
IMP destruction meets all local regulations. The IMP will be destroyed by the clinical 
trial site following completion and verification of accountability of the IMP by the 
assigned trial monitor. The trial site(s) may utilize qualified third-party vendors for IMP 
destruction. A certificate of destruction should be filed within the IMP accountability.
6.2.5
Reporting of Product Quality Complaints
A Product Quality Complaint (PQC) is any written, electronic, or oral communication 
provided by a healthcare professional, clinical trial subject, medical representative, 
regulatory agency, Partner, or other third party that alleges deficiencies related to the 
identity, quality, durability, reliability, safety, or performance of a Medical Device or 
Medicinal Product after it is released for distribution.
Examples include, but are not limited to, communications involving:

Failure of a product to meet any of its specifications

Packaging defects (eg, damaged, dirty, crushed, missing product or component, 
incorrect or missing labeling)

Product defects (eg, odor, chipped, broken, damaged, crushed, embossing illegible, 
under-filled bottle, over-filled bottle, empty bottle, no safety seal)

Loss or theft of product
6.2.5.1
Eliciting and Reporting Product Quality Complaints
The investigator or designee must record each PQC identified through any means from 
the receipt of the IMP from the sponsor or sponsor’s designee, through and including 
reconciliation and up to destruction, including subject dosing. The investigator or 
designee must notify the sponsor (or sponsor’s designee) within 24 hours of becoming 
aware of the PQC according to the procedure outlined below.
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Send PQC reporting information to the Otsuka Pharmaceutical Development & 
Commercialization, Inc (OPDC) IMP complaints mailbox email: 
IMP-PQC@otsuka-us.com.  Also indicate whether or not the complaint sample is 
available for return.
Identification of a PQC by the subject should be reported to the site investigator, who 
should then follow the reporting mechanism above.
6.2.5.2
Information Required for Reporting Purposes

Description of complaint

Reporter identification (eg, investigator, site, etc.)

Reporter contact information (eg, address, phone number, e-mail address)

Subject number

Clinical site number

ID of material (product/compound name, lot/batch number, shipment number, expiry 
date)

Clinical protocol reference (number and/or trial name)

Dosage form/strength (if known)

Pictures of complaint sample (if available)

Availability of complaint sample 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, the sponsor will provide return instructions, 
when applicable. If complaint sample is available but not at the clinical site, please 
instruct subject to bring the complaint sample to their next site visit.
It must be documented in the site accountability record that the 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
Treatment will be double-blind. Neither the investigator nor the subject will have 
knowledge of the treatment assignment. 
Treatment assignments will be based on a computer-generated randomization code 
provided by the OPDC Biostatistics Department. Sponsor personnel, including those 
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involved in monitoring, data management, and data analysis, will not have access to the 
treatment code during the trial. The bioanalytical laboratory will also be sent the 
randomization code. Access to the treatment codes will be restricted to personnel charged 
with generating and maintaining randomization files, packaging trial medication, and 
reporting serious adverse events (SAEs) to regulatory agencies. The randomization will 
be stratified by trial site and designed to allocate subjects in a 1:1:1 ratio to high dose 
centanafadine, low dose centanafadine, or placebo (see Section 6.1). 
Procedures for breaking the blind can be found in Section 8.8.8.
6.4
Subject Compliance
Responsible trial personnel will dispense the IMP according to the visits outlined in the 
Schedule of Assessments (Table 1.3-1). Subjects must be counseled on the importance of 
taking the IMP as directed at all trial visits. If poor compliance continues (eg, multiple 
missed doses resulting in less than 80% overall compliance), discontinuation of the 
subject from the trial should be considered.
This trial will utilize IMP adherence monitoring for all subjects in the trial. Additional 
information is provided in the Operations Manual. Results should be documented in the 
subject’s trial records. This compliance tool will not replace standard methods of IMP 
compliance (tablet count and reconciliation) utilized by the sites.
6.5
Concomitant Medications or Therapies
The investigator will record all medications (including prescription medications, 
over-the-counter medications, herbal remedies, etc) and therapies taken by the subject 
from 30 days prior to signing of informed consent through the end of the evaluation 
period (defined as the time period during which subjects are evaluated for primary and/or 
secondary objectives) in 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) in 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.
6.5.1
Prohibited Medications or Therapies
All subjects must agree to discontinue all prohibited medications during the screening 
period, in order to meet the protocol-specified washout periods, and during the trial as 
shown in Table 6.5.1-1
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Table 6.5.1-1
List of Medications or Therapies Prohibited/Restricted from 
the Screening Visit through the end of Safety Follow-Up 
Prohibited/Restricted Medication
Antipsychotics (including depot formulations)
Anticonvulsants
Mood stabilizers (ie, lithium)
Benzodiazepines, except for sleep (see Table 6.5.2-1)
Stimulants (lisdexamfetamine, amphetamines, methylphenidates, modafinil, armodafinil)
Non-stimulant treatment for ADHD (atomoxetine, clonidine, guanfacine)
Medications for treatment of BED, other eating disorder, or obesity; anorexics (weight loss 
supplements), or other weight management medications (and for 3 months prior to screening)
Insulin (and for 3 months prior to screening)
Started or changed the dose of any medication that can result in either weight gain or weight loss (eg, 
liraglutide, metformin, Ozempic, and Rybelsus) (and for 3 months prior to screening)
Sedating antihistamines (eg, diphenhydramine, hydroxyzine, chlorpheniramine)
Investigational compounds (and for 30 days prior to screening)
The subject’s best medical interests should guide the investigator in the management of 
conditions that are pre-existing or that develop during the trial (intercurrent illness or 
AEs). The investigator should examine the acceptability of all concomitant medications 
not explicitly prohibited. In order to ensure that appropriate concomitant therapy is 
administered, it is essential that subjects be instructed not to take any medications (either 
self-administered non-prescription drugs or prescription therapy prescribed by another 
physician) without prior consultation with the investigator.
Subjects should not start a weight loss program during the trial.
6.5.2
Permitted Medications or Therapies
The medications shown in Table 6.5.2-1 are permitted but this is not a comprehensive 
list.
Table 6.5.2-1
List of Medications Permitted During the Trial
1.
Non-sedating antihistamine medication
2.
Saline and corticosteroid nasal sprays for the treatment of illness or seasonal allergies
3.
Stable, intermittent use of bronchodilators
4.
Opioids, with approval from the medical monitor for documented and clinically appropriate 
indications (ie, episodic pain condition, tooth extraction)
5.
Hormonal contraceptives
6.
Topical numbing agents
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Table 6.5.2-1
List of Medications Permitted During the Trial
7.
Sedative hypnotics at doses not greater than those indicated below, once nightly, not in 
combination:

Lorazepam 2 mg

Temazepam 30 mg

Eszopiclone 3 mg

Zaleplon 20 mg

Zolpidem 10 mg (males), 5 mg (females)

Zolpidem CR 12.5 mg (males), 6.25 mg (females)

Melatonin 5 mg
8.
Antidepressant medication that has been stable for 3 months prior to screening.
Psychotherapy, including cognitive behavioral therapy, is permitted if it has been stable 
in terms of type, intensity, and frequency for at least 3 months prior to screening and 
continues without change throughout the trial.
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 site.
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7.3
Individual Subject Discontinuation
7.3.1
Treatment Interruption
All attempts should be made to avoid treatment interruption during the trial. If a subject’s 
IMP treatment must be interrupted for medical or surgical reasons, for example, use of a 
prohibited concomitant medication or other reasons (eg, hospital admission for an 
invasive procedure, a major medical condition, surgery, dental work, or a temporary 
situation that prevents subject compliance with the IMP dosing schedule), the subject’s 
IMP should be resumed as early as the situation allows. The investigator or designee will 
contact the medical monitor at the earliest possible time by telephone to discuss a 
subject’s interruption of treatment. If 6 or more doses of IMP are missed in a 7-day 
period, a discussion must occur with the medical monitor to determine if the subject 
should be discontinued from the trial as a result of the treatment interruption. The 
treatment interruption will be recorded in the eCRF and will be reported as a protocol 
deviation.
7.3.2
Treatment Discontinuation
After treatment assignment, a subject may stop treatment permanently for a variety of 
reasons. Treatment discontinuations may be initiated by a subject who is not satisfied 
with treatment or may become medically necessary due to AEs, required treatment with a 
disallowed medication or therapy, or other issues, as determined by the investigator. 
However, each investigator must comprehensively review the circumstances and offer the 
subject options for continued treatment to the degree possible as described in 
Section 7.3.5.
7.3.3
Documenting Reasons for Treatment Interruption or 
Discontinuation
A subject may temporarily interrupt or discontinue IMP 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

Continuing IMP places the subject at undue risk as determined by the investigator 
(eg, a safety concern that is possibly, probably, or likely related to IMP)

SAE

Other potentially IMP-related safety concerns or AEs

Death

Reasons unrelated to medical condition (provide detail and review AE history with 
subject)
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
Withdrawal by subject 

Lost to follow-up

Rash (regardless of severity or seriousness) (see Section 8.8.5)

Pregnancy (see Section 10.3)

Site terminated by sponsor

Study terminated by sponsor

Lack of efficacy

Noncompliance with study drug

Physician decision

Randomized by mistake

Randomized by mistake with study treatment

Other
If the subject temporarily interrupts or discontinues IMP due to an AE, the investigator, 
or other trial personnel, will make every effort to follow the event until it has resolved or 
stabilized. Follow-up procedures in Section 7.3.1 and Section 7.3.2 must be followed.
7.3.4
Withdrawal of Consent
Each subject has the right to withdraw their consent from further participation in the trial 
at any time without prejudice. Subjects can withdraw consent for use of data which has 
not previously been anonymously transferred into trial data sets collected as part of the 
trial and can only withdraw consent for future participation. The investigator can also 
discontinue a subject’s participation in the trial at any time if medically necessary. Unless 
the subject provides their written withdrawal of consent or there is other written 
documentation by the investigator confirming the subject’s verbal intent to completely 
withdraw from the trial, subjects should be followed for all protocol-specified evaluations 
and assessments, if possible.
Complete withdrawal of consent requires a subject’s refusal of ALL of the following 
methods of follow-up:

Participation in all follow-up procedures specified in the protocol (whether in-clinic, 
by telephone, or by a home visit).

Participation in a subset of protocol specified follow-up procedures (by a frequency 
schedule and method, as agreed by subject and trial site staff).

Contact of the subject by trial personnel, even if only by telephone, to assess current 
medical condition, and obtain necessary medical or laboratory reports relevant to the 
trial’s objectives.
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•
Contact of alternative person(s) who have been designated in source records as being 
available to discuss the subject’s medical condition, even if only by telephone, mail, 
or e-mail (eg, family, spouse, partner, legal representative, friend, neighbor, or 
physician).
•
Access to medical information from alternative sources (eg, hospital/clinic medical 
records, referring doctor’s notes, public records, dialysis, transplantation or vital 
registries, social media sources).
Withdrawal of consent is a critical trial event and, therefore, should be approached with 
the same degree of importance and care as is used in initially obtaining informed consent. 
The reasons for a subject’s intended withdrawal need to be completely understood, 
documented, and managed to protect the rights of the subject and the integrity of the trial. 
A subject may initially express their desire to interrupt, modify, or discontinue IMP 
administration, which is not equivalent to a complete withdrawal of consent for further 
participation (see Section 7.3.1 and Section 7.3.2, respectively). A subject may, however, 
indicate that further trial participation is creating a burden on their work, school, or social 
schedule. Therefore, 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 treatment and/or 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 to participate in the trial.
 
7.3.5
Procedures to Encourage Continued Trial Participation
In all cases of impending IMP discontinuation or consent withdrawal, investigators will 
be instructed to meet and discuss (without coercion) with the subject their options of 
continuing in the trial, preferably on therapy. The investigator should ensure 
understanding and documentation of the reasons for the subject’s desire to withdraw 
consent.
7.4
Definition of Subjects Lost to Follow-up
Subjects who cannot be contacted on or before Visit 8 during the treatment period, who 
do not have a known reason for discontinuation (eg, withdrew consent or AE), and for 
whom a survival status at the end of the trial cannot be determined will be classified as 
“lost to follow-up”. Survival status can be determined from a variety of sources, either by 
obtaining acceptable documentation for death (ie, death certificate, medical records, 
public records, statement by a family member or primary care physician) or acceptable 
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documentation for life (ie, direct contact with the subject, medical records, successful 
telephone contact with the subject, statement by a family member or primary care 
physician, or public records).
The site will make 3 documented attempts to contact the subject by telephone and in the 
event the site is unable to reach the subject by telephone, the site will attempt to contact 
the subject via certified mail or an alternative similar method, where appropriate, before 
assigning a “lost to follow-up” status.
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 eSource.
8
Trial Procedures
The assessments to be conducted during the trial are summarized in Table 1.3-1.
8.1
Efficacy Assessments
Efficacy will be measured by the change from baseline in binge eating days per week, the 
change from baseline in the Clinical Global Impression – Severity (CGI-S) score, 
Clinical Global Impression – Change (CGI-C) score, the change from baseline in the 
Yale-Brown Obsessive-Compulsive Scale Modified for Binge Eating (Y-BOCS-BE) 
score, the proportion of subjects with four-week cessation from binging, the change from 
baseline in number of binge episodes per week, the change from baseline in the Eating 
Disorder Examination Questionnaire - 7-Item Version (EDE-Q7), Patient Global 
Impression - Severity (PGI-S), and Patient Global Impression - Change (PGI-C) after 
treatment with centanafadine compared to placebo. It is required that adequately trained 
and experienced individuals administer the clinician rating scales. All individuals 
performing these assessments must be pre-approved by the sponsor or designee.
Efficacy assessments should be completed prior to safety and PK assessments.
8.1.1
Patient-Reported Outcomes
8.1.1.1
Binge Eating Diary
All binge episodes will be captured daily by the subject in a binge eating diary; details 
about binge eating episodes per day will be recorded. At each visit, the investigator or 
designee will review the completed diary with the subject and assess the number of 
binges for each day. The investigator assessment of number of binges for each day will 
be recorded in the eCRF. Missing data, if any, will be reviewed by the clinical site staff 
with the subject and additional training on diary completion will be provided as needed.
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8.1.1.2
Eating Disorder Examination Questionnaire and Eating 
Disorder Examination Questionnaire - 7-Item Version
The EDE-Q is a self-report version of the eating disorder examination (EDE) and measures 
eating-disorder psychopathology in the past 28 days and over longer intervals for diagnostic 
items.16,17,18,19 The EDE-Q yields scores on subscales (dietary restraint, eating concern, 
weight concern, and shape concern) as well as a global score and binge eating frequency 
variables.
The EDE-Q7 is a brief version of the EDE-Q which comprises 7 items to generate a 
global score and 3 subscales (dietary restraint, shape/weight overvaluation, and body 
dissatisfaction). Severity rating ranges from 0 to 6, where 0 represents absence of the 
feature and 6 represents an extreme degree. Frequency ratings range from 0 to 6 where 
0 = ‘No days’ or absence of the feature and 6 = ‘every day’.
8.1.1.3
Patient Global Impression - Severity 
The PGI-S is a single-item self-report of the patient’s severity of symptoms.20 Severity is 
rated on a 7-point scale (1 = no symptoms; 2 = minimal; 3 = mild; 4 = moderate; 
5 = marked; 6 = severe; 7 = very severe).
8.1.1.4
Patient Global Impression - Change
The PGI-C is a single-item, 7-point patient self-report that requires the patient to assess 
how much his/her illness has improved or worsened relative to baseline, rated as: 
1 = very much improved; 2 = much improved; 3 = minimally improved; 4 = no change; 
5 = minimally worse; 6 = much worse; or 7 = very much worse.
8.1.1.5
36-Item Short-Form Health Survey
The 36-item Short-form Health Survey Version 2 (SF-36v2) is a patient-reported 
questionnaire with a standard recall period of 4 weeks which measures generic 
health-related quality of life on 2 broad domains, physical and mental composites, across 
eight health domain scales: physical functioning, pain, role physical, general health, 
vitality/fatigue, social functioning role emotional, and mental health.21
The SF-36v2 uses norm-based scoring to generate scores on a scale of 0 to 100 where 
lower scores on the physical component summary (PCS) and mental component 
summary (MCS) represent a lower health-related quality of life and a score of 50 
references the normal US population. In addition to the composite scores and the 
individual health domain scores, the SF-36v2 provides a risk for depression score and the 
SF-6D health utility index on a scale form 0.0 (worst measured health state) to 1.0 (best 
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measured health state). The SF-36v2 will be administered on the visits as specified in 
Schedule of Assessments (Table 1.3-1).
8.1.2
Clinician Rating Scales
8.1.2.1
Clinical Global Impression - Severity
The CGI-S20 will be administered by trial site staff at the time points shown in the 
schedule of assessments (Table 1.3-1). The CGI-S is a standardized, 
clinician-administered global rating scale that measures disease severity on a 7-point 
Likert scale. A higher score on the CGI-S represents a higher severity of disease (0 = not 
assessed; 1 = normal, not at all ill; 2 = borderline ill; 3 = mildly ill; 4 = moderately ill; 
5 = markedly ill; 6 = severely ill; 7 = among the most extremely ill subjects).
8.1.2.2
Clinical Global Impression - Change
The CGI-C will be administered by trial site staff at the time points described in the 
schedule of assessments (Table 1.3-1). The CGI-C is a single-item, 7-point scale that 
requires the clinician to assess how much the subject’s illness has improved or worsened 
relative to their baseline state at the beginning of treatment, rated as: 1 = very much 
improved; 2 = much improved; 3 = minimally improved; 4 = no change; 5 = minimally 
worse; 6 = much worse; or 7 = very much worse.
8.1.2.3
Yale-Brown Obsessive-Compulsive Scale Modified for Binge 
Eating
The Y-BOCS-BE22,23 will be administered by trial site staff at the time points shown in 
the schedule of assessments (Table 1.3-1). The Y-BOCS-BE is a clinician-rated scale that 
assesses obsession with binge eating thoughts and compulsiveness of binge eating 
behaviors. It can be divided into 2 subscales: obsessions and compulsions. The 
Y-BOCS-BE is a 10-item scale, with each item rated from 0 (no symptoms) to 4 (extreme 
symptoms) and total scores ranging from 0 to 40. A score of 0 to 7 is sub-clinical; 8 to 15 is 
mild; 16 to 23 is moderate; 24 to 31 is severe; and 32 to 40 is extreme. 
8.2
Pharmacokinetic Assessments
8.2.1
Pharmacokinetic Blood Samples
Two sparse PK samples per subject will be collected, one each at Weeks 4 and 8, to 
determine centanafadine and metabolite concentrations. Samples should be collected at 
the same time as the serum chemistry samples and following the administration of 
efficacy assessments and other safety assessments (AE monitoring, vital signs 
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measurements, ECGs, medication withdrawal scales, and suicidality assessment). 
Concentrations will be evaluated for compliance with dosing. 
Samples will be collected using venipuncture (3 mL whole blood, K2EDTA, processed 
into plasma). The actual date and time of the PK sample collection and dose taken prior 
to the PK sample will be recorded on the eCRF.
8.3
Pharmacodynamic Assessments
Not applicable.
8.4
Pharmacogenomic Assessments
Not applicable.
8.5
Biomarker Assessments
Not applicable.
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8.7
Safety Assessments
Safety will be assessed by standard measurements including TEAEs, AESIs (rash), 
clinical laboratory tests (chemistry, hematology, and urinalysis), physical examinations, 
vital sign measurements, and 12-lead electrocardiograms (ECGs). The Study Medication 
Withdrawal Questionnaire (SMWQ), Hamilton Anxiety Rating Scale (HAM-A) score, 
Montgomery-Asberg Depression Rating Scale (MADRS), and the Columbia Suicide 
Severity Rating Scale (C-SSRS) will be used to assess safety. Abuse potential will be 
assessed through the active monitoring of Events Subject to Additional Monitoring 
(ESAMs) (eg, AEs related to abuse potential and AEs involving MHI). 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 and should be collected after efficacy assessments are completed if possible. 
Only if results are exclusionary at screening will a repeat test be performed prior to the 
baseline visit; the results must be available and inclusionary prior to randomization. The 
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total volume of blood to be collected during the trial will be documented in the electronic 
informed consent form (eICF).
Subjects are not required to be fasting for screening laboratory assessments. Laboratory 
assessments will be fasted if they are required to be repeated for baseline eligibility. 
Subjects should be fasting for a minimum of 8 hours prior to the blood draws, if possible.
See exclusion criteria (Section 5.2.2) based on screening laboratory tests or tests repeated 
for baseline eligibility as necessary. 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 laboratory tests will be assessed by the investigator 
or qualified designee for clinical significance.
Urine or serum pregnancy testing for subjects of CBP will be performed during the study. 
On suspicion of pregnancy, an unscheduled urine or serum pregnancy test will be 
performed. Positive urine pregnancy tests must be confirmed with a serum pregnancy 
test. The investigator (or appropriate site staff) is advised to counsel participants on the 
risk of pregnancy while participating in a clinical trial. This should be documented in 
source records. Results of the pregnancy test must be available prior to the administration 
of the IMP.
A drug screen will be performed at screening and baseline (Day −1); additional 
assessments can be conducted at any time at the discretion of the investigator. Subjects 
with a positive drug screen for confirmed use of prohibited medications at screening will 
be required to undergo a washout period. Subjects who have a positive drug screen for 
confirmed use of prohibited medications at the baseline visit will be considered screen 
failures and will not be permitted to rescreen.
8.7.2
Physical Examination
Physical examinations will be performed at the time point described in the schedule of 
assessments (Table 1.3-1). Physical examinations include height, weight, and BMI, as 
well as assessment of the head, eyes, ears, nose, and throat, thorax, abdomen, urogenital 
(at the discretion of the PI), skin and mucosae, neurological, and extremities. Directed 
physical examinations in response to reported AE will be conducted as necessary.
Any abnormalities considered by the investigator to be clinically significant are to be 
recorded as AEs on the AE eCRF.
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8.7.3
Vital Signs
Vital signs will be collected at the time points described in the schedule of assessments 
(Table 1.3-1). Vital signs include systolic and diastolic blood pressure, heart rate, 
respiratory rate, and body temperature. Blood pressure and heart rate measurements will 
be made in the supine and standing positions after the subject has been in each position 
for at least 3 minutes. The supine measurements will be performed first, followed by the 
standing measurements. Temperature and respiratory rate will be taken with the subject 
in the supine position. Vital signs scheduled for the same visit as blood samples should be 
completed before blood is drawn.
8.7.4
Electrocardiogram
Electrocardiograms will be performed at the time points described in the schedule of 
assessments (Table 1.3-1). ECGs scheduled for the same visit as blood samples should be 
completed before blood is drawn. The 12-lead ECGs will be performed in the supine 
position. 12-lead ECGs conducted at screening will be performed in triplicate, taken 
approximately 5 minutes apart. Based on the QTcF correction, a subject will be excluded 
if the correction equals or exceeds 450 msec for males and 470 msec for females for 2 or 
more of the 3 ECGs conducted. If only 1 ECG has a corrected QTcF of equal to or 
greater than 450 msec for males or 470 msec for females and it is not reproduced at either 
of the other 2 assessments, the subject meets the inclusion criteria. Only if results are 
exclusionary at screening will a repeat ECG be performed prior to the baseline visit; the 
results must be available and inclusionary prior to randomization. All subsequent ECG 
assessments require a single ECG recording. 
Any abnormalities considered by the investigator to be clinically significant are to be 
recorded as AEs on the AE eCRF.
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).
Suicidality will be monitored during the trial using the C-SSRS.24 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 
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definitions and suggested questions to solicit the type of information needed to determine 
if a suicide related thought or behavior has occurred.
The C-SSRS has a “Baseline/Screening” version, which will be completed at the 
screening visit and a “Since Last Visit” version that will be completed at all subsequent 
assessments as shown in Table 1.3-1. 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
8.7.6.1
Study Medication Withdrawal Questionnaire
The SMWQ is a questionnaire to assess withdrawal symptoms that will be completed at 
the time points shown in the Schedule of Assessments (Table 1.3-1). The SMWQ is a 
modification of the Amphetamine Withdrawal Questionnaire in which the terms 
“amphetamines and methamphetamine” are replaced with the term “the study 
medication.”25,26,27
8.7.6.2
Hamilton Anxiety Rating Scale
The HAM-A should be administered by an experienced clinician at the timepoints shown in 
the schedule of assessments (Table 1.3-1).28 The HAM-A consists of 14 items, each 
defined by a series of symptoms, and measures both psychic anxiety (mental agitation and 
psychological distress) and somatic anxiety (physical complaints related to anxiety). Each 
item is scored on a 5-point scale, ranging from 0 = not present to 4 = severe.
8.7.6.3
Montgomery-Asberg Depression Rating Scale
The MADRS is a clinician-rated assessment of the subject’s severity of depression.29 The 
measure contains 10 items that measure apparent and reported sadness, inner tension, 
reduced sleep and appetite, difficulty concentrating, lassitude, inability to feel, and 
pessimistic and suicidal thoughts. Each item is scored in a range of 0 to 6 points, with 
higher scores indicating increased depressive symptoms.
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 
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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 double-blind treatment. In more detail, TEAEs are all AEs which started after the 
start of double-blind IMP treatment; or if the event was continuous from baseline and was 
worsening, serious, IMP related, or resulted in death, discontinuation, interruption, or 
reduction of IMP.
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 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.
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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 newly 
acquired skin eruptions that are non-traumatic are considered AESIs (see Section 8.8.5) 
and are to be reported as 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 IMP discontinuation and must be reported on an IRE form and the 
Pregnancy Surveillance Form(s) to the sponsor. This includes pregnancy of the 
subject or the partner of the subject. Pregnancy will only be documented on the AE 
eCRF if the pregnancy occurs in a female subject and there is an abnormality or 
complication. 
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 in 
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.
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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 will continue until the subject’s 
last scheduled contact unless the AE must be followed further (see Section 8.8.9). All 
AEs must be reported after subject informed consent has been obtained, including 
screening failures due to AEs, irrespective of IMP administration.
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. 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 adverse event, start date, end date, 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). Patient 
confidentiality must be protected and contact information such as name, address, phone 
number or any other protected health information as determined by applicable local 
regulation must be redacted when forwarding Safety Information and supporting 
documentation. Details regarding the follow-up of IREs are included in Section 8.8.9.2 
8.8.4
Medical Device Incidents (Including Malfunctions)
Not applicable.
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8.8.5
Adverse Events of Special Interest
Newly acquired skin eruptions that are non-traumatic will be considered AESIs. These 
may include, but are not limited to eruptions such as skin rashes, skin irritations, skin 
reactions, or acneiform lesions. This does not include localized contact irritation at ECG 
lead sites due to application/removal of lead adhesive.
Refer to the separate Rash/Skin Eruption AESI Workup Instructions for complete details, 
including reporting forms, on extra measures that must be performed to characterize any 
skin AESI of a newly acquired skin eruption that is non-traumatic.
All AESIs should be reported as IREs (see Section 8.8.3).
8.8.6
Abuse Potential Monitoring Process, Events Subject to 
Additional Monitoring, and Medication Handling Irregularities
An Abuse Potential Monitoring Process (APMP) will be in place and will be shared with 
each site. A key objective of the APMP is to monitor for instances of abuse or diversion 
of the trial medication and other psychoactive substances. In addition to monitoring for 
irregularities in medication handling, AEs that may be suggestive of a developing abuse 
issue will also receive special attention. As part of the APMP, MHIs must be reported, 
and AEs related to abuse potential and AEs involving MHIs must be reported as an 
ESAM with detailed narratives. 
Investigators and site staff at each trial site will be trained on reporting potentially abuse 
related AEs (eg, recording a description of the event in the subject’s own words in the 
source documents as well as the eCRF, in addition to the clinical term, and to be aware 
that a subject’s report may encompass more than one event and that these should be 
recorded separately). The investigators will be provided with examples of potentially 
abuse-related AEs, and trained on how to handle such events (eg, additional monitoring). 
While the investigators will be provided with examples of AE terms as a guide during 
trial conduct, the analysis of potentially abuse-related AEs will be based on a search of all 
Medical Dictionary for Regulatory Activities (MedDRA) preferred terms, all verbatim 
terms, and any open text fields within the AE data to identify text strings suggestive of 
abuse potential, in line with the 2017 FDA guidance (Assessment of Abuse Potential of 
Drugs).30 Refer to the separate APMP documentation for complete details on MHIs and 
ESAMs, including documenting and reporting procedures, examples of potentially abuse 
related AE terms that meet the criteria for ESAM reporting, and guidance for the training 
of investigators and trial site staff.
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8.8.7
Potential Serious Hepatotoxicity
For a subject who experiences an elevation in aspartate aminotransferase (AST) or 
alanine aminotransferase (ALT) that is  3 times the upper limit of normal (ULN), a total 
bilirubin level should also be evaluated. If the total bilirubin is  2 times the ULN, 
complete an IRE form with all values listed and also report as an AE in the eCRF.
8.8.8
Procedure for Breaking the Blind
The investigator is encouraged to contact the sponsor’s designated medical advisor to 
discuss their rationale for unblinding. However, to prevent delays to the investigator or 
medical personnel responding to a potentially emergent situation, unblinding of IMP will 
not be dependent upon the investigator receiving approval from the sponsor’s designated 
medical advisor (ie, the investigator will be able to obtain the code break information 
independent of the sponsor’s designated medical advisor). The investigator must contact 
the sponsor’s designated medical advisor by telephone or e-mail with an explanation of 
the need for opening the treatment assignment code within 24 hours of opening the code. 
If the blind is broken, the Global Pharmacovigilance Department must be notified 
immediately (see the cover page of this protocol for contact information). Documentation 
of breaking the blind should be recorded in the subject’s medical record with the date and 
time the blind was broken and the names of the personnel involved. Once the blind is 
broken for a subject, that subject may not reinitiate treatment with the IMP.
8.8.9
Follow-up of Adverse Events
8.8.9.1
Follow-up of Nonserious Adverse Events
Nonserious AEs that are identified at any time during the trial must be recorded on the 
AE eCRF with the current status (ongoing or resolved/recovered) noted. All nonserious 
events (that are not IREs) that are ongoing at the last scheduled contact will be recorded 
as ongoing in 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).
8.8.9.2
Follow-up of Immediately Reportable Events
This trial requires that subjects be actively monitored for IREs up to 30 days after the last 
dose of IMP is administered.
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 
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scheduled contact (up to last in-clinic visit for the entire trial), 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.
8.8.9.3
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, refer to the IB.15
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8.10
Subject Assessment Recording
8.10.1
Diagnostic Criteria for Binge Eating Disorder
The subject’s DSM-57 diagnosis of BED, based on the clinical interview and 
medical/psychiatric history and confirmed by the SCID-5-CT, should be documented in 
eSource.
8.10.2
Structured Clinical Interview for DSM-5
The SCID-5-CT is a primary diagnostic measure that will be utilized to establish the 
presence of binge eating disorder in adults.
8.11
Other Assessments
Not applicable.
9
Statistical Considerations
9.1
Sample Size
Assuming a treatment difference of 1.1 points with a standard deviation of 1.7 in the 
mean change from baseline in binge eating days per week at Weeks 7-8 in either 
centanafadine dose group (high dose centanafadine or low dose centanafadine) compared 
to the placebo group (effect size = 0.65), a sample size of 114 evaluable subjects (38 in 
each treatment arm) will yield at least 80% power to detect the treatment effects at a 
2-tailed significance level of 0.05. Approximately 126 subjects will be randomized to 
ensure 114 evaluable subjects in the study. The power and sample size were obtained 
using the PASS 14 (2015) statistical computing software.
9.2
Datasets for Analysis
The following datasets are defined for this trial: 

Randomized Analysis Set: comprises all subjects who were randomized in the 
double-blind treatment period. Subjects are considered randomized when they are 
assigned a treatment group at the baseline visit.  

Safety Analysis Set: comprises those randomized subjects in the double-blind 
treatment period who receive at least 1 dose of double-blind IMP. Subjects will 
only be excluded from this population if there is documented evidence (ie, 
numbers of drug dispensed are equal to numbers of drug returned, or no IMP 
dispensed at all) that the subject did not take IMP. If a subject is dispensed IMP 
and is lost to follow-up, he/she will be considered exposed. 
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•
 Efficacy Analysis Set: comprises all subjects in the Safety Analysis Set who have 
a baseline value and at least 1 valid post-randomization efficacy evaluation in the 
double-blind treatment period. 
The core dataset for all efficacy analyses is the Efficacy Analysis Set. In order to handle 
missing data and restrictions imposed by different types of analyses (eg, change from 
baseline analysis), datasets derived from Efficacy Analysis Set will be used for the 
efficacy analysis.
9.3
Handling of Missing Data for Primary and Key Secondary Endpoint 
Analysis
The mixed-effect model repeated measures (MMRM) assumes data are missing at 
random (MAR), which is a reasonable assumption in longitudinal clinical trials in the 
binge eating disorder population. However, the possibility of “missing not at random” 
(MNAR) data can never be ruled out. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 In addition, adjustment for missing diary data related to 
the primary efficacy endpoint will be specified in the SAP.
9.4
Statistical Analyses
9.4.1
Efficacy Analyses
9.4.1.1
Primary Efficacy Endpoint Analysis
The primary efficacy endpoint is the change from baseline in binge eating days per week 
at Weeks 7-8, having binge eating day defined as a day with at least one binge eating 
episode. The primary estimand defining the treatment effect of interest in the trial uses 
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the hypothetical strategy specified in the draft ICH E9 (R1) Addendum.37 In the 
hypothetical strategy, the event of withdrawing IMP is considered missing at random 
(MAR), and the primary endpoint of the trial could be considered as a combination of the 
responses of on-treatment completers at Week 8 and the imputation of the endpoint to 
Week 8 following the trend in each treatment group using the MMRM method for 
subjects who withdraw IMP during the trial. All data collected during the trial treatment 
period will be used for statistical analysis. 
The comparison between the centanafadine groups and the placebo group will be tested at 
a significance level of 0.05 (2-sided) in a fixed sequence testing of 1) high dose 
centanafadine versus placebo, and 2) low dose centanafadine versus placebo, in which 
Test 2) won’t be performed unless Test 1) is statistically significant.  
The primary efficacy analysis will be performed by fitting an MMRM analysis with an 
unstructured variance covariance structure, in which change from baseline in binge eating 
days per week at the scheduled visits will be the dependent variable based on the OC data 
set. The model will include fixed effect terms for treatment, trial center, visit week, and 
an interaction term of treatment by visit week. The model will also include the interaction 
term of baseline values of binge eating days per week by visit week as covariates. The 
level of visit in the MMRM will include Week 1, Week 2, Week 3, Week 4, Week 6, and 
Week 8. The primary comparison between centanafadine groups and the placebo group at 
Weeks 7-8 will be estimated as the difference between Least Squares means utilizing the 
computing software SAS procedure PROC MIXED. If there is a convergence problem 
with the unstructured variance covariance matrix of the MMRM model, the following 
structures other than unstructured will be used in order of 1) heterogeneous toeplitz, 
2) heterogeneous autoregressive of order 1, and 3) heterogeneous compound symmetry 
and the first (co)variance structure converging to the best fit will be used as the primary 
analysis. If a structured covariance has to be used, the “sandwich” estimator of the 
standard error of the fixed effects parameters will be used in order to deal with possible 
model misspecification of the covariance matrix. Details of this analysis will be provided 
in the SAP.
Within MMRM analysis, baseline is defined as the last available measurement prior to 
the first dose of IMP in the double-blind treatment period and small centers will be 
pooled as needed. The linear model assumptions will also be checked. Details will be 
provided in the SAP.
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9.4.1.3
Key Secondary Efficacy Endpoint Analysis
The key secondary endpoint of change from baseline in CGI-S score at Week 8 will be 
analyzed using MMRM, similar to primary efficacy endpoint.
9.4.1.4
Other Efficacy Endpoint Analysis
Changes from baseline in Y-BOCS-BE score, PGI-S score, and SF-36v2 PCS and MCS 
scores will be analyzed using MMRM similar to primary efficacy endpoint. CGI-C score 
and PGI-C score will be analyzed using Cochran-Mantel-Haenszel (CMH) method based 
on raw mean score statistics with trial center as controlling factor. Proportion of subjects 
with four-week cessation from binging at Week 8/ET will be evaluated by the CMH 
method controlling for trial center. Change from baseline in EDE-Q7 global score will be 
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analyzed using analysis of covariance including treatment group, trial center as fixed 
factors and baseline as covariate. The other efficacy variables will be evaluated at a 
nominal 0.05 level (2-sided) without adjusting for multiplicity.
9.4.1.5
Control of Experiment-wise Type 1 Error
To control the overall experiment-wise type I error at the 0.05 level, a fixed sequence 
testing approach will be applied. The statistical test will be performed in the following 
order: 
1) Change from baseline to Weeks 7-8 in binge eating days per week between high 
dose centanafadine and placebo;
2) Change from baseline to Weeks 7-8 in binge eating days per week between low 
dose centanafadine and placebo;
3) Change from baseline to Week 8 in CGI-S score between high dose centanafadine 
and placebo;
4) Change from baseline to Week 8 in CGI-S score between low dose centanafadine 
and placebo.
The test for the subsequent hypothesis will be performed only if the test for the previous 
hypothesis is statistically significant.
9.4.1.6
Other Efficacy Endpoint Analysis
Not applicable.
9.4.2
Safety Analysis
9.4.2.1
Adverse Events
All AEs will be coded by system organ class and MedDRA preferred term. The incidence 
of the following events will be summarized by treatment group:

TEAEs

TEAEs by severity

TEAEs potentially causally related to the IMP

TEAEs with an outcome of death

Serious TEAEs

TEAEs leading to discontinuation of the IMP 
9.4.2.2
Clinical Laboratory Data
Summary statistics for changes from baseline in the routine clinical laboratory 
measurements will be provided. In addition, potentially clinically significant laboratory 
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results will be identified using criteria prospectively defined in the SAP and will be 
summarized. Change from baseline in fasting triglycerides and total cholesterol at Week 
8/ET will be analyzed using analysis of covariance including treatment group, trial center 
as fixed factors and baseline as covariate.
9.4.2.3
Physical Examination and Vital Signs Data
By-subject listings will be provided for physical examination findings. Summary 
statistics for changes from baseline in vital signs will be provided. Potentially clinically 
significant results in vital signs and body weight will also be summarized. In addition, 
change from baseline in body weight and percentage of change from baseline in body 
weight will be analyzed using MMRM.  
9.4.2.4
Electrocardiogram Data
Summary statistics for change from baseline and incidence of clinically significant 
changes will be calculated for ECG parameters.
For the analysis of QT and QTc, data from 3 consecutive complexes (representing 
3 consecutive heart beats) will be measured to determine average values. The following 
QT corrections will be used for reporting purposes in the clinical study report:

QTcF is the length of the QT interval corrected for heart rate by the Fredericia 
formula: QTcF = QT / (RR)0.33

QTcN is the length of the QT interval corrected for heart rate by the FDA 
Neuropharm Division formula: QTcN = QT / (RR)0.37
In addition, potentially clinically significant ECG results will be identified using criteria 
prospectively defined in the SAP and will be summarized.
9.4.2.5
Other Safety Data
Change from baseline in HAM-A total score, MADRS total score, medication withdrawal 
symptoms assessed by SMWQ, and suicidality monitored during the trial using the 
C-SSRS at the scheduled visit(s) will be summarized by treatment group in descriptive 
statistics. Details of the analysis will be included in the SAP.
9.4.3
Other Analyses
9.4.3.1
Analysis of Demographic and Baseline Characteristics
Baseline demographic characteristics including age, race, ethnicity, gender, weight, 
height, and BMI for the randomized subjects will be summarized using descriptive 
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statistics (frequency, mean, median, SD, maximum, minimum, and percentage when 
applicable).
Baseline disease severity and other medical history will also be summarized in 
descriptive statistics to identify any potential lack of balance between the treatment 
groups.
9.4.3.2
Pharmacokinetic Analysis
Sparse PK samples will be evaluated to confirm compliance with dosing. Concentrations 
will be listed in the bioanalytical report.
9.4.3.3
Pharmacodynamic Analysis
No PD analysis is planned.
9.4.3.4
Pharmacokinetic/Pharmacodynamic Analysis
No PK/PD analysis is planned.
9.4.3.5
Pharmacogenomic Analysis
No PGx analysis is planned.
.
9.5
Interim Analysis and Adaptive Design
Not applicable.
9.5.1
Data Monitoring Committee
Not applicable.
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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, 
applicable ICH GCP guidance, 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, IRE and any safety information, 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 all subjects (or their guardian or legally 
acceptable representative, as applicable for local laws). The informed consent form (ICF) 
will be approved by the same IRB that approves this protocol. 
Each ICF will comply with the ICH (International Council for Harmonisation) GCP 
Guidelines, 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 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 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.
Investigators may discuss trial availability and the possibility for entry with a potential 
subject without first obtaining consent. However, informed consent must be obtained and 
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documented before initiation of any procedures that are performed solely for the purpose 
of determining eligibility for this trial, including withdrawal from current medication(s). 
Potential subjects are free to refuse entry into the trial, or withdraw from the trial at any 
time, without justification, and there will be no consequences to their further care.
Prospective trial subjects will be provided with controlled access to the eICF application 
by trial site staff. When the trial site staff and the subject agree that the subject has 
enough information to make an informed decision to participate, the subject will 
electronically sign in the eICF application and an electronic date and timestamp will be 
applied to the signature. The subject will be given a printed, signed copy of the ICF. 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 by the investigator (or a qualified designee), and it has 
been documented that the subject has had the opportunity to ask questions, the 
IRB-approved written ICF will be signed and dated by both the subject and the person 
obtaining consent (investigator or designee), as well as by any other parties required by 
the IRB. The subject will receive a copy of the signed ICF; the original shall be kept on 
file by the investigator.
Subjects may be asked to sign additional ICFs if the protocol is amended and the changes 
to the protocol result in additional information that needs to be provided to the subjects, 
so that they can make a knowledgeable and voluntary decision on continued trial 
participation. Female partners of male subjects who become pregnant during the course 
of the trial may be asked to sign additional ICFs 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 
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(or their representatives) may be allowed full access to inspect and copy the records, 
consistent with local requirements. All IMPs, subject bodily fluids, and/or other materials 
collected shall be used solely in accordance with this protocol, unless otherwise agreed to 
in writing by the sponsor.
Subjects will be identified only by unique subject 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 applicable ICH GCP guidance, and applicable 
regulatory requirements and local laws. As part of a concerted effort to fulfill these 
obligations (maintain current personal knowledge of the progress of the trial), the 
sponsor’s monitors will visit the site during the trial, as well as communicate frequently 
via telephone, e-mail, and written communications. In addition, all investigators and 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 process, site operations, delegation of authority and training, and a 
review of the eCRF with source documents, as applicable. The investigator will agree to 
cooperate and 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.
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 informed consent process, IMP dispensing or subject dosing 
error, treatment assignment error, subject enrolled in violation of eligibility criteria or 
concomitant medication criteria), the investigator or designee will contact the sponsor or 
designee at the earliest possible time by telephone or via e-mail. The investigator and 
sponsor (or designee) will come as quickly as possible to a joint decision regarding the 
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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, logs, and recorded data from automated instruments or 
applications. 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 process, including any revised consents;

Documentation of the investigator’s decision to enroll the subject into the trial, the 
review of all inclusion/exclusion criteria prior to IMP administration, and 
confirmation of the subject’s actual participation in the trial;

The date of the visit and the corresponding Visit or Day in the trial schedule;

General subject status remarks, including any significant medical findings. The 
severity, frequency, duration, action taken, and outcome of any AEs and the 
investigator’s assessment of relationship to IMP must also be recorded;

Any changes in concomitant medications or dosages;

A general reference to the procedures completed, including dosing and IMP 
compliance; 

The signature (or initials) and date of the investigator (or designee) who made an 
entry in the medical record.
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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 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.
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.
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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 
applicable ICH GCP guidance 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
Food and Drug Administration (FDA) regulations require all investigators participating in 
clinical drug trials to maintain detailed clinical data for one of the following periods:

A period of at least 2 years after the date on which a New Drug Application is 
approved by the FDA;

A period of 2 years after the sponsor has notified the FDA that investigation with this 
drug is discontinued.
The investigator must not dispose of any records relevant to this trial without either 
(1) written permission from the sponsor or (2) provision of an opportunity for the sponsor 
to collect such records. The investigator will be responsible to maintain adequate and 
accurate electronic or hard copy source documents of all observations and data generated 
during this trial including any data clarification forms received from the sponsor. Such 
documentation is subject to inspection by the sponsor and relevant regulatory authorities. 
If the investigator withdraws from the trial (eg, due to relocation or retirement), all 
trial-related records should be transferred to a mutually agreed-upon designee within a 
sponsor-specified timeframe. Notice of such transfer will be given to the sponsor in 
writing.
10.1.6.5
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
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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:
Hemoglobin
Hematocrit
Mean corpuscular hemoglobin concentration
Mean corpuscular volume
Neutrophils
RBC
WBC (with differential)
Platelets
MCH
RDW
RBC morphology
Urinalysis:
Appearance
Color
Blood
Glucose
Microscopic analysis, WBC/RBC counts per high 
powered field
pH
Protein
Specific gravity
Urine drug screen:
Amphetamines
Barbiturates
Opiates
Benzodiazepines
Cocaine
THC
Methadone
Phencyclidine
Serum Chemistry:
Alkaline phosphatase
Alanine aminotransferase
Aspartate aminotransferase
Bicarbonate
Bilirubin, total
Urea nitrogen
Calcium
Chloride
Cholesterol (total)
CPK
Creatinine
Gamma glutamyl transferase
Glucose
Lactate dehydrogenase
Potassium
Protein, total
Sodium
Triglycerides
Uric acid
Additional Tests:
HbA1c (at screening only)
Alcohol test (via urine, blood, or breathalyzer)
Urine pregnancy for all subjects of CBP (a serum 
test will be confirmatory for positive urine 
pregnancy)
Coagulation Parameters:
PT
aPTT
INR
aPTT = activated partial thromboplastin time; CPK = creatine phosphokinase; INR = international 
normalized ratio; MCH = mean corpuscular hemoglobin; PT = prothrombin time; RBC = red blood 
cell count; RDW = red cell distribution width; THC = tetrahydrocannabinol; WBC = white blood cell 
count.
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10.3
Appendix 3: Contraceptive Guidance and Collection of Pregnancy 
Information
Subjects of CBP are subjects 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). Subjects of nonchildbearing potential 
do not meet definition of CBP.
For males and subjects of CBP, or their partners, 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 abstinent) to prevent 
pregnancy during the course of the trial and for 30 days after the last dose of IMP for 
female subjects, and 30 days after the last dose of IMP for male subjects and their 
partners who are of CBP. Unless the subject is sterile (ie, who have had a bilateral 
oophorectomy, have had a hysterectomy, or have been postmenopausal for at least 
12 consecutive months or subjects who have had a bilateral orchiectomy) or remains 
abstinent during the trial and for 30 days after the last dose of IMP for female subjects, 
and 30 days after the last dose of IMP for male subjects and their partners who are of 
CBP, 2 of the following approved methods of birth control must be used: vasectomy, 
tubal ligation, intrauterine device, birth control pill, birth control implant, birth control 
depot injection, birth control patch, 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. Subjects must 
also agree not to donate sperm from trial screening through 30 days/weeks/months after 
the last dose of IMP.
Before enrolling males and females in this clinical trial, investigators must review the 
below information about trial participation as part of the ICF process. The topics should 
generally include:

General information

Informed consent form

Pregnancy prevention information

Drug interactions with hormonal contraceptives

Contraceptives in current use

Follow-up of a reported pregnancy
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Before trial enrollment, males and subjects of CBP must be advised of the importance of 
avoiding pregnancy during trial participation and the potential risk factors for an 
unintentional pregnancy. Subjects must sign the ICF 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 the time points described in the schedule of assessments (Table 1.3-1) on all 
subjects of CBP. If a urine test is performed and is positive, the investigator will 
follow-up with a confirmatory serum test.
During the trial, all subjects of CBP 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 while the subject is taking IMP, the IMP must be withheld 
immediately (if reasonable, taking into consideration any potential withdrawal risks) until 
the result of the pregnancy test is known. If pregnancy is confirmed, the IMP will be 
permanently discontinued in an appropriate manner (eg, dose tapering if necessary for 
subject safety) and the subject will be withdrawn from the trial. 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 the last dose 
of IMP for female subjects, and for 30 days after the last dose of IMP for partners of male 
subjects, and record the event on the IRE form and forward it to the sponsor. The sponsor 
will forward 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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10.4
Appendix 10: 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 will require similar modification. In such cases, after 
approval/favorable opinion of the new ICF by the IRB, repeat written informed consent 
will be obtained from subjects enrolled in the trial before expecting continued 
participation and before the amendment-specified changes in the trial are implemented.
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11
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32 Little RJA. Pattern-mixture models for multivariate incomplete data. J Am Stat 
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Agreement
I, the undersigned principal investigator, have read and understand the protocol (including the 
Investigator’s Brochure) and agree that it contains all the ethical, legal and scientific information 
necessary to conduct this trial in accordance with the principles of Good Clinical Practices and as 
described herein and in the sponsor’s (or designee’s) Clinical Trial Agreement.
I will provide copies of the protocol to all physicians, nurses, and other professional personnel to 
whom I delegate trial responsibilities. I will discuss the protocol with them to ensure that they are 
sufficiently informed regarding the investigational new drug, centanafadine, the concurrent 
medications, the efficacy and safety parameters and the conduct of the trial in general. I am aware that 
this protocol must be approved by the Institutional Review Board (IRB) or receive a favorable opinion 
by the Independent Ethics Committee (IEC) responsible for such matters in the clinical trial facility 
where centanafadine 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
Synopsis Clinical Study Report 405-201-00056
4.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
77

T hi s p a g e i s a m a nif e st ati o n of a n el e ctr o ni c all y c a pt ur e d si g n at ur e
SI G N A T U R E P A G E
D o c u m e nt N a m e: 4 0 5- 2 0 1- 0 0 0 5 6 Pr ot o c ol A m e n d m e nt 2
D o c u m e nt N u m b er: 1 0 0 0 1 3 5 3 1 9
D o c u m e nt V er si o n: 4. 0
Si g n e d b y
M e a ni n g of Si g n at ur e
S er v er D at e
( d d- M M M-
y y y y h h: mi n) -
U T C ti m e z o n e
Cli ni c al A p pr o v al
2 4- J a n- 2 0 2 2
1 9: 0 9: 4 1
Bi o st ati sti c s A p pr o v al
2 4- J a n- 2 0 2 2
1 9: 0 8: 1 4
Cli ni c al A p pr o v al
2 4- J a n- 2 0 2 2
2 2: 5 8: 5 5
S y n o psis Cli nic al St u d y Re p ort 4 0 5- 2 0 1- 0 0 0 5 6
4. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
U ntil t he i nf or m ati o n herei n is rele ase d b y Ots u k a t o t he p u blic d o m ai n, t he c o nte nts of t his d oc u me nt are Ots u k a
c o nfi de nti al i nf or m ati o n a n d s h o ul d n ot be d u plic ate d or re- distri b ute d wit h o ut pri or writte n c o nse nt of Ots u k a.
7 8
P P D
P P D
P P D